In the olowingpages I have attempted to set orth, as brily as seemed to be consistent with thoroughness, the scientic basis or and the practical application of the obstetrical art. At the same time, I have endeavored to present the more practical aspects of obstetrics in such a manner as to be of direct service to the obstetrician at the bedside.

-J. Whitridge Williams (1903)

So reads the introduction to Williams' irst edition of this textbook, Obstetrics-A Text-Book or the Use of Students and Practitioners. In this 25th edition, we strive to follow the tenets described by Williams. And, each chapter begins with a quote from his original textbook.

he science and clinical practice of obstetrics is concerned with human reproduction. hrough quality perinatal care, the specialty promotes the health and well-being of the pregnant woman and her fetus. Such care entails appropriate recognition and treatment of complications, supervision of labor and delivery, initial care of the newborn, and management of the puerperium. Postpartum care promotes health and provides family planning options.

he importance of obstetrics is relected by the use of maternal and neonatal outcomes as an index of the quality of health and life among nations. Intuitively, indices that reflect poor obstetrical and perinatal outcomes would lead to the assumption that medical care for the entire population is lacking. With those thoughts, we now provide a synopsis of the current state of maternal and newborn health in the United States as it relates to obstetrics.

The National Vital Statistics System of the United States is the oldest and most successful example of intergovernmental data sharing in public health. This agency collects statistics through vital registration systems that operate in various jurisdictions. These systems are legally responsible for registration of births, fetal deaths, deaths, marriages, and divorces. Legal authority resides individually with the 50 states; two regions-the District of Columbia and New York City; and ive territoriesAmerican Samoa, Guam, the Northern Mariana Islands, Puerto Rico, and the Virgin Islands.

The standard birth certificate was revised in 1989 to include more information on medical and lifestyle risk factors and obstetrical practices. In 2003, an extensively revised Standard Certificate of Live Birth was implemented in the United States. The enhanced data categories and speciic examples of each are summarized in Table

By 2013,i35 states had implemented the revised birth certificate representing 76 percent of all births (MacDorman, 2015). Importantly, the 2003 version of the population death certificate contains a pregnancy checkbox to eventually be implemented by all states a oseph, 2017).

The uniform use of standard deinitions is encouraged by the World Health Organization as well as the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017). Such uniformity allows data comparison not only between states or regions of the country but also between countries. Still, not all deinitions are uniformly

Overview of Obstetrics

TABLE 1-1. General Categories of New Information Added to the 2003 Revision of the Birth Certificate

Risk factors in pregnancy-Examples: prior preterm birth, prior eclampsia Obstetrical procedures-Examples: tocolysis, cerclage, external cephalic version

Labor-Examples: noncephalic presentation, glucocorticoids for fetal lung maturation, antibiotics during labor Delivery-Examples: unsuccessful operative vaginal delivery, trial of labor with prior cesarean delivery Newborn-Examples: assisted ventilation, surfactant therapy, congenital anomalies applied. For example, the American College of Obstetricians and Gynecologists recommends that reporting include all fetuses and neonates born weighing at minimum 500 g, whether alive or dead. But, not all states follow this recommendation. Speciically, 28 states stipulate that fetal deaths beginning at 20 weeks' gestation should be recorded as such; eight states report all products of conception as fetal deaths; and still others use a minimum birthweight of 350 g, 400 g, or 500 g to deine fetal death. To further the confusion, the National Vital Statistics Reports tabulates fetal deaths from gestations that are 20 weeks or older (Centers for Disease Control and Prevention, 2016). his is problematic because the 50th percentile for fetal weight at 20 weeks approximates 325 to 350 g-considerably less than the 500-g deinition. Indeed, a birthweight of 500 g corresponds closely with the 50th percentile for 22 weeks' gestation.

Deinitions recommended by the National Center for Health Statistics and the Centers for Disease Control and Prevention are as follows:

Perinatal period. The interval between the birth of a neonate born after 20 weeks' gestation and the 28 completed days after that birth. When perinatal rates are based on birthweight, rather than gestational age, it is recommended that the perinatal period be deined as commencing at the birth of a 500-g neonate.

Birth. he complete expulsion or extraction from the mother of a fetus after 20 weeks' gestation. As described above, in the absence of accurate dating criteria, fetuses weighing < 500 g are usually not considered as births but rather are termed abortuses for purposes of vital statistics.

Birthweight. The weight of a neonate determined immediately after delivery or as soon thereafter as feasible. It should be expressed to the nearest gram.

Birth rate. The number of live births per 1000 population. Fertility rate. The number of live births per 1000 females aged 15 through 44 years.

Live birth. he term used to record a birth whenever the newborn at or sometime after birth breathes spontaneously or shows any other sign of life such as a heartbeat or deinite spontaneous movement of voluntary muscles. Heartbeats are distinguished from transient cardiac contractions, and respirations are diferentiated from fleeting respiratory efforts or gasps.

Stillbirth or fetal death. The absence of signs of life at or after birth.

Early neonatal death. Death of a liveborn neonate during the irst 7 days after birth.

Late neonatal death. Death after 7 days but before 29 days.

Stillbirth rate or fetal death rate. The number of stillborn neonates per 1000 neonates born, including live births and stillbirths.

Neonatal mortality rate. The number of neonatal deaths per 1000 live births.

Perinatal mortality rate. he number of stillbirths plus neonatal deaths per 1000 total births.

Infant death. All deaths of liveborn infants from birth through 12 months of age.

Infant mortality rate. The number of infant deaths per 1000 live births.

Low birthweight. A newborn whose weight is <2500 g.

Very low birthweight. A newborn whose weight is < 1500 g.

Extremely low birthweight. A newborn whose weight is < 1000 g.

Term neonate. A neonate born any time ater 37 completed weeks of gestation and up until 42 completed weeks of gestation (260 to 294 days). The American College of Obstetricians and Gynecologists (2016b) and Society for MaternalFetal Medicine endorse and encourage specific gestational age designations. Eary term refers to neonates born at 37 completed weeks up to 386/7 weeks. Full term denotes those born at 39 completed weeks up to 406r weeks. Last, late term describes neonates born at 41 completed weeks up to weeks.

Preterm neonate. A neonate born before 37 completed weeks (the 259th day). A neonate born before 34 completed weeks is early preterm, whereas a neonate born between 34 and 36 completed weeks is late preterm.

Postterm neonate. A neonate born anytime after completion of the 42nd week, beginning with day 295.

Abortus. A fetus or embryo removed or expelled from the uterus during the first half of gestation-20 weeks or less, or in the absence of accurate dating criteria, born weighing <500 g.

Induced termination of pregnancy. The purposeful interruption of an intrauterine pregnancy that has the intention other than to produce a liveborn neonate and that does not result in a live birth. This deinition excludes retention of products of conception following fetal death.

Direct maternal death. he death of the mother that results from obstetrical complications of pregnancy, labor, or the puerperium and from interventions, omissions, incorrect treatment, or a chain of events resulting from any of these factors. An example is maternal death from exsanguination after uterine rupture.

Indirect maternal death. A maternal death that is not directly due to an obstetrical cause. Death results from previously existing disease or a disease developing during pregnancy, labor, or the puerperium that was aggravated by maternal physiological adaptation to pregnancy. An example is maternal death from complications of mitral valve stenosis.

Nonmaternal death. Death of the mother that results from accidental or incidental causes not related to pregnancy. An example is death from an automobile accident or concurrent malignancy.

Maternal mortality ratio. The number of maternal deaths that result from the reproductive process per 100,000 live births. Used more commonly, but less accurately, are the terms maternal mortaliy rate or maternal death rate. The term ratio is more accurate because it includes in the numerator the number of deaths regardless of pregnancy outcome-for example, live births, stillbirths, and ectopic pregnancieswhereas the denominator includes the number of live births.

Pregnancy-associated death. The death of a woman, from any cause, while pregnant or within 1 calendar year of termination of pregnancy, regardless of the duration and the site of pregnancy.

Pregnancy-related death. A pregnancy-associated death that results from: (1) complications of pregnancy itself, (2) the chain of events initiated by pregnancy that led to death, or (3) aggravation of an unrelated condition by the physiologicalior pharmacological efects of pregnancy and that subsequently caused death.

According to the Centers for Disease Control and Prevention (CDC), the fertility rate of women aged 15 to 44 years in the United States in 2015 was 62.5 live births per 1000 women (Martin, 2017). This rate began slowly trending downward in 1990 and has now dropped below that for replacement births. This indicates a population decline (Hamilton, 2012). There were 3.98 million births in 2015, and this constituted the lowest birth rate ever recorded for the United States-12.3 per 1000 population. The birth rate decreased for all major ethnic and racial groups, for adolescents and unmarried women, and for those aged 20 to 24 years. For women older than 30 years, the birth rate rose slightly. Almost half of newborns in 2010 in the United States were minorities: Hispanic-25 percent, AfricanAmerican-14 percent, and Asian-4 percent (Frey, 2011).

he total number of pregnancies and their outcomes in 2015 are shown in Table 1-2. According to the Guttmacher Institute (2016b), 45 percent of births in the United States are unintended at the time of conception. Importantly, the overall proportion of aExciudes spontaneous abortions and ectopic pregnancies. Data from Martin, 201l7.

unintended births has declined only slightly since 2001. Unmarried women, black women, and women with less education or income are more likely to have unplanned pregnancies.

In Table 1-2, induced abortion information derives from CDC abortion surveillance data from 45 states combined with Guttmacher Institute data on induced abortion. hese data have been collected beginning in 1976. Since Roe v. Wade legalization of abortion, more than 46 million American women have chosen legalized abortions. As discussed later, this provides a compelling argument for easily accessible family planning.

Several indices are used to assess obstetrical and perinatal outcomes as measures of medical care quality. As noted, the perinatal mortality rate includes the numbers of stillbirths and neonatal deaths per 1000 total births. In 2013, the perinatal mortality rate was 9.98 per 1000 births (Fig. 1-1) (MacDorman, 2015). There were 25,972 fetal deaths at gestational ages of 20 weeks or older. Fetal deaths at 28 weeks or more have been declining since 1990, whereas rates for those between 20 and 27 weeks are static (Fig. 1-2). By way of comparison, there were a total of 19,041 neonatal deaths in 2006-meaning that nearly 60 percent of the perinatal deaths in the United States were fetal.

here were 6.1 infant deaths per 1000 live births in 2013 compared with 6.8 in 2001 (MacDorman, 2015). The three leading causes of infant death-congenital malformations, low birthweight, and sudden infant death syndrome-accounted for almost half of all deaths (Heron, 2015). Infants born at the lowest gestational ages and birthweights add substantively to these mortality rates. For example, more than half of all infant deaths in 2005 were in the 2 percent of infants born before

FIGURE ,A-, Perinatal mortality rates: United States, 2000-2013.

(Reproduced with permission from MacDorman MF, Gregory EC:

Fetal and perinatal mortality: United States, 2013. Natl Vital Stat Rep. 2015 Jul 23;64(8):1-24.) 0..C ::l� 0

Con , .�A.� 8.s

FIGURE 1-2 Fetal and neonatal deaths: United States, 2000-2013. (Modified with permission from MacDorman MF, Gregory EC: Fetal and perinatal mortality: United States, 2013. Natl Vital Stat Rep. 2015 Jul 23;64(8):1-24.) 32 weeks' gestation. Indeed, the percentage of infant deaths related to preterm birth increased from 34.6 percent in 2000 to 36.5 percent in 2005. When analyzed by birthweight, two thirds of infant deaths were in low-birthweight neonates. Of particular interest are infants with birthweights <500 g, for whom neonatal intensive care can now be ofered.

As shown in Figure 1-3, maternal mortality rates dropped precipitously in the United States during the 20th century. Pregnancy-related deaths are so uncommon as to be measured per 100,000 births. The CDC (2017a) has maintained data on pregnancy-related deaths since 1986 in its Pregnancy Mortality Surveillance System. In the latest report, Creanga and coworkers (2017) described 2009 pregnancy-related deaths during the period from 2011 to 2013. Approximately 5 percent were early-pregnancy deaths due to ectopic gestation or abortive outcomes. he deadly obstetrical triad ofhemorrhage, preeclampsia, and infection has accounted for a third of all deaths (Fig. 1-4). hromboembolism, cardiomyopathy, and other cardiovascular �CD ""..D

FIGURE 1-3 Maternal mortality rates for the United States, 19502003. (Data from Berg, 2010; Hoyert, 2007.) 11.4 �Yuf 11.8 �� � .��t ,��o

Cause of pregnancy-related deaths

FIGURE 1-4 Six common causes of pregnancy-related deaths for the United States, 2006-2010. (Data from Creanga, 2015.) disease together accounted for another third. Other signii-.

cant contributors were amnionic luid embolism (5.3 percent) and cerebrovascular accidents (6.2 percent). Anesthesia-related deaths were at an all-time low-only 0.7 percent. Similar causes were reported for selected cohorts for years 2008 to 2009 and 2013 to 2014 (MacDorman, 2017).

Shown in Figure 1-5, the pregnancy-related mortality ratio of 23.8 per 100,000 live births in 2014 is the highest during the previous 40 years. And, according to the Institute ofHealth Metrics, it was 28 per 100,000 in 2013 (Tavernise, 2016). This rise simply may be that more women are dying, however, other factors explain this doubling of the rate from 1990 to 2013 aoseph, 2017). The irst is an artiicial elevation caused by the International Statistical Classiication of Diseases, 10th Revision (ICD-I0), implemented in 1999. Second, improved ..C-) ) .=19

FIGURE 1-5 Estimated maternal mortality rates in 48 states and the District ofColumbia. (Data from MacDorman, 2016.)

Overview of Obstetrics 14.6 13.6

FIGURE 1-6 Trends in maternal mortality ratio (per 100,000 live births) by race: United States, 2005-2014. (Data from Moaddab, 2016.) reporting definitely contributes to the rise (MacDorman, 2016b, 2017). In the past, maternal deaths were notoriously underreported (Koonin, 1997). Third, and related to the second explanation, the rate of rise is at least partially due to the revised death certificate and its pregnancy checkbox described earlier (Main, 2015). Fourth, the number of pregnant women with severe chronic health conditions, which place women at higher risk, is greater (Centers for Disease Control and Prevention, 2017a). Finally, the increased proportion of births to women older than 40 years contribute to higher mortality rates (MacDorman, 2017).

Whatever the cause, the apparent sharp rise of the maternal mortality rates has galvanized the obstetrical community to action (Chescheir, 2015). According to Barbieri (2015), the Joint Commission has recommended that birthing centers establish standardized protocols and implement simulation eforts. D' Alton and colleagues (2016) described eforts of a working group to lower morbidity and mortality rates.

Another consideration is the obvious disparity of higher mortality rates among black, Hispanic, and white women as shown in Figure 1-6. Racial disparities translate to health care availability, access, or utilization (Howell, 2016; Moaddab, 2016). And, maternal mortality is disparately high in rural compared with metropolitan areas (Maron, 2017).

Importantly, many of the reported maternal deaths are considered preventable. Berg and colleagues (2005) estimated that this may be up to a third of pregnancy-related deaths in white women and up to half of those in black women. In one evaluation of an insured cohort, 28 percent of 98 maternal deaths were judged preventable (Clark, 2008). hus, although significant progress has been made, further eforts are imperative for obstetrics in the 21 st century.

his serves as another measure to guide prevention eforts. Lowering medical error rates serves to diminish risks for maternal mortality or severe maternal morbidity. The terms near misses or close calls were introduced and defined as unplanned events caused by error that do not result in patient injury but have the potential to do so (Institute for Safe Medication Practices, 2009). hese are much more common than injury events, but for obvious reasons, they are more diicult to identiy and quantiy. Systems designed to encourage reporting have been installed in various institutions and allow focused safety eforts (Clark, 20i12; Main, 2017; Shields, 2017). The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine (20 16f) have provided lists of suggested screening topics for this purpose.

Several data systems now measure indicators of unplanned events caused by errors that have injurious potential. This evolution followed inadequacies in the ability of hospitalization coding to reflect the severity of maternal complications. Thus, coding indicators or modifiers are used to allow analysis of serious adverse clinical events (Clark, 2012; King, 2012). Such a system was implemented by the World Health Organization. It has been validated in Brazil and accurately reflects maternal death rates (Souza, 2012). Similar systems are in use in Britain as the UK Obstetric Surveilance System-UKOSS (Knight, 2005,i2008). In the United States, one example is the National Partnership for Maternal Safety (D'Alton, 2016; Main, 2015).

To study severe morbidity, the CDC analyzed more than 50 million maternity records from the Nationwide Inpatient Sample from 1998 to 2009 (Callaghan, 2012). They used ICD9-CM codes and reported that 129 per 10,000 of these gravidas had at least one indicator for severe morbidity (Table 1--).hus, for every maternal death, approximately 200 women experience severe morbidity. he CDC (20 17b) estimates that 65,000 women per year have such maternal morbidity. These numbers are greatest in smaller hospitals with < 1000 deliveries annually (Hehir, 2017). Finally, as with mortality rates, there are serious racial and ethnic disparities for severe maternal morbidity, and black women are disproportionately afected (Creanga, 2014).

Various topics have been in the forefront for obstetrical providers in the 4 years since the last edition of this textbook. In the following, we discuss several of these topics.

• U.S. Health Care in Crisis

In a 2016 issue of the Jounal of the American Medical Association fAA), then-President Barack Obama presented a summary of the Afordable Care Act (ACA), so-called Obamacare. He described the successes, the challenges ahead, and the policy implications of the policy (Bauchner, 2016). He summarized three lessons from his experiences with the ACA. First, change is especially diicult in the face of hyperpartisanship. Second, special interests pose a continued obstacle to change. Third, he stressed the importance of pragmatism. Here, he was referring to the pragmatism necessary when the ACA did not work efectively on day 1 of implementation.

TABLE 1-3. Severe Maternal Morbidity Indicators

Injuries of thorax, abdomen, and pelvis Intracranial injuries

Conversion of cardiac rhythm Hysterectomy

Summarized from the Centers for Disease Control and Prevention,l2017b.

At this same time, draconian cuts to Medicaid were being proposed, and President Obama ended his JM1A report with a quotation from John Kasich, the Republican governor of Ohio. "For those that live in the shadows of life, those who are the least among us, I will not accept the fact that the most vulnerable in our state should be ignored. We can help them." hese potential efects to Medicaid ripple into the specialty of obstetrics. In 2010, it was estimated that Medicaid insured 48 percent of the births in the United States (lvlarkus, 2013). Importantly, Medicaid covered a disproportionate number of complicated births. Speciically, Medicaid insured more than half of all hospital stays for preterm and low-birthweight infants and approximately 45 percent of infant hospital stays due to birth defects.

he young, healthy Americans who were expected to financially bolster the ACA ultimately enrolled in insuicient numbers to ensure long-term ACA sustainability. hus, long-term options included repair or repeal of the ACA. hroughout Donald Trump's campaign for the presidency of the United States, he made repeal of the ACA a focus of his candidacy. As of this writing, both the United States House of Representatives and the Senate have grappled with "repeal and replace" for 6 months. According to the Congressional Budget Oice, this action would result in 23 million Americans losing health care insurance and cuts in Medicaid dollars (Fiedler, 2017). he latter was to be accomplished by transferring funding of Medicaid from the Federal government to the states.

Overview of Obstetrics 7 hese potential outcomes have prompted considerable debate among voters, and "repeal and replace" has become politically charged. Currently, the Senate has been unable to recruit suficient Republican votes for Senate passage of such a bill. We suggest that the health care crisis should be reframed and redirected instead to a critical analysis of health care costs and resource utilization.

that spending on health care in the United States in 2015 accounted for 17.8 percent of the gross domestic product

GDP (Voelker, 2010). he total amount of health-care spend ing-$3.2 trillion-equated to an estimated $10,000 per person. Moreover, compared with 12 other high-income coun tries, health-care spending in the United States as a proportion of GDP was approximately 50 percent more than the next highest country. Yet, health-care outcomes, which included infant mortality rates, were worse in the United States. And, approximately two thirds of U.S. infant deaths result from complications stemming from preterm births (Matthews, 2015). Indeed, in its 2010 annual global Premature Birth

Report Card, the United States garnered a grade of "D" from the March of Dimes for its recognition and prevention of pre term labor in the more than 540,000 neonates born annually before 37 weeks' gestation.

Causes for the excessive health care costs in the United States are attributed, in part, to greater use of medical technology and excessive prices (Squires, 2017). Two recent studies demonstrate the detrimental efect of obstetrics on health care costs. The first report by Nelson and coworkers (2017) described the inefectiveness of 17 -alpha hydroxyprogesterone caproate (17OHP-C) to prevent recurrent preterm birth. Methodology for this trial is presented in Chapter 42 (p. 817). Several lessons can be learned from this investigation. First, use of 17 -OHP-C was legitimized in the United States by a national consensus committee using expert opinion. hese opinions were promulgated, despite FDA reservations that the evidence was lacking in several important respects. However, once approved, 17 -OHP-C was sold by one pharmaceutical company for $1500 for a single, 250-mg injectable dose. Remarkably, this same dose could be compounded and purchased for $25 from local pharmacies. In the subsequent price-gouging controversy, members of the United States Congress intervened to permit continued use of the less expensive 17-0 HP -C.

he second study is a multisite prospective trial of the efectiveness of transvaginal sonography to screen for cervical-length shortening to predict preterm birth (Esplin, 2017). A total of 9410 nulliparous women were studied. he Society for Maternal-Fetal Medicine and the American College of Obstetricians and Gynecologists (2016d) both legitimized universal cervicallength screening in their joint Committee Opinion (Bloom, 2017). And, by 2015, one survey of78 Maternal-Fetal Medicine fellowship programs showed that 68 percent were using universal cervical-length screening to predict preterm birth (Khalifeh, 2017). It was estimated that a modest Medicaid rate of $237 per cervical-length ultrasound would result in approximately $350 million in added health care costs. But, Esplin and associates (2017) found that routine screening for a short cervix was not beneficial. hat is, a widely used intervention was actually inefective. his is a clear example of how unproven technology can seep into widespread practice.

These two reports highlight a substantial problem in U.S. health care, namely, inefective yet expensive interventions introduced into broad use without robust evidence. These two reports also speak to a demand for robust scientific evidence. Scrutiny of other ingredients in the health-care paradigm such as prices for hospitalization, prices for surgical procedures, and prices charged by health insurance companies may illuminate similar contributions to the health care fiscal crisis.

In past editions of this textbook, the rising cesarean delivery rate was considered problematic. his rate has leveled, but there are still imperatives in progress to help lower this rate. One collateral source of cesarean delivery morbidity is from the growing incidence of morbidly adherent placentas encountered in women with a prior hysterotomy incision, discussed in Chapters 31 and 41.

Breakthroughs in fetal testing and diagnosis continue to stun. By 2012, prenatal gene micro array techniques were used for clinical management (Dugof, 2012). he advantages of these techniques are outlined in Chapters 13 and 14. Wapner and coworkers (2012) compared chromosomal microarray analysis of maternal blood with karyotyping for chromosomal anomalies. Reddy and associates (2012) applied this technology to stillbirth evaluation and reported it to be superior to karyotyping. Another report by Talkowski and colleagues (2012) described whole-genome sequencing of a fetus using maternal blood.

Screening for fetal aneuploidy using cell-free DNA (cDNA) was first introduced in 2011. The technique is described in Chapter 14 (p. 284), and it is based on isolation of free fetal (placental) DNA in maternal blood. In a landmark study, Norton and associates (2015) found that cDNA had a higher sensitivity and speciicity compared with standard prenatal screening for trisomy 21 fetuses. Still, invasive testing is currently necessary to confirm a positive cDNA test result (Chitty, 2015; Snyder, 2015).

• The Ob/Gyn Hospitalist he term "hospitalist" was coined in the 1990s and referred to physicians whose primary professional focus was generalized care of hospitalized patients. From this concept came the obstetrical and gynecological hospitalist whose primary role was to care for hospitalized obstetrical patients and to help manage their emergencies. These physicians could also provide urgent gynecological care and emergency department consultation. Alternative terms include "obstetrical hospitalist" or "laborist," but the preferred standardized term by the American College of Obstetricians and Gynecologists (2016e) is "Ob/Gyn hospitalist." lthough not a recognized subspecialty of obstetrics and gynecology, the Ob/Gyn hospitalist movement has gained momentum. he Society of Ob-Gyn Hospitalists had 528 members in 2017 (Burkard, 2017). Various practice models are described to fit the needs of a wide spectrum of obstetrical volumes (McCue, 2016). In addition to providing lifestyle modifications, Ob/Gyn hospitalists are used by some hospitals to improve the quality and safety of their women's services and to reduce adverse events. Aside from a possible lowering of the labor induction rate, studies are needed to demonstrate improved outcomes with these providers (American College of Obstetricians and Gynecologists, 2016e; Srinivas, 2016).

he American College of Obstetricians and Gynecologists periodically surveys its fellows concerning the efect of liability on their practice. he 2015 Survey on Professional Liability is the 12th such report since 1983 (Carpentieri, 2015). From this survey, it appears that there is still a "liability crisis," and the reasons for it are complex. Because it is largely driven by money and politics, a consensus seems unlikely. Although some interests are diametrically opposite, other factors contribute to the problem's complexity. For example, each state has its own laws and opinions on tort reform. In some states, annual premiums for obstetricians approach $300,000-expenses that at least partially are borne by the patient and certainly by the entire health-care system. In 2011, all tort costs in the United States totaled nearly $265 billion. his is an astounding 1.8 percent of the gross domestic product and averages to a cost of $838 per citizen (Towers Watson, 2015).

he American College of Obstetricians and Gynecologists (2016a,c) has taken a lead in adopting a fair system for malpractice litigation-or maloccurrence itigation. And nationally, there is the possibility of federl tort reform under the Trump administration (Lockwood, 2017; Mello, 2017).

Following a slight decline from 1990 through 2004, the percentage of out-of-hospital births in the United States increased from 0.86 to 1.5 percent-almost 75 percent-through 2014 (MacDorman, 2016a). Of these home births, only a third are attended by nurse midwives certiied by the American Midwife Certiication Board (Grtinebaum, 2015; Snowden, 2015).

Proponents of home births cite successes derived from laudatory observational data from England and he Netherlands (de Jonge, 2015; Van der Kooy, 2011). Data from the United States, however, are less convincing and indicate a higher incidence of perinatal morbidity and mortality (Grtinebaum, 2014, 2015; Snowden, 2015; Wasden, 2014; Wax, 2010). hese latter findings have led Chervenak and coworkers (2013, 2015) to question the ethics of participation in planned home births. Greene and Ecker (2015) take a broader view. Given data from these more recently cited studies, they are of the view that these data empower women to make a rational decision regarding home delivery. he American College of Obstetricians and Gynecologists (20 17b) believes that hospitals and accredited birth centers ofer the safest settings, but that each woman has the right to make a medically informed decision regarding delivery.

Politics and religion over the years have led to various govern mental interferences with the reproductive rights of women.

adolescents. This is despite all reports of the overwhelming suc cess of such programs. One example is the exclusion of Planned

Parenthood ailiates from the Texas Medicaid fee-for-service family planning program. In some groups of women served, there was discontinuation of contraception and an increased rate of Medicaid binhs (Stevenson, 2016),

According to the Gurrmacher Institute (2016a), publicly funded family planning services are needed by 20 million American women. In 2014, such services prevenred nearly 2 million unintended pregnancies and 700,000 abonions in the United States. The fate of family planning services is not fully determined, while waiting for decisions regarding provisions within the 2017 American Healrh Care Ace (AHCA). or "Trumpcare." In his response ro news that the AHCA may dismantle cOlHraceptive coverage, American College of Obstetricians and Gynecologises President Dt. Haywood Brown (2017) called this a deep disregard for women's health.

According to the CDC (2014). there were 259 million prescriptions written in 2012 for opioid medications. In 2013, more than a rhird of American adults reported prescrip tion opioid use (Han, 2017). These fteely available-albeit requiring a prescription-addictive drugs are associated with opioid use disorders. It remains uncercain if opioid use is terarogenic (Lind, 2017). Still, their abuse by pregnam women has caused an unprecedented rise in the 1eonata/ abstinence syndrome. described furrher in Chapters 12 (p. 248) and 33 (p. 625). Treatment of opioid abuse in pregnancy and its sequelae result in $1.5 billion annually in hospital charges.

For obstetrical providers ro bener deal with opioid-addicted pregnant women and their fetus-newborns, the Eu.nice Kennedy Shriver National Institute of Child Helth and Human Development convened a workshop in 2016 co study many aspecrs of the problem (Reddy. 2017). he Workshop was cosponsored by the American College of Obstetricians and Gynecologisrs, the American Academy of Pediatrics, the Society for Maternal-Fetal Medicine, the CDC, and the March of Dimes. Several copies were addressed, and hopefully implementation of these indings will help improve maternal treatment and neonatal outcomes (American College of Obstetricians and Gynecologists. 2017a).

The bold new concept of in-vitro fercilization (IVF) produced the irst IVF baby in Britain in 1978. This was soon followed in 1981 with an American success. After four decades. the Society for Assisted Reproductive Technology (SART) reports that more than 1 million babies have been born in the United States using assisted reproductive technologies (ART) ofered by 440 clinics (Fox. 2017).

ter IS years of experimental preparation. the promise of a successful human uterine transplant was finally realized with n

Overview of Obstetrics 9

IVF-conceived livebon neonate in Sweden (Brinnstrom, 2015).

During pregnancy, the mother was treated with t:lcrolimus, azathioprine, and corticosteroids and underwent cesarean delivery at 32 weeks for preeclampsia and abnormal feral heart rate testing. This was followed by uterine trmsplamation programs at the C1cvebnd Clinic and Baylor Medical Center in Dallas (F1yckt. 2016. 2017, Testa. 2017). In 2017. the Swedish team had completed a nine-patient trial, in which seven women had become pregnant and ive had sllccessful deliveries (Kuehn, 2017). Also, in Dallas, the irst such newbon in the Unired Stares was born (Rice. 2017).

Meanwhile, researchers at Children's Hospital of Philadelphia pursued a 20-year goal in search of an artiicial womb (Yuko, 2017). Using incubatOr technology, [he team devised an artiicial amnionic sac. hrough this, (he umbilical vessels were perfused and drained, and the blood was retuned to systems [hat performed exrracorporeal membrane oxygenation and dialysis. To date, lamb fetuses have been kept alive for as long as 1 month. Adverse efects of cerebrovascular hypotension and hypoxemia are conjectural but highly worrisome.

1he ethical and legal challenges of these new technologies are daunting. Of those that arose from IVF, mOSt are setded. For the Q[her twO endeavors, there are likely many years of ethical and legal milestones ahead.

American Academy of Pediatrics, American College of Obstetricians and Gynecologisrs: Guidelines for perinatal care, 8th ed. Elk Grove Village, AAP,e2017

American College of Obstetricians and Gynecologists: Coping with the stress or medical profeSSional liabiliry litigation. Committee Opinion No. 551, January 2013, Reairmed 2016a

American College of Obm=tricians and Gynecologists: Deinition of term pregnancy. Comminee Opinion No. 579, November 2013, Reairmed 2016b

American College of Obstetricians and Gyneologists: Disclosure and discussion of adverse events. Committee Opinion No. 681, December 2016c

American College of Obstetricians and Gynecologists: Prediction and prevention of preterm birth. Practice Bulletin No. 130, October 2012, Reairmed 2016d

American College of Obstetricians and GynecologiSts: The obstetric and ynecologic hospitalist. Committee Opinion No. 65-, February 2016e

American College of Obstetricians and Gynecologists: Opioid use and opioid use disorder in pregnancy. Committtt Opinion No. 711, August 2017a American College of Obstetrics and Gynecologists: Planned home birth. Com mittee Opinion No. 697, April 2017b

American College of Obstetricians and Gynecologists; Society for MaternalFetal Medicine: Severe maternal morbidity: screening and review. Obstetric Care Consensus No.e5, Seprember 201M

Barbieri L: Reducing maternal mortality in the United States-let's get organized! OBG Manag 27(9):8, 2015

Bauchner H: The Afordable Care Act and the fmure of US health care. JA 316(SH92.e2016

Berg q, Callaghan WM, Syverson C, er al: Pregnany-relared mortality in the United States, 1998 TO 2005. Obsret Gynecol 116: 1302, 20 I0

Berg q, Harper MA, Atkinson SM, er al: Preventability of pregnancy-related deaths. Results of a state-wide review. Obstet Gynecol 106; 1228, 2005 Bloom SL, Leveno KJ: Unproven rechnologies in marernal-feral medicine and the high COSt of US health care. JNvlA 317(10):1025, 2017

Brannstrom M, Johannesson L, Bokstrom H, er al: Uvebinh after uterus transplantation. Lancet 385(9968):2352, 2015

Brown HL: We're seeing a deep disregard for women's health. ACOG Government Afairs, June 7, 2017

Burkhard J; Personal communication. May 2017

Callaghan M, Creanga M, Kuklina EV: Severe maternal morbidity among delivery and postpartum hospitalizatiOns in the United Stares. Obsrer Gyne001 120(S),1029. 2012

Carpentieri A\1, Lumalcuri JJ, Sh;l\\I J. e( al: Oveview of the 2015 American Congress of QhslNrics and Gynecologists survey on professional liability. Clinical Review 20: I, 20n15

Centers for Disease Conrrol and Prevention: National Center for Health Statistics: Fetal death. 2016. Available at: hnps:ll".cdc.gov/nchs/nvssl fec\l_dearh.hun. Acccs�cd Scptcmbu 6, 2017

Centers for Disease Control and Prevention: Pregnancy mortality surveillance system. 20 17a. Available at: https:I/\ww.cdc.govlrcprodllctivehealth/ matenalinfanthcalth/pmss.html. Accessed September 6.n2017

Centers for Disease Control and Prevention: Severe maternal morbidity in the United Slates. 2017b. Available at: hnps:/Iw.cdc.govlreproductivchealthfmarenalinfanrhealrh/scveremarcrnalmorbidiry.huul. Accessed Seprcmbern6,n2017

Ccnters for Disease Comrol and Prcvcntion: Vital signs: opioid painkillcr prescribing. 2014. Available at: Ilttps:llww.cdc.gov/vitalsigns/opioid-prescribinglindex.luml. Accessed September 6, 2017

Chervenak FA, Gruncbaunl A: Home birth: the ohsterrician's ethical response.

COlltemp Ob/Gyn May 8, 2015

Chervenak FA, .1cCullough LB, Brent RL, et al: Planned horne birth: (he professional responsibiliry response. Am J Ohs(e( G'necol 208(1 ):31. 2013 Chescheir NC: Enough already! Obstet GynecoIn12S(l):2, 2015

Chitty LS: Use of cell-f..-e DNA to screen for Down's syndrome. N Engl J Med 372(17),1666, 2015

Clark SL, Belforr \A, Dildy GA, et al: Maternal death in the 21st century: causes, prevcntion, and relationship to cesarean delivery. Am J Obstet Gynecol 199(1 ):36.cl, 2008

Clark SL, Meyers JA. Frye DR, et 11: A sysrematic approach to the identiication and classiication of near-miss cvems on lahor and delivery in a largc, national health care systcm. Am J Obstet Gynecol 207(5):441, 2012

Creanga A, Bateman BT, KukJina EV, e{ al: Racial and ethnic disparities in sevcre maternal morbidiry: a multisrate analysis, 2008-2010. Amn) Obsret Gynccol 21O(5):435.e1, 2014

Creanga A, Berg q, Syverson C, ct al: Pregnancy-related mortality in the United States, 2006-20 I O. Obstct Gynecol 125:5. 20n15

Creanga A, Syverson C, Seed K et al: Pregnancy-related mortality in the United States, 201n1-2013. Obstet GynecoIn130(2):366, 2017

D'AltOn rvlE, Friedman M. Smiley RM, et l: Nation:ll partnership for maternal safety: consensus bundle on venous thromboembolism. Obstet Gynecol 128,688-98, 2016 de Jonge A, GeertS CC. van der Goes BY, et al: Perinatal mortality and morbidity up fO 28 days after birth among 743,070 low-risk planned home and hospiral births: a cohort study based on three merged national pcrinaral d:uabase. BJOG 122(5):720,n2015

Dugof L: Application of genomic technology in prenatal diagnosis. N Engl J M,d 367(23),2249, 2012

Esplin MS, Eloviu MA, lams JD, '1al: Predicrivc accuracy of serial transvaginal cervicalnlengrhs and quantitative vaginal fetal flbroncctin levels of spontaneous preterm birth among nulliparous women. JAh-IA 317( 1 0): 1047,n2017

Fiedler M, Aaron HJ, Adler L, et al: Moving in the wrong direction-health care under the AHCA. N Engl J Med 376(25):2405, 2017

Flyckr R, Kodyar A, Arian S, er al: Deceased donor uterine transplantation.

Ferril Steril I07(3):eI3, 2017

Flyckr L, Farrell M, Peni US, et al: Deceased donor uterine transplantation: innovation and adaptation. Obstet GynecoIn128(4):837, 2016

Fox M: A million babies have been born in the U.S. wirh fertiliry help. Helth NBC News, April 28, 201i

Frey WH: America reaches i('s ([cmographic tipping poinr. 201n1. Available at: h t t ps:!1www.brooki ngs.cdu/blng/up-fronr/20 11/08/261 america -reaches-i rsdemographic-tipping-point.! Accessed September 6, 2017

Grttne MF, Ecker JL: ChOOSing beneits while balanCing risks. N Engl J t\lcd 373(27),2681,n2015

Gri.inebaum A, .lcCullough LB, Brelll L, e{ : Perinatal risks of planned home binhs in the United States. Am J Obstet Gynecol 212(3):350, 2015 Grunebaum A, Sapra K, Chervenak F: Term neonatal deaths resulting from hone births: an increasing trend. m J Obstet Gynecol 21O:S57, 2014

Guttmacher Institute: Fact sheer: publicly funded family planning services in [he United States. 2016a. Available at: https:II\Vw.gurtmacheLorgilct -sheet!publ idy-fu nded-fa IIi 1),-plann i ng-services-u n i ted -5ta res. Accessed September 6, 2017

Guttmacher Institute: Fact sheet: uninrended pregnancy in the United States. 2016b. A\<ailable at: lmps:llwww.gunmacher.orglact-shcct/uninrendedpregnancy-unired-states. AccCSL-d September 6, 2017

Hamilton BE, Marrin JA, OSlerman MJ, et al: Birrhs: inal dara for 2014. Natl Vital Stat Rep 54:\, 2015

Hamilton BE, Marrin JA, Ventura 5): Births: preliminary data for 2011. Nad Vital S[3( Rep 61 (5): I, 2012

Han B, Compton W.1. Blanco C, et l: Prescription opioid usc, misuse, and use disorders in U.S. adults: 2015 National Survey on Drug Use and Healrh. Ann Imern \led 167(5):293,n2017

Hehir \lP, Ananth CV, Wright JD, er al: Severe matenal morbidity and comorbid risk in hospitals performing <1000 deliveries per year. m J Obstct GynecoI 21G(2):179.el, 2017

Heron M: Deaths: leading causes for 2011. Nad Vital Srat Rep 64(7): 1, 2015 Howell A, Egorova NN, Balbierz A, e( al: Site of delivery contribution to black-white severe matenal morbidity disparity. 215(2):143, 2016

Hoyen DL: Maternal mortality and related concepts. Vital Health Stat 3(33), I, 2007

Institute for Safe �ledication Practices: ISMP survey helps deine near miss and de call. Medication Safety Alert, September 24, 2009. Available at: hn ps:ll\vww.ismp.orgl newsletters} acure.lfelanidesl20090n4 .asp. Accessed September 6,n2017

Joseph KS, Lisonkova S, Muraca GM, et al: Factors underlying the temporal increase in maternal mortaliry in the United States. 129{I ):91, 2017

KJlalifch A, Quist-Nelson ), Berghella V: Universal cervical lengTh screening for pretcnn birth prevention in the United States. J Maten Feral Neonatal Moo 30,1n500, 2017

King JC: Maternal mortality in Ihe United States-why is il imporrant and what are we doing about it? Semin PerinatoIn36(1):14, 2012

Knight M, Kurincwk JJ, Tufnell D, el al: 111e UK obstetric surveillance system for rare disorders of pregnancy. BJOG 112:263. 2005

Knight M, UKOSS: Antenatal pulmonary embolism: risk f..clOrs, management and outcomes. B)OG 11n5:453,n2008

Koonin LM, MacKay AP, Berg q, et al: Pregnancy-related morrality surveillance-United States, 1987-1990. MMWR 46(4):17,n1997

Kuehn I�M: US uterus transplant (fials under way. JAM A 317( I0): I 005,n2017

Lind )N, Interranre )D, Ailes EC, et al: Matenal usc of opioids during pregnancy and congeniral malformations: a systematic review. Pediatrics 139(6),,20164131,n201

Lockwood CJ: Is federal mOicalnliabiliry reform possible? COlHcmp OB/GYN July 2017

MacDorman MF, Declercq E: Trends and charactcristics of United States outof-hospital births 2004-20n14: new information on risk staws and access to carc. Birth 43(2): 1 16, 2016a

MacDonnan "-IF, Declercq E, Cabral H, et ;\1: Recent increases in the U.S. maternal mortality rate: disentangling trends from measuremem issues. Obstet GynecoIn128(3):447, 2016b �lacDorman MF, Declercq E, 1110ma ME: Trends in matenal mortality by sociodcmographic characteristics and cause of death in 27 states and the Dimi" of Columbia. Obstet Gynccol 129(5):811,n2017

MacDorman MF, Gregory EC: Fe!'al and perinatal mortality: United States, 2013. Nat! Vital Star R:p 64(8): 1, 2015

Main EK, Cape V, Abreo A, et al: Reduction of severe matcnal morbidity from hemorrhage using a state perinatal qualiry collaborative. Am J Obstet Gynccol 216(3):298.el, 2017

Main EK, Coffman D, Scavone B� I,et al: National partnership for materna! safety: consensus bundle on obstetric hemorrhage. Obstet Gynreol 126( I); 155, 2015 �Iarkus AR, Andres E, West D, et Il: Medicaid covered births, 2008 through 2010, in rhe concexr of the implementation of health reform. Womens Health Issues 23(5):e273. 2013 �1aron DF: 1.laternal health care is disappearing in rural America. Scientiic American, February 15,n2017

Martin JA, Hamilton BE, Osterman MJK, et al: Births: inal data for 2015.

National Vital Statistics Report 66: 1, 2017

Matthews RJ, MaeDorman MF, Thoma ME: In.1l1t mortality s:uistis from the 2013 period linked birth/in..lJl( death data set. Nat! Vital Stat Rep 64(9): 1,2015 t\IcCue B, Fagnant R, Townsend A, et al: Deinitions of obstetric and ynecologic hospitalists. Qbstel GynecoIn127(2):393, 2016 �Iello MM, Kachalia A, Sruddert D\I: Medicalnliabiliry�prospeclS for federal reform. N Engl J �Ied r6(19):1806, 2017 �loaddab A, Dildy GA, Brown H L, et al: Health care disparity and state-speciic pregnancy-related mortality in the United States, 2005-2014. Obstet Gynccol 128:869,n2016

Nelson DB, Mcintire DO, McDonald J, et al: 17-Alpha hydroxyprogestetone caprOate did not reduce the ratc of recurrent prcterm birth in a prospective cohort study. Am J Obstet Gynecol 216:600.e 1, 2017

NortOn ME. Jacobsson B, Swamy GK, et al: Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Moo 373(26):2582, 2015

Reddy UM, Davis )M, Ren Z, e1al: Opioid cin pregnancy, neonatal abstinence syndrome, and childhood Outcomes. Obsret Gynecol 130(1): 10. 201

Reddy UM, Page GP, Saade GR, et al: Karyotype versus microarra), testing for generic abnormalities after stillbirth. N Engl) Med 367(23):2185, 2012 Rice S: Baylor doctors deliver irst baby born in U.S. after uterine transplant.

Dallas i\lorning News. December 2, 2017

Shields LE, Wiesner S, Klein C, et al: Early standardized treatment of critical blood pressure elevations is associated with a reduction in eclampsia and severe maternal morbidity. Am J Obstet GynecoI216(4):415.el, 2017

Snowden JM, Tilden EL, Snyder J, et al: Planned out-of-hospital birth and birth outcomes. N Engl J Med 373:2642,r2015

Snyder M, Simmons LE, Kitzman JO, et al: Copy-number variation and false positive prenatal aneuploidy screening results. N Engl J Med 372(1 ): 1639, 2015

Souza JP, Cecatti JG, Haddad SM, et al: he WHO maternal near-miss approach and the maternal severity index model (MSI): tools for assessing the management of severe maternal morbidity. PLoS One 7(8):e44129, 2012

Squires 0, Anderson C: US health care from a global perspective, spending, use of services, prices, and health in ] 3 countries. Issue Brief (Commonw Fund) 15:1,r2015

Srinivas SK, Small OS, Macheras M, et al: Evaluating the impact of the laborist model of obstetric care on maternal and neonatal outcomes. Am J Obstet GynecoIr215:770.el,r2016

Stevenson AJ, Flores-Vazquez 1M, Allgeyer RL, et al: Efect of removal of Planned Parenthood from the Texas women's health program. N Engl J Med 374(9):853, 2016

Overview of Obstetrics 11

Talkowski ME, Ordulu Z, Pillalamarri V, et al: Clinical diagnosis by wholegenome sequencing of a prenatal sample. N EnglJ Med 367(23):2226, 2012 Tavenise S: Maternal mortality rate in U.S. rises, deying global trend, study finds. New York Times, September 21,r2016

Testa G, Koon EC, Johannesson L, et al: Living donor uterus transplantation: a single center's observations and lessons leaned from early setbacks to technical success. Am J Transplant, April 22, 2017 [Epub ahead of print]

Towers Watson: Update of U.S. tort cost trends. Available at: towerswatson. com. Accessed July 30,r201

Yan der Kooy J, Poeran J, de Graaf JP, et l: Planned home compared with planned hospital births in the Netherlands. Obstet Gynecol 118(5): 1037, 2011 Yoelker R: US preterm births: "0" is for dismal. JAMA 303(2):116,r2010 Wapner RJ, Martin CL, Levy B, et al: Chromosomal microarray versus karyo typing for prenatal diagnosing. N Engl J Med 367(23):2175, 2012

Wasden S, Perlman J, Chasen S, et al: Home birth and risk of neonatal hypoxic ischemic encephalopathy. Am J Obstet Gynecol 21 0:S251, 2014

Wax JR, Lucas FJ, Lamont M, et al: Maternal and newbon oLltcomes in planned home birth vs planned hospital births: a metaanalysis. Am J Obstet GynecoIr203(3):243,r2010

Yuko E: Weighing the ethics of artiicial wombs. New York Times, May 8,r2017

ANTERIOR ABDOMINAL WALL . . . . . . . . . . . . . . . . . . . . . 14

EXTERNAL GENERATIVE ORGANS ... .... .. 16

INTERNAL GENERATIVE ORGANS .......... ..... . 23

LOWER URINARY TRACT STRUCTURES ... . 28

MUSCULOSKELETAL PELVIC ANATOMY . .. 29

As the mechanism of labour is essentialy a process of accommodation between the oetus and the passage through which it must pass, it is apparent that obstetrics lacked a scientiic oundation until the anatomy of the bony pelvis and of the sot parts connected with it was cleary understood -J. Whitridge Williams (1903) • Skin, Subcutaneous Layer, and Fascia he anterior abdominal wall confines abdominal viscera, stretches to accommodate the expanding uterus, and provides surgical access to the internal reproductive organs. hus, a comprehensive knowledge of its layered structure is required to surgically enter the peritoneal cavity.

Langer lines describe the orientation of dermal fibers within the skin. In the anterior abdominal wall, they are arranged transversely. As a result, vertical skin incisions sustain greater lateral tension and thus, in general, develop wider scars. In contrast, low transverse incisions, such as the Pfannenstiel, follow Langer lines and lead to superior cosmetic results.

The subcutaneous layer can be separated into a superficial, predominantly fatty layer-Camper fascia, and a deeper membranous layer-Scarpa fascia. Camper fascia continues onto the perineum to provide fatty substance to the mons pubis and labia majora and then to blend with the fat of the ischioanal fossa. Scarpa fascia continues inferiorly onto the perineum as Colles fascia, described on page 19.

Beneath the subcutaneous layer, the anterior abdominal wall muscles consist of the midline rectus abdominis and pyramidalis muscles as well as the external oblique, internal oblique, and transversus abdominis muscles, which extend across the entire wall (Fig.

The ibrous aponeuroses of these three latter muscles form the primary fascia of the anterior abdominal wall. These fuse in the midline at the linea alba, which normally measures 10 to 15 mm wide below the umbilicus (Beer, 2009). n abnormally wide separation may reflect diastasis recti or hernia.

These three aponeuroses also invest the rectus abdominis muscle as the rectus sheath. The construction of this sheath varies above and below a boundary, termed the arcuate line (see Fig. 2-1). Cephalad to this border, the aponeuroses invest the rectus abdominis bellies on both dorsal and ventral surfaces. Caudal to this line, all aponeuroses lie ventral or supericial to the rectus abdominis muscle, and only the thin transversalis fascia and peritoneum lie beneath the rectus (Loukas, 2008). This transition of rectus sheath composition can be seen best in the upper third of a midline vertical abdominal incision.

he paired small triangular pyramidalis muscles originate from the pubic crest and insert into the linea alba. These muscles lie atop the rectus abdominis muscle but beneath the anterior rectus sheath.

he supericial epigastric, supericial circumlex iliac, and supericial external pudendal arteries arise from the femoral artery just below the inguinal ligament within the femoral triangle

Rectus abdominis m.

External oblique m.

Internal oblique m.

Transversus abdominis m.

Lateral cutaneous n.

Genital branch of genitofemoral n.

Internal thoracic a.

Superior epigastric a.

Inferior epigastric a.

Superficial circumflex iliac a.

External pudendal a.

with emerging round ligament, ilioinguinal & genitofemoral nn.

FIGURE 2-1 Anterior abdominal wall anatomy. (Modified with permission from Corton MM: Anatomy. In Hoffman BL, Schorge JO, Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGraw-Hili Education, 2016) (see Fig. 2-0. These vessels supply the skin and subcutaneous layers of the anterior abdominal wall and mons pubis. Of these three, the superficial epigastric vessels are surgically important to the obstetrician and course diagonally from their origin toward the umbilicus. With a low transverse skin incision, these vessels can usually be identified at a depth halway between the skin and the anterior rectus sheath. They lie above Scarpa fascia and several centimeters from the midline. Ideally, these vessels are identiied and surgically occluded.

In contrast, the inferior "deep" epigastric vessels are branches of the external iliac vessels and supply anterior abdominal wall muscles and fascia. Of surgical relevance, the inferior epigastric vessels initially course lateral to, then posterior to the rectus abdominis muscles, which they supply. Above the arcuate line, these vessels course ventral to the posterior rectus sheath and lie between this sheath and the posterior surface of the rectus muscles. Near the umbilicus, the inferior epigastric vessels anastomose with the superior epigastric artery and vein, which are branches of the internal thoracic vessels. Clinically, when a Maylard incision is used for cesarean delivery, the inferior epigastric vessels may be lacerated lateral to the rectus belly during muscle transection. Preventively, identiication and surgical occlusion are preferable. These vessels rarely may rupture following abdominal trauma and create a rectus sheath hematoma (Toicher, 2010; Wai, 2015).

On each side of the lower anterior abdominal wall, Hesselbach triangle is the region bounded laterally by the inferior epigastric vessels, inferiorly by the inguinal ligament, and medially by the lateral border of the rectus abdominis muscle. Hernias that protrude through the abdominal wall in Hesselbach triangle are termed direct inguinal hernias. In contrast, indirect inguinal hernias do so through the deep inguinal ring, which lies lateral to this triangle, and then may exit out the supericial inguinal ring.

he entire anterior abdominal wall is innervated by intercostal nerves (T 7-"i )ithe subcostal nerve (T'2)•' and the ilio hypogastric and the ilioinguinal nerves (L,). Of these, the

Intecostal n. Internaloblique m. External __.oblique m. Lateral Anterior ramus

FIGURE 2-2 Intercostal and subcostal nerves are the anterior rami of spinal nerves. In this figure, an intercostal nerve extends ventrally between the transversus abdominis and internal oblique muscles. During this path, the nerve gives rise to lateral and anterior cutaneous branches, which innervate the anterior abdominal wall. As shown by the inserted needle, the transversus abdominis plane (TAP) block takes advantage of this anatomy. (Modified with permission from Hawkins JL: Anesthesia for the pregnant woman. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al: Cunningham and Gilstraps's Operative Obstetrics, 3rd ed. New York, McGraw Hill Education, 201o7.) intercostal and subcostal nerves are anterior rami of the thoracic spinal nerves and run along the lateral and then anterior abdominal wall between the transversus abdominis and internal oblique muscles (Fig. 2-2). his space, termed the transversus abdominis plane, can be used for postcesarean analgesia blockade (Chap. 25, p. 500) (Fusco, 2015; Tawfik, 2017). Others report rectus sheath or ilioinguinaliliohypogastric nerve blocks to decrease postoperative pain (Mei, 2011; Wolfson, 2012).

Near the rectus abdominis lateral borders, anterior branches of the intercostal and subcostal nerves pierce the posterior sheath, rectus muscle, and then anterior sheath to reach the skin. hus, these nerve branches may be severed during a Pfannenstiel incision creation during the step in which the overlying anterior rectus sheath is separated from the rectus abdominis muscle.

In contrast, the iliohypogastric and ilioinguinal nerves originate from the anterior ramus of the first lumbar spinal nerve. They emerge lateral to the psoas muscle and travel retroperitoneally across the quadratus lumborum inferomedially toward the iliac crest. Near this crest, both nerves pierce the transversus abdominis muscle and course ventromedially. At a site 2 to 3 cm medial to the anterior superior iliac spine, the nerves then pierce the internal oblique muscle and course supericial to it toward the midline (Whiteside, 2003). The iliohypogastric nerve perforates the external oblique aponeurosis near the lateral rectus border to provide sensation to the skin over the suprapubic area (see Fig. 2-1). The ilioinguinal nerve in its course medially travels through the inguinal canal and exits through the supericial inguinal ring, which forms by splitting of external abdominal oblique aponeurosis fibers. This nerve supplies the skin of the mons pubis, upper labia majora, and medial upper thigh.

The ilioinguinal and iliohypogastric nerves can be severed during a low transverse incision or entrapped during closure, especially if incisions extend beyond the lateral borders of the rectus abdominis muscle (Rahn, 2010). These nerves carry sensory information only, and injury leads to loss of sensation within the areas supplied. Rarely, chronic pain may develop (Whiteside, 2005).

he T 10 dermatome approximates the level of the umbilicus. Analgesia to this level is suitable for labor and vaginal birth. Regional analgesia for cesarean delivery or for puerperal sterilization ideally extends to T4'

Mons Pubis, Labia, and Clitoris

The pudenda-commonly designated the vulva-includes all structures visible externally from the symphysis pubis to the perineal body. This includes the mons pubis, labia majora and minora, clitoris, hymen, vestibule, urethral opening, greater vestibular or Bartholin glands, minor vestibular glands, and paraurethral glands (Fig. 2-3). he vulva receives innervations and vascular support from the pudendal nerve (p. 22).

he mons pubis is a fat-illed cushion overlying the symphysis pubis. After puberty, the mons pubis skin is covered by curly hair that forms the triangular escutcheon, whose base aligns with the upper margin of the symphysis pubis. In men and some hirsute women, the escutcheon extends farther onto the anterior abdominal wall toward the umbilicus.

Labia majora usually are 7 to 8 cm long, 2 to 3 cm wide, and 1 to 1.5 cm thick. They are continuous directly with the mons pubis superiorly, and the round ligaments terminate at their upper borders. Hair covers the labia majora, and apocrine, eccrine, and sebaceous glands are abundant. Beneath the skin, a dense connective tissue layer is nearly void of muscular elements but is rich in elastic fibers and fat. his fat mass provides bulk to the labia majora and is supplied with a rich venous plexus. During pregnancy, this vasculature may develop varicosities, especially in multiparas, from increased venous pressure created by the enlarging uterus. hey appear as engorged tortuous veins or as small grapelike clusters, but they are typically asymptomatic and require no treatment.

Each labium minus is a thin tissue fold that lies medial to each labium majus. he labia minora extend superiorly, where each divides into two lamellae. From each side, the lower lamellae fuse to form the frenulum of the clitoris, and the upper lamellae merge to form the prepuce (see Fig. 2-3). Inferiorly, the labia minora extend to approach the midline as low ridges of tissue that join to form the fourchette. The labia minora dimensions vary greatly among individuals, with lengths from 2 to 10 cm and widths from 1 to 5 cm (Lloyd, 2005).

Structurally, the labia minora are composed of connective tissue with numerous vessels, elastin ibers, and very few smooth muscle ibers. hey are supplied with many nerve endings and are extremely sensitive (Ginger, 20i1i1a; Schober, 2015). The epithelia of the labia minora difer with location. Thinly keratinized stratiied squamous epithelium covers the

Glans of clitoris

Inferior fascia of levator ani mm./

External anal sphincter m.

FIGURE 2-3 Vulvar structures and subcutaneous layer of the anterior perineal triangle. Note the continuity of Colles and Scarpa fasciae. Inset: Vestibule boundaries and openings onto vestibule. (Reproduced with permission from Corton MM: Anatomy. In Hofman BL, Schorge JO, Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGraw-Hili Education, 2016.) outer surface of each labium. On their inner surface, the lateral portion is covered by this same epithelium up to a demarcating line, termed Hart line. Medial to this line, each labium is covered by squamous epithelium that is nonkeratinized. he labia minora lack hair follicles, eccrine glands, and apocrine glands. However, sebaceous glands are numerous (Wilkinson, 2011).

he clitoris is the principal female erogenous organ. It is located beneath the prepuce, above the frenulum and urethra, and projects downward and inward toward the vaginal opening. The clitoris rarely exceeds 2 cm in length and is composed of a glans, a corpus or body, and two crura (Verkauf, 1992). he glans is usually less than 0.5 cm in diameter, is covered by stratified squamous epithelium, and is richly innervated. he clitoral body contains two corpora cavernosa. Extending from the clitoral body, each corpus cavernosum diverges laterally to form a long, narrow crus. Each crus lies along the inferior surface of its respective ischiopubic ramus and deep to the ischiocavernosus muscle. The clitoral blood supply stems from branches of the internal pudendal artery. Specifically, the deep artery of the clitoris supplies the clitoral body, whereas the dorsal artery of the clitoris supplies the glans and prepuce.

In adult women, the vestibule is an almond-shaped area that is enclosed by Hart line laterally, the external surface of the hymen medially, the clitoral frenulum anteriorly, and the fourchette posteriorly (see Fig. 2-3). The vestibule is usually perforated by six openings: the urethra, the vagina, two Bartholin gland ducts, and two ducts of the largest paraurethral glands-the

Skene glands. he posterior portion of the vestibule between the fourchette and the vaginal opening is called the fossa navic ularis. It is usually observed only in nulliparas.

The bilateral Bartholin glands, also termed greater vestibular glands, measure 0.5 to 1 cm in diameter. On their respective side, each lies inferior to the vestibular bulb and deep to the inferior end of the bulbospongiosus muscle (former bulbocavernosus muscle). A duct extends medially from each gland, measures 1.5 to 2 cm long, and opens distal to the hymeneal ring-one at 5 and the other at 7 o'clock on the vestibule. Following trauma or infection, either duct may swell and obstruct to form a cyst or, if infected, an abscess. In contrast, the minor vestibular glands are shallow glands lined by simple mucinsecreting epithelium and open along Hart line.

he paraurethral glands are a collective arborization of glands whose numerous small ducts open predominantly along the entire inferior aspect of the urethra. he two largest are called Skene glands, and their ducts typically lie distally and near the urethral meatus. Clinically, inlammation and duct obstruction of any of the paraurethral glands can lead to urethral diverticulum formation. The urethral opening or meatus is in the midline of the vestibule, 1 to 1.5 cm below the pubic arch, and a short distance above the vaginal opening.

In adult women, the hymen is a membrane of varying thickness that surrounds the vaginal opening more or less completely.

Perineal body Fuseddistal segment of urethra & vagina

FIGURE 2-4 Vagina and surrounding anatomy. (Reproduced with permission from Corton MM: Anatomy. In Hofman BL, Schorge JO,

Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGraw-Hili Education, 201o6.)

It is composed mainly of elastic and collagenous connective tissue, and both outer and inner surfaces are covered by nonkeratinized stratified squamous epithelium. he aperture of the intact hymen ranges in diameter from pinpoint to one that admits one or even two ingertips. As a rule, the hymen is torn at several sites during irst coitus. However, identical tears may form by other penetration, for example, by tampons used during menstruation. The edges of the torn tissue soon reepithelialize. In pregnant women, the hymeneal epithelium is thick and rich in glycogen. Changes produced in the hymen by childbirth are usually readily recognizable. For example, over time, the hymen transforms into several nodules of various sizes, termed hymeneal or myrtiform caruncles.

Proximal to the hymen, the vagina is a musculomembranous tube that extends to the uterus and is interposed lengthwise between the bladder and the rectum (Fig. 2-4). Anteriorly, the vagina is separated from the bladder and urethra by connective tissue-the vesicovaginal septum. Posteriorly, between the lower portion of the vagina and the rectum, similar tissues together form the rectovaginal septum. The upper fourth of the vagina is separated from the rectum by the rectouterine pouch, also called the cul-de-sac or pouch of Douglas.

Normally, the anterior and posterior walls of the vaginal lumen lie in contact, with only a slight space intervening at the lateral margins. Vaginal length varies considerably, but commonly, the anterior wall measures 6 to 8 cm, whereas the posterior vaginal wall is 7 to 10 cm. The upper end of the vaginal

Posteriorcul-de-sac of Douglas sphincter m.

External anal sphincter m.

vault is subdivided by the cervix into anterior, posterior, and two lateral fornices. Clinically, the internal pelvic organs usually can be palpated through the thin walls of these fornices.

The vaginal lining is composed of nonkeratinized stratified squamous epithelium and underlying lamina propria. In premenopausal women, this lining is thrown into numerous thin transverse ridges, known as rugae, which line the anterior and posterior vaginal walls along their length. Deep to this, a muscular layer contains smooth muscle, collagen, and elastin. Beneath this muscularis lies an adventitial layer consisting of collagen and elastin (Weber, 1997).

The vagina lacks glands. Instead, it is lubricated by a transudate that originates from the vaginal subepithelial capillary plexus and crosses the permeable epithelium (Kim, 201l). Due to increased vascularity during pregnancy, vaginal secretions are notably increased. At times, this may be confused with amnionic fluid leakage, and clinical diferentiation of these two is described in Chapter 22 (p. 435).

Mter birth-related epithelial trauma and healing, fragments of stratified epithelium occasionally are embedded beneath the vaginal surface. Similar to its native tissue, this buried epithelium continues to shed degenerated cells and keratin. As a result, epidermal inclusion cysts, which are filled with keratin debris, may form. hese are a common vaginal cyst.

The vagina has an abundant vascular supply. The proximal portion is supplied by the cervical branch of the uterine artery and by the vaginal artery. he latter may variably arise from the

Vesicovaginal space (filled with loose connective tissue) uterine or inferior vesical artery or directly from the internal iliac artery. The middle rectal artery contributes supply to the posterior vaginal wall, whereas the distal walls receive contributions from the internal pudendal artery. At each level, vessels supplying each side of the vagina course medially across the anterior or posterior vaginal wall and form midline anastomoses.

An extensive venous plexus also surrounds the vagina and follows the course of the arteries. Lymphatics from the lower third, along with those of the vulva, drain primarily into the inguinal lymph nodes. Those from the middle third drain into the internal iliac nodes, and those from the upper third drain into the external, internal, and common iliac nodes.

his diamond-shaped area between the thighs has boundaries that mirror those of the bony pelvic outlet: the pubic symphysis anteriorly, ischiopubic rami and ischial tuberosities anterolaterally, sacrotuberous ligaments posterolaterally, and coccyx posteriorly. An arbitrary line joining the ischial tuberosities divides the perineum into an anterior triangle, also called the urogenital triangle, and a posterior triangle, termed the anal triangle.

he perineal body is a fibromuscular pyramidal mass found in the midline at the junction between these anterior and posterior triangles (Fig. 2-5). Also called the central tendon of the perineum, the perineal body sonographically measures 8 mm tall and 14 mm wide and thick (Santoro, 2016). It serves as the junction for several structures and provides significant perineal support (Shafik, 2007). Superficially, the bulbospongiosus, superficial transverse perineal, and external anal sphincter muscles converge on the perineal body. More deeply, the perineal membrane, portions of the pubococcygeus muscle, and internal anal sphincter contribute (Larson, 2010). The perineal body

Ischiocavernosus m.

Cut edge of Colles fascia

Bulbospongiosus m.

Superficial transverse perineal m.

External anal sphincter m.

is incised by an episiotomy incision and is torn with second-, third-, and fourth-degree lacerations.

Superficial Space of the Anterior Triangle

This triangle is bounded by the pubic rami superiorly, the ischial tuberosities laterally, and the supericial transverse perineal muscles posteriorly. It is divided into supericial and deep spaces by the perineal membrane. This membranous partition is a dense ibrous sheet that was previously known as the inferior fascia of the urogenital diaphragm. The perineal membrane attaches laterally to the ischiopubic rami, medially to the distal third of the urethra and vagina, posteriorly to the perineal body, and anteriorly to the arcuate ligament of the pubis (see Fig. 2-5) .

The supericial space of the anterior triangle is bounded deeply by the perineal membrane and supericially by Co lIes fascia. As noted earlier, Colles fascia is the continuation of Scarpa fascia onto the perineum. On the perineum, Co lIes fascia securely attaches laterally to the pubic rami and fascia lata of the thigh, inferiorly to the supericial transverse perineal muscle and inferior border of the perineal membrane, and medially to the urethra, clitoris, and vagina. As such, the superficial space of the anterior triangle is a relatively closed compartment.

his supericial pouch contains several important structures, which include the Bartholin glands, vestibular bulbs, clitoral body and crura, branches of the pudendal vessels and nerve, and the ischiocavernosus, bulbospongiosus, and supericial transverse perineal muscles. Of these muscles, the ischiocavernosus muscles each attach on their respective side to the medial aspect of the ischial tuberosity inferiorly and the ischiopubic ramus laterally. Anteriorly, each attaches to a clitoral crus and may help maintain clitoral erection by compressing the crus to obstruct venous drainage. he bilateral bulbospongiosus muscles overlie the vestibular bulbs and

Crus of clitoriS

Cut edge of ischiocavernous m.

Levator ani m.

�Gluteus maximus m.

FIGURE 2-5 Superficial space of the anterior perineal triangle and posterior perineal triangle. Structures on the left side of the image can be seen after removal of Colles fascia. Those on the right side are noted after removal of the superficial muscles of the anterior triangle. (Modified with permission from Corton MM: Anatomy. In Hoffman BL, Schorge JO, Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGraw-Hili Education, 2016.)

Bartholin glands. They attach to the body of the clitoris anteriorly and the perineal body posteriorly. The muscles constrict the vaginal lumen and aid release of secretions from the Bartholin glands. They also may contribute to clitoral erection by compressing the deep dorsal vein of the clitoris. The bulbospongiosus and ischiocavernosus muscles also pull the clitoris downward. Last, the superficial transverse perineal muscles are narrow strips that attach to the ischial tuberosities laterally and the perineal body medially. They may be attenuated or even absent, but when present, they contribute to the perineal body (Corton, 2016).

The vestibular bulbs are almond-shaped aggregations of veins that lie beneath the bulbospongiosus muscle on either side of the vestibule. They measure 3 to 4 cm long, 1 to 2 cm wide, and 0.5 to 1 cm thick. The bulbs terminate inferiorly at approximately the middle of the vaginal opening and extend upward toward the clitoris. Their anterior extensions merge in the midline, below the clitoral body. During childbirth, veins in the vestibular bulbs may be lacerated or even rupture to create a vulvar hematoma enclosed within the supericial space of the anterior triangle (Fig. 41-11, p. 765).

Deep Space of the Anterior Triangle his space lies deep to the perineal membrane and extends up into the pelvis (Mirilas, 2004). In contrast to the supericial perineal space, the deep space is continuous superiorly with the pelvic cavity (Corton, 2005). It contains portions of urethra and vagina, certain portions of internal pudendal artery branches, and muscles of the striated urogenital sphincter complex (Fig. 2-6).

Urethra. The female urethra measures 3 to 4 cm and originates within the bladder trigone (p. 28). he distal two thirds of the urethra are fused with the anterior vaginal wall. The epithelialilining of the urethra changes from transitional epithelium proximally to nonkeratinized stratiied squamous epithelium distally. The walls of the urethra consist of two layers of smooth muscle, an inner longitudinal and an outer circular. This is in turn surrounded by a circular layer of skeletal muscle referred to as the sphincter urethrae or rhabdosphincter (see Fig. 2-6). Approximately at the junction of the middle and lower third of the urethra, and just above or deep to the perineal membrane, two strap skeletal muscles called the urethrovaginal sphincter and compressor urethrae are found. Together with the sphincter urethrae, these constitute the striated urogenital sphincter complex. This complex supplies constant tonus and provides emergency relex contraction to sustain continence.

Distal to the level of the perineal membrane, the walls of the urethra consist of ibrous tissue, serving as the nozzle that directs the urine stream. Here, the urethra has a prominent submucosal layer that is lined by hormonally sensitive stratiied squamous epithelium. Within the submucosal layer on the dorsal (vaginal) surface of the urethra lie the paraurethral glands, described earlier (p. 17).

he urethra receives its blood supply from branches of the inferior vesical, vaginal, or internal pudendal arteries. Although still controversial, the pudendal nerve is believed to innervate the most distal part of the striated urogenital sphincter complex. Somatic eferent branches from 52-54 that course along the inferior hypogastric plexus variably innervate the sphincter urethrae.

Dorsal v. of clitoris Labium minus (cut) Hymeneal ring Sphincter urethrae m.}Striated Compressor urethrae m. urogenital sphincter Urethrovaginal sphincter m. complex Ischiopubic ramus (cut) Perineal membrane Ischiopubic ramus Cut edge of perineal membrane Bulbospongiosus m. (cut) Ischiocavernous m. (cut) Superficial transverse perineal m. External anal sphincter m. Gluteus maximus m. Compressor urethrae m. Urethrovaginal sphincter m. Pubococcygeus }(pubovisceral) m . Pub"ecto'" m. Levator ani mm. . lliococcygeus m."S FIGURE 2-6 Deep space of anterior triangle of the perineum. Structures on the right side of the image can be seen after remova l of the perineal membrane. Also shown are structures that attach to the perineal body: bulbospongiosus, superficial transverse perineal, external anal sphincter, and puboperinealis muscles as well as perineal membrane. (Reproduced with permission from Corton MM: Anatomy. In Hoffman BL, Schorge JO, Bradshaw KD, et al (eds): Gynecology, 3rd ed. New York, McGraw-Hili Education, 2016.) ·m. External anal sphincter m. Longitudinal smooth m. layer Circular smooth m. layer Plicae transversalis recti

Internal anal sphincter m .

FIGURE 2-7 Anal canal and ischioanal fossa. (Reproduced with permission from Corton MM: Anatomy. In Hoffman BL, Schorge JO, Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGraw-Hili Education, 2016.)

Found deep to the anterior and posterior triangles, this broad muscular sling provides substantial support to the pelvic viscera. The pelvic diaphragm is composed of the levator ani and the coccygeus muscles. The levator ani, in turn, contains the pubococcygeus, puborectalis, and iliococcygeus muscles. The pubococcygeus muscle is also termed the pubovisceral muscle and is subdivided based on points of insertion and function. These include the pubovaginalis, puboperinealis, and puboanalis muscles, which insert into the vagina, perineal body, and anus, respectively (Kearney, 2004).

Vaginal birth conveys signiicant risk for damage to the levator ani or to its innervation (DeLancey, 2003; Weidner, 2006). Evidence supports that levator ani avulsion may predispose women to greater risk of pelvic organ prolapse (Dietz, 2008; Schwertner-Tiepelmann, 2012). For this reason, current research eforts are aimed at minimizing these injuries.

his triangle contains the ischioanal fossae, anal canal, and anal sphincter complex, which consists of the internal anal sphincter, external anal sphincter, and puborectalis muscle. Branches of the pudendal nerve and internal pudendal vessels are also found within this triangle.

Ischioanal Fossae. Also known as ischiorectal fossae, these two fat-filled wedge-shaped spaces are found on either side of the anal canal and comprise the bulk of the posterior triangle (Fig. 2-7). Each fossa has skin as its supericial base, whereas its deep apex is formed by the junction of the levator ani and obturator internus muscles. Other borders include: laterally, the obturator internus muscle fascia and ischial tuberosity; inferomedially, the anal canal and sphincter complex; superomedially, the inferior fascia of the downwardly sloping levator ani; posteriorly, the gluteus maxim us muscle and sacrotuberous ligament; and anteriorly, the inferior border of the anterior tri angle.

The fat found within each fossa provides support to surrounding organs yet allows rectal distention during defecation and vaginal stretching during delivery. Clinically, injury to vessels in the posterior triangle can lead to hematoma formation in the ischioanal fossa, and the potential for large accumulation in these easily distensible spaces. Moreover, the two fossae communicate dorsally, behind the anal canal. This can be especially important because an episiotomy infection or hematoma may extend from one fossa into the other.

Anal Canal. his distal continuation of the rectum begins at the level of levator ani attachment to the rectum and ends at the anal skin. Along this 4-to 5-cm length, the mucosa consists of columnar epithelium in the uppermost portion. However, at the pectinate line, also termed dentate line, simple stratified squamous epithelium begins and continues to the anal verge. At the verge, keratin and skin adnexa join the squamous epithelium.

The anal canal has several tissue layers (see Fig. 2-7). Inner layers include the anal mucosa, the internal anal sphincter, and an intersphincteric space that contains continuation of the rectum's longitudinal smooth muscle layer. An outer layer contains the puborectalis muscle as its cephalad component and the external anal sphincter caudally.

Within the anal canal, three highly vascularized submucosal arteriovenous plexuses, termed anal cushions, aid complete closure of the canal and fecal continence when apposed. Increasing uterine size, excessive straining, and hard stool create increased pressure that ultimately leads to degeneration and subsequent laxity of the cushion's supportive connective tissue base. These cushions then protrude into and downward through the anal canal. This leads to venous engorgement within the cushionsnow termed hemorrhoids. Venous stasis results in inflammation, erosion of the cushion's epithelium, and then bleeding.

internus m.

Pudendal n.

External hemorrhoids are those that arise distal to the pectinate line. They are covered by stratiied squamous epithelium and receive sensory innevation from the inferior rectal nerve. Accordingly, pain and a palpable mass are typical complaints. Following resolution, a hemorrhoidal tag may remain and is composed of redundant anal skin and ibrotic tissue. In contrast, internal hemorrhoids are those that form above the pectinate line and are covered by insensitive anorectal mucosa. hese may prolapse or bleed but rarely become painful unless they undergo thrombosis or necrosis.

Anal Sphincter Complex. Two sphincters surround the anal canal to provide fecal continence-the external and internal anal sphincters. Both lie near the vagina and may be torn during vaginal delivery. he internal anal sphincter (lAS) is a distal continuation of the rectal circular smooth muscle layer. It receives predominantly parasympathetic ibers, which pass through the pelvic splanchnic nerves. long its length, this sphincter is supplied by the superior, middle, and inferior rectal arteries. he lAS contributes the bulk of anal canal resting pressure for fecal continence and relaxes prior to defecation. The lAS measures 3 to 4 cm in length, and at its distal margin, it overlaps the external sphincter for 1 to 2 cm (DeLancey, 1997). he distal site at which this overlap ends, called the intersphincteric groove, is palpable on digital examination.

In contrast, the external anal sphincter (EAS) is a striated muscle ring that anteriorly attaches to the perineal body and posteriorly connects to the coccyx via the anococygealiligament. The EAS maintains a constant resting contraction to aid continence, provides additional squeeze pressure when continence is threatened, yet relaxes for defecation. he external sphincter receives

Posterior labial n.

Ischiocavernosus m.

Bulbospongiosus m.

perineal m.

Perineal n.

Pudendal n.

sphincter m.

Levator ani mm.

blood supply from the inferior rectal artery, which is a branch of the internal pudendal artery. Somatic motor ibers from the inferior rectal branch of the pudendal nerve supply innervation. Clinically, the AS and EAS may be involved in third-and fourthdegree lacerations during vaginal delivery, and reunion of these rings is integral to defect repair (Chap. 27, p. 532).

This is formed from the anterior rami of S24 spinl nerves. It courses between the piriformis and cocygeus muscles and exits through the greater sciatic foramen at a location posterior to the sacrospinous ligament and just medil to the ischial spine (Barber, 2002; Maldonado, 2015). Thus, when injecting local anesthetic for a pudendal nerve block, the ischial spine serves an identifiable landmark (Chap. 25, p. 489). The pudendal nerve then runs beneath the sacrospinous ligament and above the sacrotuberous ligament as it reenters the lesser sciatic foramen to course along the obturator intern us muscle. Atop this muscle, the nerve lies within the pudendal canal, also known as Alcock canal, which is formed by splitting of the obturator internus investing fascia (Shafik, 1999). In general, the pudendal nerve is relatively fixed as it courses behind the sacrospinous ligament and within the pudendal canal. Accordingly, it may be at risk of stretch injury during downward displacement of the pelvic floor during childbirth (Lien, 2005).

he pudendal nerve leaves this canal to enter the perineum and divides into three terminal branches (Fig. 2-8). The first of these, the dorsal nerve of the clitoris, runs between the ischiocavernosus muscle and perineal membrane to supply the clitoral glans (Ginger, 2011 b). Second, the perineal nerve runs supericial to the perineal membrane (Montoya, 201l). It divides into

Ilioinguinal & genitofemoral nn. branches

Glans & crus of clitoriS sphincter mm.

/' Perineal membrane with window that exposes striated urogenital sphincter mm.

Dorsal n. & a. of

Perineal n. & a.

Perineal branch of cutaneous n.

Inferior rectal n. & a.

Gluteus maximus m.

FIGURE 2-8 Pudendal nerve and vessels. (Reproduced with permission from Corton MM: Anatomy. In Hoffman BL, Schorge JO, Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGraw-Hili Education, 2016.) posterior labial branches and muscular branches, which serve the labial skin and the anterior perineal triangle muscles, respectively. Last, the inferior rectal branch runs through the ischioanal fossa to supply the external anal sphincter, the anal mucosa, and the perianal skin (vlahakkanukrauh, 2005). The major blood supply to the perineum is via the internal pudendal artery, and its branches mirror the divisions of the pudendal nerve.

The nonpregnant uterus lies in the pelvic cavity between the bladder anteriorly and the rectum posteriorly. Almost the entire posterior wall of the uterus is covered by serosa, that is, visceral peritoneum (Fig. 2-9). The lower portion of this peritoneum forms the anterior boundary of the rectouterine cul-de-sac, or pouch of Douglas. Only the upper portion of the anterior uterine wall is covered by visceral peritoneum. At the caudal border of this portion, the peritoneum relects forward onto the bladder dome to create the vesicouterine pouch. As a result, the lower portion of the anterior uterine wall is separated from the posterior wall of the bladder only by a well-defined loose connective tissue layer-the vesicouterine space. Clinically, during cesarean delivery, the peritoneum of the vesicouterine pouch is sharply incised, and the vesicouterine space is entered. Dissection caudally within this space lifts the bladder safely of the lower uterine segment for hysterotomy and delivery (Chap. 30, p. 573).

The uterus is pear shaped and consists of two major but unequal parts. The upper, larger portion is the body or corpus, whereas the lower smaller cervix projects into the vagina. The isthmus is the union site of these two. It is of special obstetrical significance because it forms the lower uterine segment during pregnancy. At each superolateral margin of the body is a uterine cornu, from which a fallopian tube emerges. This area also contains the origins of the round and ovarian ligaments. Between the points of fallopian tube insertion is the convex upper uterine segment termed the fundus.

The bulk of the uterine body, but not the cervix, is muscle.

The inner surfaces of the anterior and posterior walls lie almost in contact, and the cavity between these walls forms a mere slit. The nulligravid uterus measures 6 to 8 cm in length compared with 9 to 10 cm in multiparas. The uterus averages 60 g and typically weighs more in parous women (Langlois, 1970; Sheikhazadi,i2010).

Pregnancy stimulates remarkable uterine growth due to muscle iber hypertrophy. The uterine fundus, a previously flattened convexity between tubal insertions, now becomes dome shaped. Moreover, the round ligaments appear to insert at the junction of the middle and upper thirds of the organ. The fallopian tubes elongate, but the ovaries grossly appear unchanged.

This portion of the uterus is cylindrical and has small apertures at each end-the internal and external cervical ora. The endocervical canal runs through the cervix and connects these ora. The cervix is divided into upper and lower portions by the vagina's attachment to its outer surface. he upper portionthe portio supravaginalis-begins at the internal os, which corresponds to the level at which the peritoneum is reflected up onto the bladder (Fig. 2-10). The lower cervical portion protrudes into the vagina as the portio vaginalis.

Before childbirth, the external cervical os is a small, regular, oval opening. After labor, especially vaginal childbirth, the orifice

FIGURE 2-9 Anterior (A), right lateral (8), and posterior (C)views of the uterus of an adult woman. a = oviduct; b = round ligament; = ovarian ligament; Ur ureter.

Tubal & ovarian branches of uterine & ovarian aa.

External iliac a.

Uterine a.

Internal iliac a.

Inferior epigastric a. & n.

vaginalis of cervix

FIGURE 2-10 Uterus, adnexa, and associated anatomy. (Reproduced with permission from Corton MM: Anatomy. In Hoffman BL, Schorge JO, Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGraw-Hili Education, 2016.) is converted into a transverse slit that is divided such that there are the so-called anterior and posterior cervical lips. If torn deeply during labor or delivery, the cervix may heal in such a manner that it appears irregular, nodular, or stellate (Fig. 36-1, p. 653).

The cervical surface that radially surrounds the external os is called the ectocervix and is lined predominantly by nonkeratinized stratified squamous epithelium. In contrast, the endocervical canal is covered by a single layer of mucin-secreting columnar epithelium, which creates deep cleftlike infoldings or "glands." Commonly during pregnancy, the endocervical epithelium moves out and onto the ectocervix in a physiological process termed eversion (Chap. 4, p. 51).

The cervical stroma is composed mainly of collagen, elastin, and proteoglycans, but very little smooth muscle. As described in Chapter 21 (p. 409), changes in the amount, composition, and orientation of these components lead to cervical ripening prior to labor onset. In early pregnancy, increased vascularity within the cervix stroma beneath the epithelium creates an ectocervical blue tint that is characteristic of Chadwick sign. Cervical edema leads to softening-Goodell sign, whereas isthmic softening is Hegar sign.

Most of the uterus is composed of myometrium, which contains smooth muscle bundles united by connective tissue with many elastic fibers. Interlacing myometrial ibers surround myometrial vessels and contract to compress these. This anatomy allows hemostasis at the placental site during the third stage of labor.

he number of myometrial muscle ibers varies by location (Schwalm, 1966). Levels progressively diminish caudally such that, in the cervix, muscle makes up only 10 percent of the tissue mass. The uterine body's inner wall has relatively more muscle than its outer layers. And, in the anterior and posterior walls, the muscle content is greater than in the lateral walls. During pregnancy, the upper myometrium undergoes marked hypertrophy, but cervical muscle content does not change significantly.

The uterine cavity is lined with endometrium, which is composed of an overlying epithelium, invaginating glands, and a supportive, vascular stroma. As discussed in Chapter 5 (p. 83), the endometrium varies greatly throughout the menstrual cycle. This layer is divided into a functionalis layer, which is sloughed with menses, and a basalis layer, which serves to regenerate the functionalis layer following each menses. During pregnancy, the endometrium is termed decidua and undergoes dramatic hormonally driven alterations.

Several ligaments extend from the uterine surface toward the pelvic sidewalls and include the round, broad, cardinal, and uterosacral ligaments (Figs. 2-10 and 2-11) . Despite their appellation, the round and broad ligaments provide no substantial uterine support, which contrasts with the cardinal and uterosacral ligaments.

he round ligament originates somewhat below and anterior to the origin of the fallopian tubes. Clinically, this orientation can aid fallopian tube identification during puerperal sterilization.

External iliac a. & v.

Lateral vaginal sulcus Adventitial layer of anterior vaginal wall Rectum

FIGURE 2-1 1 Pelvic viscera and their connective tissue support. (Reproduced with permission from Corton MM: Anatomy. In Hoffman BL, Schorge JO, Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGraw-Hili Education, 2016.) his is important if pelvic adhesions limit tubal mobility and thus, hinder fimbria visualization and tubal confirmation prior to ligation. Each round ligament extends laterally and down into the inguinal canal, through which it passes, to terminate in the upper portion of the ipsilateral labium majus. Sampson artery, a branch of the uterine artery, runs within this ligament. In nonpregnant women, the round ligament varies from 3 to 5 mm in diameter and is composed of smooth muscle bundles separated by ibrous tissue septa (Mahran, 1965). During pregnancy, these ligaments undergo considerable hypertrophy and increase appreciably in both length and diameter.

The broad ligaments are two winglike structures that extend from the lateral uterine margins to the pelvic sidewalls. Each broad ligament consists of a double-layer drape of peritoneum. The anterior and posterior layers of this drape are termed the anterior and posterior leaves, respectively. In forming the broad ligament, this peritoneum folds over structures extending from each cornu. Peritoneum that folds over the fallopian tube is termed the mesosalpinx, that around the round ligament is the mesoteres, and that over the ovarian ligament is the mesovarium. Peritoneum that extends beneath the imbriated end of the fallopian tube toward the pelvic wall forms the suspensory ligament or the infundibulopelvic ligament of the ovary. This contains nerves and the ovarian vessels, and during pregnancy, these vessels, especially the venous plexuses, are dramatically enlarged. Speciically, the diameter of the ovarian vascular pedicle increases from 0.9 cm to reach 2.6 cm at term (Hodgkinson, 1953).

The cardinal ligament-also called the transverse cervicaliligament or Mackenrodt ligament-anchors medially to the uterus and upper vagina. The cardinal ligament is the thick base of the broad ligament. As such, during cesarean hysterectomy, sturdy clamps and suture are required for its transection and ligation.

Each uterosacral ligament originates with a posterolateral attachment to the supravaginal portion of the cervix and inserts into the fascia over the sacrum, with some variations (Ramanah, 2012; Umek, 2004). These ligaments are composed of connective tissue, small bundles of vessels and nerves, and some smooth muscle. Covered by peritoneum, these ligaments form the lateral boundaries of the pouch of Douglas.

The term parametrium is used to describe the connective tissues adjacent and lateral to the uterus within the broad ligament. Paracervical tissues are those adjacent to the cervix, whereas paracolpium is that tissue lateral to the vaginal walls.

During pregnancy, there is marked hypertrophy of the uterine vasculature, which is supplied principally from the uterine and ovarian arteries (see Fig. 2-10). The uterine artery, a main branch of the internal iliac artery-previously called the hypogastric artery-enters the base of the broad ligament. he uterine artery courses medially to the lateral side of the uterus. Approximately 2 cm lateral to the cervix, the uterine artery crosses over the ureter. This proximity is of great surgical signiicance, as the ureter may be injured or ligated during hysterectomy when the uterine vessels are clamped and ligated.

Once the uterine artery has reached the supravaginal portion of the cervix, it divides. The smaller cervicovaginal artery supplies blood to the lower cervix and upper vagina. The main uterine artery branch rurns abruptly upward and travels cephalad along the lateral margin of the uterus. Along its path, this main artery provides a branch of considerable size to the upper cervix and then numerous other medial branches serially penetrate the body of the uterus to form the arcuate arteries. As indicated by the name, each branch arches across the organ by coursing within the myometrium just beneath the serosal surface. Arcuate vessels from each side anastomose at the uterine midline. Radial artery branches originate at right angles from the arcuate arteries and travel inward through the myometrium, enter the endometrium/decidua, and branch there to become either basal arteries or coiled spiral arteries. he spiral arteries supply the funcrionalis layer. Also called the straight arteries, the basal arteries extend only into the basalis layer.

As the uterine artery courses cephalad, it gives rise to Sampson artery of the round ligament. Just before the main uterine artery vessel reaches the fallopian rube, it divides into three terminal branches. The ovarian branch of the uterine artery forms an anastomosis with the terminal branch of the ovarian artery;

Internal iliac a.

the rubal branch makes its way through the mesosalpinx and supplies part of the fallopian tube; and the fundal branch penetrates the uppermost uterus.

In addition to the uterine artery, the uterus receives blood supply from the ovarian artery (see Fig. 2-10). This artery is a direct branch of the aorta and enters the broad ligament through the infundibulopelvic ligament. At the ovarian hilum, it divides into smaller branches that enter the ovary. As the ovarian artery runs along the hilum, it also sends several branches through the mesosalpinx to supply the fallopian rubes. Its main stem, however, traverses the entire length of the broad ligament toward the uterine cornu. Here, it forms an anastomosis with the ovarian branch of the uterine artery. This dual uterine blood supply creates a vascular reserve to prevent uterine ischemia if ligation of the uterine or internal iliac artery is performed to control postpartum hemorrhage.

Uterine veins accompany their respective arteries. As such, the arcuate veins unite to form the uterine vein, which empties into the internal iliac vein and then the common iliac vein. Some of the blood from the upper uterus, the ovary, and the upper part of the broad ligament is collected by several veins. Within the broad ligament, these veins form the large pampiniform plexus that terminates in the ovarian vein. From here, the right ovarian vein empties into the vena cava, whereas the left ovarian vein empties into the left renal vein.

Ureter Inferior mesenteric a.

Ovarian a.

External iliaca.

Iliolumbar a.

Obturatora.

Accessory obturator a.

Superior rectal a.

Inferior epigastric a.

Round ligament (cut) Lateralsacral a.

Medial umbilical ligament Superior gluteal a.

Superior vesical aa.

Inferior gluteal a.

Inferior vesical a.

Vaginal a.

Internal pudendala.

Uterine a. (ascending branch)

Sampson a.toround ligament Uterus

FIGURE 2-12 Pelvic arteries. (Reproduced with permission from Corton MM: Anatomy. In Hoffman BL, Schorge JO, Bradshaw KD, et al (eds):

Williams Gynecology, 3rd ed. New York, McGraw-Hili Education, 2016.)

Blood supply to the pelvis is predominantly provided by branches of the internal iliac artery (Fig. 2-12). These branches are organized into anterior and posterior divisions, and subsequent branches are highly variable between individuals. The anterior division provides blood supply to the pelvic organs and perineum and includes the inferior gluteal, internal pudendal, middle rectal, vaginal, uterine, and obturator arteries, as well as the umbilical artery and its continuation as the superior vesical artery. The posterior division branches extend to the buttock and thigh and include the superior gluteal, lateral sacral, and iliolumbar arteries. For this reason, during internal iliac artery ligation, many advocate ligation distal to the posterior division to avoid compromised blood low to the areas supplied by this division (Bleich, 2007).

The lymphatics from the uterine corpus are distributed to two groups of nodes. One set of vessels drains into the internal iliac nodes. The other set, after joining lymphatics from the ovarian region, terminates in the paraaortic lymph nodes. Lymphatics from the cervix terminate mainly in the internal iliac nodes, which are situated near the bifurcation of the common iliac vessels.

As a brief review, the peripheral nevous system is divided into a somatic division, which innervates skeletal muscle, and an autonomic division, which innervates smooth muscle, cardiac muscle, and glands. Pelvic visceral innervation is predominantly autonomic, which is further divided into sympathetic and parasympathetic components.

Sympathetic innervation to pelvic viscera begins with the superior hypogastric plexus, also termed the presacral nerve (Fig. 2-13). Beginning below the aortic bifurcation and extending downward retroperitoneally, this plexus is formed by sympathetic fibers arising from spinal levels TID through L2• At the level of the sacral promontory, this superior hypogastric plexus divides into a right and a left hypogastric nerve, which run downward along the pelvis sidewalls (Ripperda, 20i1i5).

Fibers to vestibular bulbs

FIGURE 2-13 Pelvic innervation. (Reproduced with permission from Corton MM: Anatomy. In Hofman BL, Schorge JO, Bradshaw KD, et al (eds):

Williams Gynecology, 3rd ed. New York, McGraw-Hili Education, 2016.)

In contrast, parasympathetic innervation to the pelvic viscera derives from neurons at spinal levels 52 through 54' heir axons exit as part of the anterior rami of the spinal nerves for those levels. These combine on each side to form the pelvic splanchnic nerves, also termed nervi erigentes.

Blending of the two hypogastric nerves (sympathetic) and the two pelvic splanchnic nerves (parasympathetic) gives rise to the inferior hypogastric plexus, also termed the pelvic plexus. his retroperitoneal plaque of nerves lies at the 54 and 55 level (Spackman, 2007). From here, fibers of this plexus accompany internal iliac artery branches to their respective pelvic viscera. Thus, the inferior hypogastric plexus divides into three plexuses. he vesical plexus innervates the bladder, and the middle rectal plexus travels to the rectum. he uterovaginal plexus, also termed F rankenhauser plexus, reaches the proximal fallopian tubes, uterus, and upper vagina. Extensions of the inferior hypogastric plexus also reach the perineum along the vagina and urethra to innervate the clitoris and vestibular bulbs (Montoya, 2011). Of these, the uterovaginal plexus is composed of variably sized ganglia, but particularly of a large ganglionic plate that is situated on either side of the cervix, proximate to the uterosacral and cardinal ligaments (Ramanah, 2012).

For the uterus, most of its aferent sensory fibers ascend through the inferior hypogastric plexus and enter the spinal cord via T 10 through T 12 and L] spinal nerves. These transmit the painful stimuli of contractions to the central nervous system. For the cervix and upper part of the birth canal, sensory nerves pass through the pelvic splanchnic nerves to the second, third, and fourth sacral nerves. Last, those from the lower portion of the birth canal pass primarily through the pudendal nerve. Anesthetic blocks used during delivery target these levels of innervation.

long the pelvic sidewall, each ovary usually rests in the ovarian fossa ofWaldeyer, which is a slight depression between the external and internal iliac vessels. During childbearing years, ovaries variably measure 2.5 to 5 cm in length, 1.5 to 3 cm in width, and 0.6 to 1.5 cm in thickness.

he ovarian ligament, also called the uteroovarian ligament, originates from the upper posterolateral portion of the uterus, just beneath the tubal insertion level, and extends to the uterine pole of the ovary (see Fig. 2-10). Measuring a few centimeters long and 3 to 4 mm in diameter, this ligament is made up of muscle and connective tissue and is covered by peritoneum-the mesovarium. Blood supply reaches the ovary through this double-layered mesovarium to enter the ovarian hilum.

The ovary consists of an outer cortex and inner medulla. In young women, the cortex is smooth, has a dull white surface, and is lined by single layer of cuboidal epithelium, the germinal epithelium ofWaldeyer. his epithelium is supported by a connective tissue condensation, the tunica albuginea. Beneath this, the ovarian cortex contains oocytes and developing follicles. The medulla is composed of loose connective tissue, numerous arteries and veins, and a small amount of smooth muscle ibers.

The ovaries are supplied with both sympathetic and parasympathetic nerves. he sympathetic nerves are derived primarily from the ovarian plexus that accompanies the ovarian vessels and originates in the renal plexus. Others are derived from the plexus that surrounds the ovarian branch of the uterine artery. Parasympathetic input is from the vagus nerve. Sensory aferents follow the ovarian artery and enter at T]o spinal cord level.

Also called oviducts, these serpentine tubes extend laterlly 8 to 14 cm from the uterine cornua. hey are anatomically classified along their length s an interstitial portion, isthmus, ampulla, and inundibulum (Fig. 2-14). vIost proximal, the interstitial portion is embodied within the uterine muscular wall. Next, the narrow 2-to 3-mm wide isthmus widens gradually into the 5-to 8-mm wide ampulla. Last, the inundibulum is the unnel-shaped fimbriated distal extremity of the tube, which opens into the abdominal cavity. These latter three extrauterine portions are covered by the mesosalpinx at the superior margin of the broad ligament.

In cross section, the extrauterine fallopian tube contains a mesosalpinx, myosalpinx, and endosalpinx. he outer of these, the mesosalpinx, is a single-cell mesothelial layer unctioning as visceral peritoneum. In the myosalpinx, smooth muscle is arranged in an inner circular and an outer longitudinal layer. The tubal musculature undergoes rhythmic contractions constantly, the rate of which varies with cyclical ovarian hormonal changes.

The tubal mucosa or endosalpinx is a single layer of columnar epithelium composed of ciliated, secretory, and intercalary cells resting on a sparse lamina propria. Clinically, its close proximity to the underlying myosalpinx contributes to easy invasion by ectopic trophoblast. The tubal mucosa is arranged in longitudinal folds that become progressively more complex toward the fimbria. In the ampulla, the lumen is occupied almost completely by the arborescent mucosa. The current produced by the tubal cilia is such that the direction of flow is toward the uterine cavity. Tubal peristalsis created by cilia and muscular layer contraction is believed to be an important factor in ovum transport (Croxatto, 2002).

he tubes are supplied richly with elastic tissue, blood vessels, and lymphatics. Their sympathetic innervation is extensive, in contrast to their parasympathetic innervation. This nerve supply derives partly from the ovarian plexus and partly from the uterovaginal plexus. Sensory aferent ibers ascend to T]o spinal cord levels.

Anteriorly, the bladder rests against the inner surface of the pubic bones and then, as it fills, also against the anterior abdominal wall. Posteriorly, it rests against the vagina and cer vix. he bladder is divided into a dome and a base approximately at the level of the ureteral oriices. The dome is thin walled and distensible, whereas the base is thicker and undergoes less distention during filling. The vesical trigone lies in the bladder base and contains both ureteral oriices and the internal

A B FIGURE 2-14 The fallopian tube of an adult woman with cross-sectioned illustrations of the gross structure in several portions: (A) isthmus, (B) ampUlla, and (C) infundibulum. Below these are photographs of corresponding histological sections. (Used with permission from Dr. Kelley S. Carrick.) urinary meatus (see Fig. 2-11). he urethral lumen begins at this meatus and then courses through the bladder base for less than 1 cm. This region where the urethral lumen traverses the bladder base is called the bladder neck.

The bladder wall consists of coarse bundles of smooth muscle known as the detrusor muscle, which extends into the proximal part of the urethra. A submucosal layer intervenes between this detrusor muscle and the mucosa. he bladder mucosa consists of transitional epithelium and underlying lamina propria.

The blood supply to the bladder arises from the superior vesical arteries, which are branches of the patent portion of the umbilical artery, and from the middle and inferior vesical arteries, which, when present, often arise from either the internal pudendal or the vaginal arteries (see Fig. 2-12). The nerve supply to the bladder arises from the vesical plexus, a component of the inferior hypogastric plexus (see Fig. 2-13).

As the ureter enters the pelvis, it crosses over the bifurcation of the common iliac artery and passes just medial to the ovarian vessels (see Fig. 2-10). As the ureter descends into the pelvis, it lies medial to the internal iliac branches and anterolateral to the uterosacral ligaments. The ureter then traverses through the cardinal ligament approximately 1 to 2 cm lateral to the cervix. Near the level of the uterine isthmus, it courses below the uterine artery and travels anteromedially toward the bladder base. In this path, it runs close to the upper third of the anterior vaginal wall (Rahn, 2007). Finally, the ureter enters the bladder and travels obliquely for approximately 1.5 cm before opening at the ureteral oriices.

The pelvic ureter receives blood supply from the vessels it passes: the common iliac, internal iliac, uterine, and superior vesical vessels. The ureter's course runs medial to these vessels, and thus its blood supply reaches the ureter from lateral sources. This is important during ure teral isolation. Vascular anastomoses on the connective tissue sheath enveloping the ureter form a longitudinal nenvork of vessels.

The pelvis is composed of four bonesthe sacrum, coccyx, and two innominate bones. Each innominate bone is formed by the fusion of three bones-the ilium, ischium, and pubis (Fig. 2-15). Both innominate bones are joined to the sacrum at the sacroiliac synchondroses and to one another at the symphysis pubis.

Anteriorly, the pelvic bones are joined together by the symphysis pubis. This structure consists of fibrocartilage and the superior and inferior pubic ligaments. The latter ligament is frequently designated the arcuate ligament of the pubis. Posteriorly, the pelvic bones are joined by articulations between the sacrum and the iliac portion of the innominate bones to form the sacroiliac joints.

The pelvic joints in general have a limited degree of mobility. However, during pregnancy, these joints relax remarkably at term. As one result, upward gliding of the sacroiliac joint, which is greatest in the dorsal lithotomy position, may increase the diameter of the outlet by 1.5 to 2.0 cm for delivery (Borell, 1957). Sacroiliac joint mobility also likely aids the McRoberts maneuver to release an obstructed shoulder in cases of shoulder dystocia (Chap. 27, p. 521). These changes may also contribute to the success of the modified squatting position to hasten second-stage labor (Cardosi, 1989). The squatting position may increase the interspinous diameter and the pelvic outlet diameter (Russell, 1969, 1982).

FIGURE 2-15 The innominate bone is composed of the pubis (brown), ischium (red), and ilium (blue). Of the three anteroposterior diameters of the pelvic inlet, only the diagonal conjugate can be measured clinically. The important obstetrical conjugate is derived by subtracting 15 cm from the diagonal conjugate.

• Planes and Diameters of the Pelvis

The pelvis is conceptually divided into false and true components. The false pelvis lies above the linea terminalis, and the true pelvis is below this boundary (Fig. 2-16). he false pelvis is bounded posteriorly by the lumbar vertebra and laterally by the iliac fossa. In front, the boundary is formed by the lower portion of the anterior abdominal wall.

he pelvis is described as having four imaginary planes: 1.

The plane of the pelvic inlet-the superior strait.

2.

The plane of the pelvic outlet-the inferior strait.

3.

he plane of the midpelvis-the least pelvic dimensions.

4.

he plane of greatest pelvic dimension-of no obstetrical significance.

he pelvic inlet, also called the superior strait, is the superior plane of the true pelvis. It is bounded posteriorly by the promontory and alae of the sacrum, laterally by the linea terminalis, and anteriorly by the horizontal pubic rami and the symphysis pubis. During labor, fetal head engagement is deined by the fetal head's biparietal diameter passing through this plane.

Four diameters of the pelvic inlet are usually described: anteroposterior, transverse, and two oblique diameters. Of these, distinct anteroposterior diameters have been described using specific landmarks. Most cephalad, the anteroposterior diameter, termed the true conjugate, extends from the uppermost margin of the symphysis pubis to the sacral promontory (see Fig. 2-15). he clinically important obstetrical conjugate is the shortest distance between the sacral promontory and the symphysis pubis. Normally, this measures 10 cm or more, but unfortunately, it cannot be measured directly with examining fingers. hus, the obstetrical conjugate is estimated indirectly by subtracting 1.5 to 2 cm from the diagonal conjugate. To measure the diagonal conjugate, a hand with the palm oriented laterally extends its index finger to the promontory. The distance from the fingertip to the point at which the lowest margin of the symphysis strikes the same inger's base is the diagonal conjugate.

he transverse diameter is constructed at right angles to the obstetrical conjugate and represents the greatest distance between the linea terminalis on either side (see Fig. 2-16). It usually intersects the obstetrical conjugate at a point approximately 5 cm in front of the promontory and measures approximately 13 cm.

The midpelvis is measured at the level of the ischial spines, also called the midplane or plane of least pelvic dimensions (see Fig. 2-16). During labor, the degree of fetal head descent into the true pelvis may be described by station, and the midpelvis and ischial spines serve to mark zero station. The interspinous diameter is 10 cm or slightly greater and is usually the smallest pelvic diameter. The anteroposterior diameter through the level of the ischial spines normally measures at least 11.5 cm.

The pelvic outlet consists of two approximately triangular areas whose boundaries mirror those of the perineal triangle described earlier (p. 19). They have a common base, which is a line drawn between the two ischial tuberosities. The apex of the posterior triangle is the tip of the sacrum, and the (, .Iium

FIGURE 2-16 Axial view of a normal female pelvis. The clinically important obstetrical conjugate and transverse diameter of the pelvic inlet are illustrated. The interspinous diameter of the mid pelvis is also marked.

Anthropotd ,.,• Intermediates • .. 4

FIGURE 2-17 The four parent pelvic types of the Caldwell-Moloy classification. A line passing through the widest transverse diameter divides the inlets into posterior (P) and anterior (A) segments.

lateral boundaries are the sacrotuberous ligaments and the ischial tuberosities. 'he anrerior triangle is formed by the descending inferior rami of rhe pubic bones. These rami unite at an angle of 90 [0 100 degrees ro form a rounded arch under which the fetal head must pass. Unless there is Signiicant pelvic bony disease, rhe pelvic ourler seldom obstructs vaginal delivery.

The Caldwell-Moloy (I933, 1934) anaromical classiication of rhe pelvis is based on shape, and its concepts aid an understanding of labor mechanisms. Speciically, the grearesr transverse diameter of rhe inler and its division into alHerior and posterior segmelHs are used to classiy rhe pelvis as gynecoid, anthropoid, android, or platypelloid. The posterior segmelH determines the type of pelvis, whereas the anterior segment determines the tendency. These are both determined because many pelves are nor pure but are mixed types. For example, a gynecoid pelvis with an android tendency means that rhe posterior pelvis is gynecoid and the anterior pelvis is android shaped.

From viewing the four basic types in 2-17I, the coniguration of the gynecoid pelvis would intuitively seem suited for delivery of most fetuses. Indeed, Caldwell (I 939) reported [hac rhe gynecoid pelvis was found in almost half of women.

Barher MD, Bremer E, Thor KB, er al: Innervation of the female levator ani muscles. Am J Obsrer Gynecol 187:64, 2002

Beer GM, Schuster A, Seifert B, et al: 1he normal width of the linea alba in nulliparous women. Clin Anar 22(6):706, 2009

Bleich AT, Rahn DO, Wieslander CK, et al: Posterior division of the internal iliac artery: anatomic variations and clinical applications. Am J Obstet Gynecol 197:658.e1, 2007

Borell U, Fenstrom I: Movements at the sacroiliac joillls and their importance to changes in pelvic dimensions during parturition. Acta Obstet Gynecol Scand 36:42, 1957

Caldwell WE, 'vloloy He: Anatomical variations in the female pelvis and their efect in Jabor with a suggested classiication. Am J Obstet GynecoJ 26:479, 1933

Caldwell WE, Moloy HC, D'Esopo DA: Further studies on the pelvic architecture.m J Obstet Gynecol 28:482, 1934

Caldwell WE, Moloy HC, Swenson PC The use of [he roentgen ray in obstetrics, I. Roentgen pelvimetry and cephalometry; technique of pdviroenrgenography. AJR 41 :305, 1939

Corton tdM: Anatomy. In Hoffman BL, SchorgeeJO, Bradshaw KD, et al (cds):

Williams Gynecology, 3rd ed. New York, McGraw-Hill Education, 2016 Corton t"tM: Anatomy of the pelvis: how the pelvis is built for support. Clin Ohstct Gynecol 48:611, 2005

Croxatto HB: PhysioloY of gamete and embryo transport through the fallopian tube. Reprod Biomed Online 4(2): I60, 2002

DeLancey JO, Toglia MR, Peucchini D: Imernal and extern;l] anal sphincter anatomy as it relates to midline obstetric lacerations. Obstct Gynccol 90m4,e1997

DeLancey JOL, Keaney R, Chou Q, et al: The appearance of levaror ani muscle abnormalities in magnetic resonance images after vaginal delivery. Obstet Cyneco] 101 :46, 2003

Dietz HP, Simpson JM: Levator trauma is associated with pelvic organ prol,p", BjOG lI5(8)m9, 2008

Fusco p, Scimia P, Paladini G, et al: Transversus abdominis plane block for analgesia after Cesarean delivery. A systematic review. Minerva Anesrcsioi SI(2H95,e2015

Gardosi J, Hutson N, Lynch CB: Randomised, comrolled trial of squatting in the second stage of labour. Lancet 2:74,e1989

Ginger VA, Cold j, Yang CC: Structure and innervation of the labia minora: more than minor skin folds. Female Pelvic l·led Reconsrr Surg 17(4):180, 201la

Ginger VA, Cold j, Yang CC: Surgical anatomy of the dorsal nerve of the clitoris. Neuroural Urodyn 30(3):412, 2011 b

Hawkins JL: Anesthesia for the pregnant woman. In Yeomans ER, Hofman BL, Gilstrap LC Ill, et al: Cunningham and Gilsuaps's Operative Obstetrics, 3rd ed. New York, McGraw-Hill Education, 2017

Hodgkinson CP: Physiology of the ovarian veins during pregnancy. Obstet Gynecol 1 (1):26, 19S3

Kearney R, Sawhney R, Delancey )0: Levator ani muscle anatomy evaluated by origin-insertion pairs. Obstet Gynecol 104:168,e2004

Kim SO, Oh K), Lee HS, et al: Expression of aquaporin water channels in the vagina in premenopausal women.e) Sex Med 8(7):I92S, 2011

Langlois PL: The si'Le of the normal uterus.e) Reprod Med 4:220, 1970

Larson KA, Yousuf A, Lewicky-Gaupp C, et al: Perineal body anatomy in living women: 3-dimensional analysis using thin-slice magnetic resonance imaging. Am J Obstet GynecoI203(S):494.elS, 2010 ien KC, Morgan OM, Delancey )0, et al: Pudendal nerve stretch during vaginal birth: a 3D computer simulation. m J Obstet Gynecol 192(S): 1669, 200S Lloyde). Crouch NS, Minto CL, et al: Female genital appearance: "normality" unfold" BjOG 112(5),643,e2005

Loukas M, r,1yers C, Shah R, et al: Arcuate line of the rectus sheath: clinical approach. Anat Sci Int 83(3):140, 2008

Mahakkanukrauh p, Surin p, Vaidhayakarn P: Anatomical study of the pudendal nerve adjacent to the sacrospinous ligament. Clin Anat 18:200, 200S Mahran '1: The microscopic anatomy of the round ligament. J Obstet Gynae col Br Commomv 72:614, 1965

Maldonado rA, Chin K, Garcia A, et 1: Anatomic variations of pudendal nerve within pelvis and pudendal canal: clinical applications. m ) Obstet GynecoIe213(S):727,e20IS

Mei W, lin C, Feng L, et al: Bilateral ultrasound-guided transversus abdominis plane block combined with iliOinguinal-iliohypogastric nerve block for cesarean delivey anesthesia. Anesth Analg 113(1):134,2011

Mirilas p, Skandalakis )E: Urogenital diaphragm: an erroneous concept casting its shadow over the sphincter urethrae and deep perineal space. J m Coli Surg 198:279,e2004

Montoya TI, Calver L, Carrick S, et al: Anatomic relationships of the pudendal nerve branches. Am J Obstet Gynecol 20S(S):S04.el, 2011

Rahn DO, Bleich AT, Wai CY, et al: Anatomic relationships of the distal third of the pelvic ureter, trigone, and urethra in unembalmed female cadavers. Am J Obstet Gynecol 197(6):668.e 1, 2007

Rahn DD, Phelan IN, Roshanravan SM, et al: Anterior abdominal wall nerve and vessel anatomy: clinical implications for gynecologic surgery. m ) Obstet Gyneol 202(3):234.el, 2010

Ramanah R, Berger MB, Parrarre BM, et al: Anatomy and histology of apical support: a literature review concerning cardinal and uterosacral ligaments. Int Urogynecole) 23(11):e1483, 2012

Ripperda CM, Jackson A, Phelan )N, et al: Anatomic relationships of the pelvic autonomic nervous system in female cadavers: clinical applications to pelvic surgery. Oral presentation at AUGS Annual Scientiic Meeting, 13-17 October, 20lS

Russell )G: iVloulding of the pelvic outlet. J Obstet Gynaecol Br Commonw 76:817.e1969

Russell JG: The rationale of primitive delivery positions. B)OG 89:712, 1982

Santoro GA, Shobeiri SA, Petros PP, et al: Perineal body anatomy seen by three-dimensional endovaginal ultrasound of asymptomatic nulliparae. Colorectal Dis 18(4):400, 2016

Schober J, A.lrdsma N, lvlayoglou L, et al: Terminal innervation of female genitalia, cutaneous sensory receptors of the epithelium of the labia minora. Clin Anat 28(3):392, 20lS

Schwalm H, Dubrauszky V: The structure of the musculature of the human uterus-muscles and connective tissue. m) Obstet Cynecol 94:391, 1966 Schwertner-Tiepelmann N, Thakar R, Sultan AH, et al: Obstetric levator ani muscle injuries: current status. Ultrasound Obstet GynecoI39(4):372, 2012 Shaik A, Doss SH: Pudendal canal: surgical anatomy and clinical implications.

m Surg 6S: 176, 1999

Shaik A, Sibai OE, Shaik A, et al: A novel concept for the surgical anatomy of the perineal body. Dis Colon Rectum SO(l2):2120, 2007 Sheikhazadi A, Sadr SS, Ghadyani MH, et al: Study of the normal internal organ weights in Tehran's population.) Forensic Leg Med 17(2):78, 2010 Spackman R, Wrigley B, RobertS A, et al: The inferior hypogastriC plexus: a diferent view.) Obstet Gynaecoi 27(2):130, 2007

Tawik MM, Mohamed YM, Elbadrawi E, et al: Transversus abdominis plane block versus wound iniltration for analgeSia after cesarean delivery: a randomized controlled trial. Anesth Analg 124(4):1291, 2017

Tolcher :lC, Nitsche)F, Arendt f, et al: Spontaneous rectus sheath hematoma pregnancy: case report and revie' of the literature. Obstet Cynecol Su� 65(8),517, 2010

Umek H, Morgan DM, Ashton-Miller )A, et al: Quantitative analysis of uterosacral ligament origin and insertion poims by magnetic resonance imaging. Obstet Gynecol 103:447,e2004

VerkaufBS, Von Thron J, O'Brien WF: Clitoral size in normal women. Obstet Gynecol 80(1):41, 1992 Wai C, Bhatia K, Clegg I: RecTUS sheath haematoma: a rare cause of abdominal pain in pregnancy. 1m) Obstet Anesth 24(2): 194, 2015 Weber M, Walters MD: Anterior vaginal prolapse: review of anatomy and techniques of surgical repair. Obstet Gynecol 89:311, 1997 (leidner AC, Jamison MG, Branham V, et 1: Neuropathic injury to the levator ani occurs in I in 4 primiparous women. m J Obstet Gynecole19S: 18SI, 2006

Whiteside JL, Barber MD: IIlioinguinalliliohypogastric neurectomy for management of inrractable right lower quadrant pain ater cesarean section: a case report. J Reprod IvIed SO(l 1):8S7, 200S

Whiteside JL, Barber MD, Walters MD, et 1: Anatomy of ilioinguinal and iliohypogastric nerves in relation to trocar placement and low transverse incisions. m) Obsret Gynecol 189: 1574, 2003

Wilkinson E), Massoll NA: Benign diseases of the vulva. In Kurman R), Ellenson LH, Ronnen BM (eds): Blaustein's Pathology of the Female Genital Tract, 6th ed. New York, Springer, 2011, p 3

Wolfson A, Lee A), Wong P, et al: Bilateral multi-injection iliohypogastricilioinguinal nerve block in conjunction with neuraxial morphine is superior to neuraxial morphine alone for postcesarean analgeSia. J Clin Anesth 24(4),298,e2012

GENITOURINARY TRACT DEVELOPMENT ..... . .. 33

SEXUAL DIFFERENTIATION .. . ..... ............. 38.....

DISORDERS OF SEX .... . ... . 38..........

BLADDER AND PERINEAL ABNORMALITIES ...... , ... 41

MULLERIAN ABNORMALITIES .... .. ..... ....... 41......

UTERINE FLEXION ......... , .............. , .. , ... 46

Abnormalities in the development or fusion of one or both MUllerian ducts may result in maormations which sometimes possess an obstetrical signicance. Pregnancy may be associated with anyione of these maormations, provided an ovum be cast of rom the ovaries and no serious obstacle be opposed to the upward passage of the spermatozoa and their subsequent union with it.

-]. Whitridge Williams (1903)

In females, the external genitalia, gonads, and miillerian ducts each derive from diferent primordia and in close association with the urinary tract and hindgut. Abnormal embryogenesis during this process is thought to be multifactorial and can create sporadic anomalies. Several of these can lead to infertility, subfertility, miscarriage, or preterm delivery. Thus, knowledge of genitourinary system development is essential.

• Embryology of the Urinary System

Between the 3rd and 5th gestational weeks, an elevation ofintermediate mesoderm on each side of the fetus-the urogenital ridge-begins development into the urogenital tract. Subsequently, the urogenital ridge divides into the genital ridge, destined to become the ovary, and into the nephrogenic ridge (Fig.

he nephrogenic ridges develop into the mesonephros (mesonephric kidney) and paired mesonephric ducts, also termed wolian ducts, which connect to the cloaca.

The early urinary tract develops from the mesonephros and its mesonephric ducts (Fig. 3-2A). Recall that evolution of the renal system passes sequentially through the pronephric and mesonephric stages to reach the permanent metanephric system. Between the 4th and 5th weeks, each mesonephric duct gives rise to a ureteric bud, which grows cephalad toward its respective mesonephros (Fig. 3-2B), As each bud lengthens, it induces diferentiation of the metanephros, which will become the inal kidney (Fig. 3-2C). Each mesonephros degenerates near the end of the first trimester, and without testosterone, the mesonephric ducts regress as well.

he cloaca begins as a common opening for the embryonic urinary, genital, and alimentary tracts. By the 7th week it becomes divided by the urorectal septum to create the rectum and the urogenital sinus (Fig. 3-2D). The urogenital sinus is considered in three parts: (1) the cephalad or vesicle portion, which forms the urinary bladder; (2) the middle or pelvic portion, which creates the female urethra; and (3) the caudal or phallic part, which gives rise to the distal vagina and to the greater vestibular (Bartholin) and paraurethral glands.

• Embryology of the Genital Tract he fallopian tubes, uterus, and upper vagina derive from the miillerian ducts, also termed paramesonephric ducts, which form adjacent to each mesonephros (see Fig. 3-2B). These ducts extend downward and then turn medially to meet and fuse together in the midline. he uterus is formed by this union of the two miillerian ducts at approximately the 10th week (Fig. 3-2E). Fusion to create the uterus begins in the middle and then extends both caudally and cephalad. With cellular

FIGURE 3-2 Embryonic development of the female genitourinary tract (A-F). (Reproduced with permission from Shatzkes DR, Haller JO, Velcek FT: Imaging of uterovaginal anomalies in the pediatric patient, Urol Radiol 1991;13(1):58-66.)

FIGURE 3-1 A. Cross-section of an embryo at 4 to 6 weeks. B. Large ameboid primordial germ cells migrate (arrows) from the yolk sac to the area of germinal epithelium, within the genital ridge. C. Migration of sympathetic cells from the spinal ganglia to a region above the developing kidney.

Remnant of mesonephric duct Bladder-Urethra/ F Ureter -...--Uterus ---Rectum proliferation at the upper portion, a thick wedge of tissue cre ates the characteristic piriform uterine shape. At the same time, dissolution of cells at the lower pole forms the irst uterine cav ity (Fig. 3-2F). As the upper wedge-shaped septum is slowly reabsorbed, the inal uterine cavity is usually formed by the 20th week. If the two mullerian ducts fail to fuse, then two separate uterine horns remain. In contrast, resorption failure of the common tissue between them results in various degrees of persistent uterine septum.

As the distal end of the fused mullerian ducts contacts the uro genital sinus, this induces endodermal outgrowths from the sinus termed the sinovaginal bulbs. hese bulbs proliferate and fuse to form the vaginal plate, which later resorbs to form the vaginal lumen. his vaginal canalization is generally completed by the 20th week. However, the lumen remains separated from the urogenital sinus by the hymeneal membrane. This membrane further degenerates to leave only the hymeneal ring.

The close association of the mesonephric (wolian) and paramesonephric (mullerian) ducts explains the simultaneous abnormalities in their end organs. Kenney and colleagues (1i984) showed that up to half of females with urerovaginal malformations have associated urinary tract defects. Anomalies most frequently associated with renal defects are unicornuate uterus, uterine didelphys, and agenesis syndromes, whereas arcuate and bicornuate are less commonly linked (Reichman, 2010). When mullerian anomalies are identiied, the urinary system can be evaluated with magnetic resonance (MR) imaging, sonography, or intravenous pyelography (Hall-Craggs, 2013). With mullerian anomalies, ovaries are functionally normal but have a higher incidence of anatomical maldescent into the pelvis (Allen, 2012; Dabirashrafi, 1994).

As discussed, the mesonephric ducts usually degenerate, however, persistent remnants may become clinically apparent. Mesonephric or wolian vestiges can persist as Gartner duct cysts. These are typically located in the proximal anterolateral vaginal wall but may be found at other sites along the vaginal length. They can be further characterized by MR imaging, which provides excellent image resolution at soft tissue interfaces. Most cysts are asymptomatic and benign and usually do not require surgical excision.

Intraabdominal wolian remnants in the female include a few blind tubules in the mesovarium-the epoophoronand similar ones adjacent to the uterus-paroophoron (see Fig. 3-2F) (Moore, 2013). The epoophoron or paroophoron may develop into clinically identiiable cysts in the adult.

• Embryology of the Gonads

At approximately 4 weeks, gonads derive from coelomic epithelium covering the medial and ventral surface of the nephrogenic cord at a site between the eighth thoracic and fourth lumbar segments. Because of this separate gonadal and mullerian derivation, women with mullerian defects typically have functionally normal ovaries and are phenotypic females. he coelomic epithelium thickens to form the genital ridge, also known as the gonadal ridge. Strands of these epithelial cells extend into the underlying mesenchyme as the primary sex cords. By the sixth week, primordial germ cells have migrated from the yolk sac to enter the genital ridge mesenchyme (Fig. 3-3). The primordial germ cells are then incorporated into the primary sex cords.

In the seventh week, the sexes can be distinguished, and tes tes are recognized during microscopic sectioning by their well deined radiating testis cords. These cords are separated from the coelomic epithelium by mesenchyme that is to become the tunica albuginea. The testis cords develop into the seminiferous tubules and rete testis. he rete testis establishes connection with small tubes arising of the mesonephric duct. These small tubes become the eferent ducts that drain into the epididymis and then into the vas deferens, which are main mesonephric duct derivatives.

In the female embryo, the primary sex cords give rise to the medullary cords, which persist only for a short time. The coelomic epithelium again proliferates into the underlying mesenchyme, and these strands are the cortical cords. By the fourth month, the cortical cords begin to form isolated cell clusters called primordial follicles. These follicles contain the oogonia, which derive from primordial germ cells and are surrounded by a single layer of lattened follicular cells derived from the cortical cords. Follicular cells serve as supporting nutrient cells. By 8 months, the ovary has become a long, narrow, lobulated structure that is attached to the body wall by the mesovarium. The coelomic epithelium has been separated by a band of connective tissue-tunica albuginea-from the cortex. At this stage, the cortex contains follicles and is well deined from the inner medulla, which is composed of abundant blood vessels, lymphatic vessels, and nerve ibers.

• Embryology of the External Genitalia

Early development of the external genitalia is similar in both sexes. By 6 weeks' gestation, three external protuberances have developed surrounding the cloacal membrane. These are the left and right cloacal folds, which meet ventrally to form the genital tubercle (Fig. 3-4). With division of the cloacal membrane into anal and urogenital membranes, the cloacal folds become the anal and urethral folds, respectively. Lateral to the urethral folds, genital swellings arise, and these become the labioscrotal folds. Between the urethral folds, the urogenital sinus extends onto the surface of the enlarging genital tubercle to form the urethral groove. By week 7, the urogenital membrane ruptures, exposing the cavity of the urogenital sinus to amnionic fluid.

The genital tubercle elongates to form the phallus in males and the clitoris in females. Still, it is not possible to visually diferentiate between male and female external genitalia until week 12. In the male fetus, dihydrotestosterone (DHT) forms locally by the 5-a reduction of testosterone. DHT prompts the anogenital distance to lengthen, the phallus to enlarge, and the labioscrotal folds to fuse and form the scrotum.

In the female fetus, without DHT, the anogenital distance does not lengthen, and the labioscrotal and urethral folds do not fuse (Fig. 3-4C). The genital tubercle bends caudally to become the clitoris, and the urogenital sinus forms the vestibule of the vagina. The labioscrotal folds create the labia majora, whereas the urethral folds persist as the labia minora. Female external genital diferentiation is complete by 11 weeks, whereas male external genital diferentiation is complete by 14 weeks.

Degenerating paramesonephric duct Primordial germ cell Uterine tube -FIGURE 3-3 Embryonic gonad diferentiation. TDF Persistent paramesonephric duct Coelomic epithelium Degenerating medullary cords = testis-determining factor.

Labioscrotal/ ,

FIGURE 3-4 Development ofthe external genitalia. A. Indifferent stage. B. Virilization ofexternal genitalia. C. Feminization. (Reproduced with permission from Bradshaw KD: Anatomical disorders. In Hoffman BL, Schorge JO, Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGraw Hill Education, 201o6.)

Defining gender incorporates genetic gender, gonadal gender, and phenotypic gender. Genetic gender-X or Y -is established at fertilization. However, for the irst 6 weeks, development of male and female embf) os is morphologically indistinguishable.

Gonadal gender is heralded by the diferentiation of the primordial gonad into a testis or an ovary. If a Y chromosome is present, the gonad begins developing into a testis. Testis development is directed by a protein called the testis-determiningactor (TDF), which modulates the transcription of several genes involved in gonadal diferentiation. TDF is encoded by the sexdetermining region (SR) gene, located on the short arm of the Y chromosome. But testis development is much more complex and requires other autosomal genes (Nistal, 2015a).

he importance of the SRYgene is demonstrated in severl paradoxical conditions. First, 46,X phenotypic males can result from translocation of the Y chromosome fragment containing SRY to the X chromosome during meiosis of male germ cells Wu, 2014). Similarly, 46,Y individuals can appear phenotypically female if they carry a mutation in the SRYgene (Helszer, 2013).

Last, phenoypic gender begins at 8 weeks' gestation. Before this, urogenital tract development in both sexes is indistinguishable. Thereafter, diferentiation of the internal and external genitalia to the male phenotype is dependent on testicular function. In the absence of a testis, female diferentiation ensues irrespective of genetic gender (Table 3-1).

In males, the fetal testis secretes a protein called mullerianinhibiting substance (MIS), also called antimullerian hormone (AMH) . It acts locally as a paracrine factor to cause mullerian duct regression. Thus, it prevents the development of uterus, fallopian tube, and upper vagina. AMH is produced by the Sertoli cells of the seminiferous tubules. Importantly, these tubules appear in fetal gonads and secrete AMH before diferentiation of Leydig cells, which are the cellular site of testosterone synthesis. AMH is secreted as early as 7 weeks, and mullerian duct regression is completed by 9 to 10 weeks. Because AMH acts locally near its site of formation, if a testis were absent on one side, the mullerian duct on that side would persist, and the uterus and fallopian tube would develop on that side.

Apparently through stimulation initially by human chorionic gonadotropin (hCG), and later by fetal pituitary luteinizing hormone (LH), the fetal testes secrete testosterone. his hormone acts directly on the wolian duct to efect the development of the vas deferens, epididymis, and seminal vesicles. Testosterone also enters fetal blood and acts on the external genitalia anlage. In these tissues, testosterone is converted to 5a-DHT to cause virilization of the external genitalia.

As evident from the prior discussion, abnormal sex development may involve the gonads, internal duct system, or external genitalia. Rates vary and approximate 1 in every 1000 to 4500 births (Murphy, 2011; Ocal, 2011). The nomenclature used to describe disorders of sex development (DSDs) has evolved. Current classiication of these disorders include: (1) sex chromosome DSDs, (2) 46,Y DSDs, and (3) 46,X DSDs (Table 3-2) (Hughes, 2006).

Other important terms describe the abnormal phenotypic findings that can be found. First, some disorders of sexual development are associated with abnormal, underdeveloped gonads, that is, gonadal dysgenesis. With this, if a testis is poorly formed, it is called a dysgenetic testis, and if an ovary is poorly formed, it is called a streak gona. In afected patients, the underdeveloped gonad ultimately fails, which is indicated by elevated gonadotropin levels. Another important clinical sequela is that patients bearing a Y chromosome are at high risk of developing a germ cell tumor in the dysgenetic gonad.

A second term, ambiguous genitalia, describes genitalia that do not appear clearly male or female. Abnormalities may include

TABLE 3-1. Embryonic Urogenital Structures and Their Adult Homologues

Uteroovarian and round ligaments Epoophoron, paroophoron Gartner duct

Uterus, fallopian tubes, upper vagina Bladder, urethra

Seminiferous tubules, Sertoli cells Gubernaculum testis

Efferent ductules, paradidymis Epididymis, ductus deferens,

Prostatic utricle, appendix of testis Bladder, urethra

Floor of penile urethra

TABLE 3-2. Disorders of Sex Development (DSD) Classification 45,X Turnerd 47,xXY Klinefelterd 45,X/46,XY Mixed gonadal dysgenesis 46,XX/46,XY Ovotesticular DSD 46,XY DSD 46,XX DSD aAnd syndrome variants.

AMH = antimullerian hormone; hCG = human chorionic gonadotropin; LH = luteinizing hormone.

Adapted with permission from Hughes lA, Houk C, Ahmed SF, et al: Consensus statement on management of intersex disorders. j Pediatr Urol 2:148,l2006.

hypospadias, undescended testes, micropenis or enlarged clitoris, labial fusion, and labial mass.

Last, ovotesticular deines states characterized by ovarian and testicular tissue in the same individual. It was formerly termed true hermaphroditism. In these cases, diferent types of gonads can be paired. he types of gonads that may be paired include a normal testis, a normal ovary, a streak gonad, dysgenetic testis, or an ovotestis. In the latter, both ovarian and testicular elements are combined within the same gonad. With ovotesticular DSDs, the internal ductal system structure depends on the ipsilateral gonad and its degree of determination. Speciically, the amount of AMH and testosterone determines the degree to which the internal ductal system is masculinized or feminized. Extenal genitalia are usually ambiguous and undermasculinized due to inadequate testosterone.

• Sex Chromosome Disorders of Sex

Sex chromosome disorders of sexual development typically arise from an abnormal number of sex chromosomes. Of these,

Turner and linefelter syndromes are most frequently encoun tered (Nielsen, 1990).

Turner syndrome is caused by de novo loss or severe struc tural abnormality of one X chromosome in a phenotypic female. Most afected fetuses are spontaneously aborted. How ever, in girls with Turner syndrome who survive, phenotype varies widely, bur nearly all afected patients have short stat ure. Associated problems include cardiac anomalies (especially coarctation of the aorta), renal anomalies, hearing impairment, otitis media and mastoiditis, and an increased incidence of hypertension, achlorhydria, diabetes mellirus, and Hashimoto thyroiditis. It is the most common form of gonadal dysgenesis that leads to primary ovarian failure. In these cases, the uterus and vagina are normal and capable of responding to exogenous hormones (Matthews, 2017).

Another sex chromosome disorder is Klineelter syndrome (47,Y). hese individuals tend to be tall, undervirilized males with gynecomastia and small, firm testes. They have sig nificantly reduced fertility from hypogonadism due to gradual testicular cell failure. These men are at increased risk for germ cell rumors, osteoporosis, hypothyroidism, diabetes mellirus, breast cancer, cardiovascular abnormalities, and cognitive and psychosocial problems (Aksglaede, 2013; Calogero, 2017).

Several karyotypes can create a coexistent ovary and testis, and thus ovotesticular DSD is found in all three DSD categories (see Table 3-2). In the sex chromosome group, ovotesticular DSD may arise from a 46,XX/46,XY karyotype. Here, an ovary, testis, or ovotestis may be paired. he phenotype in general mirrors that for ovotesticular disorders, which are described earlier on this page.

For others in the sex chromosome DSD group, ovotesticular disorder arises from a chromosomal mosaic such as 45,Xl46,XY. With this karyotype, a picture ofmixed gonadal dysgenesis shows a streak gonad on one side and a dysgenetic or normal testis on the other. The phenotypical appearance ranges from undervirilized male to ambiguous genitalia to Turner stigmata.

• 46,XY Disorders of Sex Development

Insuicient androgen exposure of a ferus destined to be a male leads to 46,XY DSD-formerly called male pseudohermaphroditism. he karyotype is 46,XY and testes are frequently present. he uterus is generally absent as a result of normal embryonic AMH production by Sertoli cells. hese subjects are most often sterile from abnormal spermatogenesis and have a small phallus that is inadequate for sexual function. As seen in Table 3-2, etiology of 46,XY DSD may stem from abnormal testis development or from abnormal androgen production or action.

46,XY Gonadal Dysgenesis his spectrum of abnormal gonad underdevelopment includes pure or complete, partial, or mixed 46,XY gonadal dysgenesis. These are deined by the amount of normal testicular tissue and by karyotype. Because of the potential for germ cell rumors in dysgeneric testes and intraabdominal testes, afected patients routinely have been advised to undergo gonadectomy Giang, 2016).

Of these, pure gonadal dysgenesis results from a mutation in the SRY gene or in other genes with testis-determining efects (Hutson, 2014). his leads to underdeveloped dysgenetic gonads that fail to produce androgens or AMH. Formerly named Swyer syndrome, the condition creates a normal prepubertal female phenotype and a normal miillerian system due to absentiAMH.

Partial gonaal dysgenesis deines those with gonad development intermediate between normal and dysgenetic testes. Depending on the percentage of underdeveloped testis, wolian and miille rian structures and genital ambiguity are variably expressed.

Mixed gonadal dysgenesis is one type of ovotesticular disorder of sexual diferentiation. As discussed on page 39, one gonad is streak, and the other is a normal or a dysgenetic testis. Of afected individuals, 15 percent have a 46,Y karyotype (Nistal, 20 15 b). The phenotype is wide ranging as with partial gonadal dysgenesis.

Last, testicular regression can follow initial testis development. A broad phenotypic spectrum is possible and depends on the timing of testis failure.

In some cases, 46,Y disorders of sexual diferentiation stem from abnormalities in: (1) testosterone biosynthesis, (2) LH receptor function, (3) AMH function, or (4) androgen receptor action. First, the sex steroid biosynthesis pathway can sufer enzymatic defects that block testosterone production. Depending on the timing and degree of blockade, undervirilized males or phenotypic females may result. In contrast to these central enzymatic defects, peripheral defects may be causative. Namely, abnormal 5-. reductase type 2 enzyme action leads to impaired conversion of testosterone to DHT and thus to undervirilization.

Second, hCG/LH receptor abnormalities within the testes can lead to Leydig cell aplasia/hypoplasia and impaired testosterone production. In contrast, disorders of MH and AMH receptors result in persistent miillerian duct syndrome (PMDS). Afected patients appear as males but have a persistent uterus and fallopian tubes due to failed AMH action.

Last, the androgen receptor may be defective and result in androgen-insensitivity syndrome (AIS). Resistance to androgens may be incomplete and associated with varying degrees of virilization and genital ambiguity. Milder forms have been described in men with severe male factor infertility and poor virilization.

Females with complete androgen-insensitivity syndrome (CAIS) appear as phenotypically normal females at birth. They often present at puberty with primary amenorrhea. External genitalia appear normal; scant or absent pubic and axillary hair are noted; the vagina is shortened or blind ending; and the uterus and fallopian tubes are absent. However, these individuals develop breasts during pubertal maturation due to abundant androgen to estrogen conversion. Testes may be palpable in the labia or inguinal area or may be found intraabdominally. Surgical excision of the testes after puberty is recommended to decrease the associated risk of germ cell tumors, which may be as high as 20 to 30 percent.

• 46,XX Disorders of Sex Development

As seen in Table 3-2, etiology of 46,X disorders of sexual differentiation may stem from abnormal ovarian development or from excess androgen exposure.

Disorders of ovarian development of those with a 46,X complement include: (1) gonadal dysgenesis, (2) testicular DSD, and (3) ovotesticular DSD.

With 4, X gonadal dysgenesis, similar to Turner syndrome, streak gonads develop. These lead to hypogonadism, prepubertal normal female genitalia, and normal miillerian structures, but other Turner stigmata are absent.

With 4,X testicuar DSD, several possible genetic mutations lead to testis-like formation within the ovary-streak gonad, dysgenetic testis, or ovotestis. Defects may stem from SRY translocation onto one X chromosome. In individuals without SRY translocation, other genes with testis-determining efects are most likely activated. Regardless, production of MH prompts miillerian system regression, and androgens promote wolian system development and external genitalia masculinization. Spermatogenesis, however, is absent due to a lack of needed genes on the long arm of the Y chromosome. hese individuals are not usually diagnosed until puberty or during infertility evaluation.

With 4,X ovotesticular DSD, individuals possess a unilateral ovotestis with a contralateral ovary or testis, or bilateral ovotestes. Phenotypic indings depend on the degree of androgen exposures and mirror those for other ovotesticular DSDs discussed on page 39.

Discordance between gonadal sex (46,X) and the phenotypic appearance of external genitalia (masculinized) may also result from excessive fetal androgen exposure. his was previously termed female pseudohermaphroditism. In afected individuals, the ovaries and female internal ductal structures such as the uterus, cervix, and upper vagina are present. hus, patients are potentially fertile. he external genitalia, however, are virilized to a varying degree depending on the amount and timing of androgen exposure. he three embryonic structures that are commonly afected by elevated androgen levels or ovarian development disorders are the clitoris, labioscrotal folds, and urogenital sinus. As a result, virilization may range from modest clitoromegaly to posterior labial fusion and development of a phallus with a penile urethra. Degrees of virilization can be described by the Prader score, which ranges from 0 for a normal-appearing female to 5 for a normal, virilized male.

Fetal, placental, or maternal sources can provide the excessive androgen levels. Maternally derived androgen excess may come from virilizing ovarian tumors such as luteoma and Sertoli-Leydig cell tumor or from virilizing adrenal tumors. Fortunately, these neoplasms infrequently cause fetal efects because of the tremendous ability of placental syncytiotrophoblast to convert C19 steroids-androstenedione and testosterone-to estradiol via the enzyme aromatase (Chap. 5, p. 103). As another source, drugs such as testosterone, danazol, and other androgen derivatives may cause fetal virilization.

Of fetal sources, exposure can arise from fetal congenital adrenal hyperplasia (CAH). his stems from a fetal enzyme dei ciency in the steroidogenic pathway that leads to androgen accu mulation. The most common defect is 21-hydroxylase deiciency.

CAH is a frequent cause of virilization and has an incidence approximating 1 in 10,000 to 20,000 live births (Speiser, 2010).

With CAH, phenotypes depend on the location of the enzyme defect in the steroidogenic pathway and on the severity of the resulting enzymatic deiciency (Miller, 201i1). With severe enzymatic deiciency, afected newborns have life-threatening salt wasting and virilization. Other mutations may prompt virilization alone (Auchus, 2015). he mildest abnormalities present later and are described as "nonclassic," "late-onset," or "adult-onset" CAH. In these patients, activation of the adrenal axis at puberty increases steroidogenesis and unmasks a mild enzymatic deficiency. Excess androgen provides negative feedback to gonadotropin-releasing hormone (GnRH) receptors in the hypothalamus. These patients oten present with hirsutism, acne, and anovulation. Thus, lateonset CAH may mimic polycystic ovarian syndrome (McCannCrosby, 2014). In some instances, CAH can be diagnosed antenatally. Early maternal dexamethasone therapy can dampen androgen excess to minimize virilization (Chap. 16, p. 317).

Of rare placental sources, placental aromatase deiciency from a fetal CP 19 gene mutation causes an accumulation of placental androgen and underproduction of placental estrogens (Chap. 5, p. 105) Gones, 2007). Consequently, both the mother and the 46,X fetus are virilized.

Delivery of a newborn with a disorder of sexual diferentiation is a potential medical emergency and can create possible longlasting psychosexual and social ramiications for the individual and family. Ideally, as soon as the afected neonate is stable, parents are encouraged to hold the child. he newborn is referred to as "your baby," and suggested terms include "phallus," "gonads," "folds," and "urogenital sinus" to reference underdeveloped structures. The obstetrician explains that the genitalia are incompletely formed and emphasizes the seriousness of the situation and the need for rapid consultation and laboratory testing.

Because similar or identical phenotypes may have several etiologies, identiication of a speciic DSD may require several diagnostic tools (McCann-Crosby, 2015). Relevant neonatal physicl examination evaluates: (1) ability to palpate gonads in the labioscrotal or inguinal regions, (2) ability to palpate uterus during rectl examination, (3) phallus size, (4) genitalia pigmentation, and (5) presence of other syndromic features. The newborn metabolic condition is assessed, as hyperkalemia, hyponatremia, and hypoglycemia may indicate CAH. he mother is examined for signs of hyperandrogenism. Other neonatal tests include genetic studies, hormone measurements, imaging, and in some cases endoscopic, laparoscopic, and gonadal biopsy. Sonography shows the presence or absence of miillerian/wolian structures, n locate the gonads, and can identiy associated mlformations such as renal anomalies.

Very early during embryo formation, a bilaminar cloacal membrane lies at the caudal end of the germinal disc and forms the infraumbilical abdominal wall. Normally, an ingrowth of mesoderm between the ectodermal and endodermal layers of the cloacal membrane leads to formation of the lower abdomi nal musculature and pelvic bones. Without this reinforcement, the cloacal membrane may prematurely rupture, and depend ing on the extent of the infraumbilical defect, cloacal exstrophy, bladder exstrophy, or epispadias may result.

Of these, cloacal exstrophy is rare. It includes the triad of omphalocele, bladder exstrophy, and imperforate anus.

Bladder exstrophy is uncommon and is characterized by an exposed bladder lying outside the abdomen. Associated ind symphysis pubis. At the same time, however, the uterus, fal lopian tubes, and ovaries are typically normal except for occa sional miillerian duct fusion defects. Pregnancy with bladder exstrophy is associated with greater risk for antepartum pyelonephritis, urinary retention, ureteral obstruction, pelvic organ prolapse, preterm birth, and breech presentation. The guidelines for pregnancy (Eswara, 2016). Due to the exten encountered, some recommend planned cesarean delivery at a tertiary center (Deans, 2012; Dy, 2015; Greenwell, 2003).

Epispadias without bladder exstrophy is rare and develops in association with other anomalies such as a widened, patulous tened mons pubis. Vertebral abnormalities and pubic symphy sis diathesis are also common .

Clitoral anomalies are unusual. One is clitoral duplication or biid clitoris, which is rare and usually develops in association with bladder exstrophy or epispadias. With female phallic urethra, the urethra opens at the clitoral tip. Last, clitoromegaly noted at birth suggests fetal exposure to excessive androgens (p. 40). In other cases, congenital clitoromegaly in females born extremely premature is a rare but well-recognized finding thought to be due to transient androgen levels in these neonates (Greaves, 2008).

As noted, the hymen marks the embryological boundary between structures derived from the miillerian and urogenital sinus. Hymeneal anomalies include imperforate, microperforate, cribriform (sievelike), navicular (boat-shaped), and septate hymens. They result from failure of the inferior end of the vaginal plate-the hymeneal membrane-to canalize. Their incidences approximate 1 in 1000 to 2000 females (American College of Obstetricians and Gynecologists, 2016). During the neonatal period, signiicant amounts of mucus can be secreted due to maternal estrogen stimulation. With an imperforate hymen, secretions collect to form a bulging, translucent yellow-gray mass, termed hydro-or mucocolpos, at the vaginal introitus. Most are asymptomatic and resolve as mucus is reabsorbed and estrogen levels decrease, but rarely can cause perinatal urinary retention from their mass efects Gohal, 2009).

Four principal deformities arise from defective miillerian duct embryological steps: (1) agenesis of both ducts, either focally or along the entire duct length; (2) unilateral maturation of one mullerian duct with incomplete or absent development of the opposite side; (3) absent or faulty midline fusion of the ducts; or (4) defective canalization. Various classifications have been proposed, and Table 3-3 shows the one from the American Fertility Society (1988). It separates anomalies into groups with similar clinical characteristics, prognosis for pregnancy, and treatment. It also includes one for abnormalities associated with fetal exposure to diethylstilbestrol (DES). Several other classiication systems have been crafted, but this one is the most widely used (Acien, 2011; Di Spiezio Sardo, 2015; Oppelt, 2005).

Mullerian anomalies may be suspected by symptoms or physical findings such as vaginal septa, blind-ending vagina, or duplicated cevix. Amenorrhea may be an initial complaint for those with agenesis of a mullerian component. In those with outlet obstruction, pelvic pain from occult blood that accumulates and distends the vagina, uterus, or fallopian tubes may arise from functioning endometrium. Endometriosis and its associated dysmenorrhea, dyspareunia, and chronic pain are also frequent with outlet obstruction.

Class I segmental defects are caused by mullerian hypoplasia or agenesis as shown in Figure 3-5. These developmental defects can afect the vagina, cervix, uterus, or fallopian tubes and may be isolated or may coexist with other mullerian defects.

TABLE 3-3. Classification of MU"erian Anomalies

I. Segmental mullerian hypoplasia or agenesis ab. Vaginal . Cervical c.

d.

e.

II. Unicornuate uterus a.

b.

c.

d.

III. Uterine didelphys

IV. Bicornuate uterus a.

Complete-division to internal os b.

V. Septate uterus a.

Complete-septum to internal os b.

VI. Arcuate

VII. Diethylstilbestrol related

Data from American Fertility Society: The American Fertility Society classifications of adnexal adhesions, distal tubal occlUSion, tubal occlusion secondary to tubal ligation, tubal pregnancies, Mullerian anomalies and intrauterine adhesions, Fertil Steril 1988 Jun;49(6):944-955.

Of all vaginal anomalies, vaginal agenesis is the most profound and may be isolated or associated with other mullerian anomalies. One example is the Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, in which upper vaginal agenesis is typically associated with uterine hypoplasia or agenesis. Less often, this syndrome also displays abnormalities of the renal, skeletal, and auditory systems. his triad is known by the acronym MURCS, which reflects mullerian duct aplasia, renal aplasia, and �ervicothoracic �omite dysplasia (Rall, 2015).

he obstetrical significance of vaginal anomalies depends greatly on the degree of obstruction. Complete vaginal agenesis, unless corrected operatively, precludes pregnancy by vaginal intercourse. With MRKH syndrome, a functional vagina can be created, but uterine agenesis proscribes childbearing. In these women, however, ova can be retrieved for in vitro fertilization (IVF) in a surrogate mother (F riedler, 2016). U terine transplantation is currently experimental but holds future promise for these women Qohannesson, 2016).

Of other vaginal anomalies, congenital septa may form longitudinally or transversely, and each can arise from a fusion or resorption defect. Longitudinal septa divide the vagina into right and left portions. hey may be complete and extend the entire vaginal length. Partial septa usually form high in the vagina but may develop at lower levels. Septa are typically associated with other mullerian anomalies (Haddad, 1997).

During labor, a complete longitudinal vaginal septum usually does not cause dystocia because the vaginal side through which the fetus descends dilates satisfactorily. An incomplete or partially obstructed longitudinal septum, however, may interfere with descent. Occasionally, a woman with a distal longitudinal septum presents in labor. During second-stage labor, this septum usually becomes attenuated by pressure from the fetal head. After ensuring adequate analgesia, the inferior attachment of the septum is isolated, clamped, transected, and ligated. Following placenta delivery, the superior attachment can be transected while carefully avoiding urethral injury.

A transverse septum poses an obstruction of variable thickness. It may develop at any depth within the vagina, but most are in the lower third (Williams, 2014). These mayior may not be perforate, and thus obstruction or infertility is variably present. In labor, perforate strictures may be mistaken for the upper limit of the vaginal vault, and the septal opening is misidentiied as an undilated cervical os (Kumar, 2014). If encountered during labor, and ater the external os has dilated completely, the head impinges on the septum and causes it to bulge downward. If the septum does not yield, slight stretching pressure on its opening usually leads to further dilatation, but occasionally cruciate incisions are required to permit delivery (Blanton, 2003). If there is a thick transverse septum, however, cesarean delivery may be necessary.

Developmental abnormalities of the cervix include partial or complete agenesis, duplication, and longitudinal septa.

I. Hypoplasia/agenesis II. Unicornuate A. Vaginal B. Cervical A. Communicating B. Noncommunicating C. Fundal D. Tubal E. Combined C. No cavity D. No horn III. Didelphys IV. Bicornuate A. Complete B. Partial V. Septate VI. Arcuate VII. DES related A. Complete B. Partial

FIGURE 3-5 Classification of mOllerian anomalies. DES = diethylstilbestrol.(Modified with permission from American Fertility Society:

The American Fertility Society classifications of adnexal adhesions, distal tubal occlusion,tubalocclusion secondary to tubal ligation, tubal pregnancies, MOlierian anomalies and intrauterine adhesions, Ferril Steril 1988 Jun;49(6):944-55.l

Uncorrected complete agenesis is incompatible with pregnancy, and in vitro ferrilization with gestational surrogacy is an option. Surgical correction by uterovaginal anastomosis has resulted in successful pregnancy (Kriplani, 201e2). Significant complications accompany this correcrive surgery, and rhe need for clear preoperative anatomy delineation has been emphasized by Rock (2010) and Roberrs (2011) and their colleagues. For this reason, they recommend hysterecromy for complete cervi� cal agenesis and reserve reconsrruction attemprs for carefully selected patients with cervical dysgenesis.

From a large variery, a few of the more common congenital urerine malformations are shown in Table 3-3. An accurate population prevalence of these is diicult to assess because the best diagnostiC techniques are invasive. That said, the prevalence found with imaging ranges from 0.4 to 10 percent, and rates in women with recurrent miscarriage are signiicantly higher (Byrne. 2000; Dreisler. 2014; Saravclos. 2008). In a general population, the mOSt common inding is arcuare urerus, followed in descending order by septate, bicornuate, didelphic, and unicornuate classes (Chan, 2011b).

ination, cesarean delivery, rubal sterilization, or infertility evaluation. Depending on clinical presenrarion, diagnostic tools may include sonography, hysterosalpingography, magnetic� resonance imaging, laparoscopy, and hysteroscopy. Each has limitations, and rhese may be used in combination ro completely deine anatomy. In women undergoing fertiliry evaluation, hysterosalpingography (HSG) is commonly selected for uterine cavity and tubal patency assessment. It is contraindi� cared during pregnancy. HSG poorly deines the external urerine contour and can delineate only patent cavities. Regarding patency, remember that some uniconuate rudimentary horns lack a caviry. Also, ourlet Obstructions will preclude dye illing.

In most clinical senings, rwo-dimensional transvaginal sonography (2-D VS) is initially performed. For this indication, the pooled accuracy for VS is 90 to 92 percent (Pellerito. 1992). Saline infusion sonography (SIS) improves delineation of the endome[fium and intenal merine morphology, bur only with a patent endometrial cavity. It also is contraindicated in pregnancy. Three-dimensional (3-D) sonography is more accurate than 2·D sonography because it provides uterine images from virtually any angle. Thus, coronal images can be constructed as shown in Figure 3-6, and these are essential in evaluating borh

FIGURE 3-6 Three-dimensional transvaginal sonographic images. A. Bicornuate uterus with an 8-week gestation. The external fundal contour (red doted ine) dips centrally below the intercornual line, and the endometrial cavities communicate. B. Septate uterus with a S-week gestation. The external fundal contour is normal and convex 'elow dotted ine), and the long septum (asterisk) extends caudad in the midline. C. Arcuate uterus with an 8-week gestation. The external fundal contour is normal and convex (red dotted line), but the fundal endometrial cavity is slightly indented (arrow).

internal and exrernaJ uterine contours (Grimbizis, 2016). Both 2-D and 3-D sonography arc suirable for use in pregnancy.

Several studies have reported very good concordance between 3-D TVS and MR imaging of muUerian anomalies (Deutch, 2008; Graupera, 2015). MR imaging is often preferred for complex anatomy, especially cases for which corrective surgery is planned. MR imaging provides clear delineation of both the internal and external uterine anatomy and has a reported accuracy of up to 100 percent for mullerian anomaly evaluation (Bermejo, 20 I0; Pellerito, 1992). In addition, com plex anomalies and commonly associatcd secondary diagnoses such as renal or skeletal anomalies can be concurrendy evaluated. Precautions wirh MR imaging in pregnancy are discussed in Chapter 46 (p. 910).

In some women undergoing an inferrility evaluation. hysteroscopy and laparoscopy may be selected co assess for mullerian anomalies; screen for endomctriosis, which is often coexistent; and exclude other tubal or uterine cavity pathologies (Puscheck, 2008; Saravelo" 2008). In pregnancy, these approaches are rarely used co diagnose mullerian anomalies. and hysteroscopy is contraindicated.

Wirh this abnormality, the underdeveloped or rudimentary horn may be absent. If present, it may or may nor communicatewith the domin�nr horn �nd may or may not contain an endomerrium-Iined cavity (see Fig. 3-5). General population estimates cite an incidence of I in 4000 women (Reichman, 2009). This anomaly may be detected during ferrility evaluation by HSG. Bur as nored, noncommunicating or noncavirary rudimentary horns may not ill with dye. If this anomaly is suspected. 3-D sonography increases diagnostic accuracy, but again MR imaging may be preferred. Importantly, 40 percent of afected women will have renal anomalies (Fedele, 1996).

This mullerian anomaly carries signiicant obstetrical risks, including first-and second-trimester miscarriage. malpresentation, fetal-growth restricrion. fetal demise. prematurely ruprured membranes, and preterm delivery (Chan, 2011 a; Hua, 2011; Reichman, 2009). Abnormal uterine blood Row, cervicl incompetence, and diminished cavity size and muscle mass of the hemiurerus are postulated ro underlie these risks (Donderwinkel, 1992).

Rudimentary horns also increase the risk for an ectopic pregnancy within rhe remnant, which may be disastrous. This risk includes noncommunicating cavitary rudiments, for which transperironeal sperm migration permirs ovum fertilization and pregnancy (Nahum, 2004). In a report of 70 sllch pregnancies, Rolen and associares (1966) found that the rudimentary uterine horn ruptured prior to 20 weeks in most. Nahum (2002) reviewed the literature from 1900 to 1999 and identiied 588 rudimentary horn pregnancies. Half had uterine rupture, and 80 percent did so before the third rrimesrer. Of the rotal 588, the neonatal survival race was only 6 percent.

Imaging allows an earlier diagnOSiS of rudimentary horn pregnancy so that it can be treated either medically with methotrexare or surgically before rupture (Dove, 2017; Edelman, 2003; Khati, 2012; Worley, 2008). lthough not emphasized in Figure 3-5, the anachmem sire between rhe rudimentary horn at times can be broad and vascular.

If diagnosed in a nonpregnant woman, mOSt recommend prophylactic excision of a horn thac has a cavity (Fedele, 2005; Rackow, 2007). Data regarding subsequent pregnancy after excision are scarce. In one series of eight women, all had a preterm cesarean delivery (pados, 2014).

This mullerian anomaly arises from a complere lack of fusion rhat results in twO enrirely separate hemiureri, cervices, and usually (yo vaginas (see Fig. 3-5). It is common among marsupials, for example, the American possum-Didelphys virginiana. Most women have a double vagina or a longitudinal vaginal septum. Urerine didelphys may be isolated. Or, it may compose a triad with an Qbstructed hemiyagina and with ipsilateral renal Igenesis (OHVlRA), also known as HerlynWerner-Wunderlich syndrome (Tong, 2013).

These anomalies are suspected on pelvic examinarion by identificarion of a longitudinal vaginal septum and two cervices. During HSG for fertility evaluation, contrast shows twO separate endocervical canals. These open into separare noncommunicating fusiform endometrial cavities char each ends wirh a solitary fallopian tube. In women without fertility issues, 2-or 3-D TVS is a logical initial imaging tool, and separate diver gent uterine horns with a large intervening fundal cleft are seen.

Endometrial cavities are uniformly separate. MR imaging may be valuable in cases without classic indings.

Adverse obstetrical outcomes associated with uterine didel phys are similar but less frequent than those seen with unicornu ate uterus. Increased risks include miscarriage, pre term birth, and malpresentation (Chan, 2011a; Grimbizis, 2001; Hua, 2011).

Metroplasty for either uterine didelphys or bicornuate uterus involves resection of intervening myometrium and fundal recombination (Alborzi, 2015). hese rarely performed surgeries are chosen for highly selected patients with otherwise unexplained miscarriages. Moreover, no evidence-based data conirm the eicacy of such surgical repair.

his fusion anomaly results in two hemiuteri. As shown in Figure 3-5, the central myometrium runs either partially or completely to the cervix. A complete bicornuate uterus may extend to the internal cervical os and have a single cervix (bicornuate unicollis) or reach the external os (bicornuate bicollis). As with uterine didelphys, a coexistent longitudinal vaginal septum is not uncommon.

Radiological discrimination of a bicornuate uterus from a septate uterus can be challenging. This distinction, however, is important because septate uterus can be treated with hysteroscopic septal resection. HSG or 2-D TVS may initially suggest an anomaly, but further distinction is provided by 3-D TVS or MR imaging (see Fig. 3-6). With these, an intercornual angle greater than 105 degrees typiies a bicornuate uterus, whereas one less than 75 degrees indicates a septate uterus. Fundal contour also assists, and a straight line drawn between the imaged tubal ostia serves as the defining threshold. Referent to this, an intrafundal downward cleft measuring �1 em or more is indicative of bicornuate uterus. A septate uterus shows a cleft depth < 1 em, or it may have a normal fundal contour.

Bicornuate uterus carries increased risks for adverse obstetrical outcomes that include miscarriage, preterm birth, and malpresentation. As discussed in the prior section, rare surgical correction by metroplasty is reserved for highly selected patients.

With this anomaly, a resorption defect leads to a persistent complete or partial longitudinal uterine septum (see Fig. 3-5). Less often, a complete vaginocervicouterine septum is found (Ludwin, 2013). Many septate uteri are identiied during evaluation of infertility or recurrent pregnancy loss. Although an abnormality may be identiied with HSG or 2-D TVS, typically 3-D TVS or MR imaging is required to diferentiate this from a bicornuate uterus (see Fig. 3-6).

Septate anomalies are associated with diminished fertility and increased risks for adverse pregnancy outcomes that include miscarriage, preterm delivery, and malpresentation (Chan, 201i1a; Ghi, 2012). Hysteroscopic septal resection has been shown to improve pregnancy rates and outcomes (Mollo, 2009; Pabu:cu, 2004). From their metaanalysis, Valle and colleagues (20l3) reported a 63-percent pregnancy rate and 50-percent live birth rate following resection.

his malformation is a mild deviation from the normally developed uterus. Although some studies report no increased adverse associated outcomes, others have found excessive secondtrimester losses, preterm labor, and malpresentation (Chan, 2011a; Mucowski, 2010; Woelfer, 2001).

Treatment with Cerclage

Some women with uterine anomalies and repetitive pregnancy losses may beneit from transvaginal or transabdominal cervical cerclage (Golan, 1992; Groom, 2004). Others with partial cervical atresia or hypoplasia may also benefit (Hampton, 1990; Ludmir, 1991). Candidacy for cerclage is determined by the same criteria used for women without such defects, which is discussed in Chapter 18 (p. 354).

During the 1960s, a synthetic nonsteroidal estrogen-diethylstilbestrol (DES)-was used to treat pregnant women for threatened abortion, preterm labor, preeclampsia, and diabetes. he treatment was remarkably inefective. Later, it was also discovered that women exposed as fetuses had increased risks of developing several specific reproductive-tract abnormalities. hese included vaginal clear cell adenocarcinoma, cervical intraepithelial neoplasia, small-cell cervical carcinoma, and vaginal adenosis. Afected women had identiiable structural variations in the cervix and vagina that include transverse septa, circumferential ridges, and cervical collars. Uteri potentially had smaller cavities, shortened upper uterine segments, or T-shaped and other irregular cavities (see Fig. 3-5) (Kaufman, 1984).

These women sufer impaired conception rates and higher rates of miscarriage, ectopic pregnancy, and preterm delivery, especially in those with structural abnormalities (Kaufman, 2000; Palmer, 2001). Now, more than 50 years after DES use was proscribed, most afected women are past childbearing age, but higher rates of earlier menopause, cervical intraepithelial neoplasia, and breast cancer are reported in exposed women (Hatch, 2006; Hoover, 2011; Troisi, 2016).

he fallopian tubes develop from the unpaired distal ends of the mlillerian ducts. Congenital anomalies include accessory ostia, complete or segmental tubal agenesis, and several embryonic cystic remnants. The most common is a small, benign cyst attached by a pedicle to the distal end of the fallopian tube-the hydatid of Morgagni. In other cases, benign paratubal cysts may be of mesonephric or mesothelial origin. Last, in utero exposure to DES is associated with various tubal abnormalities. Of these, short, tortuous tubes or ones with shriveled fimbria and small ostia are linked to infertility (DeCherney, 1981).

The pregnant uterus may infrequently show exaggerated flexion. Mild or moderate lexion is typically inconsequential, but congenital or acquired extremes may lead to pregnancy complications.

Antlexion describes forward angling of the uterine fundus in the sagittal plane relative to the cervix. Exaggerated degrees usually pose no problem in early pregnancy. Later, however, particularly when the abdominal wall is lax such as with diastasis recti or ventral hernia, the uterus may fall forward. In extreme cases, the fundus lies below the lower margin of the symphysis. Sometimes, this abnormal uterine position prevents proper transmission of labor contractions, but this is usually overcome by repositioning and application of an abdominal binder.

Retrolexion describes posterior uterine fundal angling in the sagittal plane. A growing retrolexed uterus will occasionally become incarcerated in the hollow of the sacrum. Symptoms include abdominal discomfort, pelvic pressure, and voiding dysfunction or retention. During bimanual pelvic examination, the cervix will be anterior and behind the symphysis pubis, whereas the uterus is appreciated as a mass wedged in the pelvis. Sonography or MR imaging can aid the clinical diagnosis (Gardner, 2013; Grossenburg, 2011; van Beekhuizen, 2003).

With continued uterine growth, the incarcerated uterus can spontaneously resolve over 1 to 2 weeks. An indwelling urinary catheter or intermittent self-catheterization may be needed in the interim to empty the bladder. Persistent cases require manual repositioning. For this, after bladder catheterization, the uterus can usually be pushed out of the pelvis when the woman is placed in a knee-chest position. Often, this is best accomplished by digital pressure applied through the rectum.

FIGURE 3-7 Anterior sacculation of a pregnant uterus. Note the markedly attenuated anterior uterine wall and atypical location of the true uterine fundus. Rood, 2014).

Conscious sedation, spinal analgesia, or general anesthesia may be necessary. Following repositioning, the catheter is left in place until bladder tone returns. Insertion of a soft pessary for a few weeks usually prevents recurrent incarceration.

Lettieri and colleagues (1994) described seven cases of uterine incarceration not amenable to these simple procedures. In two women, laparoscopy was used at 14 weeks' gestation to reposition the uterus using the round ligaments for traction. Alternatively, in case series, advancing a colonoscope or colonoscopic insulation was used to dislodge an incarcerated uterus (Dierickx, 2011; Newell, 2014; Seubert, 1999).

Rarely, sacculation may form as extensive lower uterine segment dilatation due to persistent entrapment of the pregnant uterus in the pelvis (Fig. 3-7). In these extreme cases, sonography and MR imaging are typically required to deine anatomy (Gottschalk, 2008; Lee, 2008). Cesarean delivery is necessary when sacculation is marked, and Spearing (1978) stressed the importance of clariying the distorted anatomy. An elongated vagina passing above the level of a fetal head that is deeply placed into the pelvis suggests a sacculation or an abdominal pregnancy. The Foley catheter is frequently palpated above the level of the umbilicus! Spearing (1978) recommended extending the abdominal incision above the umbilicus and delivering the entire uterus from the abdomen before hysterotomy. This will restore correct anatomical relationships and prevent inadvertent incisions into and through the vagina and bladder. Unfortunately, this may not always be possible (Singh, 2007). As a inal caveat, a true uterine diverticulum has been mistaken for uterine sacculation (Rajiah, 2009).

he uterus commonly rotates to the maternal right during pregnancy. Rarely, uterine rotation exceeds 180 degrees to cause torsion. Most cases of torsion result from uterine leiomyomas, miillerian anomalies, fetal malpresentation, pelvic adhesions, or laxity of the abdominal wall or uterine ligaments. Jensen (1992) reviewed 212 cases and reported that associated symptoms may include obstructed labor, intestinal or urinary

Anterior wall complaints, abdominal pain, uterine sacculation hypertonus, vaginal bleeding, and hypotension.

Most cases of uterine torsion are found at the time of cesarean delivery. In some women, torsion can be conirmed preoperatively with MR imaging, which shows a twisted vagina that appears X-shaped rather than its normal H-shape (Nicholson, 1995). As with uterine incarceration, during cesarean delivery, a severely displaced uterus should be repositioned anatomically before hysterotomy. In some cases, an inability to reposition or a failure to recognize the torsion may lead to a posterior hysterotomy inci sion (Albayrak, 2011; Picone, 2006;

Acitll P, Aden MI; lhe hisrory of female genital (rael malformation classiica rions and proposal of an updau'd s,slcm. Hum Reprod Update 17:693, 2011

AksgJacdc , JUlll A: Testicular �unction and lertiliry in men and Klinefelter syndrome: a review. Ellr J Endocrinol 168(4):R67, 2013

Albayrak M. 3eni:m A, Ozdemir I. Cl al: Deliberate posterior low transverse incision at cesarean section of a gr.\'id uterus in 180 degrees of [OTsion: a case report. J Reprod Med 56(3-4): 181, 20 II

Alborli S, Asejah H, Amini \1, cr al: Laparoscopic mClfoplasry in bicornuate and didelphic uteri: feasibility and outcome. Arch Gynecol Obslet 291 (5), I 167. 2015

NJen JW, Cardall S. Kitdjarukhajon M, '1 al: Incidence of ovarian mal descent in women with mulleriln dun anomalies: evaluation by MRI. A)R 198(4),W381. 2012

Am�ric;tn College of Obstetricians and Grnecologisrs: Mlillerian agenesis: , diagnOSIs, management. and Ireatment. CommiHee Opinion No. 562. May 2013, Reairmed 2016

American Fertility Society: 111e American Fertility Society classiications of �dn�(al adhesions, distal tubal occlusion. mbal occlusion secondary to tubal Ilgallon, mbal pregnancies, \liillerian anomalies and intrauterine adhesions. Fertil Steril 49:944. 1988

Auchus R): Management considerations for thc adult with congcniral adren,11 h),p·rplasia. Mol Cdl Endocrinol 408: 190. 2015

Bermelon�, ��:m�nez, Ten p, et �I: l'hree-dimensional ultrasound in the diag �10SISnol lllullenan duct anomalies and concordance with magnetic resonance .

Imagtng. Ultrasound Obstct G)'nccol 35: 593, 2010

Blanton EN, Rouse 0): Trial oflahor in women with transverse vaginal septa.

Obstet Gynecol JOI:IIIIO, 2003

Bradshaw KD: Anatomical disorders, In Hoffman BL, Schorge )0, Bradshaw

KD. ct al (eds): Williams Gynecology, 3rd ed. New York, �IcGraw-Hill

Education. 20n16

Byne ), Nussbaum-Bbsk A. Taylor WS, et al: Prevalence of �Hil1erian duct anomalies deteCled at ultrasound. Amn) Med Gener 94(1):9. 2000 Calogero E, Giagul1i VA. Mongiol LM, et al: Klineflter syndrome: cardio vascular abnormalities and metabolic disorders.n) Endocrinol Invest 40(7): 705.n2017

Chan V, )ayaprakasan K, Tan A. et al: Reproductive outcomes in women with cOllgellitalnuterine anomalies: a systematic review. Ultrasound Obstet Gynecol 38(4):rnt. 20n1lna

Chan V. )ayaprakasan K. Zamoran), et al: The prevalence of conueniral uterine anomalies in unsdecled and high-risk populations: a syste'.ttic review. Hum Rcprod Update 17(6):761, 201lb

Dabirashrai H. Mohammad K. Moghadami-Tabri.i N: Ovarian malposition in women with uterine anomalies. Obstet Gynecol 83:293. 1994

Deans R, 3anks F. liao LM. et al: Reproductive outcomes in women with cla� sic bladder exstrophy: an observational cross-sectional srudy. Am J Obstct

Gynecol 206(6):496.e I. 2012

DeChcrney AH. Cholst I. Nafcolin F: StrucUire and funcrion of the f.111opian tubes following exposure o diethylstilbestrol (DES) during gesmtion. Fenil Steril 36(6):74n1, 1981

Deutch TO, Abuhamad AZ: 111e role of 3-dimensional ultrasonography and magnctic resonance imaging in the diagnOSiS of l11illlerian ducr anol11alies: a review of the literature. ) Ultrasound Me<l r(3):413. 2008

Die�ickx I. V�n Holsbeke C, Mesens T, et al: Colonoscopy-assisted reposi

CIon ufthe IIlcarcerared u[crus in mid-pregnancy: a repOrl offour Cases and a literature review. Eur) Obstet G'necol Rcprod Bioi 158(2):153.n201 J

Di ?piezionS�rdo A. Campo R. Gordts S, et al: 111e comprehensiveness of the .

ESHRE/ESGE classiication of female genital tract congenital anomalies: a systematic review of cases not classiied by [he AFS system. Hum Reprod 30(5),n104.n2015

Dondcrwinkel PF. Dort )1'. Willemsen N: The uniconltate uterus: clinical implications. Eur) Obstet Gynccol Reprod Bioi 47(2): 135. 1992

Dove CK. Harvey SM, Spalluro LB: Sonographic indings of early pregnancy in the rudimentary hon of a uniconuatc uterus: 1 rwo case rcpon. Clin Imaging 47:25, 2017

Dreisler E. Srampe Sorensen S: Mlillerian duct anomalies diagnosed by salinc contraSt sonohystcrography: prevalence in a general population. Fenil Steril 102(2),525. 20n14

Dy GW, Willihnganz-Llwson KH. Shnorhavorian M, er al: Successful preg nancy in paci'rHS with exst'Tophy-epispadias complex: a Universiry of Iash ington experience.n) Pediatr Urol II (4):213.eI. 2015

Edelman AB. Jensen )T, Lee OM. et al: Sliccessfulnmedical abortion of a pregnancy within a noncommunicating rudimentary ucerine hon. Amn) Obstel

Gynccol J89:886, 2003 .swara)R, Kielb S, Koyle MA. et al: The recommendations of the 2015 American Urological Association (Iorking Group on Genitourinary COil genitalism. Urology 88: I, 20I6 l'edele L, Bianchi S, Agnoli B. et al: Urinary tract anomalies associated with unicornuate merus.n) Urol 155:84;'. 1996

Fedele L, Bianeli S. Zaneonato G, et II, Laparoscopie removal ofthe eavitared nOllcommunicating rudimetllary UTerine horn: surgical aspects in 10 c;lses.

Fenil Steriln83(2):432. 2005

Friedler S. Grin L. Liberti G. et al: The reproductive parential of patients with

Mayer-Rokitansky-Kiister-Hauser syndrome using gestational surrogacy: a systematic review. Reprod Biomed Online 32{ln):54, 2016

Gardner CS, Jafe TA, Hertzberg BS, et al: The incarcerated uterus: a review of MRI and ultrasound imaging appearances. A)R Am ) Roentgenol 201(1),223.n2013

Ghi T, De �'usso F, Maroni E. et at: 'fhe pregnanc)' outcome in women with incidental diagnOSiS of septate uterus at irst trimester scan. Hum Reprod 27(9),267. 2012

Golan A, Langer R. Neuman M. et al: Obstetric outcome in women with congenital uterine malformations. ) Reprod 'ed 3-:233. 1992

Gonschalk E�1. Siedenropf )P, Schoenbon I, ct 31: Prenatal sonographic and ..lRl indings in a pregnancy complicated by uterine sacculation: case reporr and review of [he litera Hire. Ultrasound Obstet GynecoIn32(4):582 ' 2008

Graupera B. Pascua! MA, Hereter , C[ al: Accuracy of three-dinensionalnultrasound compared with magnetic resonance imaging in diagnosis of miillerian duct anomalies using ESHRE-ESGE consensus on (he classiication of con genital anomalnies of the female genital tracr. Ultr..lsound Obsret Gynecol 46(5),616.n2015

Greaves R. Hunt RW, Zacharin ..l: Transient anomalies in genital appear .n ance In some extremely preterm female infants may be the result of foeral programming causing a surge in LH and the over activation of the pituirary gonadal axis. Clin Endocrinol (OxO 69(5):76, 2008

Greenwell T), Venn SN, CreighlOn SM. et al: Pregnancy after lower uri nary tract reconstruction for congenital abnormalities. B)U Int 92:773

Grimbizis GF, Camus M. Tarlanis Be. et al: Clinical implications ofurerine malformations and hysteroscopiC treatment resulrs. Hum Reprod Update -(2),161. 2001

Grimbizis GF, Di Spi'/jo Sardo A. Saravetos SH. CI al: The 1·hes.110niki ESHRElESGE consensus on diagnosis of female genital anomalies. Hum

Reprod 31(1):2, 2016

Groom J1. Jones SA, Edmonds OK. et al: Preconception tran.1bdomina! cervicoisthrnic cerclage. Amn) Obstet GYllecol 191 (I ):230, 2004

Gross"nburg N), Delane' AA, B�rg TC: Treatment of a [ate second-trimester incarcerated uterus using ultrasound-guided manual reduction. Obstet GYlleco1n1n18(2 Pt 2):436, 201n1

Haddad B, Louis-Sylvestre e. PoilOut P, et al: Longitudinal vaginal septllm: : rerroSp!ctive sllId}, of 202 cases, Em ) Obstet Gynecol Reprod Bioi ,4(2),19.• 1997

Hal�-Craggs �A, Kirkh:lnl A. Creighton SM: Renal and urological abnormali ties occunng with mlillerian anomalies.n) Pcdiatr UroI9(1):27. 2013 Hampton HL. M�ks GR. Bates GW, et al: Pregnancy after successful vagino plasty and cervical stenting for partial atresia of the cervix. Obstet Gynecol -6;900, 1990

Hatch EE, Troisi R, (Iise LA. et al: Age at natural menopause in women exposed 10 diethylstilbestrol in lItero. Am J Epidemiol 164:682. 2006 Heiner Z. Dmochowska A. Szemraj ). et al: A novel mutation (c. 341 A>G) in the SRY gene in a 46,XY female palient with gonadal dysgenesis. Gene 526(2):46-,I2013

Hoover N, H'er M, Pfeifer RM, er al: Adverse health exposed in lItero ro diethylstilbestrol. N r..led 365: 1304,n2011

Hua ..t, Odibo AO, Longman RE. et al: Congenital lIterine anomalies and adverse pregnanc), outcomes. Amn) Obstel Groecol 205(6):558.e I, 20II

Hughes lA, HVuk C, Ahmed SF. et a!: Consensus statement on management ,nof lntCrSex disorders. J Pediatr Urol 2:! 48, 2006

Hillson )M, Crover SR. O'Connell M, et al: Malformation syndromes associated with disorders of sex development. Nat Rev Endocrino! 10(8);476. 2014

Jensen )G: Ulerine torsion in pregnancy. Acta Obstet Gynecol Scand 71:260, )ian� )F. �lle W. Deng Y. Ct al: Gonadal malignancy in 202 female patients With dlsorders of sex development comaining Y-chromosome ma[crial.

Gynecol EndocrinoIn32(4):338. 2016 )oh�1 NS, Bogri� S, �llIshtaq I: Neonatal imperforate hymen causing obstruc tion of The lITtnary tracL Urology ;'3(4):750. 2009

Johannesson L. )iirvho!1l1 S: Uterus transplanration: current progress and future prospects. lilt) (Iomens He.I,h 8:43. 2016

Jones ME, Boon we, Mcinnes K, et aJ: Recognizing rare disorders: aromarase deiciency. Nat C1in Pom Eodoerino! lvletab 3(5):414, 2007

Kaufman RH, Adam E, Hatch EE, ct al: Cominued follow-up of pregnancy outcomes in diethylstilbestrol-exposed ofspring. Obstet Gynecolo96(4):483, 2000 Kaufman RH, Noller K, Adam E, et al: Upper genital tract abnormalities and pregnancy outcome in diethylstilbestrol exposed progeny. m J Obstet Gynecol 148: 973,o1984 Kenney PJ, Spirt SA, Leeson MD: Geniwurinary anomalies: radiologic-anatomic correlations. Radiographies 4(2):233, 1984

Khati Nj, Frazier A, Brindle A: The unicornuate uterus and its variants: clinical presentation, imaging indings, and associated complications. J Ultrasound Med 31(2):319, 2012

Kriplani A, Kachhawa G, Awasthi 0, et al: Laparoscopic-assisted uterovaginal anastOmosis in congenital atresia of uterine cervix: follow-up srudy, J Minim Invasive GynecoIo19(4):477, 2012

Kumar N, Tayade S: Successful pregnancy outcome in an untreated cse of concomitant transverse complete vaginal septum with unicornuare uterus, J Hum Reprod Sci 7(4):27, 2014

Lee SW, Kim MY, Yang JH, et al: Sonographic indings of uterine sacculation during pregnancy. Ultrasound Obstet GynecoIo32(4):595, 2008

Lettieri L, Rodis JF, McLean DA, et al: Incarceration of the gravid uterus.

Obstet Gynecol Suv 49:642, 1994

Ludmir J, Jackson GM, Samuels P: Transvaginal cerclage under ultrasound guidance in cases of severe cervical hypoplasia. Obstet Gynecol 78: 1067, 1991

Ludwin A, Ludwin I, Pitynski K, et al: Diferentiating between a double cervix or cervical duplication and a complete septate uterus with longitudinal vaginal septum. Taiwan J Obstet Gynecol 52(2):308, 2013

Matthews 0, Bath L, Hagler W, et l: Hormone supplementation for pubertal induction in girls. Arch Dis Child 102(10):975,o2017

McCann-Croshy B, Chen MJ, et al: Non-classical congenital adrenal hyperplasia: targets of treatment and transition. Pediatr Endocrinol Rev 12(2):224, 2014 McCann-Crosby B, Sutton VR: Disorders of sexual development. Clin PerinawIo42(2):395,o2015 Miller L, Auchus RJ: The molecular biology, biochemistry, and physiology of human sterOidogenesis and its disorders. Endocr Rev 32(1):81, 2011

Mollo A, De Franciscis P, Colacurci N, et al: Hysteroscopic resection of the septum improves the pregnancy rate of women with unexplained infertility: a prospective controlled trial. Ferri! SteriIo91(6):2628, 2009

Moore L, Persaud V, Torchia MG: he urogenital system. In The Developing Human. Philadelphia, Saunders, 2013, P 272

Mucowski SJ, Herndon CN, Rosen MP: The arcuate uterine anomaly: a critical appraisal of its diagnostiC and clinical relevance. Obstet Gynecol Surv 65(7),449,o2010

Murphy C, Allen L, Jamieson A: Ambiguous genitalia in the newborn: an overview and teaching tool. J Pediatr Adolesc GynecoIo24:236, 2011

Nahum G, Stanislaw H, McMahon C: Preventing ecropic pregnancies: how often does transperiwneal transmigration of sperm occur in efecting human pregnancy? BJOG 111:706,o2004

Nahum GG: Rudimentary uterine horn pregnancy: the 20th-century worldwide experience of 588 cases. J Reprod Med 47: 151, 2002

Newell SO, Crofts JF, Gram SR: The incarcerated gravid uterus: complications and lessons learned. Obstet Gynecol 123(2 Pt 2 Suppl (2 Pt 2 Suppl 2))A23,o2014

Nicholson K, Coulson Cc, McCoy MC, er al: Pelvic magnetic resonance imaging in the evaluation of uterine torsion. Obstet Gynecol 85(5 Pt 2),888, 1995

Nielsen J, Wohlert M: Sex chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in rhus, Denmark. Birth Defects Orig Artic Ser 26:209, 1990

Nistal IvI, Paniagua R, Gonzalez-Peramato p, et al: Perspectives in pediatric pathology, chapter I. normal development of testicular structures; from the bipotemial gonad to the fetal testis. Pediarr De\' PathoIo18(2}:88, 2015a

Nistal M, Paniagua R, Gonlez-Peramato P, et al: Perspectives in pediatric pathology, chapter 5. gonadal dysgeneSiS. Pediatr Dev PathoIo18(4):259, 2015b Ocal G: Current concepts in disorders of sexual development. J Clin Res Pediatr EndocrinoI3(3): \05,o2011

Oppelt P, Renner sr, Brucker S, et al. The VCUAM (Vagina Cervix Uterus Adnex-associated Malformation) Classiication: a new classiication for genital malformations. Ferril Sterilo84: 1493,o2005

Pabw:cu R, Gomel V: Reproductive outcome after hysteroscopic metroplasfY in women with septate uterus and othervrise unexplained infertility. Ferril Sterilo81:o1675,o2004

Pados G, Tsolakidis 0, Athanatos 0, et aI: Reproductive and obstetric outcome after laparoscopic excision of functional, non-communicating broadly attached rudimentary hon: a case series. Eur J Obstet Gynecol Reprod Bioi 182,33,o2014

Palmer JR, Hatch EE, Rao RS, et al: Infertility among womcn exposed prenatally to diethylstilbestrol. Am J Epidemiol 154:31G, 2001

Pellerito JS, lvlcCarthy S�'I, Doyle MB, et al: Diagnosis of uterine anomalies: relative accuracy of MR imaging, endovaginal sonography, and hysterosalpingography. Radiology 183:795, 1992

Picone 0, Fubini A, Ooumerc S, et al: Cesarean delivery by posterior hysterotomy due to torsion of the pregnant uterus. Obstet Gynecol 107(2 Pt 2),533, 2006

Puscheck EE, Cohen L: Congenital malformations of the uterus: the role of ultrasound. Semin Reprod Med 26(3):223, 2008

Rackow BW, Arici A: Reproductive performance of womcn with miillerian anomalies. Curr Opin Obstet Gynecol 19(3):229, 2007

Rajiah P, Eastwood KL, Gunn ML, ct aI: Uterinc diverticulum. Obstct Gynecol 113(2 Pt 2):525, 2009

Ral K, Eisenbeis S, Henninger V: Typical and atypical associated indings in a group of 346 patients with Mayer-Rokitansky-Kuester-Hauser syndrome. J Pediatr Adolesc Gynecol 28(5):362, 2015

Reichman 0, Laufer MR: Congenital uterine anomalies afecting reproduction. Best Pract Res Clin Obstet GvnaecoIo24(2):193, 2010

Reichman 0, Laufer MR, Robinson 3K: Pregnancy outcomes in unicornuate uteri: a review. Fertil Sterilo91(5): 1886,o2009

Roberts CP, Rock JA: Surgical methods in the treatment of congenital anomalies of the uterine cervix. Curr Opin Obstet Gynecol 23(4):251, 2011

Rock JA, Roberts CP, Jones HW Jr: Congenital anomalies of the uterine cervix: lessons from 30 cases managed clinically by a common protocol. Fertil Steril 94(5),1858,o2010

Rolen AC, Choquette AJ, Semmens JP: Rudimentary uterine horn: obstetric and gynecologic implications. Obstet Gynecol 27:806, 1966

Rood K, Markham KB: Torsion of a term gravid uterus: a possible cause of intrauterine growth restriction and abnormal umbilical artery Doppler indings. J Ultrasound Med 33(10):1873, 2014

Saravelos SH, Cocksedge A, Li TC: Prevalence and diagnosis of congenital uterine anomalies in women with reproductive failure: a critical appraisal. Hum Reprod Update 14(5):415,o2008

Seubert DE, Puder KS, Goldmeier P, et al: Colonoscopic release of the incarcerated gravid uterus. Obstet Gynecol 94:792, 1999

Singh MN, Payappagoudar J, Lo J: Incarcerated retroverted uterus in the third trimester complicated by postpartum pulmonary embolism. Obstet Gynecol 109A98, 2007

Spearing GJ: Uterine sacculation. Obstet GynecoIo51:IIS, 1978

Speiser PW, Azziz R, Baskin LS, ct al: Congenital adrenal hyperplasia due to steroid 2 I-hydroxylase deiciency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 95(9):4133, 2010

Tongo], Zhu L, Lang J: Clinical characteristics of 70 patients with HerlynWerner-Wunderlich syndrome. Int J Gynaecol Obstet 121 (2): 173, 2013

Troisi R, Hatch EE, Palmer JR, et al: Prenatal diethylstilbestrol exposure and high-grade squamous cell neoplasia of the lower genital traCt. Am J Obstet Gynecol 215(3):322.el, 2016

Valle RF, Ekpo GE: Hysteroscopic metroplasty for the septate uterus: review and meta-analysis. J Minim Invasive GynecoIo20(1):22, 2013

Van Beekhuizen HJ, Bodewes HW, Tepe EM, et al: Role of magnetic reso nance imaging in the diagnosis of incarceration of the gravid uterus. Obstct

Gynecol 102:1o134,o2003

Williams CE, Nakhal RS, Hall-Craggs A, et al: Transverse vaginal septae: management and long-term outcomes. BJOG 121(13):1653,o2014

Woelfer B, Salim R, Banerjee S, et al: Reproductive outcomes in women with congenital uterinc anomalies detected by three-dimensional ultrasound screening. Obstet GynecoIo98:1099, 2001

Worley KC, Hnat i'vID, Cunningham FG: Advanced xtrauterine pregnancy: diagnostic and therapeutic challenges. Am J Obstet Gynecol 198:287.e 1, 2008

WU QY, U N, Li W, et al: Clinical, molecular and cytogenetic analysis of 46,X testicular disorder of scx developmcnt with SRY-positive. BMC Urol 14:70,o2014

REPRODUCTIVE TRACT ...........................49

BREASTS....................................... 53

SKIN .......................................... 53

METABOLIC CHANGES. . . . . . . . . . . . . . . . . . . . . . . . . . . 54

HEMATOLOGICAL CHANGES ...................... 57

CARDIOVASCULAR SYSTEM ....................... 60 RESPIRATORY ............................64

URINARY SYSTEM ............................... 65

GASTROINTESTINAL TRACT .......................68

ENDOCRINE SYSTEM ................... ...... .. 68

MUSCULOSKELETAL SYSTEM ...................... 72

CENTRAL NERVOUS SYSTEM . . . . . . . . . . . . . . . . . . . . . . 72

The matenal organism reacts to a greater or lesser extent under the inluence of pregnancy, but naturaly the most characteristic changes are observed in the generative tract, and especialy the uterus, which undergoes a very marked increase in size.

-J. Whitridge Williams (1903)

In the irst edition of this textbook, Williams devoted only 10 pages to the physiology of pregnancy, and half were focused on uterine growth. Many gestational changes begin soon after fertilization and continue throughout pregnancy. Equally astounding is that the woman is returned almost completely to her prep regnancy state after delivery and lactation. Most pregnancy-related changes are prompted by stimuli provided by the fetus and placenta. Virtually every organ system undergoes alterations, and these can appreciably modiy criteria for disease diagnosis and treatment. hus, an understanding of pregnancy adaptations is essential to avoid misinterpretation. Moreover, some physiological changes can unmask or worsen preexisting disease.

In the nonpregnant woman, the uterus weighs approximately 70 g and is almost solid, except for a cavity of 10 mL or less. During pregnancy, the uterus is transformed into a thin-walled muscular organ of suicient capacity to accommodate the fetus, placenta, and amnionic luid. he total volume of the contents at term averages 5 L but may be 20 L or more! hus, by the end of pregnancy, the uterus has achieved a capacity that is 500 to 1000 times greater than the nonpregnant state. The corresponding increase in uterine weight is such that, by term, the organ weighs nearly 1100 g.

During pregnancy, uterine enlargement involves stretching and marked hypertrophy of muscle cells, whereas the production of new myocytes is limited. Fibrous tissue also accumulates, particularly in the external muscle layer, together with a considerable rise in elastic tissue content. The walls of the corpus considerably thicken and strengthen during the first few months of pregnancy but then gradually thin. By term, the myometrium is only 1 to 2 cm thick, and the fetus usually can be palpated through the soft, readily indentable uterine walls.

Uterine hypertrophy early in pregnancy probably is stimulated by the action of estrogen and perhaps progesterone. Thus, similar uterine changes can be observed with ectopic pregnancy. But after approximately 12 weeks' gestation, uterine growth is related predominantly to pressure exerted by the expanding products of conception.

Within the uterus, enlargement is most marked in the fundus. The extent of uterine hypertrophy is also influenced by the position of the placenta. Namely, the myometrium surrounding the placental site grows more rapidly than does the rest.

The uterine musculature during pregnancy is arranged in three strata. The irst is an outer hoodlike layer, which arches over the fundus and extends into the various ligaments. The middle layer is a dense network of muscle fibers perforated in all directions by blood vessels. Last is an internal layer, with sphincter-like ibers around the fallopian tube orifices and internal cervical os. Most of the uterine wall is formed by the middle layer. Here, each myocyte has a double curve so that the interlacing of any two cells forms a figure eight. This arrangement is crucial and permits myocytes to contract after delivery and constrict penetrating blood vessels to halt bleeding.

For the first few weeks, the uterus maintains its original piriform or pear shape. But, as pregnancy advances, the corpus and fundus become globular and almost spherical by 12 weeks' gestation. Subsequently, the organ grows more rapidly in length than in width and becomes ovoid. By the end of 12 weeks, the enlarged uterus extends out of the pelvis. With this, it contacts the anterior abdominal wall, displaces the intestines laterally and superiorly, and ultimately reaches almost to the liver. With uterine ascent, it usually rotates to the right, and this dextrorotation likely is caused by the rectosigmoid on the left side of the pelvis. As the uterus rises, tension is exerted on the broad and round ligaments.

With the pregnant woman standing, the longitudinal axis of the uterus corresponds to an extension of the pelvic inlet axis. The abdominal wall supports the uterus and maintains this axis, unless the wall is lax. When the pregnant woman lies supine, the uterus falls back to rest on the vertebral column and the adjacent great vessels.

Beginning in early pregnancy, the uterus contracts irregularly, and these may be perceived as mild cramps. During the second trimester, these contractions can be detected by bimanual examination. In 1872, J. Braxton Hicks first brought attention to these contractions, which now bear his name. hese appear unpredictably and sporadically and are usually nonrhythmic. Their intensity varies between 5 and 25 mm Hg (Alvarez, 1950). Until near term, these Braxton Hicks contractions are infrequent, but their number rises during the last week or two. At this time, the uterus may contract as often as every 10 to 20 minutes and with some degree of rhythmicity. Correspondingly, uterine electrical activity is low and uncoordinated early in gestation, but becomes progressively more intense and synchronized by term (Garield, 2005; Rabotti, 2015). This synchrony develops twice as fast in multiparas compared with nulliparas (Govindan, 2015). Late in pregnancy, these contractions may cause some discomfort and account for so-called false labor.

The delivery of most substances essential for fetal and placental growth, metabolism, and waste removal requires the placental intervillous space to be adequately perfused (Chap. 5, p. 94). Placental perfusion depends on total uterine blood low, but simultaneous measurement of uterine, ovarian, and collateral vessels is not yet possible, even using magnetic resonance (MR) angiography (Pates, 2010). Using ultrasound to study the uterine arteries, uteroplacental blood low has been measured to increase progressively during pregnancy-from approximately 450 mUmin in the mid trimester to nearly 500 to 750 mU min at 36 weeks (Flo, 2014; Wilson, 2007). hese measures are similar to uterine artery blood flow estimates ascertained indirectly using clearance rates of androstenedione and xenon-133 (Edman, 1981; Kauppila, 1980). These values also mirror older ones-500 to 750 mUmin-obtained with invasive methods (Assali, 1953; Browne, 1953; Metcalfe, 1955). Logically, such massively increased uteroplacental blood flow requires adaptation of the uterine veins as well. The resultant increased venous caliber and distensibility can result in uterine vein varices that in rare instances may rupture (Lim, 2014).

As noted irst from animal studies, uterine contractions, either spontaneous or induced, lower uterine blood flow proportionally to contraction intensity (Assali, 1968). A tetanic contraction yields a precipitous fall in uterine blood flow. In humans, three-dimensional power Doppler angiography has also demonstrated reduced uterine blood low during contractions Gones, 2009). Using a similar technique, resistance to blood low in both maternal and fetal vessels was found to be greater during the second stage of labor compared with the first (Baron, 2015). Given that baseline uterine blood low is diminished in pregnancies complicated by fetal-growth restriction, these fetuses may tolerate spontaneous labor less efectively (Ferrazzi, 2011; Simeone, 2017).

The vessels that supply the uterine corpus widen and elongate yet preserve their contractile function (Mandala, 2012). In contrast, the spiral arteries, which directly supply the placenta, vasodilate but completely lose contractility. This presumably results from endovascular trophoblast invasion that destroys the intramural muscular elements (Chap. 5, p. 91). It is this vasodilation that allows maternal-placental blood low to progressively rise during gestation. Given that blood flow increases proportionally to the fourth power of the radius of the vessel, small increases in vessel diameter result in tremendous augmentation of uterine artery blood low. For example, in one study, the uterine artery diameter grew from only 3.3 mm to 3.7 mm between 22 and 29 weeks' gestation, but mean velocity increased 50 percent, from 29 to 43 cm/sec (Flo, 2010).

The downstream fall in vascular resistance is another key factor that accelerates low velocity and shear stress in upstream vessels. In turn, shear stress leads to circumferential vessel growth. Nitric oxide-a potent vasodilator-appears to play a central role in regulating this process and is discussed later (p. 63). Indeed, endothelial shear stress and several hormones and growth facrors all augment endorhelial nitric oxide synthase (eNOS) and nitric oxide producrion (Crummer, 2009; Lim, 2015; Mandala, 2012; Pang, 2015). Facrors include estrogen, progesterone, activin, placental growth facror (PIG F), and vas cular endorhelial growrh factor (VEGF), which is a promoter of angiogenesis. As an impo((am aside, VEGF and PIGF signaling is attenuated in response to excess placenral secretion of their soluble recepror-soluble FMS-like yrosille kinase I (sFlt-I). An ing PIGF and VEGF concentrations and is importanr in pre eclampsia parhogenesis (Chap. 40, p. 716).

Normal pregnancy is also characterized by vascular refrac mriness CO the pressor efects of infused angiotensin II, and rhis raises ureropiacenral blood Aow (Rosenfeld, 1981,e2012).

relaxin and certain adipocyrokines (Vodsrrcil, 201e2). Chemeri1 is an adipocycokine secreted by several rissues, including the placenra (Garces, 2013; Kasher-Meron, 2014). Irs concentra tion rises as gestadon advances and serves ro increase human umbilical eNOS activity, which mediates greater blood Aow (Wang, 2015). Anorher adipocyrokine-viotil-raises VEGF cells derived from the placemal amnion (Astern, 2013). Orher adipocyrokines include lepfin, resistin, and 1diponectin, which (Pole', 2014).

Last, cenain micro RNA species mediate vascular remodeling and uterine blood low early in placentation (Sama, 2015). In particular, members of the miR-1e7-92 clusrer and miR-34 are important in spiral artery remodeling and invasion. Abnormalities of micro-RNA function have been reported in preeclampsia, fetal-growth rescriction, and gestational diaberes.

As early as 1 momh after conception, the cervix begins to soften and gain bluish mnes. These result from increased vascularity and edema of the entire cervix, from changes in the collagen necwork, and from hypertrophy and hyperplasia of the cervical glands (Peralra, 2015; Srraach, 2005). Alrhough rhe cervix contains a small amollnt of smooth muscle, its major componenr is connective (issue. Rearrangemem of rhis collagen-rich tissue aids rhe cervix in retention of the pregnancy until term, in dilatation to aid delivery, and in posrpartum repair and reconstitution ro permir a subsequenr successful pregnancy (Myers, 2015). As derailed in Chapter 21 (p. 409), cervical ripening involves connective tissue remodeling (har lowers collagen and proreoglycan concentrations and raises warer comenr compared wirh rhe nonpregnanr cervix.

Cervical glands undergo marked proliferation, and by the end of pregnancy, they occupy up to one half of the entire cervical mass. This normal pregnancy-induced change promprs an extension, or eversion, of (he proliferating columnar endocervical glands onto the ecrocervical portio (rig. 4-1). This tissue appears red and velvety and bleeds even with minor trauma, such as with Pap tesring.

FIGURE 4-1 Cervical eversion of pregnancy as viewed through a colposcope. The eversion represents columnar epithelium on the portio of the cervix. (Used with permission from Dr. Claudia Werner.)

The endocervical mucosal cells produce copious amounts of tenacious mucus thar obstruct the cervical canal soon after conception (Bastholm, 2017). This mucus is rich in immunoglobulins and cytokines and may acr as an immunological barrier to prorec( the uterine conrents against infection (Hansen, 2014; Wang, 2014). Ar labor onser, if not before, this mucus plug is expelled, resulting in a bloody show. Moreover, the cervical mucus consistency changes during pregnancy. Speciically, in most pregnant women, as a result of progesterone, when cervical mucus is spread and dried on a glass slide, it shows poor crysrallization, termed beading. In some gravidas, as a resulr of amnionic Auid leakage. an arborization of ice-like crystals, calledening, is seen microscopically.

HistOlogically, basal cells near rhe squamocolumnar junction can be prominenr in size, shape, and staining quality in pregnancy. 111ese changes are considered ro be estrogen induced. In addition, pregnancy is associated with bO[h endoccrvical gland hyperplasia and hypersecretory appearance-the Arias-Stela raction-which can make diferenriating these from truly atypical glandular cells during Pap test evaluarion particularly diiculr (Rosai, 2015).

Ovularion ceases during pregnancy, and maturation of new follicles is suspended. The single corpus luteum found in graVidas functions maximally during the irst 6 to 7 weeks of pregnancy--4 ro 5 weeks postovulation. Thereafter, ir contributes relarively linie to progesrcrone production. Surgical removal of the corpus luteum before 7 weeks prompts a rapid fall in matenal serum progesrerone levels and spontaneous abortion (Csapo, 1973). Afrer this time, however, corpus lureum excision ordinarily does nO[ cause abortion.

An extrauterine decidual reaction on and jusr beneath the ovarian surface is common in pregnancy and is usually observed ar cesarean delivery. 1l1ese slighdy elevated clear or red patches bleed easily and may, on irst glance, resemble freshly torn adhesions. Similar decidual reactions arc seen on the uterine serosa and other pelvic, or even extrapelvic, abdominal organs (Bloom. 2010). These areas arise from subcoelomic mesenchyme or eniomcrcioric lesions that have been stimulated by progesterone. They histologically appear similar to progestin-stimulated intrauterine endometrial stroma (Kim. 2015).

The enormous caliber of the ovarian veins viewed at cesarean delivery is starding. Hodgkinson (1953) found that the diametcr of the ovarian vascular pedicle increased during pregnancy from 0.9 em to approximately 2.6 em at term. Again, recall that Aow in a tubular structure increases exponentially as the diameter enlarges.

This protein hormone is secreted by the corpus lureum, the decidua. and the placenta in a pattern similar to that of human chorionic gonadotropin (hCG) (Chap. 5. p. 102). Relaxin is also expressed in brain, hean, and kidney. Ie is mentioned here because its secretion by the corpus lureum appears to aid many maternal physiological adaptations, such as remodeling of reproductive-tract connective tissue to accommodate labor (Conrad. 2013; Vrachnis. 2015). Relaxin also appears importam in initiating augmented renal hemodynamics, lowering serum osmolality, and increasing arterial compliance, which are all associated with normal pregnancy (Conrad. 2014a). Despite its name, serum relaxin levels do nOt contribute to greater peripheral joint laxity or pelvic girdle pain during pregnancy (Aldabe. 2012; Marnach. 2003; V0l1estad. 2012).

These benign ovarian lesions reAect exaggerated physiological follicle stimulation, which is termed hyperreactio luteinalis. These usually bilateral cystic ovaries are moderately to massively enlarged. The reaction is usually linked to markedly elevated serum heG levels. Logically, theca-Iurein CYStS are found frequenrlywith gestational trophoblastic disease (Fig. 20-3. p. 391). They also can develop with the placentomegaly that can accompany diabetes, anti-D alloimmunization, and multi fetal gestation (Malinowski, 2015). Hyperreactio luteinalis is associated with preeclampsia and hyperthyroidism, which may contribure to elevated risks for fetal-growth restriction and preterm birth (Cavorerro. 2014; Lynn. 2013; Mlinowski. 2015). hese cystS also are encountered in women with otherwise uncomplicated pregnancies. In these cases, an exaggerated response of the ovaries to normal levels of circulating heG is suspected (Sarmento Gon,alves. 2015).

Although usually asymptomatic, hemorrhage into the CYStS can cause acme abdominal pain (Amoah. 2011). Maternal virilization may be seen in up to 30 percent of women, however, virilization of the fetus has only rarely been reported (Malinowski. 2015). Maternal indings that include temporal balding, hirsutism, and clitoromegaly are associated with massively elevated levels of androstenedione and testosterone. The diagnosis typically is based on sonographic findings of bilateral enlarged ovaries containing multiple cysts in the appropriate clinical settings. The condition is self-limited and resolves following delivery. Its management is reviewed by Malinowski (2015) and discussed further in Chapter 63 (p. 1199).

The fallopian rube musculature, rhat is, the myosalpinx, undergoes little hypertrophy during pregnancy. The epithelium of the mdosnpinxsomwhat Ranens. Decidual cells may develop in rhe stroma of the endosalpinx, but a continuous decidual membrane is not formed.

Rarely, a fallopian tube may twisr during uterine enlarge� mem (Macedo, 2017). This torsion is more common with comorbid pararubal or ovarian cysts (Lee, 2015).

During pregnancy, greater vascularity and hyperemia develop in the skin and muscles of the perineum and vulva, and the underlying abundant connective tissue softens. This augmented vascularity prominently afects the vagina and cervix and results in the violet color characreristic of Chadwick sign.

Within the vagina, the considerably elevated volume of cervical secretions during pregnancy forms a somewhat thick, white discharge. The pH is acidic, varying from 3.5 to 6. This pH results from increased production of lactic acid by lactobacillus acidophi/us during metabolism of glycogen energy stores in the vaginal epithelium. Pregnancy is associated with an elevated risk of vulvovaginal candidiasis. particularly during the second and third trimesters. Higher infection rates may stem from immunological and hormonal changes and from greater vaginl glycogen stores (Aguin. 2015).

The vaginal walls undergo striking changes in preparation for the distention that accompanies labor and delivery. These alterations include considerable epithelial thickening, connective tissue loosening, and smooth muscle cell hypertrophy.

Pelvic Organ Prolapse Quantiication (POP-Q) and threedimensional sonography studies show that vaginal suppOrt changes across pregnancy. In particular, vaginal lengthening, posterior vaginal wall and hiatal relaxation, increased levaror hiaral area, and greater irst-trimester vaginal elastase activity are all associated with uncomplicated spontaneous vaginal delivery (Oliphant. 2014). The larger hiatal area persists in women who deliver vaginally compared with women delivering by prelabor or early-labor cesarean delivery. However. all women show greater hiatal distensibility after delivery, which is potentially a facror in later pelvic floor dysfunction (van Veelen, 2015).

In women with apical vaginal prolapse. the cervix, and occasionally a portion of the uterine body, can protrude variably from the vulva during early pregnancy. With further growth. the uterus usually rises above the pelvis and can draw the cervix up with it. If the uterus persists in its prolapsed position, symptoms of incarceration may develop at 10 to 14 weeks' gestation (Chap. 3, p. 46). s a preventive measure. [he urerus can be replaced early in pregnancy and held in position with a suitable pessary.

Attenuation of anterior vaginal wall suppOrt can lead to prolapse of the bladder, that is, a cystocele. Urinary stasis with a cystocele predisposes to infection. Pregnancy may also worsen coexistent stress urinary incontinmce (SUi), likely because urerhral closing pressures do nor risc suiciently to compensate for altered bladder neck support. Urinary incontinence afects nearly 20 percent of women during the first trimester and nearly 40 percent during the third trimester. Most cases stem from SUI rather than urgency urinary incontinence (Abdullah, 2016a; Franco, 2014; Iosif, 1980). In primigravidas, maternal age greater than 30 years, obesity, smoking, constipation, and gestational diabetes mellitus are all risk factors associated with SUI development during pregnancy (Sangsawang, 2014).

Attenuation of posterior vaginal wall support can result in a rectocele. A large defect may fill with feces that occasionally can be evacuated only digitally. During labor, a cystocele or rectocele can block fetal descent unless they are emptied and pushed out of the way. Rarely, an enterocele of considerable size may bulge into the vagina. If the mass interferes with delivery, the hernia sac and its abdominal contents are gently reduced to permit fetal descent.

In early pregnancy, women often experience breast tenderness and paresthesias. Mter the second month, the breasts grow in size, and delicate veins are visible just beneath the skin. he nipples become considerably larger, more deeply pigmented, and more erectile. Mter the first few months, a thick, yellowish luid-colosrum-can often be expressed from the nipples by gentle massage. During the same months, the areolae become broader and more deeply pigmented. Scattered through each areola are several small elevations, the glands of Montgomey, which are hypertrophic sebaceous glands. If breasts gain extensive size, skin striae similar to those observed in the abdomen may develop. Rarely, breasts can become pathologically enlarged-referred to as gigantomastia-which may require postpartum surgical reduction (Fig. 4-2) (Eler Dos Reis, 2014; Rezai,i2015).

For most normal pregnancies, prepregnancy breast size and ultimate volume of breast milk do not correlate, as multiple factors influence milk production (Hartmann, 2007). These

FIGURE 4-2 Gigantomastia in a woman near term. (Used with permission from Dr. Patricia Santiago-Munoz.) factors and gestation breast changes are further discussed in Chapter 36 (p. 656).

Skin changes are common, and Fernandes and Amaral (2015) described dermatological changes in more than 900 pregnant women. They found at least one physiological cutaneous change in 89 percent of the women examined. Dermatologic pathologies during pregnancy are found in Chapter 62.

Beginning after midpregnancy, reddish, slightly depressed streaks commonly develop in the abdominal skin and some times in the skin over the breasts and thighs. These are called striae gravidarum or stretch marks. In multiparas, glistening, silvery lines that represent the cicatrices of previous striae fre quently coexist. In one study of 800 primiparas, 70 percent their breasts; and 41 percent on their hips and thighs (Picard, 2015). The strongest associated risk factors included younger maternal age, family history, and prepregnancy weight and weight gain during pregnancy. The etiology of striae gravi darum is unknown, and there are no preventive steps or defini tive treatments (Korgavkar, 2015).

Occasionally, the muscles of the abdominal walls do not withstand the tension of the expanding pregnancy. As a result, rectus muscles separate in the midline, creating diastasis recti of varying extent. If severe, a considerable portion of the anterior uterine wall is covered by only a layer of skin, attenuated fascia, and peritoneum to form a ventral hernia.

This develops in up to 90 percent of women and is usually more accentuated in those with darker complexion (Ikino, 2015). Of speciic sites, the pigmented skin line in the midline of the anterior abdominal wall-the linea alba-takes on dark brownblack pigmentation to form the linea nigra. Occasionally, irregular brownish patches of varying size appear on the face and neck, giving rise to chloasma or melasma gravidarum-the mask of pregnancy. Pigmentation of the areolae and genital skin may also be accentuated. Mter delivery, these pigmentary changes usually disappear or at least regress considerably. Oral contraceptives may cause similar alterations (Handel, 2014).

he etiology of these pigmentary changes is incompletely understood, however, hormonal and genetic factors play a role. For example, levels of melanocyte-stimulating hormone, a polypeptide similar to corticotropin, are elevated remarkably throughout pregnancy, and estrogen and progesterone also are reported to have melanocyte-stimulating efects .

Angiomas, called vascular spiders, are particularly common on the face, neck, upper chest, and arms. These are minute, red skin papules with radicles branching out from a central lesion. he condition is often designated as nevus, angioma,

TABLE 4-1. Additional Energy Demands During Normal Pregnancya

Rates of Tissue Deposition

Energy Cost of Pregnancy Estimated from Basal Metabolic Rate and Energy Deposition aAssumes an average gestational weight gain of 12 kg.

bEfficiency of food energy utilization for protein and fat deposition estimated as 0.90. Adapted from the World Health Organization, 2004.

or telangiectasis. Palmar eythema is encountered during pregnancy. Both conditions lack clinical significance and disappear in most gravidas shortly after pregnancy. hey are likely the consequence ofhyperestrogenemia. In addition to these discrete lesions, increased cutaneous blood flow in pregnancy serves to dissipate excess heat generated by the augmented metabolism.

hroughout life, the human hair follicle undergoes a pattern of cyclic activity that includes periods of hair growth (anagen phase), apoptosis-driven involution (catagen phase), and a resting period (telogen phase). Based on a study of 116 healthy pregnant women, the anagen phase lengthens during pregnancy and the telogen rate increases postpartum (Gizlenti, 2014). Neither is exaggerated in most gravidas, but excessive hair loss in the puerperium is termed telogen fluvium.

In response to the greater demands of the rapidly growing fetus and placenta, the pregnant woman undergoes metabolic changes that are numerous and intense. By the third trimester, maternal basal metabolic rate rises by 20 percent compared with that of the nonpregnant state (Berggren, 2015). This rate grows by an additional 10 percent in women with a twin gestation (Shinagawa, 2005). Viewed another way, the additional total pregnancy energy demand associated with normal pregnancy approximates kcal (World Health Organization, 2004). This is stratified as 85, 285, and 475 kcal/d during the irst, second, and third trimester, respectively (Table 4-1). Of note, Abeysekera and coworkers (2016) reported that women accrue fat mass during pregnancy despite the increased total energy expenditure and without signiicant change in energy intake. This suggests more eicient energy storage.

Most of the normal weight gain in pregnancy is attributable to the uterus and its contents, the breasts, and expanded blood and extravascular extracellular fluid volumes. A smaller fraction results from metabolic alterations that promote accumulation of cellular water, fat, and protein, which are so-called maternal reserves. The average weight gain during pregnancy approximates 12.5 kg or 27.5 Ib, and this value has remained consistent across studies and over time (Hytten, 1991; Jebeile, 2016). Weight gain is considered in urther detail in Table 4-2 and in Chapter 9 (p. 165).

In pregnancy, greater water retention is normal and mediated in part by a drop in plasma osmolality of 10 mOsm/kg. This decline develops in early pregnancy and is induced by a reset of osmotic thresholds for thirst and vasopressin secretion (Fig. 4-3)

TABLE 4-2. Weight Gain Based on Pregnancy-Related Components

Total 650 4000 8500 12,500

Modified from Hytten, 1991l.

Weeks of pregnancy

FIGURE 4-3 Mean values (black line) ± standard deviations (blue lines) for plasma osmolality (Posm) measured at weekly intervals in nine women from preconception to 16 weeks. LMP = last menstrual period; MP = menstrual period. (Redrawn with permission from Davison JM, Dunlop W: Renal hemodynamics and tubular function in normal human pregnancy. Kidney Int 18:1o52, 1980.) (Davison, 1981; Lindheimer, 2001). Relaxin and other hormones are thought to playia role (Conrad, 2013).

At term, the water content of the fetus, placenta, and amnionic luid approximates 3.5 L. Another 3.0 L accumulates from expanded maternal blood volume and from uterus and breast growth. Thus, the minimum amount of extra water that the average woman accrues during normal pregnancy approximates 6.5 L. This corresponds to 14.3 lb.

Clearly demonstrable pitting edema of the ankles and legs is seen in most pregnant women, especially at the end of the day. This fluid accumulation, which may amount to a liter or so, results from greater venous pressure below the level of the uterus as a consequence of partial vena cava occlusion. A decline in interstitial colloid osmotic pressure induced by normal pregnancy also favors edema late in pregnancy (0ian, 1985).

Longitudinal studies of body composition show a progressive accumulation of total body water and fat mass during pregnancy. These two components as well as initial maternal weight and weight gained during pregnancy are highly associated with neonatal birthweight (Lederman, 1999; MardonesSantander, 1998). "Over-nourished" women are more likely to deliver oversized neonates, even when glucose tolerant (Di Benedetto, 2012).

The products of conception, the uterus, and maternal blood are relatively rich in protein rather than fat or carbohydrate. At term, the normally grown fetus and placenta together weigh about 4 kg and contain approximately 500 g of protein, or about half of the total pregnancy increase. The remaining 500 g is added to the uterus as contractile protein, to the breasts primarily in the glands, and to maternal blood as hemoglobin and plasma proteins.

Amino acid concentrations are higher in the fetal than in the maternal compartment and generally result from facilitated transport across the placenta (Cleal, 2011; Panitchob, 2015). This greater concentration is largely regulated by the placenta through an incompletely understood process. In particular, placental transport is variable for individuals and for diferent amino acids. For example, tyrosine is a conditionally essential amino acid in the preterm neonate but not in the fetus (Van den Akker, 2010, 2011). The placenta concentrates amino acids into the fetal circulation and is also involved in protein synthesis, oxidation, and transamination of some nonessential amino acids (Galan, 2009).

Maternal protein intake does not appear to be a critical determinant for birthweight among well-nourished women (Chong, 2015). Still, recent data suggest that current recommendations for protein intake may be too low. These guidelines are extrapolated from nonpregnant adults and may underestimate actual needs. Stephens and colleagues (2015) prospectively analyzed maternal protein intake and metabolism. They estimated average requirements of 1.22 g/kg/d of protein for early pregnancy and 1.52 g/kg/d for late pregnancy. These levels are higher than the current recommendation of 0.88 g/kg/d. The daily requirements for dietary protein intake during pregnancy are discussed in Chapter 9 (p. 167).

Normal pregnancy is characterized by mild fasting hypoglycemia, postprandial hyperglycemia, and hyperinsulinemia (Fig. 4-4). his elevated basal level of plasma insulin in normal 1 PM 6 PM 12 M SAM MEALS: SAM t t t

FIGURE 4-4 Diurnal changes in plasma glucose and insulin in normal late pregnancy. (Redrawn from Phelps, 1981o.) pregnancy is associated with several unique responses to glucose ingestion. Speciically, after an oral glucose meal, gravidas demonstrate prolonged hyperglycemia and hyperinsulinemia and a greater suppression of glucagon (Phelps, 1981). This cannot be explained by an increased metabolism of insulin because its half-life during pregnancy is not changed appreciably (Lind, 1977). Instead, this response relects a pregnancy-induced state of peripheral insulin resistance, which ensures a sustained postprandial supply of glucose to the fetus. Indeed, insulin sensitivity in late normal pregnancy is 30 to 70 percent lower than that of nonpregnant women (Lowe, 2014).

The mechanisms responsible for this reduced insulin sensitivity include numerous endocrine and inlammatory factors (Angueira, 2015). In particular, pregnancy-related hormones such as progesterone, placentally derived growth hormone, prolactin, and cortisol; cytokines such as tumor necrosis factor; and hormones derived from central adiposity, particularly leptin and its interplay with prolactin, all have a role in the insulin resistance of pregnancy. Even so, insulin resistance is not the only factor to elevate postprandial glucose values. Hepatic gluconeogenesis is augmented during both diabetic and nondiabetic pregnancies, particularly in the third trimester (Angueira, 2015).

Overnight, the pregnant woman changes from a postprandial state characterized by elevated and sustained glucose levels to a fasting state characterized by decreased plasma glucose and some amino acids. Plasma concentrations of free fatty acids, triglycerides, and cholesterol are also higher in the fasting state. his pregnancy-induced switch in fuels from glucose to lipids has been called accelerated starvation. Certainly, when fasting is prolonged in the pregnant woman, these alterations are exaggerated and ketonemia rapidly appears.

he concentrations of lipids, lipoproteins, and apolipoproteins in plasma rise appreciably during pregnancy (Appendix, p. 1259). Increased insulin resistance and estrogen stimulation during pregnancy are responsible for the maternal hyperlipidemia. Augmented lipid synthesis and food intake contribute to maternal fat accumulation during the first two trimesters (Herrera, 2014). In the third trimester, however, fat storage declines or ceases. his is a consequence of enhanced lipolytic activity, and decreased lipoprotein lipase activity reduces circulating triglyceride uptake into adipose tissue. his transition to a catabolic state favors maternal use oflipids as an energy source and spares glucose and amino acids for the fetus.

Maternal hyperlipidemia is one of the most consistent and striking changes of lipid metabolism during late pregnancy. Triacylglycerol and cholesterol levels in very-low-density lipoproteins (VLDLs), low-density lipoproteins (LDLs), and highdensity lipoproteins (HDLs) are increased during the third trimester compared with those in nonpregnant women. During the third trimester, the average level of total serum cholesterol is 267 ± 30 mg/dL, ofLDL-C is 136 ± 33 mg/dL, ofHDL-C is 81 ± 17 mg/dL, and of triglycerides is 245 ± 73 mg/dL (Lippi, 2007). After delivery, the concentrations of these lipids, lipoproteins, and apolipoproteins decline. Breastfeeding drops maternal triglyceride levels but increases those of HDL-C. The efects of breastfeeding on total cholesterol and LDL-C levels are unclear (Gunderson, 2014).

Hyperlipidemia is theoretically a concern because it is associated with endothelial dysfunction. From studies, however, endothelium-dependent vasodilation responses actually improve across pregnancy (Saarelainen, 2006). Ihis is partly because increased HDL-C concentrations likely inhibit LDL oxidation and thus protect the endothelium. hese indings suggest that the increased cardiovascular disease risk in multiparas may be related to factors other than maternal hypercholesterolemia.

This peptide hormone is primarily secreted by adipose tissue in nonpregnant humans. It plays a key role in body fat and energy expenditure regulation and in reproduction. For example, leptin is important for implantation, cell proliferation, and angiogenesis (Vazquez, 2015). Leptin deiciency is associated with anovulation and infertility, whereas certain leptin mutations cause extreme obesity (Tsai, 2015).

Among normal-weight pregnant women, serum leptin levels rise and peak during the second trimester and plateau until term in concentrations two to four times higher than those in nonpregnant women. Among obese women, leptin levels correlate with adiposity (Ozias, 2015; Tsai, 2015). In all cases, leptin levels fall after delivery, relecting the significant amounts produced by the placenta (Vazquez, 2015).

Leptin participates in regulating energy metabolism during pregnancy. Interestingly, despite the rise in leptin concentrations during pregnancy, reduced leptin sensitivity to food intake during pregnancy has been described (Chehab, 2014; Vazquez, 2015). This "leptin resistance" may serve to promote energy storage during pregnancy and for later lactation.

Higher leptin levels during pregnancy may be disadvantageous under certain situations, such as in maternal obesity. Leptin functions as a proinflammatory cytokine in white adipose tissue, which may dysregulate the inlammatory cascade and lead to placental dysfunction in obese women (Vazquez, 2015). In addition, abnormally elevated leptin levels have been associated with preeclampsia and gestational diabetes (Bao, 2015; Taylor, 2015).

Fetal leptin is important for the development of several organs that include the pancreas, kidney, heart, and brain. Fetal levels correlate with maternal body mass index (BMI) and birthweight. Lower levels are linked to fetal-growth restriction (Brifa, 2015; Tsai, 2015).

Dozens of hormones with metabolic and/or inflammatory functions are produced by adipose tissue. Adiponectin is a peptide produced primarily in maternal fat but not in the placenta (Haghiac, 2014). Adiponectin levels inversely correlate with adiposity, and it acts as a potent insulin sensitizer. Despite reduced adiponectin levels in women with gestational diabetes, directed assays are not useful for predicting diabetes development (Hauguel-de Mouzon, 2013).

Ghrelin is a peptide secreted principally by the stomach in response to hunger. It cooperates with other neuroendocrine factors, such as leptin, in energy homeostasis modulation.

Ghrelin is also expressed in the placenta and likely has a role in fetal growth and cell proliferation (Gonzalez-Dominguez, 2016). Angelidis and associates (2012) have reviewed the many functions of ghrelin in the regulation of reproductive function.

Viatin is a peptide that was first identified as a growth fac tor for B lymphocytes, but it is mainly produced within adipose tissue. Mumtaz and colleagues (2015) propose that elevated levels of visfatin and leptin impair uterine contractility. Such findings may provide a physiological basis for the observation that maternal obesity raises the risk for dysfunctional labor.

During normal pregnancy, nearly 1000 mEq of sodium and 300 mEq of potassium are retained (Lindheimer, 1987). Although the glomerular filtration rate of sodium and potassium is increased, the excretion of these electrolytes is unchanged during pregnancy as a result of enhanced tubular resorption (Brown, 1986, 1988). Although total accumulations of sodium and potassium are elevated, their serum concentrations are diminished slightly (Appendix, p. 1257). Several mechanisms may explain these lower levels (Odutayo, 2012). In the case of potassium, it possibly involves the expanded plasma volume of pregnancy. With respect to sodium, osmoregulation is altered and the threshold for arginine vasopressin release is lowered. his promotes free water retention and diminished sodium levels.

Total serum calcium levels, which include both ionized and nonionized calcium, decrease during pregnancy. his reduction consequent decline in the amount of circulating protein-bound nonionized calcium. Serum ionized calcium levels, however, remain unchanged (Olausson, 2012).

he developing fetus imposes a significant demand on maternal calcium homeostasis. For example, the fetal skeleton accretes approximately 30 g of calcium by term, 80 percent of which is deposited during the third trimester. his demand is largely met by a doubling of maternal intestinal calcium absorption mediated partly by 1,25-dihydroxyvitamin D3• hese higher levels of vitamin D are possibly stimulated by a twofold rise in PTH-related peptide levels produced by several tissues including the placenta (Kovacs, 2006; Olausson, 2012). To help compensate, dietary intake of suicient calcium is necessary to prevent excess depletion from the mother. A list of all recommended daily allowances is found in Table 9-5 (p. 167). his is especially important for pregnant adolescents, in whom bones are still developing. Unfortunately, a lack of robust data prevents drawing firm conclusions regarding the utility of calcium and vitamin D supplements during pregnancy (De-Regil, 2016).

Serum manesium levels also decline during pregnancy. Bardicef and colleagues (1995) concluded that pregnancy is actually a state of extracellular magnesium depletion. Compared with nonpregnant women, both total and ionized magnesium concentrations are significantly lower during normal pregnancy (Rylander, 2014).

Serum phosphate levels lie within the nonpregnant range (Larsson, 2008). Although calcitonin is an important regulator of serum calcium and phosphate, the importance of calcitonin as it relates to pregnancy is poorly understood (Olausson, 2012).

Iodine requirements increase during normal pregnancy for several reasons (Moleti, 2014; Zimmermann, 2012). First, maternal thyroxine production rises to maintain maternal euthyroidism and to transfer thyroid hormone to the fetus prior to fetal thyroid functioning. Second, fetal thyroid hormone production increases during the second half of pregnancy. This contributes to greater maternal iodine requirements because iodide readily crosses the placenta. hird, the primary route of iodine excretion is through the kidney. Beginning in early pregnancy, the iodide glomerular iltration rate increases by 30 to 50 percent. In sum, because of greater thyroid hormone production, fetal iodine requirements, and augmented renal clearance, dietary iodine needs are higher during normal gestation. lthough the placenta has the ability to store iodine, whether this organ functions to protect the fetus from inadequate maternal dietary iodine is currently unknown (Burns, 2011). Iodine deiciency is discussed later in this chapter (p. 71) and in Chapter 58 (p. 1126). At the other extreme, maternal supplements containing excessive iodine have been associated with congenital hypothyroidism. his stems from autoregulation in the thyroid gland-known as the Wof-Chaikof fect-to curb thyroxine production in response to iodide overconsumption (Connelly, 2012).

With respect to most other minerals, pregnancy induces little change in their metabolism other than their retention in amounts equivalent to those needed for growth. An important exception is the considerably greater requirement for iron, which is discussed subsequently.

he well-known hypervolemia associated with normal pregnancy averages 40 to 45 percent above the nonpregnant blood volume after 32 to 34 weeks' gestation (Pritchard, 1965; Zeeman, 2009). In individual women, expansion varies considerably. In some, accumulated volume rises only modestly, whereas in others blood volume nearly doubles. A fetus is not essential, as augmented blood volume develops in some with hydatidiform mole.

Pregnancy-induced hypervolemia serves several functions.

First, it meets the metabolic demands of the enlarged uterus and its greatly hypertrophied vascular system. Second, it provides abundant nutrients and elements to support the rapidly growing placenta and fetus. Third, the expanded intravascular volume protects the mother, and in turn the fetus, against the deleterious efects of impaired venous return in the supine and erect positions. Last, it safeguards the mother against the adverse efects of parturition-associated blood loss.

Maternal blood volume begins to accrue during the irst trimester. By 12 menstrual weeks, plasma volume expands by approximately 15 percent compared with that prior to pregnancy (Bernstein, 2001). Maternal blood volume grows most rapidly during the midtrimester, rises at a much slower rate during the third trimester, and reaches a plateau during the last 6.5 � 6.0 ! 5.5 5.0 4.0 3.5 • Twin pregnancy• Singleton pregnancy 3.0 7 -6 -ls 5E 4)E) 3�'5r� 2:� Menses First Second Third Postpartum

FIGURE 4-6 Estimated daily iron requirements during pregnancy in a 55-kg woman. (Modified from Koenig, 2014.) (n 10) and singletons (n 40). Data shown as medians. (Data from Thomsen, 1994.) several weeks of pregnancy (Fig. 4-5). Blood volume accrues even more dramatically in twin gestations. During blood volume expansion, plasma volume and erythrocyte number rise. Although more plasma than erythrocytes is usually added to the maternal circulation, the increase in erythrocyte volume is considerable and averages 450 mL (Pritchard, 1960). Moderate erythroid hyperplasia develops in the bone marrow, and the reticulocyte count is elevated slightly during normal pregnancy. These changes are almost certainly related to an elevated maternal plasma erythropoietin level.

Because ofgreat plasma augmentation, both hemoglobin concentration and hematocrit decline slightly during pregnancy (Appendix, p. 1255).s aresult, whole bloodviscositydecreases (Huisman, 1987). Hemoglobin concentration at term averages 12.5 g/dL, and in approximately 5 percent ofwomen it is below 11.0 g/dL. Thus, a hemoglobin concentration below 11.0 g/dL, especially late in pregnancy, is considered abnormal and usually due to irondeficiency anemia rather than pregnancy hypervolemia.

The total iron content of normal adult women ranges from 2.0 to 2.5 g, or approximately half that found normally in men. Most of this is incorporated in hemoglobin or myoglobin, and thus, iron stores of normal young women only approximate 300 mg (Pritchard, 1964). Although the lower iron levels in women may be partly due to menstrual blood loss, other factors have a role, particularly hepcidin-a peptide hormone that functions as a homeostatic regulator of systemic iron metabolism. Hepcidin levels rise with inlammation, but drop with iron deficiency and several hormones, including testosterone, estrogen, vitamin D, and possibly prolactin (Uu, 2016; Wang, 2015). Lower hepcidin levels are associated with greater absorption ofiron via ferroportin in enterocytes (Camaschella, 2015).

Of the approximate 1000 mg ofiron required for normal pregnancy, about 300 mg is actively transferred to the fetus and placenta, and another 200 mg is lost through various normal excretion routes, primarily the gastrointestinal tract. These are obligatory losses and accrue even when the mother is iron deficient. The average increase in the total circulating erythrocyte volume-about 450 mL-requires another 500 mg. Recall that each 1 mL oferythrocytes contains 1.1 mg of iron.

As shown in Figure 4-6, because most iron is used during the latter halfofpregnancy, the iron requirement becomes large after midpregnancy and averages 6 to 7 mg/d (Pritchard, 1970). In most women, this amount is usually not available from iron stores or diet. Thus, without supplemental iron, the optimal rise in maternal erythrocyte volume will not develop, and the hemoglobin concentration and hematocrit will fall appreciably as plasma volume rises. At the same time, fetal red cell production is not impaired because the placenta transfers iron even if the mother has severe iron-deficiency anemia. In severe cases, we have documented maternal hemoglobin values of 3 gldL, and at the same time, fetuses had hemoglobin concentrations of 16 gldL. The mechanisms of placental iron transport and regulation are complex (Koenig, 2014; McArdle, 2014).

Ifthe nonanemic pregnant woman is not given supplemental iron, then serum iron andferritin concentrations decline atermidpregnancy. Importantly, hepcidin levels drop early in pregnancy (Hedengran, 2016; Koenig, 2014). s noted, lower hepcidin levels aid iron transfer into the maternal circulation via ferroportin in enterocytes. Lower hepcidin levels also augment iron transport into the fetus via ferroportin in syncytiotrophoblast.

With normal vaginal delivery, 500 to 600 mL of blood is typically lost, and thus not all the maternal iron added in the form of hemoglobin is spent (Pritchard, 1965). he excess hemoglobin iron becomes stored iron.

Pregnancy is associated with suppression of various humoral and cell-mediated immunological functions (Chap. 5, p. 95). his permits accommodation of the "foreign" semiallogeneic fetal graft that contains antigens of both maternal and paternal origin (Redman, 2014). he tolerance that exists at the maternal-fetal interface remains a great unsolved medical mystery. This tolerance is complex and involves certain immune system adaptations and crosstalk among the maternal microbiome, uterine decidua, and trophoblast. In particular, areas of the uterus that were previously considered sterile are colonized with bacteria. In most cases, these microbes are believed to be commensal and play a tolerizing and protective role. Indeed, commensal organisms may inhibit the proliferation of certain pathogens. Several reviewers have described these relationships (Mor, 2015; Racicot, 2014; Sisti, 2016).

tection at the maternal-fetal interface involves the expression of the trophoblast. Recall that all cells of the body express a "badge" immune responses. For most cells of the body, this "badge" is known as MHC Class Ia. However, it is uncommon for two unrelated individuals to share compatible MHC class Ia. This creates a potential problem for reproduction because half of the fetus is composed of paternally derived antigens. To circumvent this problem, trophoblast cells express a form of MHC that does not vary between individuals. This "nonclassic" MHC is known as human leukocyte antigen class Ib and includes HLA-E, HLA

F, and HLA-G. Recognition of these HLA class Ib proteins by natural killer cells residing within the decidua inhibits their activ ity and promotes immune quiescence (Djurisic, 2014).

Another immune adaptation that promotes tolerances stems from important changes in CD4 T lymphocyte subpopulations in pregnancy. First, Th1-mediated immunity shifts to h2-mediated immunity. Indeed, an important antiinlammatory component of pregnancy involves suppression ofT-helper (Th) 1 and T-cytotoxic (Tc) 1 cells, which lower secretion of interleukin-2 (IL-2), interferon-a, and tumor necrosis factor (TNF). Moreover, suppressed Th1 response is thought to be a requisite for pregnancy continuation. It also may explain pregnancy-related remission of some autoimmune disorders such as rheumatoid arthritis, multiple sclerosis, and Hashimoto thyroiditis-which are cell-mediated immune diseases stimulated by h1 cytokines (Kumru, 2005). With suppression of Th1 cells, there is upregulation of Th2 cells to increase secretion of IL-4, IL-10, and IL-13 (Michimata, 2003). hese h2 cytokines promote humoral, or antibody-based, immunity. hus, autoimmune diseases mediated mainly by autoantibodies, such as systemic lupus erythematosus, may lare if the disease is already active in early pregnancy. But, the transition to an antibody-mediated immunity is an important defense during pregnancy and early puerperium. In cervical mucus, peak levels of immunoglobulins A and G (IgA and IgG) are significantly higher during pregnancy, and the immunoglobulin-rich cervical mucus plug creates a barrier to ascending infection (Hansen, 2014; Wang, 2014). Similarly, IgG is transferred to the developing fetus in the third trimester as a form of passive immunity, ostensibly in anticipation of birth. Further, immunoglobulins secreted into breast milk during lactation augment neonatal defenses against infection.

Other subpopulations of CD4 T lymphocytes serve mucosal and barrier immunity. These specific CD4-positive cells are known as h17 cells and Treg cells. h17 cells are proinflammatory and express the cytokine IL-17 and the retinoic acid receptor-related orphan receptors (RORs). Treg cells express the transcription factor forkhead box protein-3 (FOXP3) and confer tolerizing activity. here is a shift toward Treg CD4 cells in the first trimester, which peaks during the second trimester and falls toward delivery (Figueiredo, 2016). his shift may promote tolerance at the maternal-fetal interface (La Rocca, 2014). In particular, failure of these CD4 T lymphocyte subpopulation alterations may be related to preeclampsia development (Vargas-Rojas, 2016).

nonpregnant values, and upper values approach 15,000/jLL (Appendix, p. 1255). During labor and the early puerpe rium, values may become markedly elevated, attaining levels of 25,000/LL or greater. The cause is unknown, but the same response occurs during and after strenuous exercise. The leuko cytosis possibly represents the reappearance of leukocytes previ ously shunted out of active circulation.

The distribution of lymphocyte cell types is also altered during pregnancy. Speciically, B lymphocytes numbers are unchanged, but the absolute numbers of T lymphocytes rise and create a relative increase. Concurrently, the ratio of CD4 to

CD8 T lymphocytes does not change (Kuhnert, 1998).

Many tests performed to diagnose inlammation cannot be used reliably during pregnancy. For example, leukocyte alkaline phosphatase levels-used to evaluate myeloproliferative disorders-are elevated beginning early in pregnancy. he concentration of C-reactive protein, an acute-phase serum reactant, rises rapidly in response to tissue trauma or inflammation. Median C-reactive protein levels in pregnancy and labor are higher than for nonpregnant women (Anderson, 2013; Watts, 1991). Of nonlaboring gravidas, 95 percent had levels of 1.5 mg/ dL or less, and gestational age did not afect serum levels. Another marker of inlammation, the erythrocyte sedimentation rate (ESR), is increased in normal pregnancy because of elevated plasma globulins and ibrinogen levels. Complement actors C3 and C4 levels also significantly rise during the second and third trimesters (Gallery, 1981; Richani, 2005). Last, concentrations ofprocalcitonin, a normal precursor of calcitonin, increase at the end of the third trimester and through the irst few postpartum days. Procalcitonin levels rise with severe bacterial infections but remain low in viral infections and nonspecific inlammatory disease. However, measured levels poorly predict development of overt or subclinical chorioamnionitis after premature rupture of membranes (Thornburg, 2016).

During normal pregnancy, both coagulation and fibrinolysis are augmented but remain balanced to maintain hemostasis (Kenny, 2014). Evidence of activation includes increased concentrations of all clotting factors except factors I and III (Table 4-3).

Of procoagulants, the level and rate of thrombin generation throughout gestation progressively increase (McLean, 2012). In normal nonpregnant women, plasma ibrinogen (factor 1) averages 300 mg/dL and ranges from 200 to 400 mg/dL. During normal pregnancy, the fibrinogen concentration rises approximately 50 percent. In late pregnancy, it averages 450 mg/dL, with a range from 300 to 600 mg/dL. his contributes greatly to ap <.05.

Data shown as mean ± standard deviation.

PlT = partial thromboplastin time; tPA = tissue activator.

Data from Uchikova, 2005.

the striking increase in the ESR. Also, levels of factor XIIIibrin stabilizing oetor-signiicantly drop as normal pregnancy advances (Sharief, 2014).

The end product of the coagulation cascade is ibrin formation, and the main function of the fibrinolytic system is to remove excess ibrin (Fig. 41-29, p. 784). Tissue plasminogen activator (tP A) converts plasminogen into plasmin, which causes ibrinolysis and produces ibrin-degradation products such as D-dimers. Although somewhat conlicting, most evidence suggests that fibrinolytic activity is reduced in normal pregnancy (Kenny, 2014). As reviewed by Cunningham and Nelson (2015), these changes favor ibrin formation. Although this is countered by increased levels of plasminogen, the net result is that pregnancy is a procoagulant state. Such changes serve to ensure hemostatic control during normal pregnancy, particularly during delivery when a certain amount of blood loss is expected.

Several proteins are natural inhibitors of coagulation, including proteins C and S and antithrombin (Fig. 52-I, p. 1005). Inherited or acquired deficiencies of these and other natural regulatory proteins-collectively referred to as thrombophiliasaccount for many thromboembolic episodes during pregnancy. hey are discussed in Chapter 52 (p. 1006).

Activated protein , along with the cofactors protein Siand factor V, functions as an anticoagulant by neutralizing the procoagulants factor Va and factor VIlla. During pregnancy, resistance to activated protein C grows progressively and is related to a concomitant drop in free protein S levels and greater factor VIII concentrations. Between the irst and third trimesters, activated protein C levels decline from 2.4 to 1.9 V/mL, and free protein S concentrations diminish from 0.4 to 0.16 V/ mL (Cunningham, 2015; Walker, 1997). Antithrombin levels decrease by 13 percent between midpregnancy and term and fall 30 percent from this baseline until 12 hours after delivery. By 72 hours after delivery, there is a return to baseline Games, 2014).

Normal pregnancy promotes platelet changes. In one study, the average platelet count declined slightly during pregnancy to 213,OOO/1L compared with 250,000/1L in nonpregnant controls (Boehlen, 2000). hrombocytopenia deined as below the 2.5th percentile corresponded to a platelet count of 116,OOO/1L. Lower platelet concentrations are partially due to hemodilution. Also, platelet consumption is likely augmented and creates a greater proportion of younger and therefore larger platelets (Han, 2014; Valera, 2010). Further, levels of several markers of platelet activation rise with gestational age but drop postpartum (Robb, 2010). Because of splenic enlargement, there may be an element of "hypersplenism," in which platelets are prematurely destroyed (Kenny, 2014).

By the end of normal pregnancy, the spleen enlarges by up to 50 percent compared with that in the irst trimester (Maymon, 2007). Moreover, Gayer and coworkers (2012) found that splenic size was 68-percent greater compared with that of nonpregnant controls. he cause of this splenomegaly is unknown, but it might follow the increased blood volume and/or the hemodynamic changes of pregnancy.

Changes in cardiac function become apparent during the irst 8 weeks of pregnancy (Hibbard, 2014). Cardiac output is increased as early as the ifth week and reflects a reduced systemic vascular resistance and an increased heart rate. Compared with prepregnancy measurements, brachial systolic blood pressure, diastolic blood pressure, and central systolic blood pressure are all signiicantly lower 6 to 7 weeks from the last menstrual period (Mahendru, 2012). he resting pulse rate rises approximately 10 beats/min during pregnancy. Nelson and associates (2015) found that for both normal and overweight women, heart rate increased signiicantly between 12 and 16 weeks' and between 32 and 36 weeks' gestation. Between weeks 10 and 20, plasma volume expansion begins, and preload rises. his augmented preload results in signiicantly larger left atrial volumes and ejection fractions (Cong, 2015).

Ventricular performance during pregnancy is inluenced by both the decrease in systemic vascular resistance and changes in pulsatile arterial low. Multiple factors contribute to this overall altered hemodynamic function, which allows the physiological demands of the fetus to be met while maintaining maternal cardiovascular integrity (Hibbard, 2014). hese changes during the last half of pregnancy and efects of maternal posture are summarized in Figure 4-7.

As the diaphragm becomes progressively elevated, the heart is displaced to the left and upward and is rotated on its long axis. As a result, the apex is moved somewhat laterally from its usual position and produces a larger cardiac silhouette in chest radiographs. Furthermore, gravidas normally have some degree of benign pericardial efusion, which may enlarge the

FIGURE 4-7 Left ventricular stroke volume across pregnancy compared with 12-week postpartum (nonpregnant) values for normal-weight women in the supine and lateral positions. (Data from Nelson, 201o5.) cardiac silhouette (Enein, 1987). These factors make it dii cult to precisely identiy moderate degrees of cardiomegaly by simple radiographic studies.

graphic changes, and the most common is slight left-axis devia tion due to the altered heart position. Q waves in leads II, III and avF and lat or inverted T-waves in leads III, V1-V3 may also occur (Sunitha, 2014).

During pregnancy, many of the normal cardiac souns are modiied. hese include: (1) an exaggerated splitting ofthe irst heart sound and increased loudness ofboth components, (2) no deinite changes in the aortic and pulmonary elements of the second sound, and (3) a loud, easily heard third sound (Cut forth, 1966). In 90 percent of gravidas, they also heard a sys expiration in others and that disappeared shortly after delivery.

A soft diastolic murmur was noted transiently in 20 percent, and continuous murmurs arising from the breast vasculature in 10 percent (Fig. 49-1, p. 950).

Structurally, the expanding plasma volume seen during nor mal pregnancy is relected by enlarging cardiac end-systolic and end-diastolic dimensions. Concurrently, however, septal thick ness or ejection fraction does not change. This is because the dimensional changes are accompanied by substantive ventricu lar remodeling, which is characterized by left-ventricular mass expansion of 30 to 35 percent near term. In the nonpregnant state, the heart is capable of remodeling in response to stimuli such as hypertension and exercise. Such cardiacplasticiy likely as that in exercise, and pathological hypertrophy-such as with hypertension (Hill, 2008).

Stewart and colleagues (2016) used cardiac MR imaging to prospectively evaluate cardiac remodeling during pregnancy.

Compared with the first trimester, left ventricular mass increased signiicantly beginning at 26 to 30 weeks' gestation, and this continued until delivery (Fig. 4-8). This remodeling is concen tric and proportional to maternal size for both normal and over weight women and resolved within 3 months ofdelivery.

Certainly for clinical purposes, ventricular unction during pregnancy is normal, as estimated by the Braunwad ventricuar unction graph (Fig. 4-9). For the given illing pressures, cardiac ..I3 .g 90 ; ..c)> .J=80

FIGURE 4-8 Let ventricular mass of normal-weight and overweight women across pregnancy compared with 12-week postpartum (nonpregnant) values. (Data from Stewart, 2016.) output is appropriate andthus cardiac unction during pregnancy is eudynamic. Of the metabolic changes that occur in the heart during pregnancy, the eiciency of cardiac work-which is the product ofcardiac output X mean arterial pressure-is estimated to rise by approximately 25 percent. The associated increase in oxygen consumption is primarily accomplished via increased coronary blood low rather than increased extraction (Liu, 2014).

When measured in the lateral recumbent position at rest, cardiac output increases signiicantly beginning in earlypregnancy. It continues to rise and remains elevated during the remainder ofpregnancy. In a supine woman, a large uterus rather consistently compresses veins and diminishes venous return from the lower body. It also may compress the aorta (Bieniarz, 1968). In response, cardiac illing may be reduced and cardiac output ..J=

FIGURE 4-9 Relationship between let ventricular stroke work index (LVSWI), cardiac output, and pulmonary capillary wedge pressure (PCWP) in 10 normal pregnant women in the third trimester. (Data from Clark, 1989.)

TABLE 4-4. Central Hemodynamic Changes in 10 Normal Nulliparous Women Near Term and 6.2 ± 1.0 4.3 ± 0.9 +43% 18.0 ± 1.5 20.8 ± 1.0 -14% 10.5 ± 2.7 14.5 ± 2.5 -28% 48 ± 6 41 ± 8 NSC aMeasured in lateral recumbent position.

bChanges significant unless NSC = no significant change.

COP = colloid osmotic pressure; PCWP = pulmonary capillary wedge pressure.

Data from Clark, 1989.

lessened. Speciically, cardiac MR imaging shows that when a woman rolls from her back onto her left side, cardiac output at 26 to 30 weeks' gestation rises by approximately 20 percent and at 32 to 34 weeks by 10 percent (Nelson, 2015). Consistent with this, Simpson and James (2005) found that fetal oxygen saturation is approximately 10 percent higher ifa laboring woman lies in a lateral recumbent position compared with supine. Upon standing, cardiac output falls to the same degree as in the nonpregnant woman (Easterling, 1988).

In multifetal pregnancies, compared with singletons, maternal cardiac output is augmented further by almost another 20 percent. Ghi and coworkers (2015) used transthoracic echocardiography to show that irst-trimester cardiac output with twins (mean 5.50 Umin) was more than 20 percent greater than postpartum values. Cardiac output values in the second (6.31 L/min) and third (6.29 Umin) trimesters were increased an additional 15 percent compared with irst-trimester output. Left atrial and left ventricular end-diastolic diameters are also longer with twins due to augmented preload (Kametas, 2003). The greater heart rate and inotropic contractility imply that cardiovascular reserve is reduced in multifetal gestations.

During first-stage labor, cardiac output rises moderately.

During the second stage, with vigorous expulsive eforts, it is appreciably greater. The pregnancy-induced increase is lost ater delivery, at times dependent on blood loss.

Clark and associates (1989) conducted invasive studies to measure hemodynamic function late in pregnancy (Table 4-4). Right heart catheterization was performed in 10 healthy nulliparas at 35 to 38 weeks' gestation, and again at 11 to 13 weeks postpartum. Late pregnancy was associated with the expected increases in heart rate, stroke volume, and cardiac output. Systemic vascular and pulmonary vascular resistance both dropped signiicantly, as did colloid osmotic pressure. Pulmonary capillary wedge pressure and central venous pressure did not change appreciably. Thus, although cardiac output rises, left ventricular function as measured by stroke work index remains similar to the nonpregnant normal range (see Fig. 4-9). Put another way, normal pregnancy is not a continuous "high-output" state.

Changes in posture afect arterial blood pressure (Fig. 4-10). Brachial artery pressure when sitting is lower than that when in the lateral recumbent supine position (Bamber, 2003). Additionally, systolic blood pressure is lower in the lateral positions compared with either the flexed sitting or supine positions (Armstrong, 2011). Arterial pressure usually declines to a nadir at 24 to 26 weeks' gestation and rises thereafter. Diastolic pressure decreases more than systolic.

FIGURE 4-10 Sequential changes (±SEM) in blood pressure throughout pregnancy in 69 women in supine (blue lines) and left lateral recumbent positions (red lines). PP = postpartum. (Adapted from Wilson, 1980.)

Morris and associates (2015) studied measures of vas cular compliance before pregnancy, during pregnancy, and postpartum. Compared with healthy nonpregnant controls, stifness, measured using pulse wave velocity, were observed between the prepregnant and the postpartum time periods.

sibly help explain why the risk of preeclampsia is reduced in subsequent pregnancies.

Antecubital venous pressure remains unchanged during pregnancy. In the supine position, however, femoral venous pressure rises steadily, from approximately 8 mm Hg early in pregnancy to 24 mm Hg at term. Venous blood flow in the legs is retarded during pregnancy except when the lateral recumbent position is assumed (Wright, 1950). his tendency toward blood stagnation in the lower extremities during later pregnancy is attriburable to occlusion of the pelvic veins and inferior vena cava by the enlarged uterus. he elevated venous pressure returns to normal when the pregnant woman lies on her side and immediately after delivery (McLennan, 1943). These alterations contribute to the dependent edema frequently experienced and to the development of varicose veins in the legs and vulva, as well as hemorrhoids. These changes also predispose to deep-vein thrombosis.

In approximately 10 percent of women, supine compression of the great vessels by the uterus causes signiicant arterial hypotension, sometimes referred to as the supine hypotensive syndrome (Kinsella, 1994). Also when supine, uterine arterial pressure-and thus uterine blood flow-is signiicantly lower than that in the brachial artery. Evidence to support whether this directly afects fetal heart rate patterns in uncomplicated low-risk pregnancies is conlicting (Armstrong, 2011; Ibrahim, 2015; Tamas, 2007). Similar changes can also be seen with hemorrhage or with spinal analgesia.

• Renin, Angiotensin II, and Plasma Volume

The renin-angiotensin-aldosterone axis is intimately involved in blood pressure control via sodium and water balance. All components of this system show increased levels in normal pregnancy. Renin is produced by both the maternal kidney and the placenta, and greater amounts of renin substrate (angiotensinogen) are produced by both maternal and fetal liver. Elevated angiotensinogen levels result, in part, from augmented estrogen production during normal pregnancy and are important in irst-trimester blood pressure maintenance (Lumbers, 2014).

Gant and associates (1973) reported that nulliparas who remained normotensive became and stayed refractory to the pressor efects of infused angiotensin II. Conversely, those who ultimately became hypertensive developed, but then lost, this refractoriness. The diminished vascular responsiveness to angiotensin II may be progesterone related. Normally, pregnant women lose their acquired vascular refractoriness to angiotensin II within 15 to 30 minutes after the placenta is delivered.

Large amounts of intramuscular progesterone given during late labor delay this diminishing refractoriness.

At least two species of these-atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)-are secreted by cardiomyocytes in response to chamber-wall stretching. These peptides regulate blood volume by provoking natriuresis, diuresis, and vascular smooth-muscle relaxation. In nonpregnant and pregnant patients, levels of BNP and of amino-terminal pro-brain natriuretic peptide (Nt pro-BNP), as well as newer analytes such as suppressor of tumorigenicity 2 (ST2), may be useful in screening for depressed left ventricular systolic function and determining chronic heart failure prognosis (Ghashghaei, 2016).

During normal pregnancy, plasma ANP and BNP levels are maintained in the nonpregnant range despite greater plasma volume (Yurteri-Kaplan, 2012). In one study, median BNP levels were stable across pregnancy with values <20 pg/mL (Resnik, 2005). BNP levels are increased in severe preeclamp sia, and this may be caused by cardiac strain from increased afterload (Afshani, 2013). It would appear that ANP-induced ume expansion and in the elevated plasma aldosterone concen trations characteristic of normal pregnancy.

Elevated prostaglandin production during pregnancy is thought to have a central role in control of vascular tone, blood pressure, and sodium balance. Renal medullary prostaglandin E2 synthesis is markedly elevated during late pregnancy and is presumed to be natriuretic. Levels of prostacyclin (PGI2), the principal prostaglandin of endothelium, also rise during late pregnancy. PGI2 regulates blood pressure and platelet function. It helps maintain vasodilation during pregnancy, and its deiciency is associated with pathological vasoconstriction (Shah, 2015). Thus, the ratio of PGI2 to thromboxane in maternal urine and blood is considered important in preeclampsia pathogenesis (Majed, 2012).

Several endothelins are generated in pregnancy. Endothelin-1 is a potent vasoconstrictor produced in endothelial and vascular smooth muscle cells and regulates local vasomotor tone (George, 2011; Lankhorst, 2016). Its production is stimulated by angiotensin II, arginine vasopressin, and thrombin. Endothelins, in turn, stimulate secretion of ANP, aldosterone, and catecholamines. Vascular sensitivity to endothelin-1 is not altered during normal pregnancy. Pathologically elevated levels may playia role in preeclampsia (Saleh, 2016).

This potent vasodilator is released by endothelial cells and may modiy vascular resistance during pregnancy. Moreover, nitric oxide is an important mediator of placental vascular tone and development (Krause, 2011; Kulandavelu, 2013). Abnormal nitric oxide synthesis has been linked to preeclampsia development (Laskowska, 2015; Vignini, 2016).

Of anatomic changes, the diaphragm rises approximately 4 cm during pregnancy (Fig. 4-11). he subcostal angle widens appreciably as the transverse diameter of the thoracic cage lengthens approximately 2 cm. The thoracic circumference increases about 6 cm, but not suiciently to prevent reduced residual lung volumes created by the elevated diaphragm. Even so, diaphragmatic excursion is greater in pregnant than in nonpregnant women.

Of physiological lung changes, unctional residual capaciy (PRe) decreases by approximately 20 to 30 percent or 400 to 700 mL during pregnancy (Fig. 4-12). his capacity is composed of expiratory reserve volume-which drops 15 to 20 percent or 200 to 300 mL-and residual volume-which decreases 20 to 25 percent or 200 to 400 mL. FRe and residual volume decline progressively across pregnancy due to diaphragm elevation. Signiicant reductions are observed by the sixth month. Inspiratory capaciy, the maximum volume that can be inhaled from FRe, rises by 5 to 10 percent or 200 to 350 mL during pregnancy. Total lung capaci-the combination of FRe and inspiratory capacity-is unchanged or decreases by less than 5 percent at term Decreased plasma osmolality also results in less respiratory depression (Moen, 2014). his provides an additional mechanism for the increased minute ventilation seen in pregnancy, and one that is not dependent on progesterone.

Regarding pulmonary function, peak expiratory low rates rise progressively as gestation advances (Grindheim, 2012). Lung compliance is unafected by pregnancy. Airway conductance is increased and total pulmonary resistance reduced, possibly as a result of progesterone. The maximum breathing capaciy andorced or timed vital capaciy are not altered appreciably. It is unclear whether the critical closing volume-the lung volume at which airways in the dependent parts of the lung begin to close during expiration-is higher in pregnancy (Hegewald, 2011). Pulmonary function with a singleton pregnancy does not signiicantly difer from that with twins (MAulife, 2002; Siddiqui, 2014). Importantly, the greater oxygen requirements and perhaps the increased critical closing volume imposed by pregnancy make respiratory diseases more serious.

Demir and colleagues (2015) studied nasal physiology in 85 pregnant women. Although the minimal cross-sectional area decreased between the irst and third trimesters, subjective reports ,/ 103.5° ""

II , " \\ . (37 weeks) : (Hegewald, 2011).

The respiratory rate is essentially unchanged, but tidal volume and resting minute ven as pregnancy advances. Kolar zyk and coworkers (2005) .. -� is-7 em .--_ - reported significantly greater mean tidal volumes-0.66 to 0.8 LI min-and resting minute ventilations-10.7 to 14.1 Llmin-compared with those of nonpregnant women. The elevated minute ventilation is caused by several factors. These include enhanced respira ,;, . ,----------.---.A..,, .I \IIII,\\ ..<: ::: --------------- toy drive primarily due to the stimulatory action of proges terone, low expiratory reserve

Chest wall measurements in nonpregnant (left) and pregnant women (right). The subcostal angle increases, as does the anteroposterior and transverse diameters of the chest wall and chest wall circumference. These changes compensate for the 4-cm elevation of the diaphragm volume, and compensated respiso that total lung capacity is not significantly reduced. (Redrawn from Hegewald MJ, Crapo RO: ratory alkalosis (Heenan, 2003). Respiratory physiology in pregnancy. Clin Chest Med 32(1 ):1,2011.) 5 4 TLC 2 FVC FAC RV Not pregnant Pregnant (7-9 mos.) 4 FVC 3 2 RV

FIGURE 4-1 2 Changes in lung volumes with pregnancy. The most significant changes are reduction in functional residual capacity (FRC) and its subcomponents, expiratory reserve volume (ERV) and residual volume (RV), as well as increases in inspiratory capacity (IC) and tidal volume (). (Redrawn from Hegewald MJ, Crapo RO: Respiratory physiology in pregnancy. Clin Chest Med 32(1):1,2011.) of nasal congestion or total nasal resistance did not signiicantly difer among trimesters or compared with nonpregnant controls.

he amount ofoxygen delivered into the lungs by the increased tidal volume clearly exceeds oxygen requirements imposed by pregnancy. Moreover, the total hemoglobin mass and, in turn, total oxygen-carrying capacity rise appreciably during normal pregnancy, as does cardiac output. Consequently, the maternal arteriovenous oxygen diference is diminished. Oxygen consumption grows approximately 20 percent during pregnancy, and it is approximately 10 percent higher in multifetal gestations (Ajjimaporn, 2014). During labor, oxygen consumption increases 40 to 60 percent (Bobrowski, 2010).

A greater awareness of a desire to breathe is common even early in pregnancy (Milne, 1978). his may be interpreted as dyspnea, which may suggest pulmonary or cardiac abnormalities when none exist. This physiological dyspnea, which should not interfere with normal physical activity, is thought to result from greater tidal volume that lowers the blood Peo2 slightly and paradoxically causes dyspnea. he increased respiratory efort during pregnancy, and in turn the reduction in the partial pressure ofcarbon dioxide in blood (Peo2), is likely induced in large part by progesterone and to a lesser degree by estrogen. Progesterone acts centrally, where it lowers the threshold and raises the sensitivity ofthe chemoreflex response to carbon dioxide (C02) 0ensen, 2005).

To compensate for the resulting respiratory alkalosis, plasma bicarbonate levels normally drop from 26 to 22 mmollL. Although blood pH is increased only minimally, it does shift the oxygen dissociation curve to the left. his shift increases the ainity of maternal hemoglobin for oxygen-the Bohr fectthereby lowering the oxygen-releasing capacity of maternal blood. This is ofset because the slight pH rise also stimulates an increase in 2,3-diphosphoglycerate in maternal erythrocytes.

): �:3

This shifts the curve back to the right (Tsai, 1982). hus, reduced Peo2 from maternal hyperventilation aids CO2 (waste) transfer from the fetus to the mother while also aiding oxygen release to the fetus.

he urinary system undergoes several remarkable changes in pregnancy (Table 4-5). Kidney size grows approximately 1.0 cm (Cietak, 1985). Both theglomerulariltration rate (CPR) and renal plasma low increase early in pregnancy. he GFR rises as much as 25 percent by the second week after conception and 50 percent by the beginning of the second trimester. his hyperiltration results from two principal factors. First, hypervolemia-induced hemodilution lowers the protein concentration and oncotic pressure ofplasma entering the glomerular microcirculation. Second, renal plasma flow increases by approximately 80 percent before the end of the irst trimester (Conrad, 2014b; Odutayo, 2012). As shown in Figure 4-13, , 25

FIGURE 4-13 Percentage increment in glomerular filtration rate (GFR) and renal plasma flow (RPF) across gestation and in the puerperium. (Data from Odutayo, 201o2.)

TABLE 4-5. Renal Changes in Normal Pregnancy

Renal function Glomerular filtration rate and renal plasma flow increase ...50%

Maintenance of Decreased bicarbonate threshold; acid-base progesterone stimulates respiratory center osmotic thresholds for AVP release and thirst decrease; hormonal disposal rates increase Size returns to normal postpartum

Can be confused with obstructive uropathy; retained urine leads to collection errors; renal infections are more virulent; may be responsible for "distention syndrome"; elective pyelography should be deferred to at least 12 weeks postpartum

Serum creatinine decreases during normal gestation; >0.8 mg/dL (> 72 �mol/L) creatinine already borderline; protein, amino acid, and glucose excretion all increase

Serum bicarbonate decreased by 4-5 mEq/L; Pc02 decreased 10 mm Hg; a Pc02 of 40 mm Hg already represents CO2 retention 5 mEq/L) during normal gestation; increased placental metabolism of AVP may cause transient diabetes insipidus during pregnancy

AVP = vasopressin; IVP = intravenous pyelography; Pc02= partial pressure carbon dioxide. Modified from Lindheimer, 2000.

elevated GFR persists until term, even though renal plasma flow declines during late pregnancy. Primarily as a consequence of this elevated GFR, approximately 60 percent of nulliparas during the third trimester experience urinary frequency, and 80 percent experience nocturia (F rederice, 2013).

During the puerperium, a marked GFR persists during the first postpartum day, principally from the reduced glomerular capillary oncotic pressure. A reversal of the gestational hypervolemia and hemodilution, still evident on the first postpartum day, eventuates by the second week postpartum (Odutayo, 2012).

Studies suggest that relaxin, discussed earlier (p. 52), may mediate both increased GFR and renal blood flow during pregnancy (Conrad, 2014a; Helal, 2012). Relaxin boosts renal nitric oxide production, which leads to renal vasodilation and lowered renal aferent and eferent arteriolar resistance. This augments renal blood flow and GFR (Bramham, 2016). Relaxin may also increase vascular gelatinase activity during pregnancy, which leads to renal vasodilation, glomerular hyperiltration, and reduced myogenic reactivity of small renal arteries (Odutayo, 2012).

As with blood pressure, maternal posture may considerably inluence several aspects of renal function. Late in pregnancy, the sodium excretion rate in the supine position averages less than half that in the lateral recumbent position. The efects of posture on GFR and renal plasma low vary.

One unusual feature of the pregnancy-induced changes in renal excretion is the remarkably increased amounts of some nutrients lost in the urine. Amino acids and water-soluble vitamins are excreted in much greater amounts (Shibata, 2013).

Of renal function tests, serum creatinine levels decline during normal pregnancy from a mean of 0.7 to 0.5 mg/dL. Values of 0.9 mg/dL or reater sugest underying renal disease and prompt further evaluation. Creatinine clearance in pregnancy averages 30 percent higher than the 100 to 115 mLi min in nonpregnant women. his is a useful test to estimate renal function, provided that complete urine collection is made during an accurately timed period. If this is not done precisely, results are misleading (Lindheimer, 2000, 2010). During the day, pregnant women tend to accumulate water as dependent edema, and at night, while recumbent, they mobilize this fluid with diuresis. This reversal of the usual nonpregnant diurnal pattern of urinary flow causes nocturia, and urine is more dilute than in nonpregnant women. Failure of a pregnant woman to excrete concentrated urine after withholding fluids for approximately 18 hours does not necessarily signiy renal damage. In fact, the kidneys in these circumstances function perfectly normally by excreting mobilized extracellular fluid of relatively low osmolality.

Glucosuria during pregnancy may not be abnormal. The appreciably increased GFR, together with impaired tubular reabsorptive capacity for filtered glucose, accounts for most cases of glucosuria. Chesley (1963) calculated that about a sixth of pregnant women will spill glucose in the urine. hat said, although common during pregnancy, when glucosuria is identiied, a search for diabetes mellitus is pursued.

Hematuria frequently results from contamination during collection. If not, it most often suggests urinary tract disease or infection. Hematuria is common after diicult labor and delivery because of trauma to the bladder and urethra.

Proteinuria is typically deined in nonpregnant subjects as a protein excretion rate of more than 150 mg/ d. Because of the aforementioned hyperiltration and possible reduction of tubular reabsorption, proteinuria during pregnancy is usually considered signiicant once a protein excretion threshold total protein excretion by gestational age. Mean and 95-percent confidence limits are outlined. (Redrawn from Higby K, Suiter CR,

Phelps JY, et al: Normal values of urinary albumin and total protein excretion during pregnancy. Am J Obstet Gynecol 171 :984, 1994.) of at least 300 mg/d is reached (Odutayo, 2012). Higby and coworkers (1994) measured protein excretion in 270 normal women throughout pregnancy (Fig. 4-14). Mean 24-hour excretion for all three trimesters was 11i5 mg, and the upper 95-percent conidence limit was 260 mg/d without significant diferences by trimester. They showed that albumin excretion is minimal and ranges from 5 to 30 mg/d. Proteinuria increases with gestational age, which corresponds with the peak in CFR (see Fig. 4-13)(Odutayo, 2012).

Measuring Urine Protein. The three most commonly employed approaches for assessing proteinuria are the qualitative classic dipstick, the quantitative 24-hour collection, and the albumin/ creatinine or protein/creatinine ratio of a single voided urine specimen. he pitfalls of each approach have been reviewed by Conrad (20 14b) and Bramham (2016) and their colleagues. he principal problem with dipstick assessment is that it fails to account for renal concentration or dilution of urine. For example, with polyuria and extremely dilute urine, a negative or trace dipstick could actually be associated with excessive protein excretion.

he 24-hour urine collection is afected by urinaty tract dilatation, which is discussed in the next section. he dilated tract may lead to errors related both to retention-hundreds of milliliters of urine remaining in the dilated tract-and to timing-the remaining urine may have formed hours before the collection. To minimize these pitfalls, the patient is irst hydrated and positioned in lateral recumbency-the deinitive nonobstructive posture-for 45 to 60 minutes. After this, she is asked to void, and this specimen is discarded. Immediately following this void, her 24-hour collection begins. During the final hour of collection, the patient is again placed in the lateral recumbent position. But, at the end of this hour, the inal collected urine is incorporated into the total collected volume (Lindheimer, 2010).

Last, the protein/creatinine ratio is a promising approach because data can be obtained quickly and collection errors are ,S 200 avoided. Disadvantageously, the amount of protein per unit of creatinine excreted during a 24-hour period is not constant, and the thresholds to deine abnormal vary. Nomograms for cated pregnancies have been developed (Waugh, 2003).

After the uterus completely rises out of the pelvis, it rests on the ureters. This laterally displaces and compresses them at the pelvic brim. Above this level, elevated intraureteral tonus results, and ureteral dilatation is impressive (Rubi, 1968). It is right sided in 86 percent of women (Fig. 4-15) (Schulman, 1975). This unequal dilatation may result from cushioning provided the left ureter by the sigmoid colon and perhaps from greater right ureteral compression exerted by the dextrorotated uterus. The right ovarian vein complex, which is remarkably dilated during pregnancy, lies obliquely over the right ureter and may also contribute to right ureteral dilatation.

Progesterone likely has some additional efect. Van Wagenen and Jenkins (1939) described continued ureteral dilatation after removal of the monkey fetus but with the placenta left in situ. The relatively abrupt onset of dilatation in women at midpregnancy, however, seems more consistent with ureteral compression.

Ureteral elongation accompanies distention, and the ureter is frequently thrown into curves of varying size, the smaller of which may be sharply angulated. hese so-called kinks are

FIGURE 4-15 Hydronephrosis. Plain film from the 15-minute image of an intravenous pyelogram (IVP). Moderate hydronephrosis on the right (arrows) and mild hydronephrosis on the left (arrowheads) are both normal for this 35-week gestation.

poorly named, because the term connotes obstruction. hey are usually single or double curves that, when viewed in a radiograph taken in the same plane as the curve, may appear as acute angulations. Another exposure at right angles nearly always identiies them to be gentle curves. Despite these anatomical changes, complication rates associated with ureteroscopy in pregnant and nonpregnant patients do not difer signiicantly (Semins, 2014).

he bladder shows few significant anatomical changes before 12 weeks' gestation. Subsequently, however, increased uterine size, the hyperemia that afects all pelvic organs, and hyperplasia of bladder muscle and connective tissues elevate the trigone and thicken its intraureteric margin. Continuation of this process to term produces marked deepening and widening of the trigone. The bladder mucosa is unchanged other than an increase in the size and tortuosity of its blood vessels.

Bladder pressure in primigravidas increases from 8 cm H20 early in pregnancy to 20 cm H20 at term (Iosif, 1980). To compensate for reduced bladder capacity, absolute and functional urethral lengths increased by 6.7 and 4.8 mm, respectively. Concurrently, maximal intraurethral pressure rises from 70 to 93 cm H20, and thus continence is maintained. Still, at least half of women experience some degree of urinary incontinence by the third trimester (Abdullah, 20 16a). Indeed, this is always considered in the diferential diagnosis of ruptured membranes. Near term-particularly in nulliparas, in whom the presenting part often engages before labor-the entire base of the bladder is pushed ventral and cephalad. his converts the normally convex surface into a concavity. As a result, diiculties in diagnostic and therapeutic procedures are greatly accentuated. Moreover, pressure from the presenting part impairs blood and lymph drainage from the bladder base, often rendering the area edematous, easily traumatized, and possibly more susceptible to infection.

As pregnancy progresses, the stomach and intestines are displaced cephalad by the enlarging uterus. Consequently, the physical findings in certain diseases are altered. he appendix, for instance, is usually displaced upward and somewhat laterally. At times, it may reach the right lank.

Pyrosis (heartburn) is common during pregnancy and is most likely caused by reflux of acidic secretions into the lower esophagus. Although the altered stomach position probably contributes to its frequency, lower esophageal sphincter tone also is decreased. In addition, intraesophageal pressures are lower and intragastric pressures higher in pregnant women. Concurrently, esophageal peristalsis has lower wave speed and lower amplitude (Ulmsten, 1978).

Gastric empying time is unchanged during each trimester and compared with nonpregnant women (Macfie, 1991; Wong, 2002, 2007). During labor, however, and especially after administration of analgesics, gastric emptying time may be appreciably prolonged. As a result, one danger of general anesthesia for delivery is regurgitation and aspiration of either food-laden or highly acidic gastric contents.

Hemorrhoids are common during pregnancy (Shin, 2015). hey are caused in large measure by constipation and elevated pressure in rectal veins below the level of the enlarged uterus.

Liver size does not enlarge during human pregnancy. Hepatic arterial and portal venous blood flow, however, increase substantively (Clapp, 2000).

Some laboratory test results of hepatic function are altered in normal pregnancy (Appendix, p. 1257). Total alkaline phosphatase activity almost doubles, but much of the rise is attributable to heat-stable placental alkaline phosphatase isozymes. Serum aspartate transaminase (AST) , alanine transaminase (AL T), 1-glutamyl transpeptidase (GGT), and bilirubin levels are slightly lower compared with nonpregnant values (Cattozzo, 2013; Ruiz-Extremera, 2005).

The serum albumin concentration declines during pregnancy. By late pregnancy, albumin levels may be near 3.0 g/dL compared with approximately 4.3 g/dL in nonpregnant women (Mendenhall, 1970). Total body albumin levels rise, however, because of pregnancy-associated increased plasma volume. Serum globulin levels are also slightly higher.

Leucine aminopeptidase is a proteolytic liver enzyme whose serum levels may be increased with liver disease. Its activity is markedly elevated in pregnant women. he rise, however, results from a pregnancy-speciic enzyme(s) with distinct substrate speciicities (Song, 1968). Pregnancy-induced aminopeptidase has oxytocinase and vasopressinase activity that occasionally causes transient diabetes insipidus.

During normal pregnancy, gallbladder contractility is reduced and leads to greater residual volume (Braverman, 1980). Progesterone potentially impairs gallbladder contraction by inhibiting cholecystokinin-mediated smooth muscle stimulation, which is the primary regulator of gallbladder contraction. Impaired emptying, subsequent stasis, and the increased cholesterol saturation of bile in pregnancy contribute to the increased prevalence of cholesterol gallstones in multiparas. In one study, approximately 8 percent of women had gallbladder sludge or stones when imaged at 18 and/or 36 weeks' gestation (Ko, 2014).

he pregnancy efects on maternal serum bile acid concentrations are still incompletely characterized. his is despite the long-acknowledged propensity for pregnancy to cause intrahepatic cholestasis and pruritus gravidarum from retained bile salts. Cholestasis of pregnancy is described in Chapter 55 (p. 1059).

During normal pregnancy, the pUUltary gland enlarges by approximately 135 percent (Gonzalez, 1988). This increase may suiciently compress the optic chiasma to reduce visual fields.

Impaired vision from this is rare and usually due to macro ad enomas (Lee, 2014). Pituitary enlargement is primarily caused by estrogen-stimulated hypertrophy and hyperplasia of the lactotrophs (Feldt-Rasmussen, 2011). And, as discussed subse quently, maternal serum prolactin levels parallel the increasing size. Gonadotrophs decline in number, and corticotrophs and thyrotrophs remain constant. Somatotrophs are generally sup pressed due to negative feedback by the placental production of growth hormone.

Peak pituitary size may reach 12 mm in MR images in the irst days postpartum. he gland then involutes rapidly and sen, 2011). he incidence of pituitary prolactinomas is not increased during pregnancy (Scheithauer, 1990). When these tumors are large before pregnancy-a macroadenoma measur ing : 1 0 mm-then growth during pregnancy is more likely (Chap. 58, p. 1132).

he maternal pituitary gland is not essential for pregnancy maintenance. Many women have undergone hypophysectomy, completed pregnancy successfully, and entered spontaneous labor while receiving compensatory glucocorticoids, thyroid hormone, and vasopressin.

During the first trimester, growth hormone is secreted predominantly from the maternal pituitary gland, and concentrations in serum and amnionic luid lie within the nonpregnant range of 0.5 to 7.5 ng/mL (Kletzky, 1985). As early as 6 weeks' gestation, growth hormone secreted from the placenta becomes detectable, and by approximately 20 weeks, the placenta is the principal source of growth hormone secretion (Perez-Ibave, 2014). Maternal serum values rise slowly from approximately 3.5 ng/mL at 10 weeks to plateau at about 14 ng/mL after 28 weeks. Growth hormone in amnionic fluid peaks at 14 to 15 weeks and slowly declines thereafter to reach baseline values after 36 weeks.

Placental growth hormone-which difers from pituitary growth hormone by 13 amino acid residues-is secreted by syncytiotrophoblast in a nonpulsatile fashion (Newbern, 2011). Its regulation and physiological efects are incompletely understood, but it inluences fetal growth via up regulation of insulin-like growth factor 1 (IGF-1). Higher levels have been linked with development of preeclampsia (MinaI, 2007; PerezIbave, 2014). Further, placental expression correlates positively with birthweight but negatively with fetal-growth restriction (Koutsaki, 201l). Maternal serum levels are associated with uterine artery resistance changes (Schiessl, 2007). hat said, fetal growth still progresses in the complete absence of this hormone. Although not absolutely essential, the hormone may act in concert with placental lactogen to regulate fetal growth (Newbern, 2011).

Maternal plasma prolactin levels increase markedly during normal pregnancy. Concentrations are usually tenfold greater at term-about 150 ng/mL-compared with those of nonpregnant women. Paradoxically, plasma concentrations drop after delivery even in women who are breastfeeding. During early lactation, pulsatile bursts of prolactin secretion are a response to suckling.

The principal function of maternal prolactin is to ensure lac tation. Early in pregnancy, prolactin acts to initiate DNA syn thesis and mitosis of glandular epithelial cells and presecretory alveolar cells of the breast. Prolactin also augments the number of estrogen and prolactin receptors in these cells. Finally, pro lactin promotes mammary alveolar cell RNA synthesis, galac topoiesis, and production of casein, lactalbumin, lactose, and lipids (Andersen, 1982). A woman with isolated prolactin dei ciency failed to lactate after two pregnancies (Kauppila, 1987).

This establishes prolactin as a requisite for lactation but not for pregnancy. Grattan (2015) has reviewed the numerous physi ological roles of prolactin for facilitating maternal adaptations to pregnancy. A possible role is proposed for a prolactin frag ment in the genesis of peripartum cardiomyopathy (Chap. 49, p. 963) (Cunningham, 2012).

Prolactin is present in amnionic fluid in high concen trations. Levels of up to 10,000 ng/mL are found at 20 to 26 weeks' gestation. Thereafter, levels decline and reach a nadir after 34 weeks. Uterine decidua is the synthesis site of prolactin found in amnionic luid. Although the exact function of amni onic luid prolactin is unknown, impaired water transfer from the fetus into the maternal compartment to thereby prevent fetal dehydration is one suggestion.

These two hormones are secreted from the posterior pituitary gland. The roles of oxytocin in parturition and lactation are discussed in Chapters 21 (p. 416) and 36 (p. 657), respectively. Brown and colleagues (2013) have reviewed the complex mechanisms that promote quiescence of oxytocin systems during pregnancy. Levels of antidiuretic hormone, also called vasopressin, do not change during pregnancy.

hyrotropin-releasing hormone (TRH) is secreted by the hypothalamus and stimulates thyrotrope cells of the anterior pituitary to release thyroid-stimulating hormone (TSH), also called thyrotropin. TRH levels do not rise during normal pregnancy. However, TRH does cross the placenta and may serve to stimulate the fetal pituitary to secrete TSH (horpe-Beeston, 1991).

Serum TSH and hCG levels vary with gestational age (Fig. 4-16). As discussed in Chapter 5 (p. 98), the a-subunits of the two glycoproteins are identical, whereas the 3-subunits, although similar, difer in their amino acid sequence. As a result of this structural similarity, hCG has intrinsic thyrotropic activity, and thus, high serum hCG levels cause thyroid stimulation. Indeed, TSH levels in the irst trimester decline in more than 80 percent of pregnant women, however, they still remain in the normal range for nonpregnant women

The thyroid gland boosts production of thyroid hormones by 40 to 100 percent to meet maternal and fetal needs (Moleti, 2014). To accomplish this, the thyroid gland undergoes moderate enlargement during pregnancy caused by glandular hyperplasia and greater vascularity. Mean thyroid volume increases from 12 mL in the first trimester to 15 mL at term (Glinoer,

Week of pregnancy

FIGURE 4-16 Relative changes in maternal and fetal thyroid function across pregnancy. Maternal changes include a marked and early increase in hepatic production of thyroxine-binding globulin (TBG) and placental production of human chorionic gonadotropin (hCG). Increased TBG increases serum thyroxine (T4) concentrations. hCG has thyrotropin-like activity and stimulates maternal free T4 secretion. This transient hCG-induced increase in serum T4 levels inhibits maternal secretion of thyrotropin. Except for minimally increased free T4 levels when hCG peaks, these levels are essentially unchanged. Fetal levels of all serum thyroid analytes increase incrementally across pregnancy. Fetal triiodothyronine (T3) does not increase until late pregnancy. (Modified from Burrow, 1994.) 1990). That said, normal pregnancy does not typically cause significant thyromegaly, and thus any goiter warrants evaluation.

Early in the first trimester, levels of the principal carrier protein-thyroid-binding globulin (TBG)-rise, reach their zenith at about 20 weeks, and stabilize at approximately double baseline values for the remainder of pregnancy (see Fig. 4-16). he greater TBG concentrations result from both higher hepatic synthesis rates-due to estrogen stimulation-and lower metabolism rates due to greater TBG sialylation and glycosylation. These elevated TBG levels increase total serum thyroxine (T 4) and triiodothyronine (T 3) concentrations, but do not afect the physiologically important serum ree T4 and ree T3 levels. Specifically, total serum T4 levels rise sharply beginning between 6 and 9 weeks' gestation and reach a plateau at 18 weeks. Serum free T 4 levels rise only slightly and peak along with hCG levels, and then they return to normal.

Interestingly, T 4 and T 3 secretion is not similar for all pregnant women (G linoer, 1990). Approximately a third of women experience relative hypothyroxinemia, preferential T3 secretion, and higher, albeit normal, serum TSH levels. hus, thyroidal adjustments during normal pregnancy may vary considerably.

The fetus relies on maternal T 4, which crosses the placenta in small quantities to maintain normal fetal thyroid function (Chap. 58, p. 1118). Recall that the fetal thyroid does not begin to concentrate iodine until 10 to 12 weeks' gestation. he synthesis and secretion of thyroid hormone by fetal pituitary TSH ensues at approximately 20 weeks. At birth, approximately 30 percent of the T 4 in umbilical cord blood is of maternal origin (Leung,i2012).

Normal suppression of TSH during pregnancy may lead to a misdiagnosis of subclinical hyperthyroidism. Of greater concern is the potential failure to identiy women with early hypothyroidism because of suppressed TSH concentrations. To mitigate the likelihood of such misdiagnoses, Dashe and coworkers (2005) conducted a population-based study at Parkland Hospital to develop gestational-age-specific TSH normal curves for both singleton and twin pregnancies (Fig. 4-17). Similarly, Ashoor and associates (2010) established normal ranges for maternal TSH, free T4, and free T3 at 11 to 13 weeks' gestation.

hese complex alterations of thyroid regulation do not appear to alter maternal thyroid status as measured by metabolic studies. lthough basal metabolic rate increases progressively by as much as 25 percent during normal pregnancy, most 4.0 0.4

FIGURE 4-17 Gestational age-specific thyroid-stimulating hormone (TSH) nomogram derived from 13,599 singleton pregnancies. The nonpregnant reference values of 4.0 and 0.4 mUll are represented as solid black lines. Upper shaded area represents the 28 percent of singleton pregnancies with TSH values above the 97.5th percentile threshold that would not have been identified as abnormal based on the assay reference value of 4.0 mUll. lower shaded area represents singleton pregnancies that would have been (falsely) identified as having TSH suppression based on the assay reference value of 0.4 mUll. (Data from Dashe, 2005.) of this greater oxygen consumption can be attributed to fetal metabolic activity. If fetal body surface area is considered along with that of the mother, the predicted and observed basal metabolic rates are similar to those in nonpregnant women.

Iodine requirements increase during normal pregnancy (Chap. 58, p. 1127). In women with low or marginal intake, deiciency may manifest as low T4 and higher TSH levels. Importantly, more than a third of the world population lives in areas where iodine intake is marginal. For the fetus, early exposure to thyroid hormone is essential for the nervous system, and despite public health programs to supplement iodine, severe iodine deiciency resulting in cretinism afects more than 2 million people globally (Syed, 2015).

In one longitudinal investigation of 20 women, all markers of bone turnover rose during normal pregnancy and failed to reach baseline levels by 12 months postpartum (More, 2003). Investigators concluded that the calcium needed for fetal growth and lactation may be drawn at least in part from the maternal skeleton. he factors afecting bone turnover yield a net result favoring fetal skeletal formation at the expense of the mother, such that pregnancy is a vulnerable period for osteoporosis (Sanz-Salvador, 2015). hat said, prevention is diicult due to a paucity of identiiable risk factors.

Acute or chronic declines in plasma calcium or acute drops in magnesium levels stimulate parathyroid hormone (PTH) release. Conversely, greater calcium and magnesium levels suppress PTH levels. he action of this hormone on bone resorption, intestinal absorption, and kidney reabsorption is to raise extracellular luid calcium concentrations and lower phosphate levels.

Fetal skeleton mineralization requires approximately 30 g of calcium, primarily during the third trimester (Sanz-Salvador, 2015). Although this amounts to only 3 percent of the total calcium held within the maternal skeleton, the provision of calcium still challenges the mother. In most circumstances, augmented maternal calcium absorption provides the additional calcium. During pregnancy, the amount of calcium absorbed rises gradually and reaches approximately 400 mg/ d in the third trimester. Greater calcium absorption appears to be mediated by elevated maternal 1,25-dihydroxyvitamin D concentrations. This occurs despite decreased PTH levels during early pregnancy, which is the normal stimulus for active vitamin D production within the kidney. Indeed, PTH plasma concentrations decline during the irst trimester and then rise progressively throughout the remainder of pregnancy (Pitkin, 1979).

he increased production of active vitamin D is likely due to placental production of either PTH or a PTH-related protein (PTH-rP). Outside pregnancy and lactation, PTH-rP is usually detectable only in serum of women with hypercalcemia due to malignancy. During pregnancy, however, PTH-rP concentrations increase signiicantly. his protein is synthesized in both fetal tissues and maternal breasts.

he C cells that secrete calcitonin are located predominantly in the perifollicular areas of the thyroid gland. Calcitonin opposes actions of PTH and vitamin D and protects the matenal skeleton during times of calcium stress. Pregnancy and lactation cause profound maternal calcium stress, ostensibly for the sake of the fetus. Indeed, fetal calcitonin levels are at least twofold higher than maternal levels (Ohata, 2016). And although maternal levels fall during pregnancy, they generally rise postpartum (M011er, 2013).

Calcium and magnesium promote the biosynthesis and secretion of calcitonin. Various gastric hormones-gastrin, pentagastrin, glucagon, and pancreozymin-and food ingestion also increase calcitonin plasma levels.

In normal pregnancy, unlike their fetal counterparts, the maternal adrenal glands undergo little, if any, morphological change. The serum concentration of circulating cortisol rises, but much of it is bound by transcortin, the cortisol-binding globulin. The adrenal secretion rate of this principal glucocorticoid is not elevated, and probably it is lower than in the nonpregnant state. he metabolic clearance rate of cortisol, however, is diminished during pregnancy because its half-life is nearly doubled compared with that for nonpregnant women (Migeon, 1957). Administration of estrogen, including most oral contraceptives, causes changes in serum cortisol levels and transcortin similar to those of pregnancy Qung, 201i1).

During early pregnancy, the levels of circulating adrenocorticotropic hormone (A CTH) , also known as corticotropin, are dramatically reduced. As pregnancy progresses, ACTH and free cortisol levels rise equally and strikingly (Fig. 4-18). This ,50

FIGURE 4-18 Serial increases in serum cortisol (blue line) and adrenocorticotropic hormone (ACTH) (red line) across normal pregnancy. (Data from Carr, 1981o.) apparent paradox is not understood completely. Some suggest that greater free cortisol levels in pregnancy result from a "resetting" of the maternal feedback mechanism to higher thresholds (Nolten, 1981). his might result from tissue reractoriness to cortisol. Others assert that these incongruities stem from an antagonistic action of progesterone on mineralocorticoids (Keller-Wood, 2001). Thus, in response to elevated progesterone levels during pregnancy, an elevated free cortisol is needed to maintain homeostasis. Other theories include possible roles for higher free cortisol in preparation for the stress of pregnancy, delivery, and lactation. This pattern might also influence postpartum behavior and parenting roles (Conde, 2014).

As early as 15 weeks' gestation, the maternal adrenal glands secrete considerably increased amounts of aldosterone, the principal mineralocorticoid. By the third trimester, approximately 1 mg/d is released. If sodium intake is restricted, aldosterone secretion is even further elevated (Watanabe, 1963). Concurrently, levels of renin and angiotensin II substrate normally rise, especially during the latter half of pregnancy. his scenario promotes greater plasma levels of angiotensin II, which acts on the zona glomerulosa of the maternal adrenal glands and accounts for the markedly elevated aldosterone secretion. Some suggest the increased aldosterone secretion during normal pregnancy afords protection against the natriuretic efect of progesterone and atrial natriuretic peptide. Gennari-Moser and colleagues (2011) provide evidence that aldosterone, as well as cortisol, may modulate trophoblast growth and placental size.

Maternal plasma levels of this potent mineralocorticosteroid progressively increase during pregnancy. Indeed, plasma levels of deoxycorticosterone rise to near 1500 pg/mL by term, a more than 15-fold increase (Parker, 1980). his marked elevation does not derive from adrenal secretion but instead represents augmented kidney production resulting from estrogen stimulation. The levels of deoxycorticosterone and its sulfate in fetal blood are appreciably higher than those in maternal blood, which suggests transfer of fetal deoxycorticosterone into the maternal compartment.

In balance, androgenic aCtiVlty rises during pregnancy, and both maternal plasma levels of androstenedione and testosterone are increased. This inding is not totally explained by alterations in their metabolic clearance. Both androgens are converted to estradiol in the placenta, which increases their clearance rates. Conversely, greater plasma sex hormone-binding globulin levels in gravidas retard testosterone clearance. Thus, the production rates of maternal testosterone and androstenedione during human pregnancy are increased. he source of this higher C19-steroid production is unknown, but it likely originates in the ovary. Interestingly, little or no testosterone in maternal plasma enters the fetal circulation as testosterone. Even when massive testosterone levels are found in the circulation of pregnant women, as with androgen-secreting tumors, testosterone concentrations in umbilical cord blood are likely to be undetectable. his results from the near complete trophoblastic conversion of testosterone to 173-estradiol.

Maternal serum and urine levels of dehydroepiandrosterone suate are lower during normal pregnancy. his stems from a greater metabolic clearance through extensive maternal hepatic 16.-hydroxylation and placental conversion to estrogen (Chap. 5, p. 103).

Progressive lordosis is a characteristic feature of normal pregnancy. Compensating for the anterior position of the enlarging uterus, lordosis shifts the center of gravity back over the lower extremities. The sacroiliac, sacrococcygeal, and pubic joints have increased mobility during pregnancy. However, as discussed earlier (p. 52), increased joint laxity and associated discomfort during pregnancy do not correlate with increased maternal serum levels of estradiol, progesterone, or relaxin (Aldabe, 2012; Marnach, 2003; V0llestad, 2012). Most relaxation takes place in the first half of pregnancy. It may contribute to maternal posture alterations and in turn create lower back discomfort. s discussed in Chapter 36 (p. 661), although some symphyseal separation likely accompanies many deliveries, those greater than 1 cm may cause significant pain (Shnaekel, 2015).

Aching, numbness, and weakness also occasionally are experienced in the upper extremities. his may result from the marked lordosis and associated anterior neck flexion and shoulder girdle slumping, which produce traction on the ulnar and median nerves (Crisp, 1964). he latter may give rise to symptoms mistaken for the carpal tunnel syndrome (Chap. 60, p. 1167). Joint strengthening begins immediately following delivery and is usually complete within 3 to 5 months. Pelvic dimensions measured by MR imaging up to 3 months after delivery are not significantly diferent from prep regnancy measurements (Huerta-Enochian, 2006).

Central nervous system changes are relatively few and mostly subtle. Women often report problems with attention, concentration, and memory throughout pregnancy and the early puerperium. Systematic studies of memory in pregnancy, however, are limited and often anecdotal. Keenan and associates (1998) longitudinally investigated memory in pregnant women and a matched control group. hey found pregnancy-related memory decline that was limited to the third trimester. his decline was not attributable to depression, anxiety, sleep deprivation, or other physical changes associated with pregnancy. It was transient and quickly resolved following delivery. Others have found poorer verbal recall and processing speed and worse spatial recognition memory in pregnancy (Farrar, 2014; Henry, 2012).

Zeeman and coworkers (2003) used MR imaging to measure cerebral blood low across pregnancy. They found that mean blood flow in the middle and posterior cerebral arteries declined progressively from 147 and 56 mLimin when nonpregnant to 118 and 44 mLlmin late in pregnancy, respectively. Mechanisms and signiicance of the decline are unknown. Pregnancy does notiafect cerebrovascular autoregulation (Bergersen, 2006; Cipolla, 2014).

Intraocular pressure drops during pregnancy and is attributed partly to greater vitreous outlow. Corneal sensitivity is decreased, and the greatest changes are late in gestation. Most pregnant women demonstrate a measurable but slight increase in corneal thickness, thought to be due to edema. Consequently, they may have diiculty with previously comfortable contact lenses. Brownish-red opacities on the posterior surface of the cornea-Krukenberg spindles-are observed with a higher than expected frequency during pregnancy. Hormonal efects similar to those observed for skin lesions are believed to cause this increased pigmentation. Other than transient loss of accommodation reported with both pregnancy and lactation, visual function is unafected by pregnancy. These changes during pregnancy and pathological eye aberrations were reviewed by Grant and Chung (2013).

Beginning as early as 12 weeks' gestation and extending through the first 2 months postpartum, women have diiculty with falling asleep, frequent awakenings, fewer hours of night sleep, and reduced sleep eiciency (Pavlova, 2011). Abdullah and colleagues (2016b) concluded that sleep apnea is more common in pregnancy, especially in obese patients. he greatest disruption of sleep is encountered postpartum and may contribute to postpartum blues or to frank depression auulia Paavonen, 2017).

Abdullah B, Ayub SH, Mohd Zahid AZ, et al: Urinary incontinence in primigravida: the neglected pregnancy predicament. Eur ] Obstet Gynecol Reprod Bioi 198:110, 2016a

Abdullah HR, Nagappa M, Siddiqui N, Chung F: Diagnosis and treatment of obstructive sleep apnea during pregnancy. Curr Opin Anaesthesiol 29:317, 2016b

Abeysekera MV, Morris ]A, Davis GK, et al: Alterations in energy homeostasis to favour adipose tissue gain: a longitudinal study in healthy pregnant women. Aust N Z] Obstet Gynaecol 56:42, 2016

Afshani N, Moustaqim-Barrette A, Biccard BM, et al: Utiliry of B-rype natriuretic peptides in preeclampsia: a systematic review. Int ] Obstet Anesth 22:96,r2013

Aguin T], Sobel ]0: Vulvovaginal candidiasis in pregnancy. Curr Infect Dis Rep 17:462,r2015

Ajjimaporn A, Somprasit C, Chaunchaiyakul R: A cross-sectional study of resting cardio-respiratory and metabolic changes in pregnant women. ] Phys Ther Sci 26:779, 2014

Aldabe 0, Ribeiro DC, Milosavljevic S, et al: Pregnancy-related pelvic girdle pain and its relationship with relaxin levels during pregnancy: a systematic review. Eur Spine] 21:1769, 2012

Alvarez H, Caldeyro-Barcia R: Contractiliry of the human uterus recorded by new methods. Surg Gynecol Obstet 91: 1, 1950

Amoah C, Yassin A, Cockayne E, et al: Hyperreactio luteinalis in pregnancy.

Fertil Steril 95(7):2429.e1, 2011

Andersen ]R: Prolactin in amniotic luid and maternal serum during uncomplicated human pregnancy. Dan Med Bull 29:266, 1982

Anderson BL, Mendez-Figueroa H, Dahlke], et al: Pregnancy-induced changes in immune protection of the genital tracr: deining normal. Am ] Obstet GynecoIr208(4):321.e1,r2013

Angelidis G, Dafopoulos K, Messini CI, et al: Ghrelin: new insights into female reproductive system-associated disorders and pregnancy. Reprod Sci 19:903, 2012

Angueira AR, Ludvik AE, Reddy TE, et al: New insights into gestational glucose metabolism: lessons learned from 21st century approaches. Diabetes 64:327,r2015

Armstrong S, Fernando R, Columb M, et al: Cardiac index in term pregnant women in the sitting, lateral, and supine positions: an observational, crossover study. Anesth Analg 113:318,r2011

Ashoor G, Kametas NA, Akolekar R, et al: Maternal thyroid function at 11-13 weeks of gestation. Fetal Diagn her 27(3): 156, 2010

Assali NS, Dilts PV, Pend M, et al: Physiology of the placenta. In Assali NS (ed): Biology of Gestation, Vol I. The Maternal Organism. New York, Academic Press, 1968

Assali NS, Douglas A, Baird W: Measurement of uterine blood low and uterine metabolism. IV. Results in normal pregnancy. Am] Obstet Gynecol 66(2):248, 1953

Astern ]M, Collier AC, Kendal-Wright CE: Pre-B cell colony enhancing factor (PBEF/NAMPT/Visfatin) and vascular endothelial growth factor (VEGF) cooperate to increase the permeabiliry of the human placental amnion. Placenta 34:42, 2013

Bamber ]H, Dresner M: Aortocaval compression in pregnancy: the efect of changing the degree and direction of lateral tilt on maternal cardiac output. Anesth Analg 97:256, 2003

Bao W, Baecker A, Song Y, et al: Adipokine levels during the irst or early second trimester of pregnancy and subsequent risk of gestational diabetes mellitus: a systematic review. Metabolism 64:756, 2015

Bardicef M, Bardicef 0, Sorokin Y, et al: Extracellular and intracellular magnesium depletion in pregnancy and gestational diabetes. Am ] Obstet Gynecol 172:1009,r1995

Baronr], Shwarzman, Sheiner E, et al: Blood low Doppler velocimetry measured during active labor. Arch Gynecol Obstet 291:837,2015

Bastholm SK, Samson MH, Becher N, et al: Trefoil factor peptide 3 is positively correlated with the viscoelastic properties of the cervical mucus plug. Acta Obstet Gynecol Scand 96(1):47, 2017

Bergersen TK, Hartgill W, Pirhonen]: Cerebrovascular response to normal pregnancy: a longitudinal study. Am] Physiol Heart Circ Physiolr290: 1856,r2006 Berggren EK, Presley L, Amini SB, et al: Are the metabolic changes of pregnancy reversible in the first year postpartum? Diabetologia 58:1561,r2015

Bernstein 1M, Ziegler W, Badger G]: Plasma volume expansion in early pregnancy. Obstet Gynecol 97:669, 2001

Bieniarz ], Branda A, Maqueda E, et al: Aortocaval compression by the uterus in late pregnancy, 3. Unreliabiliry of the sphygmomanometric method in estimating uterine artery pressure. Am ] Obstet Gynecol 102: 11 06, 1968

Bloom SL, Uppot R, Roberts 0]: Case 32-2010: a pregnant woman with abdominal pain and fluid in the peritoneal caviry. N Engl ] Med 363(17):1657,r2010

Bobrowski A: Pulmonary physiology in pregnancy. Clin Obstet Gynecol 53(2):286, 2010

Boehlen F, Hohlfeld P, Extermann P, et al: Platelet count at term pregnancy: a reappraisal of the threshold. Obstet Gynecol 95:29, 2000

Bramham K, Hladunewich A, Jim B, et al: Pregnancy and kidney disease.

NephSAP Neprology Self-Assessment Program 15(2):115,r2016

Braverman DZ, Johnson ML, Kern F ]r: Efects of pregnancy and contraceptive steroids on gallbladder function. N Engl] Med 302:362, 1980

Brifa ]F, McAinch A], Romano T, et al: Leptin in pregnancy and development: a contributor to adulthood disease? Am ] Physiol Endocrinol Metab 308:E335,r2015

Brown CH, Bains ]S, Ludwig M, et al: Physiological regulation of magnocellular neurosecretory cell activiry: integration of intrinsic, local and aferent mechanisms.r] NeuroendocrinoIr25:678, 2013

Brown A, Gallery EDM, Ross MR, et al: Sodium excretion in normal and hypertensive pregnancy: a prospective study. Am] Obstet Gynecol 159:297, 1988

Brown A, Sinosich M], Saunders OM, et al: Potassium regulation and progesterone-aldosterone interrelationships in human pregnancy: a prospective study. Am] Obstet Gynecol 155:349, 1986

Browne ]C, Veall N: The maternal placental blood low in normotensive and hypertensive women.r] Obstet Gynaecol Br Emp 60(2):141,r1953

Burns R, Azizi F, Hedayati M, et al: Is placental iodine content related to dietary iodine intake? Clin Endocrinol 75(2):261, 2011

Burrow GN, Fisher DA, Larsen PR: Maternal and fetal thyroid function. N Engl] Med 331:1072,r1994

Camaschella C: Iron deiciency anemia. N Engl] Med 372: 1832, 2015

Carr BR, Parker CR ]r, Madden ]0, et al: Maternal plasma adrenocorticotropin and cortisol relationships throughout human pregnancy. Am ] Obstet GynecoIr139:416,r1981

Cattozzo G, Calonaci A, lbeni e, et al: Reference values for alanine aminotransferase, a-amylase, aspartate aminotransferase, l-glutamyltransferase and lactate dehydrogenase measured according to the IFCC standardization during uncomplicated pregnancy. Clin Chen Lab Med 51:e239, 2013

Cavoretto P, Giorgione V, Sigismondi e, et al: Hyperreactio luteinalis: timely diagnosis minimizes the risk of oophorectomy and alerts clinicians to the associated risk of placental insuiciency. Eur J Obstet Gynecol Reprod Bioi 176:10,r2014

Chehab FF: 20 years ofleptin: leptin and reproduction: past milestones, present undertakings, and future endeavors. J Endocrinol 223:T37, 2014

Chesley LC: Renal function during pregnancy. In Carey HM (ed): Modern Trends in Human Reproductive Physiology. London, Butterworth, 1963

Chong MF, Chia AR, Colega M, et al: Maternal protein intake during pregnancy is not associated with ofspring birth weight in a multiethnic Asian population. J Nutr 145:1303,r2015

Cietak A, Newton JR: Serial quantitative maternal nephrosonography in pregnancy. Br J Radiol 58:405, 1985

Cipolla MJ, Zeeman GG, Cunningham FG: Cerebrovascular (patho)physiology in preeclampsia/eclampsia. In Taylor RN, Roberts JM, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 2014

Clapp JF III, Stepanchak W, Tomaselli J, et al: Portal vein blood Bow-efects of pregnancy, gravity, and exercise. Am J Obstet Gynecol 183: 167,r2000 Clark SL, Cotton DB, Lee W, et al: Central hemodynamic assessment of nor mal term pregnancy. Am J Obstet Gynecol 161:1439, 1989

Cleal JK, Glazier JD, Ntani G et al: Facilitated transporters mediate net elux of amino acids to the fetus across the basal membrane of the placental syncytiotrophoblast. J Physiol 589:987, 201r1

Conde A, Figueiredo B: 24-h urinary free cortisol from mid-pregnancy to 3-months postpartum: gender and parity diferences and efects. Psychoneuroendocrinology 50:264, 2014

Cong J, Yang X, Zhang N, et al: Quantitative analysis of left atrial volume and function during normotensive and preeclamptic pregnancy: a realtime three-dimensional echocardiography study. Int J Cardiovasc Imaging 31:805,r2015

Connelly KJ, Boston BA, Pearce EN, et al: Congenital hypothytoidism caused by excess prenatal maternal iodine ingestion. J Pediatr 161:760,r2012

Conrad KP, Baker VL: Corpus luteal contribution to matenal pregnancy physiology and outcomes in assisted reproductive technologies. Am J Physiol Regul Integr Comp Physiol 304(2):R69, 2013

Conrad KP, Davison JM: The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin? Am J Physiol Renal Physiol 306:F 1121, 2014a

Conrad KP, Gaber L W, Lindheimer MD: The kidney in normal pregnancy and preeclampsia. In Taylor RN, Roberts JM, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press,r2014b

Crisp WE, DeFrancesco S: he hand syndrome of pregnancy. Obstet Gynecol 23:433, 1964

Csapo AI, Pulkkinen MO, Wiest WG: Efects of luteectomy and progesterone replacement therapy in early pregnant patients. Am J Obstet Gynecol 115(6):759, 1973

Cunningham FG: Peripartum cardiomyopathy: we've come a long way, but ...

Obstet Gynecol 120(5):992,r2012

Cunningham FG, Nelson DB: Disseminated intravascular coagulation syndromes in obstetrics. Obstet Gynecol 126:999,r2015

Cutforth R, MacDonald CB: Heart sounds and mrmurs in pregnancy. Am Heart J 1:741, 1966

Dashe JS, Casey BM, Wells CE, et al: hyroid-stimulating hormone in singleton and rwin pregnancy: importance of gestational age-speciic reference ranges. Obstet Gynecol 106:753, 2005

Davison JM, Dunlop W: Renal hemodynamics and tubular function in normal human pregnancy. Kidney Int 18: 152, 1980

Davison JM, Vallotton MB, Linclheimer MD: Plasma osmollity and urinary concentration and dilution during and ter pregnancy: evidence that lateral recumbency inhibits maximal urinary concentrating ability. BJOG 88:472, 1981

Demir UL, Demir BC, Oztosun E, et al: The efects of pregnancy on nasal physiology. Int Forum Allergy Rhinol 5:162, 2015

De-Regil LM, Palacios e, Lombardo LK, et al: Vitamin 0 supplementation for women during pregnancy. Cochrane Database Syst Rev I:CD008873, 2016

Di Benedetto A, D'anna R, Cannata ML, et al: Efects of prepregnancy body mass index and weight gain during pregnancy on perinatal outcome in glucose-tolerant women. Diabetes Metab 38:63, 2012

Djurisic S, Hviid TV: HLA Class Ib molecules and immune cells in pregnancy and preeclampsia. Front Immunol 5:652, 2014

Easterling TR, Schmucker Be, Benedetti TJ: The hemodynamic efects of orthostatic stress during pregnancy. Obstet Gynecol 72:550, 1988

Edman CD, Toofanian A, MacDonald pe, et al: Placental clearance rate of maternal plasma androstenedione through placental estradiol formation: an indirect method of assessing utero placental blood Bow. Am J Obstet Gynecol 141:1029, 1981

Eler Dos Reis P, Blunck Santos NQ, Barbosa Pagio FA, et al: Management and follow-up of a case of gestational gigantomastia in a Brazilian hospital. Case Rep Obstet Gyneco1r2014:610363, 2014

Enein M, Zina A, Kassem M, et al: Echocardiography of the pericardium in pregnancy. Obstet GynecoI69:851, 1987

Farrar 0, Tufnell 0, Neill j, et al: Assessment of cognitive function across pregnancy using CANTAB: a longitudinal study. Brain Cogn 6, 2014

Feldt-Rasmussen U, Mathiesen ER: Endocrine disorders in pregnancy: physiological and hormonal aspects of pregnancy. Best Pract Res Clin Endocrinol Metab 25(6):875, 201r1

Fernandes LB, Amaral WN: Clinical study of skin changes in low and high risk pregnant women. An Bras Dermatol 90:822, 2015

Ferrazzi E, Rigano S, Padoan A, et al: Uterine artery blood Bow volume in pregnant women with an abnormal pulsatility index of the uterine arteries delivering normal or intrauterine growth restricted newborns. Placenta 32:487, 2011

Figueiredo AS, Schumacher A: he Thrlr7/Treg paradigm in pregnancy. Immunology 148:13,r2016

Flo K, Widnes C, Vartun A, et al: Blood Aow to the scarred gravid uterus at 22-24 weeks of gestation. BJOG 121:210,r2014

Flo K, Wilsgaard T, Vartun A, et al: A longitudinal study of the relationship berween maternal cardiac output measured by impedance cardiography and uterine artery blood Aow in the second half of pregnancy. BJOG :837, 2010

Franco EM, Pares 0, Colome NL, et al: Urinary incontinence during pregnancy: is there a diference berween irst and third trimester? Eur J Obstet Gynecol Reprod BioI 182:86,r2014

Frederice CP, Amaral E, Ferreira Nde 0: Urinary symptoms and pelvic Aoor muscle function during the third trimester of pregnancy in nulliparous women. J Obstet Gynaecol Res 39: 188, 2013

Galan HL, Marconi M, Paolini CL, et al: The transplacental transport of essential amino acids in uncomplicated human pregnancies. Am J Obstet Gynecol 200(1):91.e 1, 2009

Gallery ED, Raftos J, Gyory AZ, et al: A prospective study of serum complement (C3 and C4) levels in normal human pregnancy: efect of the development of pregnancy-associated hypertension. Aust N Z J Med 11 :243, 1981

Gant NF, Daley GL, Chand S, et al: A study of angiotensin II pressor response throughout primigravid pregnancy. J Clin Invest 52:2682, 1973

Garces MF, Sanchez E, Rufz-Parra AI, et al: Serum chemerin levels during normal human pregnancy. Pep tides 42: 138,2013

Garield RE, Maner L, MacKay LB, et al: Comparing uterine electromyography activity of antepartum patients versus term labor patients. Am J Obstet Gynecol 193:23, 2005

Gayer G, Ben Ely A, Maymon R, et al: Enlargement of the spleen as an incidental inding on CT in post-partum females with fever. Br J Radiol 85 (1014): 53,r2012

Gennari-Moser e, Khankin EV, Schuller S, et al: Regulation of placental growth by aldosterone and cortisol. Endocrinology 152(1):263, 201r1 George EM, Granger JP: Endothelin: key mediator of hypertension in preeclam psia. Am J H ypertens 24(9) :964, 2011

Ghashghaei R, Arbit B, Maisel AS: Current and novel biomarkers in heart failure: bench to bedside. Curr Opin Cardiol 31:191, 2016

Ghi T, Degli Esposti 0, Montaguti E, et al: Maternal cardiac evaluation during uncomplicated twin pregnancy with emphasis on the diastolic function. Am J Obstet Gynecol 213:376.el, 2015

Gizlenti S, Ekmekci TR: The changes in the hair cycle during gestation and the post-partum period. J Eur Acad Dermatol Venereol 28:878, 2014

Glinoer 0, de Nayer P, Bourdoux P, et al: Regulation of maternal thyroid during pregnancy. J Clin Endocrinol Metab 71 :276, 1990

Gonzalez JG, Elizondo G, Saldivar 0, et al: Pituitary gland growth during normal pregnancy: an in vivo study using magnetic resonance imaging. Am J Med 85:217,r1988

Gonzalez-Dominguez MI, Lazo-de-Ia-Vega-Monroy ML, Zaina S, et al: Association of cord blood des-acyl ghrelin with birth weight, and placental GHS-Rl receptor expression in SGA, AGA, and LGA newborns. Endocrine 53:182,r2016

Govindan RB, Siegel E, Mckelvey S, et al: Tracking the changes in synchrony of the electro physiological activity as the uterus approaches labor using magnetomyographic technique. Reprod Sci 22:595, 2015

Grant AD, Chung SM: The eye in pregnancy: ophthalmologic and neuroophthalmologic changes. Clin Obstet Gynecol 56(2):397, 2013

Grattan DR: The hypothalamo-prolactin axis. J Endocrinol 226:7101, 2015

Grindheim G, Toska K, Estensen ME, et al: Changes in pulmonary function during pregnancy: a longitudinal cohort study. BJOG 119(1):94,r2012

Grummer NiA, Sullivan JA, Magness RR, et al: Vascular endothelial growth facror acts through novel, pregnancy-enhanced recepror signaling pathways to stimulate endothelial nitric oxide synthase activiry in uterine artery endothelial cells. Biochem J 417(2):501, 2009

Gunderson EP: Impact of breastfeeding on maternal metabolism: implications for women with gestational diabetes. Curr Diab Rep 14:460,2014 Haghiac M, Basu S, Presley L, et al: Patterns of adiponectin expression in term pregnancy: impact of obesiry. J Clin Endocrinol Metab 99:3427, 2014

Han L, Liu X, Li H, et al: Blood coagulation parameters and platelet indices: changes in normal and preeclamptic pregnancies and predictive values for preeclampsia. PLoS One 9:el14488, 2014

Handel AC, Lima PB, Tonolli VM, et al: Risk factors for facial melasma in women: a case-conrrol study. Br] Dermarol 171 :588, 2014

Hansen LK, Becher N, Bastholm S, et al: he cervical mucus plug inhibits, but does not block, the passage of ascending bacteria from the vagina during pregnancy. Acta Obstet Gynecol Scand 93: 1 02, 2014

Hartmann PE: The lactating breast: an overview from down under. Breastfeed Med 2:3, 2007

Hauguel-de Mouzon S, Catalano P: Adiponectin: are measurements clinically useful in pregnancy? Diabetes Care 36: 1434, 2013

Hedengran KK, Nelson 0, Andersen MR, et al: Hepcidin levels are low during pregnancy and increase around delivery in women without iron deiciencya prospective cohort study. J Matern Fetal Neonatal Med 29: 1506, 2016

Heenan AP, Wolfe A: Plasma osmolality and the strong ion diference predict respiratory adaptations in pregnant and nonpregnant women. Canr] Physiol Pharmacol 81:839, 2003

Hegewald MJ, Crapo RO: Respirarory physiology in pregnancy. Clin Chest Med 32(1): 1,2011

Helal 1, Fick-Brosnahan GM, Reed-Giromer B, et al: Glomerular hyperiltration: deinitions, mechanisms and clinical implications. Nat Rev Nephrol 8(5):293,r2012

Henry JF, Sherwin BB: Hormones and cognitive functioning during late pregnancy and postpartum: a longitudinal study. Behav Neurosci 126(1):73, 2012

Herrera E, Ortega-Senovilla H: Lipid metabolism during pregnancy and its implications for fetal growth. Curr Pharm Biotechnol 15:24,r2014

Hibbard jU, ShrofSG, Cunningham FG: Cardiovascular alterations in normal and preeclamptic pregnancies. In Taylor RN, Roberts JM, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 2014

Higby K, Suiter CR, Phelps JY, et al: Normal values of urinary albumin and rotal protein excretion during pregnancy. Am J Obstet Gynecol 171:984, 1994 Hill JA, Olson EN: Cardiac plasticiry. N Engl J Med 358: 1370, 2008 Hodgkinson CP: Physiology of the ovarian veins in pregnancy. Obstet Gynecol 1:26, 1953

Huerta-Enochian GS, Katz VL, Fox LK, et al: \lagnetic resonance-based serial pelvimetry: do maternal pelvic dimensions change during pregnancy? Am J Obstet Gynecol 194:1689,r2006

Huisman A, Aanoudse ]G, Heuvelmans JH, et al: Whole blood viscosiry during normal pregnancy. BJOG 94:1143,r1987

Hytten FE: Weight gain in pregnancy. In Hytten FE, Chamberlain G (eds):

Clinical Physiology in Obstetrics, 2nd ed. Oxford, Blackwell, 1991, p 173

Ibrahim S, Jarefors E, Nel DG, et al: Efect of maternal position and uterine activity on periodic matenal heart rate changes before elective cesarean section at term. Acta Obstet Gynecol Scand 94:1359, 2015 lkino jK, Nunes DH, Silva VP, et al: Melasma and assessment of the quality of life in Brazilian women. An Bras Dermarol 90: 196, 2015

Iosif S, lngemarsson I, Ulmsten U: Urodynamic studies in normal pregnancy and in puerperium. Amr] Obstet Gynecol 13 :696, 1980

James AH, Rhee E, hames B, et al: Characterization of antithrombin levels in pregnancy. hromb Res 134:648,2014

J ebeile H, Mijatovic J, Louie J C, et al: A systematic review and meta-analysis of energy intake and weight gain in pregnancy. Am J Obstet GynecoIr214:465, 2016

Jensen D, Wolfe A, Slatkovska L, et al: Efects of human pregnancy on the ventilatory chemorelex response to carbon dioxide. Am J Physiol Regul Integr Comp Physiol 288:R1369, 2005

Jones NW, Raine-Fenning N], ]ayaprakasan K, et al: Changes in myometrial "perfusion" during normal labor as visualized by three-dimensional power Doppler angiography. Ultrasound Obstet Gynecol 33:307, 2009 j ung C, Ho ]T, T orpy OJ, et al: A longitudinal study of plasma and urinary cortisol in pregnancy and postpartum. J Clin Endocrinol Metab 96(5):1533, 201r1 Juulia Paavonen E, Saarenpaa-Heikkila 0, P61kki P, et al: Maternal and paternal sleep during pregnancy in the Child-sleepbirth cohort. Sleep Med 29:47,

Kametas NA, McAulife F, Krampl E, et al: Maternal cardiac function in rwin pregnancy. Obstet Gynecol 102:806, 2003

Kasher-Meron M, Mazaki-Tovi S, Barhod E, et al: Chemerin concentrations in maternal and fetal compartments: implications for metabolic adaptations to normal human pregnancy.r] Perinat Med 42:371,r2014

Kauppila A, Chatelain P, Kirkinen P, et al: Isolated prolactin deiciency in a woman with puerperal alactogenesis. J Clin Endocrinol Metab 64:309, 1987

Kauppila A, Koskinen M, Puolakka j, et al: Decreased intervillous and unchanged myometrial blood low in supine recumbency. Obstet Gynecol 55:203, 1980

Keenan PA, Yaldoo DT, Stress ME, et al: Explicit memory in pregnant women.

9: 31, 1998

Keller-Wood M, Wood CE: Pregnancy alters cortisol feedback inhibition of stimulated ACTH: studies in adrenalectomized ewes. Am J Physiol Regul Integr Comp Physiol 280:RI790, 2001

Kenny L, McCrae K, Cunningham FG: Platelets, coagulation, and the liver.

In Taylor RN, Roberts JM, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 2014

Kim HS, Yoon G, Kim BG, et al: Decidualization of intranodal endometriosis in a postmenopausal woman. Int J Clin Exp Pathol 8:1025, 2015 Kinsella SM, Lohmann G: Supine hypotensive syndrome. Obstet Gynecol 83:774, 1994

Kletzky OA, Rossman F, Bertolli S1, et al: Dynamics of human chorionic gonadotropin, prolactin, and growth hormone in serum and amniotic luid throughout normal human pregnancy. Am J Obstet Gynecol 151 :878, 1985

Ko CW, Napolitano PG, Lee SP, et al: Physical activity, matenal metabolic measures, and the incidence of gallbladder sludge or stones during pregnancy: a randomized trial. Am J Perinatol 31:39, 2014

Koenig MD, Tussing-Humphreys L, Day J, et al: Hepcidin and iron homeostasis during pregnancy. Nutrients 6:3062, 2014

Kolarzyk E, Szot WM, Lyszczarz J: Lung function and breathing regulation parameters during pregnancy. Arch Gynecol Obstet 2 2:53, 2005 Korgavkar K, Wang F: Stretch marks during pregnancy: a review of topical prevention. Br J Dermatol 1 2:606,r2015

Koutsaki M, Sifakis S, Zaravinos A, et al: Decreased placental expression of hPGH, IGF-I and IGFBP-1 in pregnancies complicated by fetal growth restriction. Growth Horm IGF Res 21:31, 2011

Kovacs CS, Fuleihan GE: Calcium and bone disorders during pregnancy and lactation. Endocrin Metab Clin North Am 35:21, 2006

Krause BJ, Hanson iA, Casanello P: Role of nitric oxide in placental vascular development and function. Placenta 32(1r1):79 ,201r1

Kuhnert M, Strohmeier R, Stegmuller M: Changes in lymphocyte subsets during normal pregnancy. Eur ] Obstet Gynecol Reprod Bioi 76: 147, 1998

Kulandavelu S, Whiteley KJ, Bainbridge SA, et al: Endothelial NO synthase augments fetoplacental blood low, placental vascularization, and fetal growth in mice. Hypertension 61(1):259, 2013

Kumru S, Boztosun A, Godekmerdan A: Pregnancy-associated changes in peripheral blood lymphocyte subpopulations and serum cytokine concentrations in healthy women. J Reprod Med 50:246, 2005

Lankhorst S, Jan Danser AH, van den Meiracker AH: Endothelin-l and antiangiogenesis. Am J Physiol Regul Integr Comp PhysioIr310:R230, 2016

La Rocca C, Carbone F, Longobardi S, et al: The immunology of pregnancy: regulatory T cells control maternal immune tolerance toward the fetus. Immunol Lett 162:41,r2014

Larsson A, Palm M, Hansson LO, et al: Reference values for clinical chemistry tests during normal pregnancy. BjOG 11r5:874,r2008

Laskowska M, Laskowska K, Oleszczuk J: he relation of maternal serum eNOS, NOSTRlN and ADNiA levels with aetiopathogenesis of preeclampsia and/or intrauterine fetal growth resrriction. J Maten Fetal Neonatal Med 28:26,r2015

Lederman SA, Paxton A, Heymsfield SB, et al: Maternal body fat and water during pregnancy: do they raise infant birth weight? Am ] Obstet Gynecol 180:235, 1999

Lee DH, Park K: Isolated fallopian tube torsion during pregnancy: a case report. Clin Exp Obstet Gynecol 42:681, 2015

Lee HR, Song JE, Lee KY: Developed diplopia and ptosis due to a nonfunctioning pituitary macroadenoma during pregnancy. Obstet Gynecol Sci 57:66,r2014

Leung AM: Thyroid function in pregnancy. J Trace Elem Med Bioi 26(2-3): lr,r2012

Lim PS, Ng SP, Shaiee MN, et al: Spontaneous rupture of uterine varicose veins: a rare cause for obstetric shock. J Obstet Gynaecol Res 40: 1791, 2014

Lim R, Acharya R, Delpachitra P, et al: Activin and NADPH-oxidase in preeclampsia: insights from in vitro and murine studies. Am J Obstet Gynecol 212:86.el, 2015

Lind T, Bell S, Gilmore E, et al: Insulin disappearance rate in pregnant and non-pregnant women, and in non-pregnant women given GHRIH. Eur ] Clin Invest 7:47, 1977

Lindheimer MD, Davison ]M, Katz AI: he kidney and hypertension in pregnancy: twenty exciting years. Semin NephroI21:173, 2001

Lindheimer MD, Griinfeld ]P, Davison ]M: Renal disorders. In Barran WM, Lindheimer MD (eds): Medical Disorders During Pregnancy, 3rd ed. St. Louis, Mosby, 2000, p 39

Lindheimer MD, Kanter D: Interpreting abnormal proteinuria in pregnancy: the need for a more pathophysiological approach. Obstet Gynecol 115(2 Pt 1):365,r2010

Lindheimer MD, Richardson DA, Ehrlich EN, et al: Potassium homeostasis in pregnancy.r] Reprod Med 32:517,r1987

Lippi G, Albiero A, Montagnana M, et al: Lipid and lipoprotein profile in physiological pregnancy. Clin Lab 53: 173, 2007

Liur], Sun B, Yin H, et al: Hepcidin: a promising therapeutic target for iron disorders: a systematic review. Medicine (Baltimore) 95:e3150, 2016

Liu X, Arany Z: Maternal cardiac metabolism in pregnancy. Cardiovasc Res 101:545,r2014 Lowe L, Karbanr]: Genetics, genomics and metabolomics: new insights into maternal metabolism during pregnancy. Diabet Med 31 :254, 2014

Lumbers ER, Pringle KG: Roles of the circulating renin-angiotensin-aldosterone system in human pregnancy. Am] Physiol Regul Integr Comp Physiol 306:R91,r2014

Lynn N, Steinkeler ]A, Wilkins-Haug LE, et al: Hyperreactio luteinalis (enlarged ovaries) during the second and third trimesters of pregnancy: common clinical associations.r] Ultrasound Med 32:1285,r2013

Macedo M, Kim B, Khoury R, et al: A rare case of right lower quadrant abdominal pain. Am] Emerg Med 35(4):668.e1, 2017

Macfie AG, Magides D, Richmond MN, et al: Gastric emptying in pregnancy. Br] Anaesth 67:54, 1991

Mahendru A, Everett TR, Wilkinson IB, et al: Maternal cardiovascular changes from pre-pregnancy to very early pregnancy. ] Hypertens 30(11):2168,r2012

Majed BH, Khalil A: Molecular mechanisms regulating the vascular prostacyclin pathways and their adaptation during pregnancy and in the newborn. Pharmacol Rev 64(3):540, 2012

Malinowski AK, Senr], Sermer M: Hyperreactio luteinalis: maternal and fetal efects.r] Obstet Gynaecol Can 37:715, 2015

Mandala M, 0501 G: Physiological remodeling of the maternal uterine circulation during pregnancy. Basic Clin Pharmacol ToxicolrllO:12, 2012 Mardones-Santander F, Salazar G, Rosso P, et al: Maternal body composition near term and birth weight. Obstet GynecoIr91:873, 1998

Marnach ML, Ramin D, Ramsey PS, et al: Characterization of the relationship between joint laxity and maternal hormones in pregnancy. Obstet Gynecolr101:331,r2003

Maymon R, Zimerman L, Strauss S, et al: Maternal spleen size throughout normal pregnancy. Semin Ultrasound CT MRI 28:64, 2007

McArdle H], Gambling L, Kennedy C: Iron deficiency during pregnancy: the consequences for placental function and fetal outcome. Proc Nutr Soc 73:9, 2014

McAulife F, Kametas N, Costello ], et al: Respiratory function in singleton and twin pregnancy. B]OG 109:765,r2002

McLean KC, Bernstein 1M, Brummel-Ziedins E: Tissue factor-dependent thrombin generation across pregnancy. Am] Obstet GynecoIr207(2):135.e1, 2012 McLennan CE: Antecubital and femoral venous pressure in normal and tox emic pregnancy. Am] Obstet GynecoI45:568, 1943

Mendenhall HW: Serum protein concentrations in pregnancy. 1. Concentrations in maternal serum. Am] Obstet Gynecolr106:388, 1970

Metcalfe], Romney SL, Ramsey LH, et al: Estimation of uterine blood Bow in normal human pregnancy at term.] Clin Invest 34(11): 1632, 1955

Michimata T, Sakai M, Miyazaki S, et al: Decrease ofT-helper 2 and T-cyrotoxic 2 cells at implantation sites occurs in unexplained recurrent spontaneous abortion with normal chromosomal content. Hum Reprod 18:1r523,r2003

Migeon C], Bertrand ], Wall PE: Physiological disposition of 4_14C cortisol during late pregnancy.] Clin Invest 36:1350, 1957

Milne ]A, Howie AD, Pack AI: Dyspnoea during normal pregnancy. B]OG 85:260, 1978

Mittal P, Espinoza], Hassan S, et al: Placental growth hormone is increased in the maternal and fetal serum of patients with preeclampsia. ] Matern Fetal Neonatal Med 20:651, 2007

Moen V, Brudin L, Rundgren M, et al: Osmolality and respiratory regulation in humans: respiratory compensation for hyperchloremic metabolic acidosis is absent after infusion of hypertonic saline in healthy volunteers. Anesth Analg 119:956,r2014

Moleti M, Trimarchi F, Vermiglio F: Thyroid physiology in pregnancy. Endocr Pract 20:589,r2014

M0ller UK, Streym S, Mosekilde L, et al: Changes in calcitropic hormones, bone markers and insulin-like growth factor I (IGF-I) during pregnancy and postpartum: a controlled cohort study. Osteoporos Int 24:1307,r2013

Mor G, Kwon ]Y: Trophoblast-microbiome interaction: a new paradigm on immune regulation. Am] Obstet GynecoIr213:S131, 2015

More C, Bhattoa HP, Bettembuk P, et al: The efects of pregnancy and lactation on hormonal status and biochemical markers of bone turnover. Eur J Obstet Gynecol Reprod Bioi 106:209,r2003

Morris A, Hale SA, Badger G], et al: Pregnancy induces persistent changes in vascular compliance in primiparous women. m] Obstet GynecoIr212:633. e1,r2015

Mumtaz S, AlSaif S, Wray S, et al: Inhibitory efect of visfatin and leptin on human and rat myometrial contractility. Life Sci 125:57,r2015

Myers KM, Feltovich H, Mazza E, et al: The mechanical role of the cervix in pregnancy.r] Biomech 48:1511,r2015

Nelson DB, Stewart D, Matulevicius SA, et al: he efects of maternal position and habitus on maternal cardiovascular parameters as measured by cardiac magnetic resonance. Am] PerinatoI32:1318, 2015

Newbern D, Freemark M: Placental hormones and the control of maternal metabolism and fetal growth. Curr Opin Endocrinol Diabetes Obes 18:409,r2011 Nolten E, Rueckert PA: Elevated free cortisol index in pregnancy: possible regulatory mechanisms. Am ] Obstet Gynecol 139:492, 1981

Odutayo A, Hladunewich M: Obstetric nephrology: renal hemodynamic and metabolic physiology in normal pregnancy. Clin ] Am Soc Nephrol 7:2073, 2012

Ohata Y, Ozono K, Michigami T: Current concepts in perinatal mineral metabolism. Clin Pediatr EndocrinoI25:9, 2016 0ian P, Maltau ]M, Noddeland H, et al: Oedema-preventing mechanisms in subcutaneous tissue of normal pregnant women. B]OG 92: 1113, 1985 Olausson H, Goldberg GR, Laskey A: Calcium economy in human preg nancy and lactation. Nutr Res Rev 25:40,r2012

Oliphant SS, Nygaard IE, Zong W, et al: Vfaternal adaptations in preparation for parturition predict uncomplicated spontaneous delivery outcome. Am ] Obstet GynecoIr211:630.e1, 2014

Ozias MK, Li SQ, Hull HR, et al: Relationship of circulating adipokines to body composition in pregnant women. Adipocyte 4:44, 2015

Pang Y, Dong ], Thomas P: Progesterone increases nitric oxide synthesis in human vascular endothelial cells through activation of membrane progesterone receptor-.. Am] Physiol Endocrinol Metab 308:E899, 2015

Panitchob N, Widdows L, Crocker IP, et al: Computational modeling of amino acid exchange and facilitated transport in placental membrane vesicles.r] heor Bioi 365:352, 2015

Parker CR ]r, Everett RB, Whalley P], et al: Hormone production during pregnancy in the primigravid patients. II. Plasma levels of deoxycorticosterone throughout pregnancy of normal women and women who developed pregnancy-induced hypertension. Am] Obstet Gynecol 138:626, 1980

Pates ]A, Hatab MR, Mcintire DD, et al: Determining uterine blood Bow in pregnancy with magnetic resonance imaging. Magn Reson Imaging 28(4):507,r2010

Pavlova M, Sheikh LS: Sleep in women. Semin NeuroI31(4):397, 2011 Peralta L, Rus G, Bochud N, et al: Mechanical assessment of cervical remodeling in pregnancy: insight from a synthetic model.] Biomech 48: 1557,2015

Perez-Ibave DC, Rodriguez-Sanchez IP, Garza-Rodriguez ML, et al: Extrapituitary growth hormone synthesis in humans. Growth Horm IGF Res 24:47, 2014

Phelps L, Metzger BE, Freinkel N: Carbohydrate metabolism in pregnancy, 17. Diurnal profiles of plasma glucose, insulin, free fatty acids, triglycerides, cholesterol, and individual amino acids in late normal pregnancy. Am ] Obstet Gynecol 140:730, 1981

Picard D, Sellier S, Houivet E, et al: Incidence and risk factors for striae gravidarum. ] Am Acad DermatoIr273:699, 2015

Pitkin M, Reynolds WA, Williams GA, et al: Calcium metabolism in normal pregnancy: a longitudinal study. Amr] Obstet GynecoIr133:781, 1979

Polec A, Fedorcsik P, Eskild A, et al: The interplay of human chorionic gonadotropin (hCG) with basic fibroblast growth factor and adipokines on angiogenesis in vitro. Placenta 35:249,r2014

Pritchard ]A: Changes in the blood volume during pregnancy and delivery.

Anesthesiology 26:393, 1965

Pritchard ]A, Adams RH: Erythrocyte production and destruction during pregnancy. Amr] Obstet Gynecol 79:750, 1960

Pritchard ]A, lason A: Iron stores of normal adults and their replenishment with oral iron therapy.]AMA 190:897, 1964

Pritchard ]A, Scott DE: Iron demands during pregnancy. In Iron DeficiencyPathogeneSis: Clinical Aspects and herapy. London, Academic Press, 1970, p 173

Rabotti C, Mischi M: Propagation of electrical activity in uterine muscle during pregnancy: a review. Acta PhysioIr213:406, 2015

Racicot K, Kwon ]Y, ldo P, et al: Understanding the complexity of the immune system during pregnancy. Am] Reprod Immunol 72: 107,r2014

Redman CW, Sargent IL, Taylor N: Immunology of normal pregnancy and preeclampsia. In Taylor RN, Roberts ]M, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 2014

Resnik ]L, Hong e, Resnik R, et al: Evaluation of B-type natriuretic peptide (BNP) levels in normal and preeclamptic women. Amr] Obstet Gynecol 193:450,r2005

Rezai S, Nakagawa ]T, Tedesco ], et al: Gestational gigantomastia complicating pregnancy: a case report and review of the literature. Case Rep Obstet GynecoIr2015:892369,r2015

Richani K, Soto E, Romero R, et al: Normal pregnancy is characterized by systemic activation of the complement system. J Matern Fetal Neonat Med 17:239, 2005

Robb AO, Din ]N, Mills NL, et al: The influence of the menstrual cycle, normal pregnancy and pre-eclampsia on platelet activation. Thromb Haemost 103:372,r2010

Rosair], Young RH: Javier Arias-Stella and his famous reaction. Int J Gynecol Pathol 34:314, 2015

Rosenfeld CR, DeSpain K, Word A, et al: Diferential sensitivity to angiotensin II and norepinephrine in human uterine arteries. ] Clin Endocrinol Metab 97(1):138, 2012

Rosenfeld CR, Gant NF ] r: The chronically instrumented ewe: a model for studying vascular reactivity to angiotensin II in pregnancy. ] Clin Invest 67:486, 1981

Rubi A, Sala NL: Ureteral function in pregnant women. 3. Efect of diferent positions and of fetal delivety upon ureteral tonus. Amr] Obstet Gynecol 101:230, 1968

Ruiz-Extremera A, Lopez-Garrido A, Barranco E, et al: Activity of hepatic enzymes from week sixteen of pregnancy. Am J Obstet Gyneco1r193:20 1 0, 2005 Rylander R: Magnesium in pregnancy blood pressure and pre-eclampsia-a review. Pregnancy Hypertens 4:146, 2014

Saarelainen H, Laitinen T, Raitakari OT, et al: Pregnancy-related hyperlipidemia and endothelial function in healthy women. Circr] 70:768, 2006 Saleh L, Verdonk K, Visser W, et al: he emerging role of endothelin-l in the pathogenesis of pre-eclampsia. her Adv Cardiovasc Dis 10(5):282, 2016

Sangsawang B: Risk factors for the development of stress urinary incontinence during pregnancy in primigravidae: a review of the literature. Eur J Obstet Gynecol Reprod Bioi 178:27, 2014

Santa LM, Teshima LY, Forero lV, et al: AngiomiRs: potential biomarkers of pregnancy's vascular pathologies. J Pregnancy 2015:320386,2015

Sanz-Salvador L, Garda-Perez A, Tarin ]J, et al: Bone metabolic changes during pregnancy: a period of vulnerability to osteoporosis and fracture. Eur J EndocrinoIr172:R53, 2015

Sarmento Gon:alves I, Malafaia S, Belchior H, et al: Hyperreactio luteinalis encountered during caesarean delivety of an uncomplicated spontaneous singleton pregnancy. BM] Case Rep doi: 10.1136/bcr-2015-211349: 1,r2015

Scheithauer BW, Sano T, Kovacs KT, et al: The pituitary gland in pregnancy: a clinicopathologic and immunohistochemical study of 69 cases. Mayo Clin Proc 65:461, 1990

Schiessl B, Strasburger q, Bidlingmeier M, et al: Role of placental growth hormone in the alteration of maternal arterial resistance in pregnancy. J Reprod Med 52:313, 2007

Schulman A, Herlinger H: Urinary tract dilatation in pregnancy. Br J Radiol 48:638, 1975

Semins M], Matlaga BR: Kidney stones during pregnancy. Nat Rev Urol 11:163,r2014

Shah DA, Khalil A: Bioactive factors in uteroplacental and systemic circulation link placental ischemia to generalized vascular dysfunction in hypertensive pregnancy and preeclampsia. Biochem Pharmacol 95 :211, 2015

Sharief LT, Lawrie AS, Mackie I], et al: Changes in factor XIII level during pregnancy. Hemophilia 20:e 144, 2014

Shibata K, Fukuwatari T, Sasaki S, et al: Urinaty excretion levels of watersoluble vitamins in pregnant and lactating women in Japan.r] Nutr Sci Vitaminol 59:178, 2013

Shin GH, Toto EL, Schey R: Pregnancy and postpartum bowel changes: constipation and fecal incontinence. Am J Gastroenterol 110:521, 2015 Shinagawa S, Suzuki S, Chihara H, et al: Maternal basal metabolic rate in twin pregnancy. Gynecol Obstet Invest 60: 145, 2005

Shnaekel L, Magann EF, Ahmadi S: Pubic symphysis rupture and separation during pregnancy. Obstet Gynecol Surv 70:713,r2015

Siddiqui AH, Tauheed N, hmad A, et al: Pulmonary function in advanced uncomplicated singleton and twin pregnancy. J Bras PneumoI40:244, 2014

Simeone S, Marchi L, Canarutto R, et al: Doppler velocimetry and adverse outcome in labor induction for late IUGR. J Matern Fetal Neonatal Med 30(3):323,r2017

Simpson KR, James DC: Eicacy of intrauterine resuscitation techniques in improving fetal oxygen status during labor. Obstet Gynecolrl05:1362, 2005

Sisti G, Kanninen TT, Witkin SS: Maternal immunity and pregnancy outcome: focus on preconception and autophagy. Genes Immun 17:1,r2016 Song CS, Kappas A: he influence of estrogens, progestins and pregnancy on the liver. Vitam Horm 26:147, 1968

Stephens V, Payne M, Ball RO, et al: Protein requirements of healthy pregnant women during early and late gestation are higher than current recommendations. J Nutr 145:73,r2015

Stewart D, Nelson DB, Matulevicius SA, et al: Cardiac magnetic resonance imaging to assess the impact of maternal habitus on cardiac remodeling during pregnancy. Am] Obstet GynecoI214:640.e1, 2016

Straach KJ, Shelton ]M, Richardson ]A, et al: Regulation of hyaluronan expression during cervical ripening. Glycobiology 15:55, 2005

Sunitha M, Chandrasekharappa S, Brid SV: Electrocradiographic QRS axis, Q wave and T-wave changes in 2nd and 3rd trimester of normal pregnancy. J Clin Diagn Res 8:BC17, 2014

Syed S: Iodine and the "near" eradication of cretinism. Pediatrics 135:594,2015 Tamas p, Szilagyi A, Jeges S, et al: Efects of maternl central hemodynamics on fetal heart rate patterns. Acta Obstet Gynecol Scand 86:71r1, 2007

Taylor BD, Ness RB, Olsenr], et al: Serum leptin measured in early pregnancy is higher in women with preeclampsia compared with normotensive pregnant women. Hypertension 65:594, 2015 homsen ]K, Fogh-Andersen N, Jaszczak P, et al: Atrial natriuretic peptide, blood volume, aldosterone, and sodium excretion during twin pregnancy. Acta Obstet Gynecol Scand 73(1):14,r1994

Thornburg LL, Queenan R, Brandt-Griith B, et al: Procalcitonin for prediction of chorioamnionitis in preterm premature rupture of membranes. ] Matern Fetal Neonatal Med 29:2056, 2016 horpe-Beeston ]G, Nicolaides KH, Snijders R]M, et al: Fetal thyroid-stimulating hormone response to maternal administration of thyrotropin-releasing hormone. Am] Obstet GynecoIr164:1244, 1991

Tsai CH, de Leeuw NK: Changes in 2,3-diphosphoglycerate during pregnancy and puerperium in normal women and in 3-thalassemia heterozygous women. Am] Obstet Gynecol 142:520, 1982

Tsai PJ, Davisr], Bryant-Greenwood G: Systemic and placentalrleptin and its receptors in pregnancies associated with obesity. Reprod Sci 22:189, 2015 Uchikova EH, Ledjev 11: Changes in haemostasis during normal pregnancy.

Eur J Obstet Gynecol Reprod Bioi 119: 185, 2005

Ulmsten U, Sundstrom G: Esophageal manometty in pregnant and nonpregnant women. Am] Obstet Gynecol 132:260, 1978

Valera MC, Parant 0, Vayssiere C, et al: Physiological and pathologic changes of platelets in pregnancy. Platelets 21(8):587, 2010

Van den Akker CH, Schierbeek H, et al: Amino acid metabolism in the human fetus at term: leucine, valine, and methionine kinetics. Pediatr Res 70:566, 2011

Van den Akker CH, Van Goudoever ]B: Recent advances in our understanding of protein and amino acid metabolism in the human fetus. Curr Opin Clin Nutr Metab Care 13:75,r2010 van Veelen GA, Schweitzer KJ, van Hoogenhuijze NE, et al: Association between levator hiatal dimensions on ultrasound during irst pregnancy and mode of delivery. Ultrasound Obstet GynecoI45:333, 2015

Van Wagenen G, Jenkins RH: An experimental examination of factors causing ureteral dilatation of pregnancy. J UroIr42:1010, 1939

Vargas-Rojas MI, Solleiro-Villavicencio H, Soto-Vega E: h1, h2, Th17 and Treg levels in umbilical cord blood in preeclampsia. J Matern Fetal Neonatal Med 29:1642,r2016

Vazquez M], Ruiz-Romero A, Tena-Sempere M: Roles of leptin in reproduction, pregnancy and polycystic ovary syndrome: consensus knowledge and recent developments. Metabolism 64:79, 2015

Vignini A, Cecati M, Nanetti L, et al: Placental expression of endothelial and inducible nitric oxide synthase and NO metabolism in gestational hypertension: a case-control study.] Matern Fetal Neonatal Med 29:576, 2016

Vodstrcil A, Tare M, Novakr], et al: Relaxin mediates uterine artety compliance during pregnancy and increases uterine blood flow. FASEB J 26(10):4035,r2012

V0llestad NK, Torjesen PA, Robinson HS: Association between the serum levels of relaxin and responses to the active straight leg raise test in pregnancy. Man her 17:225,r2012

Vrachnis N, Grigoriadis C, Siristatidis C, et al: he Janus face of maternal serum relaxin: a facilitator of birth, might it also induce preterm birth? J Matern Fetal Neonatal Med 28:218, 2015

Walker Me, Garner PR, Keely EJ, et al: Changes in activated protein C resistance during normal pregnancy. Am J Obstet Gynecol 177: 162, 1997

Wang L, Liu G, Xu Z, et al: Hepcidin levels in hyperprolactinemic women monitored by nanopore thin film based assay: correlation with pregnancyassociated hormone prolactin. N anomedicine. 11: 871, 2015

Wang L, Yang T, Ding Y, et al: Chemerin plays a protective role by regulating human umbilical vein endothelial cell-induced nitric oxide signaling in preeclampsia. Endocrine 48:299, 2015

Wang Y, Kannan A, Nunn L,et al: IgG in cervicovaginal mucus traps HSV and prevents vaginal herpes infections. lucosal Immunol 7: 1036, 2014 Watanabe M, Meeker CI, Gray MJ, et al: Secretion rate of aldosterone in normal pregnancy. J Clin Invest 42:1619, 1963

Watts DH, rohn A, Wener MH, et al: C-reactive protein in normal pregnancy. Obstet Gynecol 77:176,r1991

Waugh J, Bell SC, Kilby MO, et al: Urinary microalbumin/creatinine ratios: reference range in uncomplicated pregnancy. Clin Sci 104:103,r2003 Williams JW: Williams Obstetrics, New York, O. Appleton and Co., 1903 Wilson M, Morganti A, Zervoudakis I, et al: Blood pressure, the renin-aldo sterone system and sex steroids throughout normal pregnancy. Am J Med 68:97, 1980

Wilson MJ, Lopez M, Vargas M, et al: Greater uterine artery blood low during pregnancy in multigenerational (Andean) than shorter-term (European) highaltitude residents. AmJ Physiol Regul Integr Comp Physio1r293:R1313, 200 Wong CA, Lofredi M, Ganchif IN, et al: Gastric emptying of water in term pregnancy. Anesthesiology 96: 1395, 2002

Wong CA, McCarthy RJ, Fitzgerald PC, et al: Gastric emptying of water in obese pregnant women at term. Anesth Analg 105:751,r2007

World Health Organization: Human energy requirements. Food and nutrition technical report series 1. Rome, Food and Agriculture Organization of the United Nations, 2004, p 53

Wright HP, Osborn SB, Edmonds DG: Changes in rate of low of venous blood in the leg during pregnancy, measured with radioactive sodium. Surg Gynecol Obstet 90:481, 1950

Yurteri-Kaplan L, Saber S, Zamudio S: Brain natriuretic peptide in term pregnancy. Reprod Sci 19(5):520,r2012 Zeeman GG, Cunningham FG, Pritchard JA: The magnitude of hemoconcentration with eclampsia. Hypertens Pregnancy 28(2): 127, 2009

Zeeman GG, Hatab M, Twickler OM: Maternal cerebral blood low changes in pregnancies. Am J Obstet Gynecol 189:968,2003

Zimmermann MB: The efects of iodine deiciency in pregnancy and infancy.

Paediatr Perinat Epidemiolr26(Supp 1):108,r2012

OMETRIAL CYCLE. . .... 80

DECIDUA. . .... 85

FORMATION.. ............ . . .... 87

PLACENTA AND CHORION . .90

AMNION . . .... 95

UMBILICAL CORD ................... . . .... ..... 97

PLACENTAL HORMONES. .98

INTERACTIONS. . . . . .... . . . . . . ...... . . . . . .. . ... 104

Almost immediately ater the impamltio1 of the ovum, its trophoblast begins to prolerate and lJ1d, the s.rrounding decidual tissue. As it does so, it breaks through the walls of the moumal capilaries, from which the blood escapes and orms cavities, which are bounded party by trophobast and party by decidua. ?he maternal blood spaces established in this manner represent the earliest stages of the intervillous blood spaces of the inure placenta.

-). Whitridge Williams (1903)

In 1903, the histopathological and embryological descrip tions of ovum implanrarion and placental development had been extensively studied and described. However, the origins and functions of pregnancy hormones were largely unknown. Indeed, it was another 25 to 30 years before estrogen and progesterone were discovered. In the past 50 years, remarkable strides have followed to uncover the steps of implantation and placental structure and function.

All obstetricians should understand the basic biological steps required for women to successully achieve pregnancy. Several abnormalities can fect each of these and lead to infertili' or pregnancy loss. In most women, spontaneous, cyclical ovulation continues during almost 40 years between menarche and menopause. Without contraception, there are approximately 400 opportunities for pregnancy, namely, the day of ovulation and its few preceding days. his narrow window for fertilization is controlled by tightly regulated production of ovarian steroids. Moreover, these hormones promote optimal endometrial regeneration after menstruation in preparation for the next implantation window.

If fertilization occurs, events thac begin ater blastocyst implantation persist until parturition. hese derive from a unique interaction between fetal trophoblasts and the maternal endometrium. which has been transformed into the decidua. The ability of a mother and her fetus to coexist as two distinct immunological systems results from endocrine. paracrine. and immunological modiication of fetal and maternal tissues in a manner not seen elsewhere. In addition. the placenta mediates a unique fetal-maternal communication system. which creates a hormonal environment that initially maintains pregnancy and eventually initiates events leading to parturition.

Predictable. regular. cyclical. and spontaneous ovulatory menstrual cycles are regulated by complex interactions of the hypothalamic-pituitay-ovarian axis. Concurrently, cyclical changes in endometrial histology are faithfully reproduced ;-1). Essentials players in this process include follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which are pituitary-derived gonadotropins, and the ovarian sex steroid hormones estrogen and progesterone.

FIGURE 5-1 Gonadotropin control of the ovarian and endometrial cycles. The ovarian-endometrial cycle has been structured as a 28-day cycle. The follicular phase (days 1 to 14) is characterized by rising estrogen levels, endometrial thickening, and selection of the dominant "ovulatory" follicle. During the luteal phase (days 14 to 21 I, the corpus luteum (ell produces estrogen and progesterone, which prepare the endometrium for implantation. If implantation occurs, the developing blastocyst begins to produce human chorionic gonadotropin (hCG) and rescues the corpus luteum, thus maintaining progesterone production. FSH = follicle-stimulating hormone; LH = luteinizing hormone.

The average cycle duration approximates 28 days but ranges from 25 to 32 days, even for a given woman. The follicular or proliferative phase shows considerable phase-length variation. This contrasts with the luteal or secretory POStovulatory phase of the cycle, which is remarkably constant at 12 to 14 days.

The human ovary contains 2 million oocytes at birth, and approximately 400,000 follicles are present at puberty onset (Baker, 1963). These are depleted at a rate of approximately 1000 follicles per month until age 35, when this rate accelerates (Faddy, 1992). Only 400 follicles are normally released during female reproductive life. Therefore, more than 99.9 percent of these undergo atresia through a process of cell death termed apoptosis (Gougeon, 1996; Kaipia, 1997).

Follicular development consists of several stages. Primordial follicles undergo gonadotropin-independent recruitment from the resting pool and then progress from primary and secondary follicles to the antral stage. This appears to be controlled by locally produced growth factors. Two members of the transforming growth factor-3 family include growth diferentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP-15), which regulate granulosa cell proliferation and diferentiation as primary follicles grow (Trombly, 2009; Yan, 2001). hey also stabilize and expand the cumulus oocyte complex in the oviduct (Hreinsson, 2002). These factors are produced by oocytes, suggesting that the early steps in follicular development are, in part, oocyte controlled. As antral follicles develop, surrounding stromal cells are recruited, by a yet-to-be-deined mechanism, to become thecal cells.

Although not required for early follicular maturation, FSH is required for further development of large antral follicles (Hillier, 2001). During each ovarian FOLLICULAR PHASE LUTEAL PHASE/PREGNANCY cycle. a group of antral follicles, known as a cohon, begins a phase of semisynchro ________ •! CAMP--------.! phase of rhe previous cycle. This FSH increase leading to further follicular developmenr is called the seection winow of

C',,""'.o me ovarian cycle (Macklon, 2001). Only follicles progressing to this stage develop Basement membrane the capacity [Q produce estrogen.

During rhe follicular phase, estro gen levels rise in proportion to growth � of a dominant follicle and {Q rhe , increase in its number of granulosa cells , , l.

(see Fig. 5-1). These cells are rhe exclucAMP sive site of FSH receptor expression. Cholesterol lle elevation of Circulating FSH levels during the late luteal phase of the previous cycle stimulates an increase in FSH FSH receptors and subsequently, the ability

FIGURE 5-2 The two-cell, two-gonadotropin principle of ovarian steroid hormone produc tion. During the follicular phase (left panen, luteinizing hormone (LH) controls theca cell granulosa cells to conven androstenedi production of androstenedione, which diffuses into the adjacent granulosa cells and acts as one into estradiol. The requirement for precursor for estradiol biosynthesis. The granulosa cell capacity to convert androstenedione thecal cells, which respond ro LH, and to estradiol is controlled by follicle-stimulating hormone (FSH), After ovulation (right panen, granulosa cells, which respond to FSH, the corpus luteum forms and both theca-lutein and granulosa-lutein cells respond to LH. represents the two-gonadotropin, twoThe theca-lutein cells continue to produce androstenedione, whereas granulosa-lutein cells ceH hypothesis for estrogen biosynthesis greatly increase their capacity to produce progesterone and to convert androstenedione to estradiol. LH and hCG bind to the same LH-hCG receptor. If pregnancy occurs (right pane�, (Short, 1962). As shown in 5-2, human chorionic gonadotropin (hCG) rescues the corpus luteum through their shared LH hCG receptor. Low-density lipoproteins (LOL) are an important source of cholesterol for sion of the antrum of growing follicles.

steroidogenesis, cAMP =cyclic adenosine monophosphate.

The follicle within the cohorr that is most responsive to FSH is likely to be the irst to produce estradiol and initiate expression of LH precise predictor of ovulation. It occurs 34 to 36 hours before receptors. ovum release from the follicle (see Fig. 5-1). LH secretion peaks

Mrer the appearance of LH receptors, the preovulatory 10 to 12 hours before ovulation and stimulatcs resumption of granulosa cells begin to secrete small quantities of progesterone. meiosis in the ovum and release of the irst polar body. Studies The preovulatory progesterone secrecion, although somewhat suggest that in response to LH, greater progesterone and proslimited, is believed to exert positive feedback on the estrogentaglandin production by the cumulus cells, as well as GDF9 primed pituitary to either calise or augment LH release. In addiand BMP-15 by the oocyte, activates expression of genes critition, during the late follicular phase, LH stimulates thecal cell cal to formarion of a hyaluronan-rich extracellular matrix by production of androgens, particularly androstenedione, which the cumulus complex (Richards, 2007). As seen in are then transferred to the adjacent follicles where they are aroduring synthesis of this matrix, cumulus cells lose contact with matized to esnadiol (see Fig. 5-2). During the early follicular one another and move outward from the oocyte along the hyalphase, granulosa cells also produce in hi bin 3, which can feed uronan polymer-this process is called expansion. This results back on the pituitary to inhibit FSH release (Groome, 1996). in a 20-fold augmentation of the cumulus complex volume and As the dominant foHicle begins to grow, estradiol and inhibin coincides with an LH-induced remodeling of the ovarian extraproduction rises and results in a decline of follicular-phase cellular matrix. hese allow release of the mature oocyte and FSH. This drop in FSH levels is responsible for the failure of its surrounding cumulus cells through the surface epirhelium. other follicles to reach preovulatory status-the Graaian folActivation of proteases likely plays a pivotal role in weakening licle stage-during any one cycle. Thus, 95 percent of plasma the follicular basement membrane and ovulation (Curry, 2006; estradiol produced at this time is secreted by the dominant Ny, 2002). follicle-thc one destined to ovulate. Concurrently, the con tralateral ovary is relatively inactive.

Following ovulation, rhe corpus luteum develops from the remains of the Graaian follicle in a process referred to as The onset of rhe gonadotropin surge resulting from increasluteiniation. The basement membrane separating the granuing estrogen secretion by preovulatory follicles is a relatively losa-lutein and theca-lutein cells breaks down, and by day 2

FIGURE 5-3 An ovulated cumulus-oocyte complex. An oocyte is at the center of the complex. Cumulus cells are widely separated from each other by the hyaluronan-rich extracellular matrix. (Used with permission from Dr. Kevin J. Doody.) postovulation, blood vessels and capillaries invade the granulosa cell layer. The rapid neo�ascularization of the once-avascular granulosa may be due to angiogenic factors that include vas by theca-lutein and granulosa-lutein cells in response to LH (Albrecht, 2003; Fraser, 2001). During luteinization, these cells undergo hypertrophy and increase their capacity to synthesize hormones.

LH is the primary luteotropic factor responsible for corpus luteum maintenance (Vande Wiele, 1970). Indeed, LH injec tions can extend the corpus luteum life span in normal women by 2 weeks (Segalof, 1951).

The hormone secretion pattern of the corpus luteum difers from that of the follicle (see Fig. 5-1). As depicted in Figure 5-2, the greater capacity of granulosa-lutein cells to produce progesterone results from enhanced access to considerably more steroidogenic precursors through blood-borne, low-densiry lipoprotein (LDL)-derived cholesterol (Carr, 1981a). Ovarian progesterone production peaks at 25 to 50 mg/d during the midluteal phase. With pregnancy, the corpus luteum continues progesterone production in response to placental human chorionic gonadotropin (hCG), which binds to the same receptor as LH.

Estrogen levels follow a more complex pattern of secretion.

Specifically, just after ovulation, estrogen levels decline, but then exhibit a secondary rise that reaches a peak production of 0.25 mg/d of 173-estradiol in the midluteal phase. Toward the end of the luteal phase, estradiol production again drops.

The human corpus luteum is a transient endocrine organ that, in the absence of pregnancy, will rapidly regress 9 to 11 days after ovulation via apoptosis (Vaskivuo, 2002). The mechanisms that control luteolysis, that is, the regression of the corpus luteum, remain unclear. However, it results in part from dropping levels of circulating LH in the late luteal phase and rising LH insensitivity by luteal cells (Duncan, 1996; Filicori, 1986). he role of other factors is less established. The dramatic drop in circulating estradiol and progesterone levels initiate molecular events that lead to menstruation.

Estrogen is the essential hormonal signal on which most events in the normal menstrual cycle depend. They function in many cell types to regulate follicular development, uterine receptivity, and blood flow. The most biologically potent naturally occur ring estrogen is 173-estradiol, which is secreted by granulosa cells of the dominant follicle and luteinized granulosa cells of the corpus luteum. Estradiol action is complex and appears estrogen receptor a (ERa) and 3 (ER3) (Katzen ellenbogen, 2001). These isoforms are the products of separate genes and can exhibit distinct tissue expression. Both estradiol-receptor complexes act as transcriptional factors that become associ ated with the estrogen-response element of speciic genes. They share a robust activation by estradiol. However, diferences in their binding ainities to other estrogens and their cell-speciic may have both distinct and overlapping function (Saunders, 2005).

Most progesterone actions on the female reproductive tract are mediated through the nuclear hormone receptors, progesterone-receptor type A (PR-A) and B (PR-B). Progesterone enters cells by difusion, and in responsive tissues it becomes associated with its receptors (Conneely, 2002). Progesteronereceptor isoforms arise from a single gene and regulate transcription of target genes. hese receptors have unique actions. When PR-A and PR-B receptors are coexpressed, it appears that PR-A can inhibit PR-B gene regulation. The endometrial glands and stroma appear to have diferent expression patterns for progesterone receptors that vary during the menstrual cycle (Mote, 1999).

Progesterone can also evoke rapid responses, such as changes in intracellular free calcium levels, which cannot be explained by genomic mechanisms. G-protein-coupled membrane receptors for progesterone have been identiied, but their role in the ovarian-endometrial cycle remains to be elucidated (Peluso, 2007).

In the endometrium, epithelial cells line the endometrial glands and are supported by stromal cells. These cells and supplying blood vessels replicate rapidly and cyclically in reproductiveaged women and are regenerated each ovarian-endometrial cycle. The superficial endometrium, termed the functionalis layer, is shed and reconstructed from the deeper basalis layer (Fig. 5-4). There is no other example in humans of such cyclical shedding and regrowth of an entire tissue.

Fluctuations in estrogen and progesterone levels produce striking efects on the endometrium. Follicular-phase estradiol production is the most important factor in endometrial recovery following menstruation, and both ERa and ER3 receptors are expressed here. Although up to rwo thirds of the functionalis endometrium is fragmented and shed with menses, reepithelialization begins even before menstrual bleeding has ceased. By the fifth day of the endometrial cycle-ifth day of menses-the

FIGURE 5-4 The endometrium consists of two layers, the functionalis layer and basalis layer. These are supplied by the spiral and basal arteries, respectively. Numerous glands also span these layers. As the menstrual cycle progresses, greater coiling of the spiral arteries and increased gland folding can be seen. Near the end of the menstrual cycle (day 27), the coiled arteries constrict, deprive blood supply to the functionalis layer, and lead to necrosis and sloughing of this layer.

epithelial surface of the endometrium has been restored, and revascularization has begun. he preovulatory endometrium is characterized by proliferation of glandular, stromal, and vascular endothelial cells. During the early part of the proliferative phase, the endometrium is usually less than 2 mm thick. he glands are narrow, tubular structures that pursue almost a straight and parallel course from the basalis layer toward the endometrial cavity. Mitotic igures, especially in the glandular epithelium, are identiied by the fifth cycle day. Mitotic activity in both epithelium and stroma persists until day 16 to 17, that is, 2 to 3 days after ovulation. Blood vessels are numerous and prominent.

Clearly, reepithelialization and angiogenesis are important to cessation of endometrial bleeding (Chennazhi, 2009; Rogers, 2009). hese are dependent on tissue regrowth, which is estrogen regulated. Epithelial cell growth also is regulated in part by epidermal growth factor and transforming growth factor a (TGPa). Stromal cells proliferate through paracrine and autocrine actions of estrogen and greater local levels of fibroblast growth factor-9 (Tsai, 2002). Estrogens also raise local production ofVEGF, which causes angiogenesis through vessel elongation in the basalis (Gargett, 2001; Sugino, 2002).

By the late proliferative phase, the endometrium thickens from both glandular hyperplasia and augmented stromal ground substance, which is edema and proteinaceous material. he loose stroma is especially prominent, and the glands in the functionalis layer are widely separated. his is compared with those of the basalis layer, in which the glands are more crowded and the stroma is denser.

At midcycle, as ovulation nears, glandular epithelium becomes taller and pseudostratiied. he surface epithelial cells acquire numerous microvilli, which increase epithelial surface area, and develop cilia, which move endometrial secretions during the secretory phase (Perenczy, 1976).

After ovulation, the estrogen-primed endometrium responds to rising progesterone levels in a highly predictable manner. By day 17, glycogen accumulates in the basal portion of glandular epithelium, creating subnuclear vacuoles and pseudostratification. hese changes likely result from direct progesterone action through receptors expressed in glandular cells (Mote, 2000). On day 18, vacuoles move to the apical portion of the secretory non ciliated cells. By day 19, these cells begin to secrete glycoprotein and mucopolysaccharide contents into the gland lumen (Hafez, 1975). Glandular cell mitosis ceases with secretory activity due to rising progesterone levels, which antagonize the mitotic efects of estrogen. Estradiol action also diminishes because of glandular expression of the type 2 isoform of 173-hydroxysteroid dehydrogenase. his converts estradiol to the less active estrone (Casey, 1996). On cycle days 21 to 24, the stroma becomes edematous. Next, on days 22 to 25, stromal cells surrounding the spiral arterioles begin to enlarge, and stromal mitosis becomes apparent. Days 23 to 28 are characterized by pre decidual cells, which surround spiral arterioles.

Between days 22 and 25, the secretory-phase endometrium undergoes striking changes associated with predecidual transformation of the upper two thirds of the functionalis layer. The glands exhibit extensive coiling, and luminal secretions become visible. Changes within the endometrium also can mark the so-called window of implantation seen on days 20 to 24. Epithelial surface cells show fewer microvilli and cilia, but luminal protrusions appear on the apical cell surface (Nikas, 2003). hese pinopodes help prepare for blastocyst implantation. hey also coincide with changes in the surface glycocalyx that allow acceptance of a blastocyst (Aplin, 2003).

Another highlight of the secretory phase is the continuing growth and development of the spiral arteries. hese vessels arise from the radial arteries, which are myometrial branches of the arcuate and, ultimately, uterine vessels (see Fig. 5-4).

he morphological and functional properties of the spiral arter ies are unique and essential to blood flow changes seen during menstruation or implantation. During endometrial growth, spiral arteries lengthen at a rate appreciably greater than the rate of endometrial tissue thickening. his growth discordance obliges even greater coiling. Spiral artery development relects a marked induction of angiogenesis, with widespread vessel sprouting and extension. Such rapid angiogenesis is regulated, in part, through estrogen-and progesterone-regulated synthesis ofVEGF (Ancelin, 2002; Chennazhi, 2009).

The midluteal-secretory phase of the endometrial cycle is a tiation. With corpus luteum rescue and continued progesterone secretion, the endometrium is transformed into the decidua.

With luteolysis and declining luteal progesterone production, events leading to menstruation are initiated (Critchley, 2006;

Thiruchelvam, 2013).

In the late premenstrual-phase endometrium, the stroma is invaded by neutrophils to create a pseudo inflammatory appearance. These cells iniltrate primarily on the day or two immediately preceding menses onset. he endometrial stromal and epithelial cells produce interleukin-8 (IL-8), a chemotactic-activating factor for neutrophils (Arici, 1993). Similarly, monocyte chemotactic protein-1 (MCP-1) is synthesized by endometrium and promotes monocyte recruitment (Arici, 1995).

Leukocyte iniltration is considered key to both endometrial extracellular matrix breakdown and repair of the functionalis layer. The term "inflammatory tightrope" refers to the ability of macrophages to assume phenotypes that vary from proinflammatory and phagocytic to immunosuppressive and reparative. These are likely relevant to menstruation, in which tissue breakdown and restoration occur simultaneously (Evans, 2012; Maybin, 2015). Invading leukocytes secrete enzymes that are members of the matrix metalloprotease (MMP) family. These add to the proteases already produced by endometrial stromal cells and efectively initiate matrix degradation. During menses as tissue shedding is completed, microenvironment-regulated changes in macrophage phenotype then promote repair and resolution (Evans, 2012; Thiruchelvam, 2013).

The classic study by Markee (1940) described tissue and vascular alterations in endometrium before menstruation. With endometrial regression, spiral artery coiling becomes suiciently severe that resistance to blood flow rises to cause endometrial hypoxia. Resultant stasis is the primary cause of endometrial ischemia and tissue degeneration. Intense spiral artery vasoconstriction precedes menstruation and also serves to limit menstrual blood loss.

Prostaglandins playia key role in the events leading to menstruation that include vasoconstriction, myometrial contractions, and upregulation of proinflammatory responses (Abel, 2002).

Large amounts of prostaglandins are present in menstrual blood. Painful menstruation is common and likely caused by myometrial contractions and uterine ischemia. This response is believed to be mediated by prostaglandin F2a (PGF2a)-induced spiral artery vasoconstriction, which render the uppermost endometrial zones hypoxic. The hypoxic environment is a potent inducer of angiogenesis and vascular permeability factors such as VEGF.

Progesterone withdrawal increases expression of cyclooxygenase 2 (COX-2), also called prostaglandin synthase 2, to synthesize prostaglandins. Withdrawal also lowers expression of 15-hydroxyprostaglandin dehydrogenase (PGDH), which degrades prostaglandins (Casey, 1980, 1989). The net result is higher prostaglandin production by endometrial stromal cells and greater prostaglandin-receptor density on blood vessels and surrounding cells.

Actual menstrual bleeding follows rupture of spiral arterioles and consequent hematoma formation. With a hematoma, the superficial endometrium is distended and ruptures. Subsequently, fissures develop in the adjacent functionalis layer, and blood and tissue fragments are sloughed. Hemorrhage stops with arteriolar constriction. Changes that accompany partial tissue necrosis also serve to seal vessel tips.

he endometrial surface is restored by growth of langes, or collars, that form the everted free ends of the endometrial glands (Markee, 1940). These flanges rapidly grow in diameter, and epithelial continuity is reestablished by fusion of the edges of these sheets of migrating cells.

his is a specialized, highly modiied endometrium of pregnancy. It is essential for hemochorial placentation, that is, one in which maternal blood contacts trophoblasts. This relationship requires trophoblast invasion, and considerable research has focused on the interaction between decidual cells and invading trophoblasts. Decidualization, that is, transformation oO proliferating endometrial stromal cells into specialized secretory cells, is dependent on estrogen, progesterone, androgens, and factors secreted by the implanting blastocyst (Gibson, 2016). The decidua produces factors that regulate endometrial receptivity and modulate immune and vascular cell functions within the maternal-fetal microenvironment. The special relationship existing between the decidua and the invading trophoblasts ensures success of the pregnancy semiallograft yet seemingly deies the laws of transplantation immunology.

The decidua is classiied into three parts based on anatomical location. Decidua directly beneath blastocyst implantation is modiied by trophoblast invasion and becomes the decidua basalis. The decidua capsularis overlies the enlarging blastocyst and initially separates the conceptus from the rest of the uterine cavity (Fig. 5-5). This portion is most prominent during the second month of pregnancy and consists of stromal decidual cells covered by a single layer of lattened epithelial cells. Internally, it contacts the avascular, extraembryonic fetal membrane-the chorion laeve. he remainder of the uterus is lined by decidua parietalis. During early pregnancy, there is a space between the decidua capsularis and parietalis because the gestational sac does not fill the entire uterine cavity. The gestation sac is the extraembryonic coelom and also called the chorionic cavity. By 14 to 16 weeks' gestation, the expanding sac has enlarged to completely ill the uterine cavity. The resulting apposition of the decidua capsularis and parietalis creates the decidua vera, and the uterine cavity is functionally obliterated.

Decidua basalis Cervical canal parietal is Chorionic villi cavity

FIGURE 5-5 Three portions of the decidua-the basalis, capsularis, and parietalis-are illustrated.

In early pregnancy, the decidua begins to thicken, eventually attaining a depth of 5 to 10 mm. With magnification, furrows and numerous small openings, representing the mouths of uterine glands, can be detected. Later in pregnancy, the decidua becomes thinner, presumably because of pressure exerted by the expanding uterine contents.

he decidua parietalis and basalis are composed of three layers. here is a surface or compact zone-zona compacta; a middle portion or spongy zone-zona spongiosa-with remnants of glands and numerous small blood vessels; and a basal zone-zona basalis. The zona compacta and spongiosa together form the zona functionalis. The basal zone remains after delivery and gives rise to new endometrium.

In human pregnancy, the decidual reaction is completed only with blastocyst implantation. Predecidual changes, however, commence irst during the midluteal phase in endometrial stromal cells adjacent to the spiral arteries and arterioles. hereafter, they spread in waves throughout the uterine endometrium and then from the implantation site. The endometrial stromal cells enlarge to form polygonal or round decidual cells. he nuclei become vesicular, and the cytoplasm becomes clear, slightly basophilic, and surrounded by a translucent membrane.

As a consequence of implantation, the blood supply to the decidua capsularis is lost as the embryo-fetus grows. Blood supply to the decidua parietalis through spiral arteries persists. These arteries retain a smooth-muscle wall and endothelium and thereby remain responsive to vasoactive agents.

In contrast, the spiral arterial system that supplies the decidua basalis and ultimately the placental intervillous space is altered remarkably. These spiral arterioles and arteries are invaded by trophoblasts, and during this process, the vessel walls in the basalis are destroyed. Only a shell without smooth muscle or endothelial cells remains. Importantly, as a result, these vascular conduits of maternal blood-which become the utero placental vessels-are unresponsive to vasoactive agents. Conversely, the fetal chorionic vessels, which transport blood between the placenta and the fetus, contain smooth muscle and thus do respond to vasoactive agents.

Early in pregnancy, the zona spongiosa of the decidua consists of large distended glands, often exhibiting marked hyperplasia and separated by minimal stroma. At first, the glands are lined by typical cylindrical uterine epithelium with abundant secretory activity that contributes to blastocyst nourishment. With advanced pregnancy, the glandular elements largely disappear.

he decidua basalis contributes to formation of the placental basal plate (Fig. 5-6). he spongy zone of the decidua basalis consists mainly of arteries and widely dilated veins, and by term, glands have virtually disappeared. Also, the decidua basalis is invaded by many interstitial trophoblasts and trophoblastic giant cells. Although most abundant in the decidua, the giant cells commonly penetrate the upper myometrium. Their number and invasiveness can be so extensive as to resemble choriocarcinoma.

The Nitabuch layer is a zone of fibrinoid degeneration in which invading trophoblasts meet the decidua basalis. If the decidua is defective, as in placenta accreta, the Nitabuch layer is usually absent (Chap. 41, p. 778). here is also a more supericial, but inconsistent, deposition of ibrin-Rohr stria-at the bottom of the intervillous space and surrounding the anchoring

FIGURE 5-6 Section through a junction of chorion, villi, and decidua basalis in early first-trimester pregnancy. (Used with permission from Dr. Kurt Benirschke.) villi. Decidual necrosis is a normal phenomenon in the irst and probably second trimesters (McCombs, 1964). hus, necrotic decidua obtained through curettage after spontaneous abortion in the irst trimester should not necessarily be interpreted as either a cause or an efect of the pregnancy loss.

Both decidua types contain numerous cell groups whose composition varies with gestational stage (Loke, 1995). he primary cellular components are the true decidual cells, which diferentiated from the endometrial stromal cells, and numerous maternal bone marrow-derived cells. Accumulation of lymphocytes with unique properties at the maternal-fetal interface is essential to evoke tolerance mechanisms that prevent maternal immune rejection of the fetus. These include regulatolY T cells, decidual macrophages, and decidual natural killer cells. Collectively, these cells not only provide immunotolerance but also play an important role in trophoblast invasion and vasculogenesis (PrabhuDas, 2015).

In addition to placental development, the decidua potentially provides other functions. The decidua is the source of prolactin, which is present in enormous amounts in amnionic luid (Colander, 1978; Riddick, 1979). Decidual prolactin is a product of the same gene that encodes for anterior pituitary prolactin, but the exact physiological role of decidual prolactin is unknown. Notably, decidual prolactin is not to be confused with placental lactogen (hPL), which is produced only by syncytiotrophoblast.

Prolactin preferentially enters amnionic luid, and little enters maternal blood. Consequently, prolactin levels in amnionic luid are extraordinarily high and may reach 10,000 ng/mL at 20 to 24 weeks' gestation (Tyson, 1972). This compares with fetal serum levels of 350 ng/mL and maternal serum levels of 150 to 200 ngl mL. As a result, decidual prolactin is a classic example of paracrine function between maternal and fetal tissues.

The ferus is dependent on the placenta for pulmonary, hepatic, and renal functions. These are accomplished through the anatomical relationship of the placenta and its uterine interface. In overview, maternal blood spurts from uteroplacental vessels into the placental intervillous space and bathes the outer syncytiotrophoblast. his allows exchange of gases, nutrients, and other substances with fetal capillary blood within the core of each villus. hus, fetal and maternal blood does not normally mix in this hemochorial placenta. A paracrine system also links mother and ferus through the anatomical and biochemical juxtaposition of the maternal decidua parietalis and the extraembryonic chorion laeve, which is fetal. This is an extraordinarily important arrangement for communication between fetus and mother and for maternal immunological acceptance of the conceptus (Cuzeloglu-Kayisli, 2009).

With ovulation, the secondary oocyte and adhered cells of the cumulus-oocyte complex are freed from the ovary. Although technically this mass of cells is released into the peritoneal cavity, the oocyte is quickly engulfed by the fallopian tube infundibulum. Further transport through the tube is accomplished by directional movement of cilia and tubal peristalsis. Fertilization, which normally occurs in the oviduct, must take place within a few hours, and no more than a day after ovulation. Because of this narrow window, spermatozoa must be present in the fallopian tube at the time of oocyte arrival. Almost all pregnancies result when intercourse occurs during the 2 days preceding or on the day of ovulation.

Fertilization is highly complex. Molecular mechanisms allow spermatozoa to pass between follicular cells; through the zona pellucida, which is a thick glycoprotein layer surrounding the oocyte cell membrane; and into the oocyte cytoplasm. Fusion of the two nuclei and intermingling of maternal and paternal chromosomes creates the zygote.

Early human development is described by days or weeks postfertilization, that is, postconceptional. By contrast, in most chapters of this book, clinical pregnancy dating is calculated from the irst day of the last menstrual period (LMP). hus, 1 week postfertilization corresponds to approximately 3 weeks from the LMP in women with regular 28-day cycles. As an example, 8 weeks' gestation refers to 8 completed weeks following the LMP.

After fertilization, the zygote-a diploid cell with 46 chromosomes-undergoes cleavage, and zygote cells produced by this division are called blastomeres (Fig. 5-7). In the two-cell

FIGURE 5-7 Zygote cleavage and blastocyst formation. The morula period begins at the 12-to 16-cell stage and ends when the blastocyst forms, which occurs when there are 50 to 60 blastomeres present. The polar bodies, shown in the 2-cell stage, are small nonfunctional cells that soon degenerate.

zygote, the blastomeres and polar body continue to be surrounded by the zona pellucida. he zygote undergoes slow cleavage for 3 days while still remaining in the fallopian tube. As the blastomeres continue to divide, a solid mulberry-like ball of cells-the morula-is produced. The morula enters the uterine cavity approximately 3 days after fertilization. Gradual accumulation of luid beween the morula cells leads to formation of the early blastocyst.

As early as 4 to 5 days after fertilization, the 58-cell blastula diferentiates into ive embryo-producing cells-the inner cel mass (see Fig. 5-7). he remaining 53 outer cells, called the trophectoderm, are destined to form trophoblasts (Hertig, 1962).

Interestingly, the 107 -cell blastocyst is found to be no larger than the earlier cleavage stages, despite the accumulated fluid within the blastocyst cavity. At this stage, the eight formative, embryo-producing cells are surrounded by 99 trophoblastic cells. And, the blastocyst is released from the zona pellucida secondary to secretion of specific proteases from the secretoryphase endometrial glands (O'Sullivan, 2002).

Release from the zona pellucida allows blastocyst-produced cytokines and hormones to directly influence endometrial receptivity (Lindhard, 2002). IL-la and IL-lj are secreted by the blastocyst, and these cytokines likely directly influence the endometrium. Embryos also have been shown to secrete hCG, which may influence endometrial receptivity (Licht, 2001; Lobo, 2001). The receptive endometrium is thought to respond by producing leukemia inhibitoY factor (LIF), follistatin, and colony-stimulating factor-l (CSF-l). LIF and follistatin activate signaling pathways that collectively inhibit proliferation and promote diferentiation of the endometrial epithelia and stroma to enable uterine receptivity (Rosario, 20 16b). At the maternal-fetal interface, CSF-1 has proposed immunomodulatory actions and pro angiogenic actions that are required for implantation (Rahmati, 2015).

Six or 7 days after fertilization, the blastocyst implants into the uterine wall. This process can be divided into three phases: (1) apposition-initial contact of the blastocyst to the uterine wall; (2) adhesion-increased physical contact between the blastocyst and decidua; and (3) invasion-penetration and invasion of syncytiotrophoblast and cytotrophoblasts into the decidua, inner third of the myometrium, and uterine vasculature.

Successful implantation requires a receptive endometrium appropriately primed with estrogen and progesterone by the corpus luteum. Such uterine receptivity is limited to days 20 to 24 of the cycle. Adherence is mediated by cell-surface receptors at the implantation site that interact with blastocyst receptors (Carson, 2002; Lessey, 2002; Lindhard, 2002). If the blastocyst approaches the endometrium after cycle day 24, the potential for adhesion is diminished because antiadhesive glycoprotein synthesis prevents receptor interactions (N avot, 1991).

At the time of its interaction with the endometrium, the blastocyst is composed of 100 to 250 cells. The blastocyst loosely adheres to the decidua by apposition. This most commonly occurs on the upper posterior uterine wall. Attachment of the blastocyst trophectoderm to the decidual surface by apposition and adherence appears to be closely regulated by paracrine interactions between these two tissues.

Successful endometrial blastocyst adhesion involves modiication in expression of cellular adhesion molecules (CMs). The integrins-one of four families of CAMs-are cell-surface receptors that mediate cell adhesion to extracellular matrix proteins (Lessey, 2002). Endometrial integrins are hormonally regulated, and a specific set of integrins is expressed at implantation (Lessey, 1995). Recognition-site blockade of integrins needed for binding will prevent blastocyst attachment (Kaneko, 2013).

Human placental formation begins with the trophectoderm, which gives rise to a trophoblast cell layer encircling the blastocyst. From then until term, trophoblasts playia critical part at the fetal-maternal interface. Trophoblasts exhibit the most variable structure, function, and developmental pattern of all placental components. Their invasiveness promotes implantation, their nutritional role for the conceptus is relected in their name, and their endocrine organ function is essential to maternal physiological adaptations and to pregnancy maintenance.

By the eighth day postfertilization, after initial implantation, trophoblasts have diferentiated into an outer multinucleated syncytium-primitive syncytiotrophoblast, and an inner layer of primitive mononuclear cells-cytotrophoblasts. The latter are germinal cells for the syncytium. As cytotrophoblasts proliferate, their cell walls disappear, and the cells fuse to add to the expanding outer layer of syncytiotrophoblast. Each cytotrophoblast has a well-demarcated cell border, a single nucleus, and ability to undergo DNA synthesis and mitosis (Arnholdt, 1991). These are lacking in the syncytiotrophoblast, which provides transport functions of the placenta. It is so named because instead of individual cells, it has an amorphous cytoplasm without cell borders, nuclei that are multiple and diverse in size and shape, and a continuous syncytial lining. This coniguration aids transport.

After implantation is complete, trophoblasts further differentiate along two main pathways, giving rise to villous and extravillous trophoblasts. As shown in Figure 5-8, both have distinct functions (Loke, 1995). Villous trophoblasts generate chorionic villi, which primarily transport oxygen, nutrients, and other compounds between the fetus and mother. Extravillous trophoblasts migrate into the decidua and myometrium and also penetrate maternal vasculature, thus coming into contact with various maternal cell types (Pijnenborg, 1994). Extravillous trophoblasts are further classiied as interstitial trophoblasts and endovascular trophoblasts. he interstitial trophoblasts invade the decidua and eventually penetrate the myometrium to form placental-bed giant cells. These trophoblasts also surround spiral arteries. The endovascular trophoblasts penetrate the spiral artery lumens (Pijnenborg, 1983). hese are both discussed in greater detail in subsequent sections.

Early End of 1st pregnancy trimester

FIGURE 5-8 Extravillous trophoblasts are found outside the villus and can be subdivided into endovascular and interstitial categories. Endovascular trophoblasts invade and transform spiral arteries during pregnancy to create low-resistance blood flow that is characteristic of the placenta. Interstitial trophoblasts invade the decidua and surround spiral arteries.

After gentle erosion between epithelial cells of the surface endometrium, invading trophoblasts burrow deeper. At 9 days of development, the blastocyst wall facing the uterine lumen is a single layer of lattened cells. By the 10th day, the blastocyst becomes totally encased within the endometrium (Fig. 5-9). he blastocyst wall opposite the uterine lumen is thicker and comprises two zones-the trophoblasts and the embryo-forming inner cell mass. As early as 7Y2 days postfertilization, the inner cell mass or embryonic disc diferentiates into a thick plate of primitive ectoderm and an underlying layer of endoderm. Some small cells appear between the embryonic disc and the trophoblasts and enclose a space that will become the amnionic cavity.

FIGURE 5-9 Drawing of sections through implanted blastocysts. A. At 10 days. B. At 12 days ater fertilization. This stage is characterized by the intercommunication of the lacunae filled with maternal blood. Note in (B) that large cavities have appeared in the extraembryonic mesoderm, forming the beginning of the extraembryonic coelom. Also note that extraembryonic endodermal cells have begun to form on the inside of the primitive yolk sac. (Redrawn from Moore KL, Persaud, W, Torchia, MG (eds): The Developing Human. Clinically Oriented Embryology, 9th edition, Philadelphia, Saunders, 201o3.)

Extraembryonic mesenchyme first appears as groups of isolated cells within the blastocyst cavity, and later this mesoderm completely lines the cavity. Spaces form and then fuse within the extraembryonic mesoderm to form the chorionic cavity (extraembryonic coelom). The chorion is composed of trophoblasts and mesenchyme. Some mesenchymal cells eventually will condense to form the body stalk. his stalk joins the embryo to the nutrient chorion and later develops into the umbilical cord. The body stalk can be recognized at an early stage at the caudal end of the embryonic disc (Fig. 7-3, p. 126).

As the embryo enlarges, more maternal decidua basalis is invaded by syncytiotrophoblast. Beginning approximately 12 days after conception, the syncytiotrophoblast is permeated

FIGURE 5-10 Electron micrograph of term human placenta villus. A villus capillary filled with fetal red blood cells (asterisks) is seen in close proximity to the microvilli border. (Reproduced with permission from Boyd JD, Hamilton WJ: The Human Placenta. Cambridge, Heffer, 1970.) 90 Placentation, Embryogenesis, and Fetal Development by a system of intercommunicating channels called trophoblastic lacunae. After invasion of supericial decidual capillary walls, lacunae become filled with maternal blood. At the same time, the decidual reaction intensifies in the surrounding stroma. This is characterized by decidual stromal cell enlargement and glycogen storage.

With deeper blastocyst invasion into the decidua, solid primary villi arise from buds of cytotrophoblasts that protrude into the primitive syncytium before 12 days postfertilization. Primary villi are composed of a cytotrophoblast core covered by syncytiotrophoblast. s the lacunae join, a complicated labyrinth is formed that is partitioned by these solid cytotrophoblastic columns. The trophoblast-lined channels form the intervillous space, and the solid cellular columns form theprimay villous stalks.

Beginning on approximately the 12th day after fertilization, mesenchymal cords derived from extraembryonic mesoderm invade the solid trophoblast columns. These form seconday villi. Once angiogenesis begins in the mesenchymal cords, tertiay villi are formed. Although maternal venous sinuses are tapped early in implantation, maternal arterial blood does not enter the intervillous space until around day 15. By approximately the 17th day, however, fetal blood vessels are functional, and a placental circulation is established. The fetal-placental circulation is completed when the blood vessels of the embryo are connected with chorionic vessels. In some villi, angiogenesis fails from lack of circulation. They can be seen normally, but the most striking exaggeration of this process is seen with hydatidiform mole (Fig. 20-1, p. 389).

Villi are covered by an outer layer of syncytiotrophoblast and an inner layer of cytotrophoblasts, which are also known as Langhans cels. Cytotrophoblast proliferation at the villous tips produces the trophoblastic cell columns that form anchoring villi. hey are not invaded by fetal mesenchyme, and they are anchored to the decidua at the basal plate. Thus, the base of the intervillous space faces the maternal side and consists of cytotrophoblasts from cell columns, the covering shell of syncytiotrophoblast, and maternal decidua of the basal plate. The base of the chorionic plate forms the roof of the intervillous space. It consists of two layers of trophoblasts externally and fibrous mesoderm internally. The "deinitive" chorionic plate is formed by 8 to 10 weeks as the amnionic and primary chorionic plate mesenchyme fuse together. This formation is accomplished by expansion of the amnionic sac, which also surrounds the connective stalk and the allantois and joins these structures to form the umbilical cord (Kaufmann, 1992).

Interpretation of the ine structure of the placenta came from electron microscopic studies of Wislocki and Dempsey (1955). There are prominent microvilli on the syncytial surface that correspond to the so-called brush border described by light microscopy. Associated pinocytotic vacuoles and vesicles are related to absorptive and secretory placental functions. Microvilli act to increase surface area in direct contact with maternal blood. This contact between the trophoblast and maternal blood is the deining characteristic of a hemochorial placenta (Fig. 5-10).

In early pregnancy, the villi are distributed over the entire periphery of the chorionic membrane (Fig. 5-11). As the blastocyst with its surrounding trophoblasts grows and expands into the decidua, one pole faces the endometrial cavity. he opposite pole will form the placenta. Here, chorionic villi in contact with the decidua basalis proliferate to form the chorion rondosumor leay chorion. As growth of embryonic and extraembryonic tissues continues, the blood supply to the chorion facing the endometrial cavity is restricted. Because of this, villi in contact with the decidua capsularis cease to grow and then degenerate. his portion of the chorion becomes the avascular fetal membrane that abuts the decidua parietalis and is called the chorion laeve-or smooth chorion. This smooth chorion is composed of cytotrophoblasts and fetal mesodermal mesenchyme.

Until near the end of the third month, the chorion laeve is separated from the amnion by the exocoelomic cavity. hereater, they are in intimate contact to form an avascular amniochorion. These two structures are important sites of molecular transfer and metabolic activity. Moreover, they constitute an important paracrine arm of the fetal-maternal communication system.

• Regulators of Trophoblast Invasion

Implantation and endometrial decidualization activate a unique population of maternal immune cells that iniltrate the uterus and play critical functions in trophoblast invasion, angiogenesis, spiral artery remodeling, and maternal tolerance to fetal alloantigens. Decidual natural killer cells (dNK) make up 70 percent of decidual leukocytes in the first trimester and are found in direct contact with trophoblasts. In contrast to natural killer cells in peripheral blood, these cells lack cytotoxic functions. They produce specific cytokines and angiogenic factors to regulate invasion of fetal trophoblasts and spiral artery remodeling (Hanna, 2006). hese and other unique properties distinguish dNK cells from circulating natural killer cells and from natural killer cells in the endometrium before pregnancy (Fu, 2013; Winger, 2013). dNK cells express both IL-8 and interferoninducible protein-1 0, which bind to receptors on invasive trophoblastic cells to promote their decidual invasion toward the spiral arteries. dNK cells also produce proangiogenic factors, including VEGF and placental growth factor (PIGF), which both promote vascular growth in the decidua.

FIGURE 5-1 1 Complete abortion specimens. A. Initially, the entire chorionic sac is covered with villi, and the embryo within is not visible B. With further growth, stretch and pressure prompt partial regression of the villi. Remaining villi form the future placenta, whereas the smooth portion is the chorion.

Trophoblasts also secrete speciic chemokines that attract the dNK cells to the maternl-fetal interface. hus, both cell types simultaneously attract each other. Decidual macro phages account for approximately 20 percent of leukocytes in the first trimester and elicit an M2-immunomodulatory phenotype (Williams, 2009). Remember, M1 macrophages are pro inflammatory, and M2 macrophages counter proinflammatory responses and promote tissue repair. In addition to a role in angiogenesis and spiral artery remodeling, dNK cells promote phagocytosis of cell debris (Faas, 2017). Concurrent with the critical role of maternal dNK cells and macro phages, T cell subsets aid tolerance toward the allogenic fetus. Regulatory T cells (Tregs) are essential for promoting immune tolerance. Other T cell subsets are present, such s Th 1, Th2 and Th 17, although their unctions are tightly regulated (Ruocco, 2014) .

Extravillous trophoblasts of the first-trimester placenta are highly invasive. his process occurs under low-oxygen conditions, and regulatory factors that are induced under hypoxic conditions are contributory (Soares, 2012). Invasive trophoblasts secrete numer vate proteinases already present in the decidua. Trophoblasts produce urokinase-type plasminogen activator, which converts plasminogen into the broadly acting serine protease, plasmin.

This in turn both degrades matrix proteins and activates M.1Ps.

One member of the MMP family, MMP-9, appears to be criti cal. The timing and extent of trophoblast invasion is regulated by a balanced interplay between pro-and anti invasive factors.

he relative ability to invade maternal tissue in early preg nancy compared with limited invasiveness in late pregnancy is ual factors. Trophoblasts secrete insulin-like growth factor II that promotes invasion into the decidua. Decidual cells secrete insulin-like growth factor binding-protein type 4, which blocks this autocrine loop.

Low estradiol levels in the irst trimester are critical for trophoblast invasion and remodeling of the spiral arteries. nimal studies suggest that the rise in second-trimester estradiol levels suppresses and limits vessel remodeling by reducing trophoblast expression of VEGF and speciic integrin receptors (Bonagura, 2012). Namely, extravillous trophoblasts express integrin receptors that recognize the extracellular matrix proteins collagen IV, laminin, and ibronectin. Binding of these matrix proteins and integrin receptors initiates signls to promote trophoblast cell migration and differentiation. However, as pregnancy advances, rising estradiol levels downregulate VEGF and integrin receptor expression. This represses and controls the extent of uterine vessel transformation.

One of the most remarkable features of human placental development is the extensive modification of maternal vasculature by trophoblasts, which are by definition of fetal origin. These events occur in the first half of pregnancy and are considered in detail because of their importance to uteroplacental blood flow. They are also integral to some pathological conditions such as preeclampsia, fetal-growth restriction, and preterm birth. Spiral artery modiications are carried out by two populations of extravillous trophoblasts-endovascular trophoblasts, which penetrate the spiral-artery lumen, and interstitial trophoblasts, which surround the arteries (see Fig. 5-8).

Interstitial trophoblasts constitute a major portion of the placental bed. They penetrate the decidua and adjacent myometrium and aggregate around spiral arteries. Although less defined, their functions may include vessel preparation for endovascular trophoblast invasion.

Endovascular trophoblasts irst enter the spiral artery lumens and initially form cellular plugs. They then destroy vascular endothelium via an apoptosis mechanism and invade and modiy the vascular media. hus, fibrinoid material replaces smooth muscle and connective tissue of the vessel media. Spiral arteries later regenerate endothelium. Invading endovascular trophoblasts can extend several centimeters along the vessel lumen, and they must migrate against arterial flow. Of note, invasion by trophoblasts involves only the decidual spiral arteries and not decidual veins.

Uteroplacental vessel development proceeds in two waves or stages (Ramsey, 1980). The irst occurs before 12 weeks' postfertilization, and spiral arteries are invaded and modiied up to the border between the decidua and myometrium. he second wave, between 12 and 16 weeks, involves some invasion of the intramyometrial segments of spiral arteries. Remodeling converts narrow-lumen, muscular spiral arteries into dilated, low-resistance uteroplacental vessels. Molecular mechanisms of these crucial events, their regulation by cytokines, signaling pathways, and their significance in the pathogenesis of preeclampsia and fetal-growth restriction has been reviewed by several authors (Pereira de Sousa, 2017; ie, 2016; Zhang, 2016).

Approximately 1 month after conception, maternal blood enters the intervillous space in fountain-like bursts from the spiral arteries. Blood is propelled outside of the maternal vessels and sweeps over and directly bathes the syncytiotrophoblast.

Although certain villi of the chorion frondosum extend from the chorionic plate to the decidua to serve as anchoring villi, most villi arborize and end freely within the intervillous space. s gestation proceeds, the short, thick, early stem villi branch to form progressively iner subdivisions and greater numbers of increasingly smaller villi (Fig. 5-12). Each of the truncal or main stem villi and their ramiications constitutes a placental lobule, or cotyledon. Each lobule is supplied with a single chorionic artery. And each lobule has a single vein, so that lobules constitute the functional units of placental architecture.

FIGURE 5-12 Electron micrographs (A, C) and photomicrographs (B, D) of early and late human placentas. A and B. Limited branching of villi is seen in this early placenta. C and D. With placental maturation, increasing villous arborization is seen, and villous capillaries lie closer to the surface of each villus. (Photomicrographs used with permission from Dr. Kurt Benirschke. Electron micrographs reproduced with permission from King BF, Menton DN: Scanning electron microscopy of human placental villi from early and late in gestation. Am J Obstet Gynecol 122:824, 1975.)

In the irst trimester, placental growth is more rapid than that of the fetus. But by approximately 17 weeks' gestation, placen tal and fetal weights are approximately equal. By term, placen tal weight is approximately one sixth of fetal weight.

he mature placenta and its variant forms are discussed in detail in Chapter 6 (p. 112). Briely, viewed from the mater nal surface, the number of slightly elevated convex areas, called lobes, varies from 10 to 38. Lobes are incompletely separated by grooves of variable depth that overlie placental septa, which arise as upward projections of decidua. he total number of placental lobes remains the same throughout gestation, and individual lobes continue to grow-although less actively in the inal weeks (Crawford, 1959). Although grossly visible lobes are commonly referred to as cotyledons, this is not accurate.

Correctly used, lobules or cotyledons are the functional units supplied by each main stem villus.

As villi continue to branch and the terminal ramiications become more numerous and smaller, the volume and promi nence of cytotrophoblasts decrease. As the syncytium thins, the fetal vessels become more prominent and lie closer to the sur face (see Fig. 5-10). he villous stroma also exhibits changes as gestation progresses. In early pregnancy, the branching connec tive-tissue cells are separated by an abundant loose intercellular matrix. Later, the villous stroma becomes denser, and the cells are more spindly and closely packed.

Another change in the stroma involves the iniltration of Hobauer cels, which are fetal macrophages. hese are nearly round with vesicular, often eccentric nuclei and very granular or vacuolated cytoplasm. hey grow in number and maturational state throughout pregnancy and appear to be important mediators of protection at the maternal-fetal interface Qohnson, 2012). These macrophages are phagocytic, have an immunosuppressive phenotype, can produce various cytokines, and are capable of paracrine regulation of trophoblastic functions (Cervar, 1999; Reyes, 2017). As discussed further in Chapter 64 (p. 1219), recent studies suggest that Zika virus can infect Hofbauer cells to allow fetal transmission (Simoni, 2017).

Some of the histological changes that accompany placental growth and maturation improve transport and exchange to meet advancing fetal metabolic requirements. Among these changes are a thinner syncytiotrophoblst, signiicantly reduced cytotrophoblast number, decreased stroma, and increased number of capillaries with close approximation to the syncytial surface. By 16 weeks' gestation, the apparent continuity of the cytotrophoblasts is lost. At term, villi may be focally reduced to a thin layer of syncytium covering minimal villous connective tissue in which thinwalled fetal capillaries abut the trophoblast and dominate the villi.

There are some changes in placental architecture that can cause decreased placental exchange eiciency if they are substantive. These include thickening of the basal lamina of trophoblast or capillaries, obliteration of certain fetal vessels, greater villous stroma, and ibrin deposition on the villous surface.

FIGURE 5-1 3 Uterus showing a normal placenta and its membranes in situ.

Because the placenta is functionally an intimate approximation of the fetal capillary bed to maternal blood, its gross anatomy primarily concerns vascular relations. he fetal surface is covered by the transparent amnion, beneath which chorionic vessels course. A section through the placenta includes amnion, chorion, chorionic villi and intervillous space, decidual (basal) plate, and myometrium (Figs. 5-13 and 5-14).

FIGURE 5-14 Photomicrograph of early implanted blastocyst. Trophoblasts are seen invading the decidua basalis. eNS central nervous system. (Used with permission from Dr. Kurt Benirschke.)

Deoxygenated venous-like fetal blood flows to the placenta through the two umbilical arteries. As the cord joins the placenta, these umbilical vessels branch repeatedly beneath the amnion as they run across the chorionic plate. Branching continues within the villi to ultimately form capillary networks in the terminal villous branches. Blood with signiicantly higher oxygen content returns from the placenta via a single umbilical vein to the fetus.

The branches of the umbilical vessels that traverse along the fetal surface of the placenta in the chorionic plate are referred to as the placental surface or chorionic vessels. These vessels are responsive to vasoactive substances, but anatomically, morphologically, histologically, and functionally, they are unique. Chorionic arteries always cross over chorionic veins. Vessels are most readily recognized by this interesting relationship, but they are diicult to distinguish by histological criteria.

Truncal arteries are perforating branches of the surface arteries that pass through the chorionic plate. Each truncal artery supplies one main stem villus and thus one cotyledon. As the artery penetrates the chorionic plate, its wall loses smooth muscle, and its caliber increases. The loss of muscle continues as the truncal arteries and veins branch into their smaller rami.

Before 10 weeks' gestation, there is no end-diastolic low pattern within the umbilical artery at the end of the fetal cardiac cycle (Fisk, 1988; Loquet, 1988). After 10 weeks, however, end-diastolic low appears and is maintained throughout normal pregnancy. Clinically, these flow patterns are studied with Doppler sonography to assess fetal well-being (Chap. 10, p. 213).

Mechanisms of placental blood low must allow blood to leave syncytiotrophoblast, rather than remaining in contact with villi long enough for adequate exchange. For this, maternal blood enters through the basal plate and is driven high up toward the chorionic plate by arterial pressure before laterally dispersing (Fig. 5-15). After bathing the external microvillous surface of chorionic villi, maternal blood drains back through venous oriices in the basal plate and enters uterine veins. Thus, maternal blood traverses the placenta randomly without preformed channels. The previously described trophoblast invasion of the spiral arteries creates low-resistance vessels that can accommodate massive increase in uterine perfusion during gestation. Generally, spiral arteries are perpendicular to, but veins are parallel to, the uterine wall. his arrangement aids closure of veins during a uterine contraction and prevents the exit of maternal blood from the intervillous space. The number of arterial openings into the intervillous space is gradually reduced by cytotrophoblastic invasion. here are about 120 spiral arterial entries into the intervillous space at term (Brosens, 1963). hese discharge blood in spurts that bathes the adjacent villi (Borell, 1958). After the 30th week, a prominent venous plexus lies between the decidua basalis and myometrium and helps develop the cleavage plane needed for placental separation after delivery.

Both inlow and outlow are curtailed during uterine contractions. BIeker and associates (1975) used serial sonography during normal labor and found that placental length, thickness, and surface area grew during contractions. They attributed this to distention of the intervillous space by impairment of venous outlow compared with arterial inlow. During contractions, therefore, a somewhat larger volume of blood is available for exchange even though the rate of low is decreased. Similarly, Doppler velocimetry has shown that diastolic low veloci ty in spiral arteries is diminished during uterine contractions. Thus, principal factors regulating intervillous space blood low are arterial blood pressure, intrauterine pressure, uterine contraction pattern, and factors that act specifically on arterial walls.

• Breas in the Placental"Barrier" he placenta does not maintain absolute integrity of the fetal and maternal circulations. here are numerous examples of

FIGURE 5-15 Schematic drawing of a section through a full-term placenta. Maternal blood flows into the intervillous spaces in funnel-shaped spurts. Exchanges occur with fetal blood as maternal blood flows around the villi. Infiowing arterial blood pushes venous blood into the endometrial veins, which are scattered over the entire surface of the decidua basalis. Note also that the umbilical arteries carry deoxygenated fetal blood to the placenta and that the umbilical vein carries oxygenated blood to the fetus. Placental lobes are separated from each other by placental (decidual) septa.

traicking cells between mother and fetus in both directions.

This situation is best exempliied clinically by erythrocyte

D-antigen alloimmunization (Chap. 15, p. 301). Fetal cell admixtures likely are small in most cases, although rarely the fetus exsanguinates into the maternal circulation.

Fetal cells can also engraft in the mother during pregnancy and can be identiied decades later. Fetal lymphocytes, CD34+ mesenchymal stem cells, and endothelial colony-forming cells all reside in maternal blood, bone marrow, or uterine vascula ture (Nguyen, 2006; Piper, 2007; Sipos, 2013). Termed micro chimerism, such residual stem cells have been implicated in the disparate female:male ratio of autoimmune disorders (Greer, 2011; Stevens, 2006). As discussed in Chapter 59 (p. 1139), they are associated with the pathogenesis of lymphocytic thy roiditis, scleroderma, and systemic lupus erythematosus.

Survival of the semi allogenic fetal graft requires complex interactions between fetal trophoblasts and maternal decidual immune cells. The fetal-maternal interface is not immunologically inert. Rather, it is an active hub of interactions that allows implantation and appropriate placental development and ensures immuno tolerance of the fetus. Despite this, a functional immune system must be maintained to protect the mother.

Immunogenicity of the Trophoblasts

Trophoblastic cells are the only fetus-derived cells in direct contact with maternal tissues and blood. Fetal syncytiotrophoblast synthesizes and secretes numerous factors that regulate the immune responses of maternal cells both at the implantation site and systemically.

Human leukocyte antigens (HLAs) are the human analogue of the major histocompatibility complex (MHC) (Hunt, 1992). There are 17 HLA class I genes, including three classic genes, HLA-A, -B, and -C, that encode the major class I (class Ia) transplantation antigens. Three other class I genes, designated HLA-E, -F, and -G, encode class Ib HLA antigens. MHC class I and II antigens are absent from villous trophoblasts, which appear to be immunologically inert at all gestational stages (Weetman, 1999). Invasive extravillous cytotrophoblasts do express MHC class I molecules. Thus, the ability of these cells to bypass transplantation rejection is the focus of considerable study.

Mofett-King (2002) reasoned that normal implantation depends on controlled trophoblastic invasion of maternal decidua and spiral arteries. Such invasion must proceed far enough to provide for normal fetal growth and development, but a mechanism must regulate invasion depth. She suggests that dNK cells combined with unique expression of three speciic HLA class I genes in extravillous cytotrophoblasts act in concert to permit and subsequently limit trophoblast invasion.

Class I antigens in extravillous cytotrophoblasts are accounted for by the expression of classic HLA-C and nonclassic class Ib molecules of HLA-E and HLA-G. HLA-G antigen is expressed only in humans, with expression restricted to extravillous cytotrophoblasts contiguous with maternal tissues. Embryos used for in vitro fertilization do not implant if they do not express a soluble HLA-G isoform (Fuzzi, 2002). hus, HLA-G may be immunologically permissive of the maternalfetal antigen mismatch (LeBouteiller, 1999). HLA-G has a proposed role in protecting extravillous trophoblasts from immune rejection via modulation of dNK functions (Apps, 2011; Rajagopalan, 2012). Last, Goldman-Wohl and associates (2000) have provided evidence for abnormal HA-G expression in extravillous trophoblasts from women with preeclampsia.

Natural killer cells are the predominant population of leukocytes present in midluteal phase endometrium and in decidua throughout the first trimester Oohnson, 1999). By term, however, relatively few dNK cells are present in decidua. In first-trimester decidua, dNK cells lie close to extravillous trophoblasts, and there they purportedly serve to regulate invasion. These dNKs have a distinct phenotype characterized by a high surface density of CD56 or neural cell adhesion molecules (Manaster, 2008; Mofett-King, 2002). Their infiltration is increased by progesterone and by stromal cell production of IL-15 and decidual prolactin (Dunn, 2002; Gubbay, 2002). Although dNK cells have the capacity for cytotoxicity, they are not cytotoxic toward fetal trophoblasts. Their cytotoxic potential is prevented by molecular cues from decidual macrophages. In addition, the expression of specific HLA molecules protects against dNK killing. Also, dNK cells function to restrict trophoblast invasiveness to protect the mother.

Of other cell types, decidual macro phages are distinct from proinflammatory M 1 or antiinlammatory M2 macro phages. Decidual macro phages express the complement receptor COlIc at high or low levels: CD11cHI and CD11cLO. These cells function to regulate adaptive T cell responses; control dNK diferentiation, activation, and cytotoxicity; and produce antiinlammatory cytokines such as IL-10 to ensure fetal tolerance and inhibition of harmful immune responses.

Dendritic cells are cells that present antigens to T cells. hey play an important role in the development of a receptive endometrium for implantation.

Maternal T cels, as part of the adaptive immune response, increase in number and function after encounter with a speciic antigen. These cells subsequently retain the ability to respond rapidly in a subsequent encounter with the same antigen. Specific populations of Treg cells persist and can protect against aberrant immune responses. During pregnancy, there is a systemic expansion of maternal Treg cell populations. These cells are FOXP3+ cells with defined fetal speciicity. They are immunosuppressive and playia role in fetal tolerance.

At term, the amnion is a tough and tenacious but pliable membrane. his innermost avascular fetal membrane is contiguous with amnionic fluid and plays a role of incredible importance in human pregnancy. he amnion provides almost all tensile strength of the fetal membranes. Thus, its resilience to rupture is vitally important to successful pregnancy outcome. Indeed, preterm rupture of fetal membranes is a major cause of preterm delivery (Chap. 42, p. 819).

FIGURE 5-16 Photomicrograph of fetal membranes. From left to right: AE = amnion epithelium; AM = amnion mesenchyme; S zona spongiosa; eM = chorionic mesenchyme; TR = trophoblast; 0= decidua. (Used with permission from Dr. Judith R. Head.)

Bourne (1962) described five separate amnion layers. he inner surface, which is bathed by amnionic luid, is an uninterrupted, single layer of cuboidal epithelium (Fig. 5-16). his epithelium is attached irmly to a distinct basement membrane that is connected to an acellular compact layer composed primarily of interstitial collagens. On the outer side of the compact layer, there is a row of ibroblast-like mesenchymal cells, which are widely dispersed at term. here also are a few fetal macrophages in the amnion. he outermost amnion layer is the relatively acellular zona spongiosa, which is contiguous with the second fetal membrane, the chorion laeve. he human amnion lacks smooth muscle cells, nerves, lymphatics, and importantly, blood vessels.

Early during implantation, a space develops between the embryonic cell mass and adjacent trophoblastic cells (see Fig. 5-9). Small cells that line this inner surface of trophoblasts have been called amniogenic cells-precursors of amnionic epithelium. The amnion is irst identiiable on the 7th or 8th day of embryo development. It is initially a minute vesicle, which then develops into a small sac that covers the dorsal embryo surface. As the amnion enlarges, it gradually engulfs the growing embryo, which prolapses into its cavity (Benirschke, 2012).

Distention of the amnionic sac eventually brings it into contact with the interior surface of the chorion laeve. Apposition of the chorion laeve and amnion near the end of the irst trimester then causes an obliteration of the extraembryonic coelom. he amnion and chorion laeve, although slightly adhered, are never intimately connected and can be separated easily. Placental amnion covers the placental surface and thereby is in contact with the adventitial surface of chorionic vessels. Umbilical amnion covers the umbilical cord. With diamnionic-monochorionic placentas, there is no intervening tissue between the fused amnions. In the conjoined portion of membranes of diamnionic-dichorionic twin placentas, amnions are separated by fused chorion laeve.

Amnionic luid ills this amnionic sac. Until about 34 weeks' gestation, the normally clear fluid increases in volume as pregnancy progresses. Mter this, the volume declines. At term, amnionic luid averages 1000 mL, although this may vay widely in normal and especially abnormal conditions. The origin, composition, circulation, and function of amnionic luid are discussed further in Chapter 11 (p. 225).

Epithelial cells of the amnion derive from fetal ectoderm of the embryonic disc. hey do not arise by delamination from trophoblasts. his is an important consideration from both embryological and functional perspectives. For example, HLA class I gene expression in amnion is more akin to that in embyonic cells than to that in trophoblasts.

he ibroblast-like mesenchymal cell layer of the amnion is likely derived from embryonic mesoderm. Early in human embryogenesis, the amnionic mesenchymal cells lie immediately adjacent to the basal surface of the amnion epithelium. At this time, the amnion surface is a two-cell layer with approximately equal numbers of epithelial and mesenchymal cells. Simultaneously with growth and development, interstitial collagens are deposited between these two cell layers. his marks formation of the amnion compact layer, which separates the two layers of amnion cells.

As the amnionic sac expands, the compactness of the mesenchymal cells is progressively reduced, and they become sparsely distributed. Early in pregnancy, amnionic epithelium replicates at a rate appreciably faster than mesenchymal cells. At term, these cells form a continuous uninterrupted epithelium on the fetal amnionic surface. Conversely, mesenchymal cells are widely dispersed, being connected by a ine lattice network of extracellular matrix with the appearance of long slender ibrils.

he apical surface of the amnionic epithelium is replete with highly developed microvilli. This structure relects its function as a major site of transfer between amnionic luid and amnion. This epithelium is metabolically active, and its cells synthesize tissue inhibitor of MMP-l, prostaglandin E2 (PGE2), and fetal ibronectin (FN) (Rowe, 1997). Although epithelia produce FN, recent studies suggest that ibronectin functions in the underlying mesenchymal cells. Here, FN promotes synthesis of MMPs that break down the strength-bearing collagens and enhance prostaglandin synthesis to prompt uterine contractions (Mogami, 2013). This pathway is upregulated in premature rupture of membranes induced by thrombin or infection-induced release of FN (Chigusa, 2016; Mogami, 2014).

Epithelial cells may respond to signals derived from the fetus or the mother, and they are responsive to various endocrine or paracrine modulators. Examples include oxytocin and vasopressin, both of which increase PGE2 production in vitro (Moore, 1988). They may also produce cytokines such as IL-8 during labor initiation (Elliott, 2001).

Amnionic epithelium also synthesizes vasoactive pep tides, including endothelin and parathyroid hormone-related protein (Economos, 1992; Germain, 1992). he tissue produces brain natriuretic peptide (BNP) and corticotropin-releasing hormone (CRH), which are peptides that invoke smooth-muscle relaxation (Riley, 1991; Warren, 1995). BNP production is positively regulated by mechanical stretch in fetal membranes and is proposed to function in uterine quiescence. Epidermal growth factor, a negative regulator ofBNP, is up regulated in the membranes at term and leads to a decline in BNP-regulated uterine quiescence (Carvaj al, 2013). It seems reasonable that vasoactive peptides produced in amnion gain access to the adventitial surface of chorionic vessels. hus, the amnion may be involved in modulating chorionic vessel tone and blood low. Amnionderived vasoactive peptides function in both maternal and fetal tissues in diverse physiological processes. AOter their secretion, these bioactive agents enter amnionic luid and thereby are available to the fetus by swallowing and inhalation.

Mesenchymal cells of the amnionic ibroblast layer are responsible for other major functions. Synthesis of interstitial collagens that compose the compact layer of the amnion-the major source of its tensile strength-takes place in mesenchymal cells (Casey, 1996). At term the generation of cortisol by l1�-hydroxysteroid dehydrogenase may contribute to membrane rupture via reduction of collagen abundance (Mi, 2017). Mesenchymal cells also synthesize cytokines that include IL-6, IL-8, and MCP-I. Cytokine synthesis rises in response to bacterial toxins and IL-1. his functional capacity of amnion mesenchymal cells is an important consideration in amnionic fluid study of labor-associated accumulation of inlammatory mediators (Garcia-Velasco, 1999). Finally, mesenchymal cells may be a greater source of PGE2 than epithelial cells, especially in the case of premature membrane rupture (Mogami, 2013; Whittle, 2000).

During tests of tensile strength, the decidua and then the chorion laeve give way long before the amnion ruptures. Indeed, the membranes are elastic and can expand to twice normal size during pregnancy (Benirschke, 2012). The amnion tensile strength resides almost exclusively in the compact layer, which is composed of cross-linked interstitial collagens I and III and lesser amounts of collagens V and VI.

Collagens are the primary macromolecules of most connective tissues. Collagen I is the major interstitial collagen in tissues characterized by great tensile strength, such as bone and tendon. In other tissues, collagen III is believed to contribute to tissue integrity and provides both tissue extensibility and tensile strength. For example, the ratio of collagen III to collagen I in the walls of a number of highly extensible tissues-amnionic sac, blood vessels, urinary bladder, bile ducts, intestine, and gravid uterus-is greater than that in nonelastic tissues a efrey, 1991).

Amnion tensile strength is regulated in part by fibrillar collagen assembly. his process is influenced by the interaction fibrils with proteoglycans such as decorin and biglycan (Chap. 21, p. 409). Reduction of these proteoglycans is reported to perturb fetal membrane function (Horgan, 2014; Wu, 2014). Fetal membranes overlying the cervix have a regional shift in gene expression and lymphocyte activation that set in motion an inflammatory cascade (Marcellin, 2017). his change may contribute to tissue remodeling and loss of tensile strength in the amnion (Moore, 2009).

The amnion is metabolically active, is involved in solute and water transport for amnionic fluid homeostasis, and produces an impressive array of bioactive compounds. The amnion is responsive both acutely and chronically to mechanical stretch, which alters amnionic gene expression (Carvajal, 2013; Nemeth, 2000). This in turn may trigger both autocrine and paracrine responses that include production of MMPs, IL-8, and collagenase (Bryant-Greenwood, 1998; Mogami, 2013). Such factors may modulate changes in membrane properties during labor.

he yolk sac and the umbilical vesicle into which it develops are prominent early in pregnancy. At irst, the embryo is a lattened disc interposed between amnion and yolk sac (see Fig. 5-9). Its dorsal surface grows faster than the ventral surface, in association with the elongation of its neural tube. Thus, the embryo bulges into the amnionic sac, and the dorsal part of the yolk sac is incorporated into the embryo body to form the gut. The allantois projects into the base of the body stalk from the caudal wall of the yolk sac and later, from the anterior wall of the hindgut.

As pregnancy advances, the yolk sac becomes smaller and its pedicle relatively longer. By the middle of the third month, the expanding amnion obliterates the extraembryonic coelom, fuses with the chorion laeve, and covers the bulging placental disc and the lateral surface of the body stalk. The latter is then called the umbilical cord-or funis. A more detailed description of this cord and potential abnormalities is found in Chapter 6 (p. 117).

he cord at term normally has two arteries and one vein (Fig. 5-17). The right umbilical vein usually disappears early during fetal development, leaving only the original left vein.

The umbilical cord extends from the fetal umbilicus to the fetal surface of the placenta, that is, the chorionic plate. Blood flows from the umbilical vein toward the fetus. Blood then takes a path of least resistance via two routes within the fetus. One is the ductus venosus, which empties directly into the inferior vena cava (Fig. 7-9, p. 130). The other route consists of numerous smaller openings into the hepatic circulation. Blood from the liver flows into the inferior vena cava via the hepatic vein. Resistance in the ductus venosus is controlled by a sphincter that is situated at the origin of the ductus at the umbilical recess and is innervated by a vagus nerve branch.

Blood exits the fetus via the two umbilical arteries. These are anterior branches of the internal iliac artery and become obliterated after birth to form the medial umbilical ligaments.

FIGURE 5-17 Cross-section of umbilical cord. The large umbilical vein carries oxygenated blood to the fetus (right). To its left are the two smaller umbilical arteries, carrying deoxygenated blood from the fetus to the placenta. (Used with permission from Dr. Mandolin

S. Ziadie.)

The production of steroid and protein hormones by human trophoblasts is greater in amount and diversity than that of any single endocrine tissue in all of mammalian physiology. A compendium of average production rates for various steroid hormones in nonpregnant and in near-term pregnant women is given in Table

It is apparent that alterations in steroid hormone production that accompany normal human pregnancy are incredible. he human placenta also synthesizes an enormous amount of protein and peptide hormones, summarized in Table 5-2. Another remarkable feature is the successful

TABLE 5-1 . Steroid Production Rates in Nonpregnant and Near-Term Pregnant Women aEstrogens and progesterone are produced by placenta. Aldosterone is produced by the maternal adrenal in response to the stimulus of angiotenoin II. Deoxycorticosterone is produced in extraglandular tissue sites by way of the 21-hydroxylation of plasma progesterone. Cortisol production during pregnancy is not increased, even though the blood levels are elevated because of decreased clearance caused by increased cortisol-binding globulin.

physiological adaptations of pregnant women to the unique endocrine milieu, and this is discussed throughout Chapter 4 (p. 49).

Chorionic gonadotropin is a glycoprotein with biological activity similar to that of LH, and both act via the same LH-hCG receptor. hCG has with a molecular weight of 36,000 to 40,000 Da and has the highest carbohydrate content of any human hormone-30 percent. The carbohydrate component, and especially the terminal sialic acid, protects the molecule from catabolism. As a result, the 36-hour plasma half-life of intact hCG is much longer than the 2 hours for LH. he hCG molecule is composed of two dissimilar subunits termed . and � subunits. hese are noncovalently linked and are held together by electrostatic and hydrophobic forces. Isolated subunits are unable to bind the LH-hCG receptor and thus lack biological activity.

hCG is produced almost exclusively in the placenta, but low levels are synthesized in the fetal kidney. Other fetal tissues produce either the �-subunit or intact hCG molecule (McGregor, 1981,i1983).

The hCG hormone is structurally related to three other glycoprotein hormones-LH, FSH, and TSH. All four glycoproteins share a common a-subunit. However, each of their 3-subunits, although sharing certain similarities, is characterized by a distinctly diferent amino acid sequence.

Synthesis of the .-and 3-chains of hCG is regulated separately. A single gene located on chromosome 6 encodes the a-subunit. Seven genes on chromosome 19 encode for the �-hCG-3-LH family of subunits. Six genes code for 3-hCG and one for 3-LH (Miller-Lindholm, 1997). Both subunits are synthesized as larger precursors, which are then cleaved by endopeptidases. Intact hCG is then assembled and rapidly released by secretory granule exocytosis (Morrish, 1987). There are multiple forms of hCG in maternal plasma and urine that vary enormously in bioactivity and immunoreactivity. Some result from enzymatic degradation, and others from modifications during molecular synthesis and processing.

Before 5 weeks, hCG is expressed both in the syncytiotrophoblast and in cytotrophoblasts (Mamo, 1992). Later, in the irst trimester when maternal serum levels peak, hCG is produced almost solely in the syncytiotrophoblast (Beck, 1986; Kurman, 1984). At this time, mRNA concentrations of both .-and 3-subunits in the syncytiotrophoblast are greater than at term (Hoshina, 1982). This may be an important consideration when hCG is used as a screening procedure to identiy abnormal fetuses.

Circulating free levels of 3-subunit are low to undetectable throughout pregnancy. In part, this is the result of its rate-limiting synthesis. Free a-subunits that do not combine with the 3-subunit are found in placental tissue and maternal plasma. Levels of the a-subunit rise gradually and steadily until they plateau at approximately 36 weeks' gestation. At this time, they account for 30 to 50 percent of hormone (Cole, 1997). Thus, .-hCG secretion roughly corresponds to placental mass, whereas secretion of complete hCG molecules is maximal at 8 to 10 weeks.

TABLE 5-2. Protein Hormones Produced by the Human Placenta

Primary Non-placental Shares Structural or Hormone Site of Expression Function Similarity Functions

LH, FSH,lTSH

GH, prolactin

The combined hCG molecule is detectable in plasma of pregnant women 7 to 9 days after the midcycle surge of LH that precedes ovulation. hus, hCG likely enters maternal blood at the time of blastocyst implantation. Plasma levels rise rapidly, doubling every 2 days in the first trimester (Fig. 5-18). Appreciable fluctuations in levels for a given patient are observed on the same day.

Intact hCG circulates as multiple highly related isoforms with variable cross-reactivity between commercial assays. hus, calculated serum hCG levels can vary considerably among the more than a hundred available assays. his emphasizes the need to use the same assay type when clinically measuring serial hCG levels. Peak maternal plasma levels reach approximately 50,000 to 100,000 mIU/mL between the 60th and 80th days after menses. At 10 to 12 weeks' gestation, plasma levels begin to decline, and a nadir is reached by approximately 16 weeks. Plasma levels are maintained at this lower level for the remainder of pregnancy.

The pattern of hCG appearance in fetal blood is similar to that in the mother. Fetal plasma levels, however, are only about 3 percent of those in maternal plasma. Amnionic fluid hCG concentration early in pregnancy is similar to that in maternal plasma. As pregnancy progresses, hCG concentration in

Aids maternal adaptation to fetal energy requirements

Relaxes smooth-muscle; initiates parturition? Promotes fetal and maternal glucocorticoid production Regulates trophoblast hCG production

Regulates transfer of calcium and other solutes; regulates fetal mineral homeostasis nizing hormone; TSH = thyroid-stimulating hormone.

amnionic fluid declines, and near term the levels are approximately 20 percent of those in maternal plasma.

Maternal urine contains the same variety of hCG degradation products as maternal plasma. The principal urinary form is the terminal product of hCG degradation, namely, the 500 400 300�I 0E , 200£:) 100 , ..--, , , ,

I I 4, , I :t > II II ,, 3.1 c 40 I \ , , c

I \, " , , 2

FIGURE 5-18 Distinct profiles for the concentrations of human chorionic gonadotropin (hCG), human placental lactogen (hPL), and corticotropin-releasing hormone (CRH) in serum of women throughout normal pregnancy.

�-core fragment. Concentrations of this fragment follow the same general pattern as that in maternal plasma, peaking at approximately 10 weeks' gestation. Importantly, the so-called �-subunit antibody used in most pregnancy tests reacts with both intact hCG-the major form in the plasma, and with fragments of hCG-the major forms found in urine.

Placental gonadotropin-releasing hormone (GnRH) is likely involved in the regulation of hCG formation. Both GnRH and its receptor are expressed by cytotrophoblasts and by the syncytiotrophoblast (Wolfahrt, 1998). GnRH administration elevates circulating hCG levels, and cultured trophoblasts respond to GnRH treatment and raise hCG secretion (Iwashita, 1993; Siler-Khodr, 1981). Pituitary GnRH production also is regulated by inhibin and activin. In cultured placental cells, activin stimulates and inhibin inhibits GnRH and hCG production (Petraglia, 1989; Steele, 1993).

Renal clearance of hCG accounts for 30 percent of its metabolic clearance. he remainder is likely cleared by metabolism in the liver (Wehmann, 1980). Clearances of�-and .-subunits are approximately 10-and 30-fold, respectively, greater than that of intact hCG. In pregnancies complicated by chronic renal disease, hCG clearance can be markedly decreased.

Both hCG subunits are required for binding to the LH-hCG receptor in the corpus lute un and the fetal testis. LH-hCG receptors are present in various other tissues, but their roles there are less defined.

he best-known biological function of hCG is the so-called rescue and maintenance of corpus luteum function-that is, continued progesterone production. This is only an incomplete explanation for the physiological function of hCG in pregnancy. For example, maximum plasma hCG concentrations are attained well after hCG-stimulated corpus luteum secretion of progesterone has ceased. Speciically, luteal progesterone synthesis begins to decline at about 6 weeks despite continued and increasing hCG production.

A second hCG role is stimulation of fetal testicular testosterone secretion. This is maximum approximately when hCG levels peak. hus, at a critical time in male sexual diferentiation, hCG enters fetal plasma from the syncytiotrophoblast. In the fetus, it acts as an LH surrogate to stimulate Leydig cell replication and testosterone synthesis to promote male sexual differentiation (Chap. 3, p. 35). Before approximately 110 days, there is no vascularization of the fetal anterior pituitary from the hypothalamus. Thus, pituitary LH secretion is minimal, and hCG acts as LH before this time. hereafter, as hCG levels fall, pituitary LH maintains modest testicular stimulation.

The maternal thyroid gland is also stimulated by large quantities of hCG. In some women with gestational trophoblastic disease, biochemical and clinical evidence of hyperthyroidism sometimes develops (Chap. 20, p. 391). This once was attributed to formation of chorionic thyrotropins by neoplastic trophoblasts. It was subsequently shown, however, that some forms ofhCG bind to TSH receptors on thyrocytes (Hershman, 1999). And, treatment of men with exogenous hCG increases thyroid activity. The thyroid-stimulatory activity in plasma of irst-trimester pregnant women varies appreciably from sample to sample. Modiications of hCG oligosaccharides likely are important in the capacity of hCG to stimulate thyroid function. For example, acidic isoforms stimulate thyroid activity, and some more basic isoforms stimulate iodine uptake (Kraiem, 1994; Tsuruta, 1995; Yoshimura, 1994). Finally, the LH-hCG receptor is expressed by thyrocytes, which suggests that hCG stimulates thyroid activity via the LH-hCG receptor as well as by the TSH receptor (Tomer, 1992).

Other hCG functions include promotion of relaxin secretion by the corpus luteum (Duy, 1996). LH-hCG receptors are found in myometrium and in uterine vascular tissue. It has been hypothesized that hCG may promote uterine vascular vasodilatation and myometrial smooth muscle relaxation (Kurtzman, 2001). Chorionic gonadotropin also regulates expansion of dNK cell numbers during early stages of placentation, thus ensuring appropriate establishment of pregnancy (Kane, 2009).

here are several clinical circumstances in which substantively higher maternal plasma hCG levels are found. Some examples are multifetal pregnancy, erythroblastosis fetalis associated with fetal hemolytic anemia, and gestational trophoblastic disease. Relatively higher hCG levels may be found in women carrying a fetus with Down syndrome. This observation is used in biochemical screening tests (Chap. 14, p. 281). The reason for the elevation is not clear, but reduced placental maturity has been speculated. Various malignant tumors also produce hCG, sometimes in large amounts-especially trophoblastic neoplasms (Chaps. 9, p. 159 and 20, p. 391).

Relatively lower hCG plasma levels are found in women with early pregnancy wastage, including ectopic pregnancy (Chap. 19, p. 373). hCG is produced in very small amounts in normal tissues of men and nonpregnant women, perhaps primarily in the anterior pituitary gland. Nonetheless, the detection of hCG in blood or urine almost always indicates pregnancy (Chap. 9, p. 158).

This is a single, nonglycosylated polypeptide chain with a molecular weight of 22,279 Da. The sequences of hPL and of human growth hormone (hGH) are strikingly similar, with 96-percent homology. Also, hPL is structurally similar to human prolactin (hPRL), with a 67-percent amino acid sequence similarity. Because of these similarities, it was called human placental lactogen or chorionic growth hormone. Currently, human placental lactogen is used by most.

here are ive genes in the growth hormone-placental lactogen gene cluster that are linked and located on chromosome 17. hPL is concentrated in syncytiotrophoblast, but similar to hCG, hPL is demonstrated in cytotrophoblasts before 6 weeks (Grumbach, 1964; Maruo, 1992). Within 5 to 10 days after conception, hPL is demonstrable in the placenta and can be detected in maternal serum as early as 3 weeks. Levels of mRNA for hPL in syncytiotrophoblast remain relatively con stant throughout pregnancy. his inding supports the idea that the hPL secretion rate is proportional to placental mass. Levels rise steadily until 34 to 36 weeks' gestation. The hPL produc tion rate near term-approximately 1 g/d-is by far the great est of aRY known hormone in humans. The hal-life of hPL in maternal plasma is between 10 and 30 minutes (Walker, 1991).

In late pregnancy, maternal serum concentrations reach levels of5 to 15 �g/mL (see Fig. 5-18).

Very little hPL is detected in fetal blood or in the urine of the mother or newborn. Amnionic fluid levels are somewhat lower than in maternal plasma. hPL is secreted primarily into the maternal circulation, with only very small amounts in cord blood. hus, its role in pregnancy is believed to be mediated through actions in maternal rather than in fetal tissues. None theless, interest continues for the possibility that hPL serves select functions in fetal growth.

cesses. First, hPL promotes maternal lipolysis with increased circulating free fatty acid levels. This provides an energy source for maternal metabolism and fetal nutrition. In vitro cytiotrophoblast (Coya, 2005). Prolonged maternal starvation in the irst half of pregnancy leads to higher hPL plasma con centrations.

Second, hPL may aid maternal adaptation to fetal energy requirements. For example, increased maternal insulin resistance ensures nutrient flow to the fetus. It also favors protein synthesis and provides a readily available amino acid source to the fetus. To counterbalance the greater insulin resistance and prevent maternal hyperglycemia, maternal insulin levels are increased. Both hPL and prolactin signal through the prolactin receptor to increase maternal beta cell proliferation to augment insulin secretion (Georgia, 2010). In animals, prolactin and hPL upregulate serotonin synthesis, which increases beta cell proliferation (Kim, 2010). Short-term changes in plasma glucose or insulin, however, have relatively little efect on plasma hPL levels. In vitro studies of syncytiotrophoblast suggest that hPL synthesis is stimulated by insulin and insulin-like growth factor-1 and inhibited by PGE2 and PGF2: (Bhaumick, 1987; Genbacev, 1977).

Last, hPL is a potent angiogenic hormone. It may serve an important function in fetal vasculature formation (Corbacho, 2002).

capacity to synthesize numer ous peptide hormones, including some that are analogous or related to hypothalamic and pituitary hormones. In contrast to their counterparts, some of these placental peptide/protein hormones are not subject to feedback inhibition.

he known hypothalamic-releasing or -inhibiting hormones include GnRH, CRH, thyrotropin-releasing hormone (TRH), growth hormone-releasing hormone, and somatostatin. For each, there is an analogous hormone produced in the human placenta (Petraglia, 1992; Siler-Khodr, 1988).

GnH in the placenta shows its highest expression in the first trimester (Siler-Khodr, 1978, 1988). Interestingly, it is found in cytotrophoblasts, but not syncytiotrophoblast. Pla centa-derived GnRH functions to regulate trophoblast hCG ofMMP-2 and MMP-9 (Peng, 2016). Placenta-derived GnRH is also the likely cause of elevated maternal GnRH levels in pregnancy (Siler-Khodr, 1984).

CH is a member of a larger family of CRH-related pep tides that includes CRH and urocortins (Dautzenberg, 2002).

Maternal serum CRH levels increase from 5 to 10 pmollL in the nonpregnant woman to approximately 100 pmollL in the early third trimester of pregnancy and to almost 500 pmollL abruptly during the last 5 to 6 weeks (see Fig. 5-18). Urocortin also is produced by the placenta and secreted into the maternal circulation, but at much lower levels than seen for CRH (Flo rio, 2002). After labor begins, maternal plasma CRH levels rise even further (Petraglia, 1989, 1990).

he biological function of CRH synthesized in the placenta, membranes, and decidua has been somewhat deined. CRH receptors are present in many tissues including placenta. Trophoblast, amniochorion, and decidua express both CRH-R1 and CRH-R2 receptors and several variant receptors (Florio, 2000). Both CRH and urocortin enhance trophoblast secretion of adrenocorticotropic hormone (ACTH), supporting an autocrine-paracrine role (Petraglia, 1999). Large amounts of trophoblast CRH enter maternal blood.

Other proposed biological roles include induction of smooth-muscle relaxation in vascular and myometrial tissue and immunosuppression. The physiological reverse, however, induction of myometrial contractions, has been proposed for the rising CRH levels seen near term. One hypothesis suggests that CRH may be involved with parturition initiation (Wadhwa, 1998). Some evidence suggests that urocortin 2 expression is induced at term and induces expression of pro inlammatory markers and prostaglandin F receptor expression in the placenta and myometrium (Voltolini, 2015). Prostaglandin formation in the placenta, amnion, chorion laeve, and decidua is increased with CRH treatment Oones, 1989b). hese observations further support a potential action in parturition timing.

Glucocorticoids act in the hypothalamus to inhibit CRH release, but in the trophoblast, glucocorticoids stimulate CRH gene expression Oones, 1989a; Robinson, 1988). hus, there may be a novel positive feedback loop in the placenta by which placental CRH stimulates placental ACTH to stimulate fetal and maternal adrenal glucocorticoid production with quent stimulation of placental CRH expression (Nicholson, 2001; Riley, 1991).

Growth hormone-releasing hormone has an unknown role (Berry, 1992). Ghrelin is another regulator of hGH secretion that is produced by placental tissue (Horvath, 2001). Trophoblast ghrelin expression peaks at midpregnancy and is a paracrine regulator of diferentiation or is a potential regulator of human growth hormone variant production, described next (Fuglsang, 2005; Gualillo, 2001).

ACTH, lipotropin, and �-endorphin, which are all proteolytic products of pro-opiomelanocortin, are recovered from placental extracts (Genazzani, 1975; Odagiri, 1979). he physiological action of placental ACTH is unclear. As discussed, placental CRH stimulates synthesis and release of chorionic ACTH.

A human growth hormone variant (hGH-J that is not expressed in the pituitary is expressed in the placenta. The gene encoding hGH-V is located in the hGH-hPL gene cluster on chromosome 17. Sometimes referred to as placental growth hormone, hGH-V is a 191-amino-acid protein that difers in 15 amino acid positions from the sequence for hGH. Although hGH-V retains growth-promoting and antilipogenic functions similar to those of hGH, it has reduced diabetogenic and lactogenic functions relative to hGH (Vickers, 2009). Placental hGH-V presumably is synthesized in the syncytiotrophoblast. It is believed that hGH-V is present in maternal plasma by 21 to 26 weeks' gestation, rises in concentration until approximately 36 weeks, and remains relatively constant thereafter. There is a correlation between the levels of hGH-V in maternal plasma and those of insulin-like growth factor-I. lso, hGH-V secretion by trophoblast in vitro is inhibited by glucose in a dosedependent manner (Patel, 1995). Overexpression ofhGH-V in mice causes severe insulin resistance, making it a likely candidate to mediate insulin resistance of pregnancy (Liao, 2016).

Expression of relaxin has been demonstrated in human corpus luteum, decidua, and placenta (Bogic, 1995). This peptide is synthesized as a single, 105-amino-acid preprorelaxin molecule that is cleaved to A and B molecules. Relaxin is structurally similar to insulin and insulin-like growth factor. Two of the three relaxin genes-H2 and H3-are transcribed in the corpus luteum (Bathgate, 2002; Hudson, 1983, 1984). Decidua, placenta, and membranes express H 1 and H2 (Hansell, 1991).

The rise in maternal circulating relaxin levels seen in early pregnancy is attributed to corpus luteum secretion, and levels parallel those of hCG. Relaxin, along with rising progesterone levels, may act on myometrium to promote relaxation and the quiescence of early pregnancy (Chap. 21, p. 407). In addition, the production of relaxin and relaxin-like factors within the placenta and fetal membranes may play an autocrine-paracrine role in postpartum regulation of extracellular matrix remodeling (Qin, 1997a,b). One important relaxin function is enhancement of the glomerular iltration rate (Chap. 4, p. 66).

In pregnancy, circulating parathyroid hormone-related protein (PTH-rP) levels are significantly elevated within maternal but not fetal circulation (Bertelloni, 1994; Saxe, 1997). Many functions of this hormone have been proposed. PTH-rP synthesis is found in several normal adult tissues, especially in reproductive organs that include myometrium, endometrium, corpus luteum, and lactating mammary tissue. PTH-rP is not produced in the parathyroid glands of normal adults. Placentaderived PTH-rP may have an important function to regulate genes involved in transfer of calcium and other solutes. It also contributes to fetal mineral homeostasis in bone, amnionic luid, and the fetal circulation (Simmonds, 2010).

This hormone is normally secreted by adipocytes. It functions as an antiobesity hormone that decreases food intake .through its hypothalamic receptor. It also regulates bone growth and immune unction (Cock, 2003; La Cava, 2004). In the placenta, leptin is synthesized by both cytotrophoblasts and syncytiotrophoblast (Henson, 2002). Relative contributions of leptin from maternal adipose tissue versus placenta are currently not well defined, although recent evidence highlights a key regulatory role of placental leptin in placental amino acid transport and fetal growth (Rosario, 20 16a). Maternal serum levels are significantly higher than those in nonpregnant women. Fetalileptin levels correlate positively with birth weight and likely function in fetal development and growth. Studies suggest that reductions in leptin availability contribute to adverse fetal metabolic programing in intrauterine growth-restricted ofspring (Nusken, 2016).

This 36-amino-acid peptide is widely distributed in brain. It also is found in sympathetic neurons innervating the cardiovascular, respiratory, gastrointestinal, and genitourinary systems. Neuropeptide Y has been isolated from the placenta and localized in cytotrophoblasts (Petraglia, 1989). Trophoblasts possess neuropeptide Y receptors, and treatment of these with neuropeptide Y causes CRH release (Robidoux, 2000).

hese glycoprotein hormones are expressed in male and female reproductive tissues and belong to the transforming growth factor-� family Gones, 2006). Inhibin is a heterodimer made up of one a-subunit and one of two distinct �-subunits, either �A or �B. his yields either inhibin A or inhibin B, respectively. Activin is formed by the combination of the two �-subunits. Activin, inhibin, and their respective receptors are expressed in the placenta. Both activin and inhibin A have proposed functions during cytotrophoblast fusion into the syncytiotrophoblast (Debieve, 2000; Jones, 2006). Activin also stimulates production of placental hormones such as hCG, hPL, progesterone, and estrogen (Luo, 2002; Morrish, 1991; Petraglia, 1989; Song, 1996). Inhibin A opposes activin action in the placenta to inhibit production of hCG and steroidogenesis (Petraglia, 1989). Abnormal levels of inhibin or activin correlate with placental pathologies. For example, elevation in inhibin A levels in the second trimester is indicative of fetal Down syndrome. Further, low inhibin levels early in pregnancy may indicate pregnancy failure (Prakash, 2005; Wallace, 1996). Elevations in circulating inhibin and activin levels are reported in women with preeclampsia (Bersinger, 2003).

After 6 to 7 weeks' gestation, little progesterone is produced in the ovary (Diczfalusy, 1961). Surgical removal of the corpus luteum or even bilateral oophorectomy during the 7th to 10th week does not decrease excretion rates of urinary pregnanediol, 100.0 50.0 10.0 n ..) 5.0 1.0 ):l u 0.5 0.1 0.05

FIGURE 5-19 Plasma levels of progesterone, estradiol, estrone, estetrol, and estriol in women during the course of gestation. (Modified and redrawn with permission from Mesiano S: The endocrinology of human pregnancy and fetoplacental neuroendocrine development. In Strauss JF, Barbieri RL (eds) Yen and Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 6th ed. Philadephia, Saunders, 2009.) the principal urinary metabolite of progesterone. Before this time, however, corpus luteum removal will result in spontaneous abortion unless an exogenous progestin is given (Chap. 63, p. 1198). After approximately 8 weeks, the placenta assumes progesterone secretion, resulting in a gradual increase in maternal serum levels throughout pregnancy (Fig. 5-19). By term, these levels are 10 to 5000 times those found in nonpregnant women, depending on the stage of the ovarian cycle.

The daily production rate of progesterone in late, normal, singleton pregnancies approximates 250 mg. In mulrifetal pregnancies, the daily production rate may exceed 600 mg. Progesterone is synthesized from cholesterol in a two-step enzymatic reauiuI1. r.l�., L-l1UI:�L:lUl ;� C0il v'ci'tC. tv plcg.cidciC ';;ithi� the mitochondria, in a reaction catalyzed by cytochrome P450 cholesterol side-chain cleavage enzyme. Pregnenolone leaves the mitochondria and is converted to progesterone in the endoplasmic reticulum by 33-hydroxysteroid dehydrogenase. Progesterone is released immediately through a process of difusion.

Although the placenta produces a prodigious amount of progesterone, the syncytiotrophoblast has a limited capacity for cholesterol biosynthesis. Radiolabeled acetate is incorporated into cholesterol by placental tissue at a slow rate. he rate-limiting enzyme in cholesterol biosynthesis is 3-hydroxy3-methylglutaryl coenzyme A (HMG-CoA) reductase. Because of this, the placenta must rely on an exogenous source, that is, maternal cholesterol, for progesterone formation. he tro biosynthesis (Simpson, 1979, 1980). This mechanism difers from placental production of estrogens, which relies principally on fetal adrenal precursors.

Although there is a relationship between fetal well-being and placental estrogen production, this is not the case for placen tal progesterone. Thus, placental endocrine function, including the formation of protein hormones such as hCG and proges terone biosynthesis, may persist for weeks after fetal demise.

he metabolic clearance rate of progesterone in pregnant women is similar to that found in men and nonpregnant women. During pregnancy, the plasma concentration of 5a-dihydroprogesterone disproportionately rises due to syn progesterone and fetus-derived precursor (Dombroski, 1997).

hus, the concentration ratio of this progesterone metabolite to progesterone is elevated in pregnancy. The mechanisms for this are not deined completely. Progesterone also is converted to the potent mineralocorticoid deoxycorticosterone in preg nant women and in the fetus. The concentration of deoxy corticosterone is strikingly higher in both maternal and fetal compartments (see Table 5-1). The extraadrenal formation of most of its production in pregnancy (Casey, 1982a,b).

During the first 2 to 4 weeks of pregnancy, rising hCG levels maintain production of estradiol in the maternal corpus luteum. Production of both progesterone and estrogens in the maternal ovaries drops signiicantly by the 7th week of pregnancy. At this time, there is a luteal-placental transition. By the 7th week, more than half of estrogen entering maternal circulation is produced in the placenta (MacDonald, 1965a; Siiteri, 1963,i1966). Subsequently, the placenta produces a continually increasing magnitude of estrogen. Near term, normal human pregnancy is a hyperestrogenic state, and syncytiotrophoblast is producing estrogen in amounts equivalent to that produced in 1 day by the ovaries of no fewer than 1000 ovulatory women. This hyperestrogenic state terminates abruptly after delivery of the placenta.

In human trophoblast, neither cholesterol nor, in turn, proges :e�8!e :�� �e�.'e !s F"�C�!!S0!" For �'tr0g�n hi)"ynth�."is. Thi� is because steroid 17a-hydroxylasel1,20-yase (CP17Al) is not expressed in the human placenta. This essential enzyme converts 17-0H progesterone (a C2I steroid) to androstenedione, which is a C'9 steroid and an estrogen precursor. Consequently, the conversion of C2I steroids to C'9 steroids is not possible.

However, dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) are also C'9 steroids and are produced by maternal and fetal adrenal glands. These two steroids can serve as estrogen precursors (Fig. 5-20). Ryan (1959a) found that the placenta had an exceptionally high capacity to convert appropriate C'9 steroids to estrone and estradiol. The conversion of DHEA-S to estradiol requires placental expression of four key enzymes

FIGURE 5-20 Schematic presentation of estrogen biosynthesis in the human placenta. Dehydroepiandrosterone sulfate (DHEAS), secreted in prodigious amounts by the fetal adrenal glands, is converted to 16a-hydroxydehydroepiandrosterone sulfate (16aOHDHEAS) in the fetal liver. These steroids, DHEAS and 16aOHDHEAS, are converted in the placenta to estrogens, that is, 17�-estradiol (E) and estriol (E3). Near term, half of E2 is derived from fetal adrenal DHEAS and half from maternal DHEAS. On the other hand, 90 percent of E3 in the placenta arises from fetal 16aOHDHEAS and only 10 percent from all other sources.

that are located principally in syncytiotrophoblast (Bonenfant, 2000; Salido, 1990). First, the placenta expresses high levels of steroid sulfatase (STS), which converts the conjugated DHEAS to DHEA. DHEA is then acted upon by 33-hydroxysteroid dehydrogenase type 1 (33HSD) to produce androstenedione. Cytochrome P450 aromatase (CYP19) then converts androstenedione to estrone, which is then converted to estradiol by 173-hydroxysteroid dehydrogenase type 1 (173HSDl).

DHEA-S is the major precursor of estrogens in pregnancy (Baulieu, 1963; Siiteri, 1963). However, maternal adrenal glands do not produce suicient amounts of DHA-S to account for more than a fraction oftotal placental estrogen biosynthesis. he fetal adrenal glands are quantitatively the most important source of placental estrogen precursors in human pregnancy. hus, estrogen production duringpregnancy relects the unique interactions among fetal adrenal glands, fetal liver, placenta, and maternal adrenal glands.

More than 90 percent of estradiol and estriol formed in syncytiotrophoblast 'enters maternal plasma (Gurpide, 1966). And, 85 percent or more of placental progesterone enters maternal plasma, and little maternal progesterone crosses the placenta to the fetus (Gurpide, 1972).

his directional movement ofnewly formed steroid into the maternal circulation stems from basic characteristics of hemochorioendothelial placentation. In this system, steroids secreted from syncytiotrophoblast can enter maternal blood directly. Steroids that leave the syncytium do not enter fetal blood directly. hey must irst traverse the cytotrophoblast layer and then enter the stroma of the villous core and then fetal capillaries. From either ofthese spaces, steroids can reenter the syncytium. he net result of this hemochorial arrangement is that entry of steroids into the maternal circulation is substantially greater than that into fetal blood.

Morphologically, functionally, and physiologically, the fetal adrenal glands are remarkable. At term, the fetal adrenal glands weigh the same as those of the adult. More than 85 percent of the fetal gland is composed of a unique fetal zone, which has a great capacity for steroid biosynthesis. Daily steroid production of fetal adrenal glands near term is 100 to 200 mg/d. This compares with resting adult steroid secretion of 30 to 40 mg/d.

The fetal zone is lost in the irst year of life and is not present in the adult. In addition to ACTH, fetal adrenal gland growth is influenced by factors secreted by the placenta. This is exempliied by the continued growth of the fetal glands throughout gestation and by rapid involution immediately after birth and placental delivery.

Estradiol is the primary placental estrogen product at term. In addition, significant levels of estriol and estetrol are found in the maternal circulation, and levels also rise, particularly late in gestation (see Fig. 5-19). hese hydroxylated forms of estro gen derive from the placenta using substrates formed by the combined eforts of the fetal adrenal gland and fetal liver. For this, high levels of fetal hepatic 16a-hydroxylase act on adre nal-derived steroids. Ryan (1959b) and MacDonald and Siiteri (1965b) found that 16a-hydroxylated C19 steroids, particu larly 16a-hydroxydehydroepiandrosterone (16-0HDHEA), were converted to estriol by placental tissue. Thus, the dispro portionate increase in estriol formation during pregnancy is accounted for by placental synthesis of estriol principally from plasma-borne 16-0HDHEA-sulfate. Near term, the fetus is the source of 90 percent of placental estriol and estetrol precur sors in normal human pregnancy.

Maternal estriol and estetrol are produced almost solely by fetal steroid precursors. hus, in the past, levels of these steroids were used as an indicator of fetal well-being. However, the low sensitivity and speciicity of such tests have caused them to be discarded.

The precursor for fetal adrenal steroidogenesis is cholesterol. he steroid biosynthesis rate in the fetal gland is so great that its steroidogenesis alone is equivalent to a fourth of the total daily LDL cholesterol turnover in adults. Fetal adrenal glands synthesize cholesterol from acetate. All enzymes involved in cholesterol biosynthesis are elevated compared with those of the adult adrenal gland (Rainey, 2001). Thus, the de novo cholesterol synthesis rate by fetal adrenal tissue is extremely high. Even so, it is insuicient to account for the steroids produced by fetal adrenal glands. Therefore, cholesterol must be assimilated from the fetal circulation and mainly from LDL (Carr, 1980, 1981 b, 1982; Simpson, 1979).

Most fetal plasma cholesterol arises by de novo synthesis in the fetal liver (Carr, 1984). The low LDL cholesterol level in fetal plasma is not the consequence of impaired fetal LDL synthesis, but instead results from the rapid use ofLDL by the fetal adrenal glands for steroidogenesis (Parker, 1980, 1983).

Several fetal disorders alter the availability of substrate for placental steroid synthesis and thus highlight the interdependence of fetal development and placental function.

Fetal demise is followed by a striking reduction in urinary estrogen levels. Similarly, after ligation of the umbilical cord with the fetus and placenta left in situ, placental estrogen production declines markedly (Cassmer, 1959). However, as previously discussed, placental progesterone production is maintained. In sum, an important source of precursors of pla cental estrogen-but not progesterone-biosynthesis is elimi nated with fetal death.

Anencephalic etuses have markedly atrophic adrenal glands.

his stems from absent hypothalamic-pituitary function, which precludes adrenal stimulation by ACTH. With absence of the adrenal cortex fetal zone, the placental formation of estrogen-especially estriol-is severely limited because of diminished availability of C19 steroid precursors. Indeed, uri nary estrogen levels in women pregnant with an anencephalic fetus are only about 10 percent of those found in normal preg nancy (Frandsen, 1961). With an anencephalic fetus, almost all estrogens produced arise from placental use of maternal plasma DHEA-S.

Fetal adrenal cortical hypoplasia occurs in perhaps 1 in 12,500 births (McCabe, 2001). Estrogen production in these pregnan cies is limited, which suggests the absence of C19 precursors.

Fetal-placental suatase diciency is associated with very low estrogen levels in otherwise normal pregnancies (France, 1969). Namely, sulfatase deficiency precludes the hydrolysis of C19 steroid sulfates, the first enzymatic step in the placental use of these circulating prehormones for estrogen biosynthesis. This deficiency is an X-linked disorder, and thus all afected fetuses are male. Its estimated frequency is 1 in 2000 to 5000 births and is associated with delayed labor onset. It also is associated with the development of ichthyosis in afected males later in life (Bradshaw, 1986).

Fetal-placental aromatase diciency is a rare autosomal recessive disorder in which individuals cannot synthesize endogenous estrogens (Grumbach, 2011; Simpson, 2000). To recall, fetal adrenal DHA-S is converted in the placenta to androstenedione, but in cases of placental aromatase deiciency, androstenedione cannot be converted to estradiol. Rather, androgen metabolites of DHEA produced in the placenta, including androstenedione and some testosterone, are secreted into the maternal or fetal circulation, or both. This can cause virilization of the mother and the female fetus (Belgorosky, 2009; Harada, 1992; Shozu, 1991).

Trisomy 21-Down syndrome screening searches for abnormal levels ofhCG, alpha-fetoprotein, and other analytes (Chap. 14, p. 281). It was discovered that serum unconjugated estriol levels low in women with Down syndrome fetuses (Benn, 2002). The likely reason for this is inadequate formation of C19 steroids in the adrenal glands of these trisomic fetuses.

Fetal eythroblastosis in some cases of severe fetal D-antigen alloimmunization can lead to elevated maternal plasma estrogen levels. A suspected cause is the greater placental mass from hypertrophy, which can be seen with such fetal hemolytic anemia (Chap. 15, p. 300).

Glucocorticoid treatment can cause a striking reduction in placental estrogen formation. Glucocorticoids inhibit ACTH secretion from the maternal and fetal pituitary glands. This diminishes maternal and fetal adrenal secretion of the placental estrogen precursor DHEA-S.

With Addison disease, pregnant women show lower estrogen levels, principally estrone and estradiol levels (Baulieu, 1956). The fetal adrenal contribution to estriol synthesis, particularly in later pregnancy, is quantitatively much more important.

Maternal androgen-producing tumors can present the placenta with elevated androgen levels. Fortunately, placenta is extraordinary eicient in the aromatization of C19 steroids. For example, Edman and associates (1981) found that virtually all androstenedione entering the intervillous space is taken up by syncytiotrophoblast and converted to estradiol. None of this C19 steroid enters the fetus. Second, a female fetus is rarely virilized if there is a maternal androgen-secreting tumor. The placenta eiciently converts aromatizable C19 steroids, including testosterone, to estrogens, thus precluding transplacental passage. Indeed, virilized female fetuses of women with an androgenproducing tumor may be cases in which a nonaromatizable C19 steroid androgen is produced by the tumor-for example, 5a-dihydrotestosterone. Another explanation is that testosterone is produced very early in pregnancy in amounts that exceed the placental aromatase capacity at that time.

Complete hydatidiorm mole and gestational trophoblastic neoplasias lack a fetus and also a fetal adrenal source of C19 steroid precursors for trophoblast estrogen biosynthesis. Consequently, placental estrogen formation is limited to the use of C 19 steroids from the maternal plasma, and therefore estradiol is principally produced (MacDonald, 1964, 1966).

Abel MH: Prostanoids and menstruation. In Baird DT, Michie EA (eds):

Mechanisms of Menstrual Bleeding. New York, Raven, 2002

Albrecht ED, Pepe GJ: Steroid hormone regulation of angiogenesis in the primate endometrium. Front Biosci 8:0416, 2003 Ancelin M, Buteau-Lozano H, Meduri G, et al: A dynamic shift of VEGF isoforms with a transient and selective progesterone-induced expression of VEGF189 regulates angiogenesis and vascular permeability in human uterus. Proc Nad Acad Sci USA 99:6023,r2002 Aplin JD: MUC-l glycosylation in endometrium: possible roles of the apical glycocalyx at implantation. Hum Reprod 2:17,r2003 Apps R, Sharkey A, Gardner L, et al: Ex vivo functional responses to HLA-G difer between blood and decidual NK cells. Mol Hum Reprod 17(9):577, 2011 Arici A, Head JR, MacDonald pc, et al: Regulation of interleukin-8 gene expression in human endometrial cells in culture. Mol Cell Endocrinol 94:195,r1993 Arici A, MacDonald Pc' Casey ML: Regulation of monocyte chemotactic protein-l gene expression in human endometrial cells in cultures. Mol Cell Endocrinol 107:189, 1995 Amholdt H, Meisel F, Fandrey K, et al: Proliferation of villous trophoblast of the human placenta in normal and abnormal pregnancies. Virchows Arch B Cell Pathol Incl Mol PathoIr60:365, 1991 Baker T: A quantitative and cytological study of germ cells in human ovaries. Proc R Soc Lond B BioI Sci 158:417, 1963 Bathgate A, Samuel CS, Burazin TC, et al: Human relxin gene 3 (H3) and the equivalent mouse relaxin (M3) gene. Novel members of the relaxin peptide family. J BioI Chem 277:1148, 2002 Baulieu EE, Bricaire H, Jayle MF: Lack of secretion of -hydroxycorticosteroids in a pregnant woman with Addison's disease. J Clin Endocrinol 16:690, 1956 Baulieu EE, Dray F: Conversion of3H-dehydroepiandrosterone (3Beta-hydroxydelta5-androsten-17-one) sulfate to 3H-estrogens in normal pregnant women. J Clin Endocrinol 23: 1298, 1963

Beck T, Schweikhart G, Stolz E: Immunohistochemical location of HPL, SPI and beta-HCG in normal placentas of varying gestational age. Arch Gynecol 239:63, 1986

Belgorosky A, Guercio G, Pepe C, et al: Genetic and clinical spectrum of aromatase deficiency in infancy, childhood and adolescence. Horm Res 2(6):321,r2009

Benirschke K, Burton GJ, Baergen RN: Pathology of the Human Placenta, 6th ed. Heidelberg, Springer, 2012

Benn PA: Advances in prenatal screening for Down syndrome: 1. General principles and second trimester testing. Clin Chim Acta 323: 1, 2002

Berry SA, Srivastava CH, Rubin LR, et al: Growth hormone-releasing hormone-like messenger ribonucleic acid and immunoreactive peptide are present in human testis and placenta. J Clin Endocrinol Metab 75:281, 1992

Bersinger NA, Smarason AK, Muttukrishna S, et al: Women with preeclampsia have increased serum levels of pregnancy-associated plasma protein A (PAPP-A), inhibin A, activin A and soluble E-selectin. Hypertens Pregnancy 22(1):45, 2003

Bertelloni S, Baroncelli GI, Pelletti A, et al: Parathyroid hormone-related protein in healthy pregnant women. Calcif Tissue Int 54: 195, 1994

Bhaumick B, Dawson EP, Bala RM: he efects of insulin-like growth factorI and insulin on placental lactogen production by human term placental explants. Biochem Biophys Res Commun 144:674, 1987

BIeker 0, Kloostermans G, Mieras 0, et al: Intervillous space during uterine contractions in human subjects: an ultrasonic study. Am J Obstet Gynecol ,1975

Bogic LV, Mandel M, Bryant-Greenwood GO: Relaxin gene expression in human reproductive tissues by in situ hybridization. J Clin Endocrinol Metab 80:130, 1995

Bonagura TW, Babischkin JS, Aberdeen GC, et al: Prematurely elevating estradiol in early baboon pregnancy suppresses uterine artety remodeling and expression of extravillous placental vascular endothelial growth factor and albl integrins. Endocrinology ,2012

Bonenfant M, Provost PR, Drolet R, et al: Localization of type 1 beta-hydroxysteroid dehydrogenase mRNA and protein in syncytiotrophoblasts and invasive cytotrophoblasts in the human term villi. J Endocrinol 165:217, 2000

Borell U, Fernstrom I, Westman A: An arteriographic study of the placental circulation. Geburrshilfe Frauenheilkd 18:1, 1958

Bourne GL: he Human Amnion and Chorion. Chicago, Year Book, 1962 Boyd JD, Hamilton ): The Human Placenta. Cambridge, England, Hefer, 1970

Bradshaw KD, Carr BR: Placental sulfatase deficiency: maternal and fetal expression of steroid sulfatase deiciency and X-linked ichthyosis. Obstet Gynecol Surv 41:401,r1986

Brosens I, Dixon H: he anatomy of the maternal side of the placenta. Eur J Endocrinol 73:357, 1963 Bryant-Greenwood GO: he extracellular matrix of the human fetal membranes: structure and function. Placenta 19:1, 1998

Carr BR, Ohashi M, Simpson ER: Low density lipoprotein binding and de novo synthesis of cholesterol in the neocortex and fetal zones of the human fetal adrenal gland. Endocrinology 110: 1994, 1982

Carr BR, Porter JC, MacDonald Pc, et al: Metabolism of/ow density lipoprotein by human fetal adrenal tissue. Endocrinology 107: 1034, 1980

Carr BR, Sadler RK, Rochelle DB, et al: Plasma lipoprotein regulation of progesterone biosynthesis by human corpus luteum tissue in organ culture. J Clin Endocrinol Metab 52:8 5, 1981a

Carr BR, Simpson ER: Cholesterol synthesis by human fetal hepatocytes: efect of lipoproteins. Am J Obstet Gynecol 150:551, 1984

Carr BR, Simpson ER: Lipoprotein utilization and cholesterol synthesis by the human fetal adrenal gland. Endocr Rev 2:306, 1981 b Carson DO: he glycobiology of implantation. Front Biosci 7:dI535, 2002

Carvajal JA, Delpiano AM, Cuello A, et al: Mechanical stretch increases brain natriuretic peptide production and secretion in the human fetal membranes. Reprod Sci 20(5):597,r2013

Casey ML, Delgadillo M, Cox A, et al: Inactivation of prostaglandins in human decidua vera (parietalis) tissue: substrate speciicity of prostaglandin dehydrogenase. Am J Obstet Gynecol 160:3, 1989

Casey ML, Hemsell DL, MacDonald Pc, et al: NAD+ -dependent 15-hydroxyprostaglandin dehydrogenase activity in human endometrium. Prostaglandins 19:115,r1980

Casey ML, MacDonald PC: Extraadrenal formation of a mineralocorticosteroid: deoxycorticosterone and deoxycorticosterone sulfate biosynthesis and metabolism. Endocr Rev 3:396, 1982a

Casey ML, MacDonald PC: Metabolism of deoxycorticosterone and deoxycorticosterone sulfate in men and women. J Clin Invest 70:312, 1982b Casey ML, MacDonald PC: The endothelin-parathyroid hormone-related protein vasoactive peptide system in human endometrium: modulation by transforming growth factor-beta. Hum Reprod 11(SuppI2):62, 1996

Cassmer 0: Hormone production of the isolated human placenta. Studies on the role of the foetus in the endocrine functions of the placenta. Acta Endocrinol Suppl 32(SuppIr45):1, 1959

Cervar M, Blaschitz A, Dohr G, et al: Paracrine regulation of distinct trophoblast functions in vitro by placental macrophages. Cell Tissue Res 295:297, 1999

Chennazhi, Nayak NR: Regulation of angiogenesis in the primate endometrium: vascular endothelial growth factor. Semin Reprod Med 27(1):80, 2009

Chigusa Y, Kishore AH, Mogami H, et al: Nrf2 activation inhibits efects of thrombin in human amnion cells and thrombin-induced preterm birth in mice. J Clin Endocrinol Metab 101(6):2612,r2016

Cock TA, Auwerx]: Leptin: cL1Cting the fat off the bone. Lancet 362: 1572, 2003 Cole A: Immunoassay of human chorionic gonadotropin, its free subunits, and metabolites. Clin Chen 43:2233, 1997

Conneely OM, Mulac-]ericevic B, DeMayo F, et al: Reproductive functions of progesterone receptors. Recent Prog Horm Res 57:339, 2002

Corbacho M, Martinez DL, Clapp C: Roles of prolactin and related members of the prolactin/growth hormone/placental lactogen family in angiogenesis. J Endocrinol 173:219, 2002

Coya R, Manul P, Algortar], et al: Progesterone and human placental lactogen inhibit leptin secretion on cultured trophoblast cells from human placentas at term. Gynecol Endocrinol 21 :27, 2005

Crawford]: A study of human placental growth with observations on the placenta in erythroblastosis foetalis. BjOG 66:855, 1959

Critchley HO, Kelly RW, Baird DT, et al: Regulation of human endometrial function: mechanisms relevant to uterine bleeding. Reprod Bioi Endocrinol 4 Suppl 1 :S5, 2006

Cuny TE Jr, Smith MF: Impact of extracellular matrix remodeling on ovulation and the folliculo-luteal transition. Semin Reprod Med 24(4):228, 2006 Dautzenberg FM, Hauger RL: he CRF peptide family and their receptors: yet more partners discovered. Trends Pharmacol Sci 23:71, 2002

Debieve F, Pampfer S, Thomas K: Inhibin and activin production and subunit expression in human placental cells cultured in vitro. Mol Human Reprod 6(8): 43, 2000

Diczfalusy E, Troen P: Endocrine functions of the human placenta. Vitam Horm 19:229, 1961

Dombroski A, Casey ML, MacDonald PC: 5-Alpha-dihydroprogestetone formation in human placenta from 5alpha-pregnan-3beta/alpha-ol-20-ones and 5-pregnan-3beta-yl-20-one sulfate. j Steroid Biochem Mol Bioi 63: 155, 1997

DuY DM, Hutchison jS, Stewart DR, et al: Stimulation of primate luteal function by recombinant human chorionic gonadotropin and modulation of steroid, but not relaxin, production by an inhibitor of 3 beta-hydroxysteroid dehydrogenase during simulated early pregnancy. j Clin Endocrinol Metab 81:2307,r1996

Duncan WC, McNeilly AS, Fraser HM, et al: Luteinizing hormone receptor in the human corpus luteum: lack of down-regulation during maternal recognition of pregnancy. Hum Reprod 11 :2291, 1996

Dunn CL, Critchley HO, Kelly RW: IL-15 regulation in human endometrial stromal cells. j Clin Endocrinol Metab 87:1898, 2002

Economos K, MacDonald pc, Casey ML: Endorhelin-1 gene expression and protein biosynthesis in human endometrium: potential modulator of endometrial blood flow. J Clin Endocrinol Metab 74: 14, 1992

Edman CD, Toofanian A, MacDonald PC, et al: Placental clearance rate of maternal plasma androstenedione through placental estradiol formation: an indirect method of assessing uteroplacental blood flow. Am J Obstet Gynecol 141:1029, 1981

Elliott CL, Allport Vc, Loudon jA, et al: Nuclear factor-kappa B is essential for up-regulation of interleukin-8 expression in human amnion and cervical epithelial cells. Mol Hum Reprod 7:787,r200r1

Evans J, Salamonsen A: Inflammation, leukocytes and menstruation. Rev Endocr Metab Disord 13(4):277,r2012

Faas MM, de Vos P: Uterine NK cells and macrophages in pregnancy. Placenta 56:44,r2017

Faddy Mj, Gosden RG, Gougeon A, et al: Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum Reprod 7:1342, 1992

Ferenczy A: Studies on the cytodynamics of human endometrial regeneration.

1. Scanning electron microscopy. Am j Obstet Gynecol 124:64, 1976

Filicori M, Santoro N, Merriam GR, et al: Characterization of the physiological pattern of episodic gonadotropin secretion throughout the human menstrual cycle. j Clin Endocrinol [etab 62: 1136, 1986

Fisk NM, MacLachlan N, Ellis C, et al: Absent end-diastolic flow in irst trimester umbilical artery. Lancet 2: 1256, 1988

Florio P, Franchini A, Reis FM, et al: Human placenta, chorion, amnion and decidua express diferent variants of corticotropin-releasing factor receptor messenger RNA. Placenta 21r:32, 2000

Florio P, Mezzesimi A, Turchetti V, et al: High levels of human chromogranin A in umbilical cord plasma and amniotic luid at parturition. J Soc Gynecol Investig 9:32, 2002

France JT, Liggins GC: Placental sulfatase deiciency. J Clin Endocrinol Metab 29:] 38, 1969

Frandsen VA, Stakemann G: The site of production of oestrogenic hormones in human pregnancy: hormone excretion in pregnancy with anencephalic foetus. Acta Endocrinol 38:383, 1961

Fraser HM, Wulf C: Angiogenesis in the primate ovary. Reprod Ferril Dev 13:557,r2001

Fu B, Li X, Sun R, et al: Natural killer cells promote immune tolerance by regulating inlammatory TH 17 cells at the human matenal-fetal interface. Proc Nat! Acad Sci USA 11O(3):E231, 2013

Fuglsang j, Skjaerbaek C, Espelund U, et al: Ghrelin and its relationship to growth hormones during normal pregnancy. Clin Endocrinol (Oxf) 62(5):554, 2005

Fuzzi B, Rizzo R, Criscuoli L, et al: HLA-G expression in early embryos is a fundamental prerequisite for the obtainment of pregnancy. Eur] Immunol 32:31r1, 2002

Garcia-Velasco JA, Arici A: Chemokines and human reproduction. Fertil Steril 71:983, 1999 Gargett CE, Rogers P A: Human endometrial angiogenesis. Reproduction 121:181, 2001

Genazzani AR, Fraioli F, Hurlimannr], et al: Immunoreactive ACTH and cortisol plasma levels during pregnancy. Detection and partial puriication of corticotrophin-like placental hormone: the human chorionic corticotrophin (HCC). Clin Endocrinol (Ox) 4:1,r1975

Genbacev 0, Ratkovic M, Kraincanic M, et al: Efect of prostaglandin PGE2alpha on the synthesis of placental proteins and human placental lactogen (HPL). Prostaglandins 13:723, 1977

Georgia S, Bhushan A: Pregnancy hormones boost beta cells via serotonin. Nat Med 16(7):756,r2010

Germain A, Attaroglu H, MacDonald PC, et al: Parathyroid hormone-related protein mRNA in avascular human amnion. ] Clin Endocrinol Metab 75:1173,r1992

Gibson DA, Simitsidelis 1, Cousins FL, et al: Intracrine androgens enhance decidualization and modulate expression of human endometrial receptiviry genes. Sci Rep 286, 2016

Golander A, Hurley T, Barrett J, et al: Prolactin synthesis by human choriondecidual tissue: a possible source of prolactin in the amniotic luid. Science 202:311, 1978

Goldman-Wohl DS, Ariel I, Greenfield C, et al: HLA-G expression in extravillous trophoblasts is an intrinsic property of cell diferentiation: a lesson learned from ectopic pregnancies. Mol Hum Reprod 6:535, 2000

Gougeon A: Regulation of ovarian follicular development in primates: facts and hypotheses. Endocr Rev 17: 121, 1996

Greer LG, Casey BM, Halvorson LM, et al: Antithyroid antibodies and parity: further evidence for microchimerism in autoimmune thyroid disease. Am ] Obstet Gynecol 205(5):471.e1, 2011

Groome NP, Illingworth Pj, O'Brien M, et al: Measurement of dimeric inhibin B throughout the human menstrual cycle. j Clin Endocrinol Metab 81:1401, 1996

Grumbach MM: Aromatase deiciency and its consequences. Adv Exp Med Bioi 707:19, 2011

Grumbach MM, Kaplan SL: On placental origin and puriication of chorionic growth hormone prolactin and its immunoassay in pregnancy. Trans N Y Acad Sci : 167, 1964

Gualillo 0, Caminos J, Blanco M, et al: Ghrelin, a novel placental-derived hormone. Endocrinology 142:788, 2001

Gubbay 0, Critchley HO, Bowen JM, et al: Prolactin induces ERK phosphorylation in epithelial and CD56(+) natural killer cells of the human endometrium. J Clin Endocrinol Metab 87:2329, 2002

Gurpide E, Schwers J, Welch MT, et al: Fetal and maternal metabolism of estradiol during pregnancy. J Clin Endocrinol Metab 26:1355, 1966 Gurpide E, Tseng j, Escarcena L, et al: Fetomaternal production and transfer of progesterone and uridine in sheep. m J Obstet Gynecol 113:21,

Guzeloglu-Kayisli 0, Kayisli UA, Taylor HS: The role of growth factors and cytokines during implantation: endocrine and paracrine interactions. Semin Reprod Med 27(1):62, 2009

Hafez ES, Ludwig H, Metzger H: Human endometrial luid kinetics as observed by scanning electron microscopy. 1 J Obstet Gynecol 122:929, 1975

Hannar], Goldman-Wohl 0, Hamani Y, et al: Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med 12:1065,r2006

Hansell Dj, Bryant-Greenwood GD, Greenwood FC: Expression of the human relaxin HI gene in the decidua, trophoblast, and prostate. J Clin Endocrinol Metab 72:899, 1991

Harada N, Ogawa H, Shozu M, et al: Biochemical and molecular genetic analyses on placental aromatase (P-450AROM) deficiency. J Bioi Chen 26 :4781, 1992

Henson MC, Castracane VD: Leptin: roles and regulation in primate pregnancy. Semin Reprod Med 20: 113, 2002 Hershman JM: Human chorionic gonadotropin and the thyroid: Hyperemesis gravidarum and trophoblastic tumors. Thyroid 9:653, 1999

Hertig AT: The placenta: some new knowledge about an old organ. Obstet Gynecol 20:859, 1962

Hillier SG: Gonadotropic control of ovarian follicular growth and development. Mol Cell Endocrinol 179:39,r2001

Horgan CE, Roumimper H, Tucker R, et al: Altered decorin and Smad expression in human fetal membranes in PPROM. Bioi Reprod 91(5):105, 2014

Horvath TL, Diano S, Sotonyi P, et al: Minireview: ghrelin and the regulation of energy balance-a hypothalamic perspective. Endocrinology 142:4163, 2001

Hoshina M, Boothby M, Boime 1: Cytological localization of chorionic gonadotropin alpha and placental lactogen mRNAs during development of the human placenta. J Cell Bioi 93: 190, 1982

Hreinsson JG, SCOtt JE, Rasmussen C, et al: Growth diferentiation factor-9 promotes the growth, development, and survival of human ovarian follicles in organ culture. J Clin Endocrinol Metab 87:316, 2002

Hudson P, Haley J, John M, et al: Structure of a genomic clone encoding biologically active human relaxin. Nature 301:628, 1983

Hudson P, John M, Crawford R, et al: Relaxin gene expression in human ovaries and the predicted structure of a human preprorelaxin by analysis of eDNA clones. EMBO J 3:2333, 1984

HuntJS, Orr HT: HLA and maternal-fetal recognition. FASEB J 6:2344,r1992

Iwashita M, Kudo Y, Shinozaki Y, et al: Gonadotropin-releasing hormone increases serum human chorionic gonadotropin in pregnant women. Endocr J 40:539, 1993

Jefrey J: Collagen and collagenase: pregnancy and parturition. Semin Perinatol 15:118, 1991

Johnson EL, Chakraborty R: Placental Hofbauer cells limit HIV-1 replication and potentially ofset mother to child transmission (MTCT) by induction of immunoregulatory cytokines. Retrovirology 9: 101, 2012

Johnson PM, Christmas SE, Vince GS: Immunological aspects of implantation and implantation failure. Hum Reprod 14(suppIr2):26, 1999

Jones L, Stoikos C, Findlay JK, et al: TGF-3 superfamily expression and actions in the endometrium and placenta. Reproduction 132:21 , 2006

Jones SA, Brooks AN, Challis JR: Steroids modulate corticotropin-releasing hormone production in human fetal membranes and placenta. J Clin Endocrinol Metab 68:825, 1989a

Jones SA, Challis JR: Local stimulation of prostaglandin production by corticotropin-releasing hormone in human fetal membranes and placenta. Biochem Biophys Res Commun 159: 192, 1989b

Kaipia A, Hsueh AJ: Regulation of ovarian follicle atresia. Annu Rev Physiol 59:349, 1997

Kane N, Kelly R, Saunders PTK, et al: Proliferation of uterine natural killer cells is induced by hCG and mediated via the man nose receptor. Endocrinology 150(6) :2882, 2009

Kaneko Y, Murphy CR, Day ML: Extracellular matrix proteins secreted from both the endometrium and the embryo are required for attachment: a study using a co-culture model of rat blastocysts and Ishikawa cells. J Morphol 2741(1):63,r2013

Katzenellenbogen BS, Sun J, Harrington R, et al: Structure-function relationships in estrogen receptors and the characterization of novel selective estrogen receptor modulators with unique pharmacological profiles. Ann NY Acad Sci 949:6, 2001r,

Kaufmann P, Schefen 1: Placental development. In Polin R, Fox W (eds): Fetal and Neonatal Physiology. Philadelphia, Saunders, 1992

Kim H, Toyofuku Y, Lynn FC; et al: Serotonin regulates pancreatic beta cell mass during pregnancy. Nat Med 16(7):804,2010

King BF, Menton DN: Scanning electron microscopy of human placental villi from early and late in gestation. Am J Obstet Gynecol 122:824, 1975

Kraiem Z, Sadeh 0, Blithe DL, et al: Human chorionic gonadotropin stimulates thyroid hormone secretion, iodide uptake, organification, and adenosine 3',5'-monophosphate formation in cultured human thyrocytes. J Clin Endocrinol Metab 79:595, 1994

Kurman RJ, Young RH, Norris HJ, et al: Immunocytochemical localization of placental lactogen and chorionic gonadotropin in the normal placenta and trophoblastic tumors, with emphasis on intermediate trophoblast and the placental site trophoblastic tumor. Int J Gynecol Pathol 3: 101, 1984

Kurtzman JT, Wilson H, Rao CV: A proposed role for hCG in clinical obstetrics. Semin Reprod Med 19:63,2001

La Cava A, Alviggi C, Matarese G: Unraveling the multiple roles of leptin in inflammation and autoimmunity. J Mol Med 82:4, 2004

LeBouteiller P, Solier C, Proll J, et al: Placental HLA-G protein expression in vivo: where and what for? Hum Reprod Update 5:223, 1999

Lessey BA, Castelbaum ]: Integrins and implantation in the human. Rev Endocr Metab Disord 3: 10 , 2002

Lessey BA, Castelbaum AJ, Sawin SW, et al: Integrins as markers of uterine receptivity in women with primary unexplained infertility. Ferti! Steri! 63:535, 1995

Liao S, Vickers MH, Taylor RS, et al: Human placental growth hormone is increased in maternal serum at 20 weeks of gestation in pregnancies with large-for-gestation-age babies. Growth Factors 34(5-6):203, 2016

Licht P, Russu V, Wildt L: On the role of human chorionic gonadotropin (hCG) in the embryo-endometrial microenvironment: implications for differentiation and implantation. Semin Reprod Med 19:37,r2001

Lindhard A, Bentin-Ley U, Ravn V, et al: Biochemical evaluation of endometrial function at the time of implantation. Fertil Steril 78:221, 2002

Lobo SC, Srisuparp S, Peng X, et al: Uterine receptivity in the baboon: modulation by chorionic gonadotropin. Semin Reprod Med 19:69,2001

Loke YM, King A: Human Implantation. Cell Biology and Immunology.

Cambridge, Cambridge University Press, 1995

Loquet P, Broughton-Pipkin F, Symonds E, et al: Blood velocity waveforms and placental vascular formation. Lancet 2:1252, 1988

Luo S, Yu H, Wu D, et al: Transforming growth factor 31 inhibits steroidogenesis in human trophoblast cells. Molecular Human Reproduction 8(3):318,r2002

MacDonald PC: Placental steroidogenesis. In Wynn RM (ed): Fetal Homeostasis, Vol. I. New York, New York Academy of Sciences, 1965a MacDonald PC, Siiteri PK: Origin of estrogen in women pregnant with an anencephalic fetus. J Clin Invest 44:465, 1965b

MacDonald Pc, Siiteri PK: Study of estrogen production in women with hydatidiform mole. J Clin Endocrinol Metab 24:685, 1964

MacDonald Pc, Siiteri PK: The in vivo mechanisms of origin of estrogen in subjects with trophoblastic tumors. Steroids 8:589, 1966

Macklon NS, Fauser BC: Follicle-stimulating hormone and advanced follicle development in the human. Arch Med Res 32:595, 2001

Manaster I, Mizrahi S, Goldman-Wohl D, et al: Endometrial NK cells are special immature cells that await pregnancy. J Immunol 181: 1869, 2008

Marcellin L, Schmitz T, Messaoudene M, et al: Immune modifications in fetal membranes overlying the cervix precede parturition in humans. J Immunol 198(3):1345,r2017

Markee J: Menstruation in intraocular endometrial transplants in the rhesus monkey. Contrib EmbryoIr28:219, 1940

Mamo T, Ladines-Llave CA, Matsuo H, et al: A novel change in cytologic localization of human chorionic gonadotropin and human placental lactogen in first-trimester placenta in the course of gestation. Am J Obstet GynecoIr167:217,r1992

Maybin JA, Critchley HO: Menstrual physiology: implications for endometrial pathology and beyond. Hum Reprod Update 21(6):748,r2015

McCabe ER: Adrenal hypoplasias and aplasias. In Scriver CR, Beaudet L, Sly WE, et al (eds): The Metabolic and Molecular Bases of Inherited Disease. New York, McGraw-Hill, 2001

McCombs H, Craig M: Decidual necrosis in normal pregnancy. Obstet Gynecol 24:436, 1964

McGregor WG, Kuhn RW, Jafe RB: Biologically active chorionic gonadotropin: synthesis by the human fetus. Science 220:306, 1983

McGregor WG, Raymoure J, Kuhn RW, et al: Fetal tissue can synthesize a placental hormone. Evidence for chorionic gonadotropin beta-subunit synthesis by human fetal kidney. J Clin Invest 68:306, 1981

Mesiano S: The endocrinology of human pregnancy and fetoplacental neuroendocrine development. In Strauss JF, Barbieri L (eds): Yen and Jafe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 6th ed. Philadelphia, Saunders, 2009

Mi Y, Wang W, Zhang C, et al: Autophagic degradation of collagen 1A1 by cortisol in human amnion fibroblasts. Endocrinology 158(4):1005, 2017

Miller-Lindholm AK, LaBenz q, Ramey J, et al: Human chorionic gonadotropin-beta gene expression in first trimester placenta. Endocrinology 138:5459, 1997

Mofett-King A: Natural killer cells and pregnancy. Nat Rev Immunol 2:656, 2002

Mogami H, Keller PW, Shi H, et al: Efect of thrombin on human amnion mesenchymal cells, mouse fetal membranes, and preterm birth. J Bioi Chen 289(19):13295,r2014

Mogami H, Kishore AH, Shi H, et al: Fetal fibronectin signaling induces matrix metalloproteases and cyclooxygenase-2 (COX-2) in amnion cells and preterm birth in mice. J Bioi Chen 288(3):1953,r2013

Moore J], Dubyak GR, Moore vl, et al: Oxytocin activates the inositol-phospholipid-protein kinase-C system and stimulates prostaglandin production in human amnion cells. Endocrinology 123:1771,r1988

Moore L, Persaud TV, Torchia MG (eds): The Developing Human. Clinically Oriented Embryology, 9th ed. Philadelphia, Saunders, 2013

Moore M, Redline RW, Kumar D, et al: Diferential expression of fibulin family proteins in the para-cervical weak zone and other areas of human fetal membranes. Placenta 30(4):335,s2009

Morrish DW, Bhardwaj D, Paras MT: Transforming growth factor beta 1 inhibits placental diferentiation and human chorionic gonadotropin and human placental lactogen secretion. Endocrinology 129(1):22, 1991

Morrish DW, Marusyk H, Siy 0: Demonstration of speciic secretory granules for human chorionic gonadotropin in placenta. J Histochem Cytochem 35:93, 1987

Mote PA, Balleine L, McGowan EM, et al: Colocalization of progesterone receptors A and B by dual immunoluorescent histochemistry in human endometrium during the menstrual cycle. J Clin Endocrinol Metab 84:2963, 1999

Mote PA, Balleine RL, McGowan EM, et al: Heterogeneity of progesterone receptors A and B expression in human endometrial glands and stroma. Hum Reprod 15(suppl 3):48, 2000

Navot D, Bergh P: Preparation of the human endometrium for implantation.

Ann NY Acad Sci 622:212, 1991

Nemeth E, Tashima LS, Yu Z, et al: Fetal membrane distention: I. Diferentially expressed genes regulated by acute distention in amniotic epithelial (WISH) cells. Am J Obstet GynecoIs182:50, 2000

Nguyen H, Dubernard G, Aractingi S, et al: Feto-maternal cell traicking: a transfer of pregnancy associated progenitor cells. Stem Cell Rev 2: Ill, 2006 Nicholson RC, King BR: Regulation of CRH gene expression in the placenta.

Front Horm Res 27:246, 2001

Nikas G: Cell-surface morphological events relevant to human implantation.

Hum Reprod 2:37, 2003

Nusken E, Wohlfarth M, Lippach G, et al: Reduced perinatalsleptin availability may contribute to adverse metabolic programming in a rat model of uteroplacental insuiciency. Endocrinology 157(5):1813,s2016

Ny T, Wahlberg P, Brandsrrom IJ: Matrix remodeling in the ovary: regulation and functional role of the plasminogen activator and matrix metalloproteinase systems. Mol Cell Endocrinol 187:29,2002

O'Sullivan CM, Liu SY, Karpinka JB, et al: Embryonic hatching enzyme strypsinlISP 1 is expressed with ISP2 in endometrial glands during implantation. Mol Reprod Dev 62:328, 2002

Odagiri E, Sherrell BJ, Mount CD, et al: Human placental immunoreactive corticotropin, lipotropin, and beta-endorphin: evidence for a common precursor. Proc Nat! Acad Sci USA 76:2027, 1979

Parker CRJr, Carr BR, Simpson ER, et al: Decline in the concentration oflowdensity lipoprotein-cholesterol in human fetal plasma near term. Metabolism 32:919, 1983

Parker CR Jr, Simpson ER, Bilheimer DW, et al: Inverse relation between low-density lipoprotein-cholesterol and dehydroisoandrosterone sulfate in human fetal plasma. Science 208:512, 1980

Patel N, Alsat E, Igout A, et al: Glucose inhibits human placental GH secretion, in vitro. J Clin Endocrinol Metab 80: 1743, 1995

Peluso JJ: Non-genomic actions of progesterone in the normal and neoplastic mammalian ovary. Semin Reprod Med 25:198, 2007

Peng B, Zhu H, Klausen C, et al: GnRH regulates trophoblast invasion via RUNX2-mediated MMP2/9 expression. Mol Hum Reprod 22(2):119, 2016

Pereira de Sousa FL, Chaiwangyen W, Morales-Prieto DM, et al: Involvement of ST AT1 in proliferation and invasiveness of trophoblastic cells. Reprod Bioi 17(3):218, 2017

Petraglia F, Florio P, Benedetto C, et al: Urocortin stimulates placental adrenocorticotropin and prostaglandin release and myometrial contractility in vitro. J Clin Endocrinol Metab 84: 1420, 1999

Petraglia F, Giardino L, Coukos G, et al: Corticotropin-releasing factor and parturition: plasma and amniotic luid levels and placental binding sites. Obstet Gynecol 75:784, 1990

Petraglia F, Vaughan J, Vale W: Inhibin and activin modulate the release of gonadotropin-releasing hormone, human chorionic gonadotropin, and progesterone from cultured human placental cells. Proc Nat! Acad Sci USA 86:5114,s1989

Petraglia F, Woodruf TK, Botticelli G, et al: Gonadotropin-releasing hormone, inhibin, and activin in human placenta: evidence for a common cellular localization. J Clin Endocrinol Metab 74:1184, 1992

Pijnenborg R: Trophoblast invasion. Reprod Med Rev 3:53, 1994

Pijnenborg R, Bland JM, Robertson B, et al: Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy. Placenta 4:397, 1983

Piper KP, McLarnon A, Arrazi J, et al: Functional HY-speciic CD8+ T cells are found in a high proportion of women following pregnancy with a male fetus. BioI Reprod 76:96, 2007

PrabhuDas M, Bonney E, Caron K, et al: Immune mechanisms at the maternalfetal interface: perspective and challenges. Nat ImmunoIs16(4):328, 2015

Prakash A, Laird S, Tuckerman E, et al: Inhibin A and activin A may be used to predict pregnancy outcome in women with recurrent miscarriage. Fertil Steril 83(6): 1758, 2005

Qin X, Chua PK, Ohira RH, et al: An autocrine/paracrine role of human decidual relaxin. II. Stromelysin-1 (MMP-3) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1). BioI Reprod 56:812, 1997a

Qin X, Garibay-Tupas J, Chua PK, et al: An autocrine/paracrine role of human decidual relaxin. I. Interstitial collagenase (matrix metalloproteinase-1) and tissue plasminogen activator. BioI Reprod 56:800, 1997b

Rahmati M, Petitbarat M, Dubanchet S, et al: Colony stimulating factors 1, 2, 3 and early pregnancy steps: from bench to bedside. J Reprod Immunol 109:1,s2015

Rainey WE, Carr BR, Wang ZN, et al: Gene proiling of human fetal and adult adrenals. J Endocrinol 1 1 :209, 2001

Rajagopalan S, Long EO: Cellular senescence induced by CD 158d reprograms natural killer cells to promote vascular remodeling. Proc Nat! Acad Sci USA 109(50):20596,s2012

Ramsey EM, Donner MW: Placental Vasculature and Circulation. Philadelphia, Saunders, 1980

Reyes L, Wolfe B, Golos T: Hofbauer cells: placental macro phages of fetal origin. Results Probl Cell Difer 62:45, 2017

Richards JS: Genetics of ovulation. Semin Reprod Med 25(4):235, 2007 Riddick DH, Luciano A, Kusmik WF, et al: Evidence for a nonpituitary source of amniotic luid prolactin. Ferti! Steri! 31 :35, 1979

Riley S, Walton J, Herlick J, et al: he localization and distriburion of corticotropin-releasing hormone in the human placenta and fetal membranes throughout gestation. J Clin Endocrinol Metab 72: 1001, 1991

Robidoux J, Simoneau L, St Pierre S, et al: Characterization of neuropeptide Y-mediated corticotropin-releasing factor synthesis and release from human placental trophoblasts. Endocrinology 141 :2795, 2000

Robinson BG, Emanuel L, Frim DM, et al: Glucocorticoid stimulates expression of corticotropin-releasing hormone gene in human placenta. Proc Nat! Acad Sci USA 85:5244, 1988

Rogers PA, Donoghue JF, Walter LM, et al: Endometrial angiogenesis, vascular maturation, and lymphangiogenesis. Reprod Sci 16(2):147,s2009

Rosario FJ, Powell TL, Jansson T: Activation of placental insulin and mTOR signaling in a mouse model of maternal obesity associated with fetal overgrowth. Am J Physiol Regul Integr Comp PhysioIs310(1):R87, 2016a

Rosario GX, Stewart CL: The multifaceted actions of leukaemia inhibitory factor in mediating uterine receptivity and embryo implantation. Am J Reprod Immunol 75(3):246, 2016b

Rowe T, King L, MacDonald PC, et al: Tissue inhibitor of metalloproteinase-1 and tissue inhibitor of metalloproteinase-2 expression in human amnion mesenchymal and epithelial cells. Am J Obstet Gynecol 176:915, 1997

Ruocco MG, Chaouat G, Florez L, et al: Regulatory T-cells in pregnancy: historical perspective, state of the art, and burning questions. Front Immunol 5:389,s2014

Ryan KJ: Biological aromatization of steroids. J BioI Chen 234:268, 1959a Ryan KJ: Metabolism of C-16-oxygenated steroids by human placenta: the formation of estriol. J BioI Chen 234:2006, 1959b

Salido EC, Yen PH, Barajas L, et al: Steroid sulfatase expression in human placenta: immunocytochemistry and in situ hybridization study. J Clin Endocrinol Metab 70: 1564, 1990

Saunders PT: Does estrogen receptor beta playsa signiicant role in human reproduction? Trends Endocrinol Metab 16:222,s2005

Saxe A, Dean S, Gibson G, et al: Parathyroid hormone and parathyroid hormone-related peptide in venous umbilical cord blood of healthy neonates. J Perinat Med 25:288, 1997

Segalof A, Sternberg W, Gaskill C: Efects of luteotrophic doses of chorionic gonadotropin in women. J Clin Endocrinol Metab 11:936, 1951

Short R: Steroids in the follicular luid and the corpus luteum of the mare. A "two cell type" theory of ovarian steroid synthesis. J EndocrinoI24:59, 1962

Shozu M, Akasofu K, Harada T, et al: A new cause of female pseudohermaphroditism: placental aromatase deiciency. J Clin Endocrinol Metab 72:560, 1991

Siiteri PK, MacDonald PC: Placental estrogen biosynthesis during human pregnancy. J Clin Endocrinol Metab 26:751,s1966

Siiteri PK, MacDonald PC: he utilization of circulating dehydroisoandrosterone sulfate for estrogen synthesis during human pregnancy. Steroids 2:713, 1963

Siler-Khodr TM: Chorionic peptides. In McNellis D, Challis JRG, MacDonald PC, et al (eds): he Onset of Labor: Cellular and Integrative Mechanisms. Ithaca, Perinatology Press, 1988

Siler-Khodr TM, Khodr GS: Content of luteinizing hormone-releasing factor in the human placenta. Am J Obstet GynecoI 130:216, 1978

Siler-Khodr TM, Khodr GS: Dose response analysis of GnRH stimulation of hCG release from human term placenta. BioI Reprod 25:353, 1981

Siler-Khodr TM, Khodr GS, Valenzuela G: Immunoreactive gonadotropinreleasing hormone level in maternal circulation throughout pregnancy. Am J Obstet Gynecol 150:376, 1984

Simmonds CS, Karsenty G, Karaplis AD, et al: Parathyroid hormone regulates fetal-placental mineral homeostasis. J Bone Miner Res 25(3):594, 2010 Simoni MK, Jurado A, Abrahams VM, et al: Zika virus infection of Hofbauer cells. Am J Reprod Immunol (2): 1,2017

Simpson ER: Genetic mutations resulting in loss of aromatase activiry in humans and mice. J Soc Gynecol Investig 7:S18, 2000

Simpson ER, Burkhart MF: Acyl CoA:cholesterol acyl transferase activity in human placental microsomes: inhibition by progesterone. Arch Biochem Biophys 200:79, 1980

Simpson ER, Carr BR, Parker CR Jr, et al: The role of serum lipoproteins in steroidogenesis by the human fetal adrenal cortex. J Clin Endocrinol Metab 49:146,s1979

Sipos PI, Rens W, Schlecht H, et al: Uterine vasculature remodeling in human pregnancy involves functional macrochimerism by endothelial colony forming cells offetal origin. Stem Cells 31:1363, 2013

Soares MJ, Chakraborty 0, Renaud SJ, et al: Regulatory pathways controlling the endovascular invasive trophoblast cell linear. J Reprod Dev 58(3):283, 2012

Song Y, Keelan J, France JT: Activin-A stimulates, while transforming growth factor beta 1 inhibits, chorionic gonadotrophin production and aromatase activity in cultures human placental trophoblasts. Placenta 17(8):603, 1996

Steele GL, Currie WD, Yuen BH, et al: Acute stimulation of human chorionic gonadotropin secretion by recombinant human activin-A in first trimester human trophoblast. Endocrinology 133:297, 1993

Stevens vl: Microchimeric cells in systemic lupus erythematosus: targets or innocent bystanders? Lupus 15:820, 2006

Sugino N, Kashida S, Karube-Harada A, et al: Expression of vascular endothelial growth facto� (VEGF) and its receptors in human endometrium throughout the menstrual cycle and in early pregnancy. Reproduction 123:379, 2002 hiruchelvam U, Dransield I, Saunders PTK, et al: he importance of the macrophage within the human endometrium. J Leukoc BioI 93(2):217, 2013

Tomer Y, Huber GK, Davies TF: Human chorionic gonadotropin (hCG) interacts directly with recombinant human TSH receptors. J Clin Endocrinol Metab , 1992

Trombly OJ, Woodruf TK, Mayo KE: Roles for transforming growth factor beta superfamily proteins in early folliculogenesis. Semin Reprod Med 27(1):14,s2009

Tsai SJ, Wu MH, Chen HM, et al: Fibroblast growth factor-9 is an endometrial stromal growth factor. Endocrinology 143:2715, 2002

Tsuruta E, Tada H, Tamaki H, et al: Pathogenic role of asialo human chorionic gonadotropin in gestational thyrotoxicosis. J Clin Endocrinol Metab 80:350, 1995

Tyson JE, Hwang P, Guyda H, et al: Studies of prolactin secretion in human pregnancy. Am J Obstet Gynecol 113: 14, 1972 Vande Wiele L, Bogumil J, Dyrenfurth I, et al: Mechanisms regulating the menstrual cycle in women. Recent Prog Horm Res 26:63, 1970

Vaskivuo TE, Ottander U, Oduwole 0, et al: Role of apoptosis, apoptosisrelated factors and 17 beta-hydroxysteroid dehydrogenases in human corpus luteum regression. Mol Cell Endocrinol 194(1-2): 191, 2002

Vickers MH, Gilmour S, Gertler A, et al: 20-kDa placental hGH-V has diminished diabetogenic and lactogenic activities compared with 22-kDa hGH-N while retaining antilipogenic activity. Am J Physiol Endocrinol Metab 297(3):E629, 2009

Voltolini C, Battersby S, Novembri R, et al: Urocortin 2 role in placental and myometrial inflammatory mechanisms at parturition. Endocrinology 156(2):670, 2015

Wadhwa PO, Porto M, Garite TJ, et al: Maternal corticotropin-releasing hormone levels in the early third trimester predict length of gestation in human pregnancy. Am J Obstet GynecoIs179:1079, 1998

Walker WH, Fitzpatrick SL, Barrera-Saldana HA, et al: he human placental lactogen genes: structure, function, evolution and transcriptional regulation. Endocr Rev 12:316, 1991

Wallace EM, Swanston A, McNeilly AS, et al: Second trimester screening for Down's syndrome using maternal serum dimeric inhibin A. Clin Endocrinol (Ox) 44(1):17,s1996

Warren W, Silverman A: Cellular localization of corticotrophin releasing hormone in the human placenta, fetal membranes and decidua. Placenta ,1995

Weetman AP: he immunology of pregnancy. Thyroid 9:643, 1999 Wehmann RE, Nisula BC: Renal clearance rates of the subunits of human chorionic gonadotropin in man. J Clin Endocrinol Metab 50:674, 1980

Whittle WL, Gibb W, Challis JR: he characterization of human amnion epithelial and mesenchymal cells: the cellular expression, activity and glucocorticoid regulation of ptostaglandin output. Placenta 21 :394, 2000

Williams PJ, Searle F, Robson Sc, et al: Decidual leucocyte populations in early to late gestation normal human pregnancy. J Reprod Immunol 82(1):24, 2009

Winger EE, Reed JL: The multiple faces of the decidual natural killer cell. Am J Reprod Immunol 70:1, 2013

Wislocki GB, Dempsey EW: Electron microscopy of the human placenta. Anat Rec 123:133, 1955 Wolfahrt S, Kleine B, Rossmanith WG: Detection of gonadotrophin releasing hormone and its receptor mRNA in human placental trophoblasts using in situ reverse transcription-polymerase chain reaction. Mol Hum Reprod 4:999, 1998

Wu Z, Horgan CE, Carr 0, et al: Biglycan and decorin diferentially regulate signaling in the fetal membranes. Matrix Bioi 34:266, 2014

Xie L, Sadovsky Y: he function of miR-519d in cell migration, invasion, and proliferation suggests a role in early placentation. Placenta 48:34, 2016

Yan C, Wang P, DeMayo J, et al: Synergistic roles of bone morphogenetic Protein 15 and growth diferentiation Factor 9 in ovarian function. Mol Endocrinol 15:854, 2001

Yoshimura M, Pekary AE, Pang XP, et al: hyrotropic activity of basic isoelectric forms of human chorionic gonadotropin extracted from hydatidiform mole tissues. J Ciin Endocrinol Metab 78:862, 1994 Zhang M, Muralimanoharan S, Wortman AC, et al: Primate-speciic miR-515 family members inhibit key genes in human trophoblast differentiation and are up regulated in preeclampsia. Proc Natl Acad Sci USsA 113(45):E7069, 2016

NORMAL PLACENTA . . . . . . . . . . . . . . . . . . . . . . . . . . .. 111

SHAPE AND SIZE VARIANTS . . . . . . . . . . . . . . . . . . . . .. 112

EXTRACHORIAL PLACENTATION . . . . . . . . . . . . . . . . .. 113

CIRCULATORY DISTURBANCES . . . . . . . . . . . . . . . . . .. 113

PLACENTAL CALCIFICATION. . . . . . . . . . . . . . . . . . . . .. 115 PLACENTAL TUMORS ........................... 115

AMNIOCHORION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 116

UMBILICAL CORD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 117

The placenta, as a rule, presents more or less rounded outlines, but now and again when inserted in the neighbourhood of the internal os it may take on a horseshoe-like appearance, its two branches running partialy around the oriice.

-J. Whitridge Williams (1903) he placenta is a fantastic organ in its own right. As discussed in Chapter 5 (p. 88), it provides the indispensable interface between mother and fetus. Indeed, placental anatomy, ogy, and molecular structure remain some of the most intriguing and understudied topics in obstetrics.

Although a placental examination by the obstetrician is recommended, by consensus, routine pathological examination is not mandatory. Indeed, speciic conditions that merit submission for detailed inspection are still debated. By way of example, the College of American Pathologists has recommended placental examination for an extensive list of indications (Langston, 1997). Data, however, are insuicient to support all of these.

At minimum, the placenta and cord should be inspected in the delivery room. he decision to request pathological examination should be based on clinical and placental findings (Redline, 2008; Roberts, 2008). Listed in Table 6-1 are some of the indications at Parkland Hospital for placental anatomical and histopathological examination.

At term, the typical placenta weighs 470 g, is round to oval with a 22-cm diameter, and has a central thickness of 2.5 cm (Benirschke, 2012). It is composed of a placental disc, extraplacental membranes, and three-vessel umbilical cord. The disc surface that lies against the uterine wall is the basal plate, which is divided by clefts into portions-termed cotyledons. he fetal surface is the chorionic plate, into which the umbilical cord inserts, typically in the center. Large fetal vessels that originate from the cord vessels then spread and branch across the chorionic plate before entering stem villi of the placenta parenchyma. In tracing these, fetal arteries almost invariably cross over veins. he chorionic plate and its vessels are covered by thin amnion, which can be easily peeled away from a postdelivery specimen.

As recommended by the American Institute of Ultrasound in Medicine (2013), placental location and relationship to the internal cervical os are recorded during prenatal sonographic examinations. As visualized ultrasonically, the normal placenta is homogenous and 2 to 4 cm thick, lies against the myometrium, and indents into the amnionic sac. The retroplacental space is a hypoechoic area that separates the myometrium from the basal plate and measures less than 1 to 2 cm. The umbilical cord is also imaged, its fetal and placental insertion sites examined, and its vessels counted.

Many placental lesions can be identiied grossly or sonographically, but other abnormalities require histopathological examination for clariication. A detailed description of these

Antepartum infection with fetal risks Anti-CDE alloimmunization Cesarean hysterectomy Oligohydramnios or hydramnios Peripartum fever or infection Preterm delivery Postterm delivery

Systemic disorders with known effects Thick or viscid meconium Unexplained late pregnancy bleeding

Admission to an acute care nursery Birth weight � 10th or �95th percentile Feta! anemia

Vanishing twin beyond the first trimester alndications are organized alphabetically.

is beyond the scope of this chapter, and interested readers are referred to textbooks by Benirschke (2012), Fox (2007), and Faye-Petersen (2006) and their colleagues. Moreover, the placenta accrete syndrome and gestational trophoblastic disease are presented in detail in Chapters 20 and 41, respectively.

Of variants, placentas may infrequently form as separate, nearly equally sized discs. his bilobate placenta may also be called bipartite placenta or placenta duplex. In these, the cord inserts between the two placental lobes-either into a connecting chorionic bridge or into intervening membranes. A placenta containing three or more equivalently sized lobes is rare and termed multilobate. Unlike this equal distribution, one or more

TABLE 6-1. Some Indications for Placental Pathological Examinationa

FIGURE 6-1 Succenturiate lobe. A. Vessels extend from the main placental disc to supply the small round succenturiate lobe located beneath it. (Used with permission from Dr. Jaya George.) B. Sonographic imaging with color Doppler shows the main placental disc implanted posteriorly (asterisk). The succenturiate lobe is located on the anterior uterine wall across the amnionic cavity. Vessels are identified as the long red and blue crossing tubular structures that travel within the membranes to connect these two portions of placenta.

disparately smaller accessory lobes-succenturiate lobes-may develop in the membranes at a distance from the main placenta (Fig. 6-1). hese lobes have vessels that course through the membranes. Of clinical importance, if these vessels overlie the cervix to create a vasa previa, dangerous fetal hemorrhage can follow vessel laceration (p. 118). n accessory lobe can also be retained in the uterus after delivery to cause postpartum uterine atony and hemorrhage or later endometritis.

Rarely, the placental surface area varies from the norm. With placenta membranacea, villi cover all or nearly all the uterine cavity. This may occasionally give rise to serious hemorrhage because of associated placenta previa or accreta (Greenberg, 1991; Pereira, 2013). A ring-shaped placenta may be a variant of placenta membranacea. his placenta is annular, and a partial or complete ring of placental tissue is present. hese abnormalities appear to be associated with a greater likelihood of tion (Faye-Petersen, 2006; Steemers, 1995). With placenta fenestrata, the central portion of a placental disc is missing. In some instances, there is an actual hole in the placenta, but more often, the defect involves only villous tissue, and the chorionic plate remains intact. Clinically, it may erroneously prompt a search for a retained placental cotyledon.

During pregnancy, the normal placenta increases its thickness at a rate of approximately 1 mm per week. lthough not measured as a component of routine sonographic evaluation, this thickness typically does not exceed 40 mm (Hoddick, 1985). Placentomegay deines those thicker than 40 mm and commonly results from striking villous enlargement. his may be secondary to maternal diabetes or severe maternal anemia, or to fetal hydrops, anemia, or infection caused by syphilis, toxoplasmosis, parvovirus, or cytomegalovirus. In these conditions, the placenta is homogeneously thickened. Less commonly with placentomegaly, fetal parts are present, but villi are edematous and appear as small placental cysts, such as in cases of partial mole (Chap. 20, p. 391). Cystic vesicles are also seen with placental mesenchymal dysplasia. Vesicles in this rare condition correspond to enlarged stem villi, but unlike molar pregnancy, trophoblast proliferation is not excessive (Woo, 2011).

Rather than villous enlargement, placentomegaly often may result from collections of blood or ibrin, which impart heterogeneity to the placenta. Examples of this are discussed on page 114 and include massive perivillous fibrin deposition, intervillous or subchorionic thromboses, and large retroplacental hematomas.

he chorionic plate normally extends to the periphery of the placenta and has a diameter similar to that of the basal plate. With extrachorial placentation, however, the chorionic plate fails to extend to this periphery and leads to a chorionic plate that is smaller than the basal plate (Fig. 6-2). Circummarginate and circumvallate placentas are the two types. In a circummarginate placenta, ibrin and old hemorrhage lie between the placenta and the overlying sheer amniochorion. In contrast, with a circumvallate placenta, the chorion periphery is a thickened, opaque, gray-white circular ridge composed of a double fold of chorion and amnion. Sonographically, the double fold can be seen as a thick, linear band of echoes extending from one placental edge to the other. On cross section, however, it appears as two "shelves," with each lying above an opposing placental margin (see Fig. 6-2). his anatomy can help diferentiate this shelf from amnionic bands and amnionic sheets, which are described on page 116.

In relatively small observational studies of circumvallate placenta diagnosed postpartum, it was associated with increased risk for antepartum bleeding, abruption, fetal demise, and preterm birth (Lademacher, 1981; Suzuki, 2008; Taniguchi, 2014). In a prospective sonographic investigation of 17 cases, however, Shen and associates (2007a) found most circumvallate placentas to be transient. Persistent cases were benign. In general, most otherwise uncomplicated pregnancies with either type of extrachorial placentation have normal outcomes, and no increased surveillance is usually required.

Functionally, placental perfusion disorders can be grouped into: (1) those in which maternal blood low to or within the intervillous space is disrupted, and (2) those with disturbed fetal blood flow through the villi. These lesions are frequently identiied in the normal, mature placenta. Although they can limit maximal placental blood flow, functional reserve within the placental prevents harm in most cases. Indeed, some estimate that up to 30 percent of placental villi can be lost without untoward fetal efects (Fox, 2007). If extensive, however, these lesions can profoundly limit fetal growth.

Lesions that disrupt perfusion are frequently seen grossly or sonographically, whereas smaller lesions are seen only histologically. With sonography, many of these, such as subchorionic fibrin deposition, perivillous ibrin deposition, and intervillous thrombosis, appear as focal sonolucencies within the placenta. Importantly, in the absence of maternal or fetal

FIGURE 6-2 A. In this illustration, circummarginate (left) and circumvallate (right) varieties of extrachorial placentation are shown.

Double fold of amnion & chorion

A circummarginate placenta is covered by a single layer of amniochorion. B. This transabdominal gray-scale sonographic image shows a circumvallate placenta. The double fold of amnion and chorion creates a broad, opaque white ring and ridge on the fetal surface.

complications, isolated placental sonolucencies are considered incidental indings.

These collections are caused by slowing of maternal blood low within the intervillous space. In the portion of this space near the chorionic plate, blood stasis is prominent and leads to subsequent ibrin deposition. In viewing the placental fetal surface, subchorionic lesions are commonly seen as white or yellow, firm, round, elevated plaques just beneath the chorionic plate.

Stasis of maternal blood flow around an individual villus also results in fibrin deposition and can lead to diminished villous oxygenation and necrosis of syncytiotrophoblast (Fig. 6-3). These small yellow-white placental nodules are grossly visible within the parenchyma of a sectioned placenta. Within limits, these relect normal placental aging.

Maternal Floor Infarction. his extreme variant of perivillous fibrin deposition is a dense ibrinoid layer within the placental basal plate and is erroneously termed an infarction. Maternal loor inarction has a thick, yellow or white, irm corrugated surface that impedes normal maternal blood low into the intervillous space. In specific cases that extend beyond the basal plate to entrap villi and obliterate the intervillous space, the term massive perivillous ibrin deposition is used. The etiopathogenesis is unclear, but maternal auto-or alloimmunity appears contributory (Faye-Peterson, 2017; Romero, 2013). Antiphospholipid antibody syndrome and angiogenic factors involved with preeclampsia have also been implicated (Sebire, 2002, 2003; Whitten, 2013).

These lesions are not reliably imaged with prenatal sonography, but they may create a thicker basal plate. Afected pregnancies are associated with miscarriage, fetal-growth restriction, preterm delivery, and stillbirth (Andres, 1990; Mandsager, 1994). Importantly, these adverse outcomes can recur in subsequent pregnancies.

This is a collection of coagulated maternal blood normally found in the intervillous space mixed with fetal blood from a break in a villus. Grossly, these round or oval collections vary in size up to several centimeters. hey appear red if recent or white-yellow if older, and they develop at any placental depth. Intervillous thrombi are common and typically not associated with adverse fetal sequelae. Because there is potential for a communication between maternal and fetal circulations, large lesions can cause elevated maternal serum alpha-fetoprotein levels (Salaia, 1988).

Chorionic villi themselves receive oxygen solely from maternal circulation supplied to the intervillous space. Any uteroplacental disease that diminishes or obstructs this supply can result in infarction of an individual villus. These are common lesions in mature placentas and are benign in limited numbers. If numerous, however, placental insuiciency can develop. When they are thick, centrally located, and randomly distributed, they may be associated with preeclampsia or lupus anticoagulant.

As depicted in Figure 6-3, the maternal-placental-fetal unit can develop several hematoma types. These include: (1) retroplacental hematoma-between the placenta and its adjacent decidua; (2) marginal hematoma-between the chorion and

FIGURE 6-3 Potential sites of maternally and fetally related placental circulatory disturbances. (Adapted from Faye-Petersen, 2006.) decidua at the placental periphery-known clinically as sub chorionic hemorrhage; (3) subamnionic hematoma-these are of fetal vessel origin and found beneath the amnion but above the chorionic plate, and (4) subchorial thrombus along the roof of the intervillous space and beneath the chorionic plate. With this last type, massive subchorionic hematomas are also known as a Breus mole.

Sonographically, hematomas evolve with time and appear hyperechoic to isoechoic in the irst week after hemorrhage, hypoechoic at 1 to 2 weeks, and inally, anechoic after 2 weeks. Most subchorionic hematomas visible sonographically are fairly small and of no clinical consequence. However, extensive retroplacental, marginal, and subchorial collections have been associated with higher rates of miscarriage, stillbirth, placental abruption, and preterm delivery (Ball, 1996; Fung, 2010; vladu, 2006; Tuuli, 2011). In essence, placental abruption is a large, clinically signiicant retroplacental hematoma.

Placental lesions that arise from fetal circulatory disturbances are also depicted in Figure 6-3. Deoxygenated fetal blood lows from the two umbilical arteries into arteries within the chorionic plate that divide and send branches out across the placental surface. hese eventually supply individual stem villi, and their thrombosis will obstruct fetal blood low. Distal to the obstruction, afected portions of the villus become nonfunctional. Thrombi in limited numbers are normally found in mature placentas. If many villi are afected, which can be seen with preeclampsia, the fetus may sufer growth restriction, stillbirth, or nonreassuring fetal heart rate patterns (Chisholm, 2015; Lepais, 2014; Saleemuddin, 2010).

here is a spectrum of villous capillary lesions. Chorangiosis describes an increased number of capillaries within terminal villi. Its deinition requires :::10 capillaries to be present in :::10 villi in :::10 ields viewed through a lOx microscope lens (Altshuler, 1984). Clinically, long-standing hypoperfusion or hypoxia is thought to be causative (Stanek, 2016). It is often associated with maternal diabetes mellitus (Ogino, 2000). Chorangiomatosis describes increased capillary number in stem villi, but terminal villi are spared. his inding has been linked with fetal-growth restriction and anomalies (Bagby, 2011). Despite these associations, the clinical signiicance of both vascular conditions remains unclear. Chorioangiomas are described subsequently.

As indicated earlier, these hematomas lie between the chorionic plate and amnion. They most often are acute events during third-stage labor when cord traction ruptures a vessel near the cord insertion.

Large chronic antepartum lesions may cause fetomaternal hemorrhage or fetal-growth restriction (Deans, 1998). They also may be confused with other placental masses such as chorio angioma. In most cases, Doppler interrogation will show absent internal blood low within a hematoma and permit differentiation (Sepulveda, 2000).

Calcium salts can be deposited throughout the placenta but are most common on the basal plate. Calciication accrues with advancing gestation, and greater degrees are associated (Bedir Findik, 2015; Klesges, 1998; McKenna, 2005). These hyperechoic deposits can easily be seen sonographically, and a grading scale from 0 to 3 relects increasing calciication with increasing numerical grade (Grannum, 1979). Following this scheme, a grade 0 placenta is homogeneous, lacks calciication, and displays a smooth, lat chorionic plate. A grade 1 placenta lations. Grade 2 shows echogenic stippling at the basal plate.

Large, echogenic comma shapes originate from an indented chorionic plate, bur their curve falls short of the basal plate.

Last, a grade 3 placenta has echogenic indentations extending from the chorionic plate to the basal plate, which create discrete components that resemble cotyledons. Basal plate densities also increase.

As a predictor, this grading scale is not useful for neona tal outcome near term (Hill, 1983; McKenna, 2005; Montan, 1986). However, data from two small studies link grade 3 pla centa prior to 32 weeks with stillbirth and some other adverse pregnancy outcomes (Chen, 2011, 2015).

These benign tumors have components similar to blood vessels and stroma of the chorionic villus. lso called chorangiomas, these placental tumors occur with an incidence of approximately 1 percent (Guschmann, 2003). In some cases, fetal-to-maternal hemorrhage across tumor capillaries leads to elevated levels of maternal serum alpha-fetoprotein (MSAFP), prompting sonographic evaluation. heir characteristic sonographic appearance shows a well-circumscribed, rounded, predominantly hypoechoic lesion lying near the chorionic plate and protruding into the amnionic cavity (Fig. 6-4). Documenting increased blood low by color Doppler helps to distinguish these lesions from other placental masses such as hematoma, partial hydatidiform mole, teratoma, metastases, and leiomyoma (Prapas, 2000). Although rare, chorangiocarcinoma tumors clinically mirror chorangiomas (Huang, 2015).

Small chorioangiomas are usually asymptomatic. Large tumors, typically those measuring >4 em, can create signiicant arteriovenous shunting within the placenta to cause high-output heart failure, hydrops, and fetal death (l Wattar, 2014). Compression of fetal erythrocytes within tumor vessels can lead to hemolysis and microangiopathic anemia (Bauer, 1978). Hydramnios, pre term delivery, and fetal-growth restriction are other sequelae. Rare cases include tumor vessel rupture, hemorrhage, and fetal death (Batukan, 2001). At the other extreme, rare rumor infarction can lead to symptom reversal (Zalel, 2002).

FIGURE 6�4 Placental chorioangioma. A. Color Doppler imaging displays blood flow through a large chorioangioma with its border outlined by white arrows. B. Grossly, the chorioangioma is a round, well-circumcised mass protruding from the fetal surface.

Gray-scale and color Doppler interrogation of the placenta and amnionic fluid volume are used to identiy these tumors. Diagnostic tools that can airm associated fetomaternal hemorrhage include MSAFP level and Kleihauer-Betke stain. With fetal concern, echocardiography assesses cardiac function, whereas middle cerebral artery interrogation is used to identiy fetal anemia.

Several fetal therapies interfere with the vascular supply to the tumor and reverse fetal heart failure. At specialized perinatal centers, endoscopic laser ablation of feeder vessels to the tumor is most frequently used and is associated with favorable fetal outcomes (Hosseinzadeh, 2015). Of other therapy, fetal transfusion can treat serious anemia, amnioreduction can temporize hydramnios, and digoxin therapy can assist fetal heart failure.

Maternal malignant tumors rarely metastasize to the placenta. Of those that do, melanomas, leukemias and lymphomas, and breast cancer are the most common (Al-Adnani, 2007). Tumor cells usually are confined within the intervillous space. As a result, metastasis to the fetus is uncommon but is most often seen with melanoma (lexander, 2003).

Similarly, cases in which fetal malignancy metastasizes to the placenta are rare (Reif, 2014). hese are predominantly fetal neuroectodermal tumors, and only one case in the literature describes transplantation of tumor to the maternal uterus (Nath, 1995).

Normal genital-tract flora can colonize and infect the membranes, umbilical cord, and eventually the fetus. Bacteria most commonly ascend after prolonged membrane rupture and during labor to cause infection. Organisms initially infect the chorion and adjacent decidua in the area overlying the internal os. Subsequently, progression leads to full-thickness involvement of the membranes-chorioamnionitis. Organisms often then spread along the chorioamnionic surface to colonize and replicate in amnionic luid. Inlammation of the chorionic plate and of the umbilical cord-unisitis-may follow (Kim, 2015; Redline, 2012).

Most commonly, there is microscopic or occult chorioamnionitis, which is caused by a wide variety of microorganisms. his is frequently cited as a possible explanation for many otherwise unexplained cases of ruptured membranes, preterm labor, or both as discussed in Chapter 42 (p. 810). In some cases, gross infection is characterized by membrane clouding and is sometimes accompanied by a foul odor that depends on bacterial species.

Amnion nodosum is a condition characterized by numerous small, light-tan nodules on the amnion overlying the chorionic plate. hese may be scraped of the fetal surface and contain deposits of fetal squames and fibrin that relect prolonged and severe oligohydramnios (Adeniran, 2007).

Two notable bandlike structures can be formed by the fetal membranes. Of these, amnionic band sequence is an anatomical disruption sequence in which amnion bands tether, constrict, or amputate fetal parts. Amnionic bands commonly cause limb-reduction defects, facial clefts, or encephalocele (Barzilay, 2015; Guzman-Huerta, 2013). Umbilical cord compromise is another sequela (Barros, 2014; Heifetz, 1984b). Severe defects of the spine or ventral wall that accompany amnionic bands suggest a limb-body wall complex, described in Chapter 10 (p. 206).

Clinically, sonography often irst identiies the sequelae of this sequence rather than the bands themselves. As with any fetal anomaly, targeted sonography is indicated. Identiication of a limb-reduction defect, an encephalocele in an atypical location, or an extremity with edema or positional deformity should prompt careful evaluation for amnionic bands.

Management depends on the degree of anatomic deformity.

Fetoscopic laser interruption of the band may be suitable in highly selected antepartum cases Qavadian, 2013; Mathis, 2015).

In contrast, an amnionic sheet is formed by normal amniochorion draped over a preexisting uterine synechia. Generally, these sheets pose little fetal risk, although slightly higher rates of preterm membrane rupture and placental abruption have been described (Korbin, 1998; Nelson, 2010; Tuuli, 2012).

Most umbilical cords at delivery are 40 to 70 cm long, and very few measure <30 cm or > 100 cm. Cord length is inluenced positively by both amnionic luid volume and fetal mobility (Miller, 1982). In retrospective studies, short cords have been linked with congenital malformations and intrapartum distress (Baergen, 2001; Krakowiak, 2004; Yamamoto, 2016). Excessively long cords are linked with cord entanglement or prolapse and with fetal anomalies (Olaya-C, 2015; Rayburn, 1981).

Because antenatal determination of cord length is technically limited, cord diameter has been evaluated as a predictive marker for fetal outcomes. Some have linked lean cords with poor fetal growth and large-diameter cords with macrosomia (Proctor, 2013). However, the clinical utility of this parameter is still unclear (Barbieri, 2008; Cromi, 2007; Raio, 1999b, 2003).

Cord coiling characteristics have been reported but are not currently part of standard sonographic evaluation. Usually the umbilical vessels spiral through the cord in a sinistral, that is, let-twisting direction (Fletcher, 1993; Lacro, 1987). he number of complete coils per centimeter of cord length is termed the umbilical coiling index-Uel (Strong, 1994). A normal, antepartum, sonographically derived UCI is 0.4, and this contrasts with a normal, postpartum, physically measured value of 0.2 (Sebire, 2007). UCls < 10th percentile are considered hypocoile, and those > 90th percentile are hypercoiled. Clinically, the signiicance of coiling extremes is controversial. Some studies evaluating large, unselected cohorts ind no associations between UCI values and poor neonatal outcome Qessop, 2014; Pathak, 2010). In others, extremes are linked with various adverse outcomes but most consistently with intrapartum fetal heart rate abnormalities, preterm labor, or fetal-growth restriction (Chitra, 2012; de Laat, 2006; Predanic, 2005; Rana, 1995).

Counting cord vessel number is a standard component of anatomical evaluation during fetal sonographic examination and immediately after delivery (Fig. 6-5). Embryos initially have two sonographically in the second trimester. They encircle the fetal bladder (asterisk) as extensions of the superior vesical arteries. In this color Doppler sonographic image, a single umbilical artery, shown in red, runs along the bladder wall before joining the umbilical vein (blue) in the cord. Below this, the two vessels of the cord, seen as a larger red and smaller blue circle, are also seen floating in a cross section of a cord segment.

umbilical veins. In the irst trimester, the right vein typically atrophies to leave one large vein to accompany the two, thick-walled umbilical arteries. Four-vessel cords are rare and often associated with congenital anomalies (Puvabanditsin, 2011). If it is an isolated inding, however, prognosis can be good (Avnet, 2011).

The most common aberration is that of a single umbilical artery (SUA), with a cited incidence of 0.63 percent in liveborn neonates, 1.92 percent with perinatal deaths, and 3 percent in twins (Heifetz, 1984a). Fetuses with major malformations frequently have a single artery. Thus, its identiication often prompts consideration for targeted sonography and possibly fetal echocardiography. The most frequent anomalies are cardiovascular and genitourinary (Hua, 2010; Murphy-Kaulbeck, 2010). In an anomalous fetus, a single artery greatly increases the aneuploidy risk, and amniocentesis is recommended (Dagklis, 2010; Lubusky, 2007).

If target sonography inds otherwise normal anatomy, an isolated single artery in an otherwise low-risk pregnancy does not significantly increase the fetal aneuploidy risk. However, as in isolated inding, it has been associated with fetal-growth restriction and perinatal death in some but not all studies (ChettyJohn, 2010; Gutvirtz, 2016; Hua, 2010; Murphy-Kaulbeck, 2010; Voskamp, 2013). hus, while clinical monitoring of growth is reasonable, the value of sonographic surveillance is unclear.

A rare anomaly is that of a fused umbilical artery with a shared lumen. It arises from failure of the two arteries to split during embryological development. The common lumen may extend through the entire cord, but, if partial, it is typically found near the placental insertion site (Yamada, 2005). In one report, these were associated with a higher incidence of marginal or velamentous cord insertion, but not congenital fetal anomalies (Fujikura, 2003).

Found in most placentas, the Hyrtl anastomosis is a connection between the two umbilical arteries and lies near the cord insertion into the placenta. This anastomosis acts as a pressureequalizing system between the arteries (Gordon, 2007). As a result, redistribution of pressure gradients and blood flow improves placental perfusion, especially during uterine contractions or during compression of one umbilical artery. Fetuses with a single umbilical artery lack this safety valve (Raio, 1999a, 2001).

Several structures are housed in the umbilical cord during fetal development, and their remnants may be seen when the mature cord is viewed transversely. Indeed, J auniaux and colleagues (1989) sectioned 1000 cords, and in one fourth of the specimens, they found remnants of vitelline duct, allantoic duct, and embryonic vessels. These were not associated with congenital malformations or perinatal complications.

Cysts occasionally are found along the course of the cord.

They are designated according to their origin. True cysts are epithelium-lined remnants of the allantoic or vitelline ducts and tend to be located closer to the fetal insertion site. In contrast, the more common pseudocysts form from local degeneration of Wharton jelly and occur anywhere along the cord. Both have a similar sonographic appearance. Single umbilical cord cysts identified in the irst trimester tend to resolve completely, however, multiple cysts may portend miscarriage or aneuploidy (Ghezzi, 2003; Hannaford, 2013). Cysts persisting beyond this time are associated wi th a risk for structural defects and chromosomal anomalies (Bonilla, 2010; Zangen, 2010).

The cord normally inserts centrally into the placental disc, but eccentric, marginal, or velamentous insertions are variants. Of these, eccentric insertions in general pose no identifiable fetal risk. Marginal insertion is a common variant-sometimes referred to as a battledore placenta-in which the cord anchors at the placental margin. In one population-based study, the rate was 6 percent in singleton gestations and 11 percent in twins (Ebbing, 20l3). This common insertion variant rarely causes problems, but it and velamentous insertion occasionally result in the cord being pulled of during delivery of the placenta (Ebbing, 2015; Luo, 20l3). In monochorionic twins, this insertion may be associated with weight discordance (Kent, 2011).

With velamentous insertion, the umbilical vessels characteristically travel within the membranes before reaching the placental margin (Fig. 6-6) The incidence of velamentous insertion approximates 1 percent but is 6 percent with twins (Ebbing, 2013). It is more commonly seen with placenta previa (Papinniemi, 2007; Raisanen, 2012). Antenatal diagnosis is possible sonographically, and with velamentous insertion, cord vessels are seen traveling along the uterine wall before entering the placental disc. Clinically, vessels are vulnerable to compression, which may lead to fetal hypoperfusion and acidemia. Higher associated rates of low Apgar scores, stillbirth, preterm delivery, and small for gestational age have been noted (Ebbing, 2017; Esakof, 2015; Heinonen, 1996; Vahanian, 2015). Accordingly, monitoring of fetal growth is reasonable either clinically or sonographically (Vintzileos, 2015).

Last, with the very uncommon furcate insertion, umbilical vessels lose their protective Wharton jelly shortly before they insert. As a result, they are covered only by an amnion sheath and prone to compression, twisting, and thrombosis.

With this condition, vessels travel within the membranes and overlie the cervical os. here, they can be torn with cervical dilatation or membrane rupture, and laceration can lead to rapid fetal exsanguination. Over the cervix, vessels can also be compressed by a presenting fetal part. Fortunately, vasa previa is uncommon and has an incidence of 2 to 6 per 10,000 pregnancies

FIGURE 6-6 Velamentous cord insertion. A.The umbilical cord inserts into the membranes. From here, the cord vessels branch and are supported only by membrane until they reach the placental disc. B. When viewed sonographically and using color Doppler, the cord vessels appear to lie against the myometrium as they travel to insert marginally into the placental disc, which lies at the top of this image.

(Ruiter, 2016; Sullivan, 2017). Vasa previa is classiied as type 1, in which vessels are part of a velamentous cord insertion, and type 2, in which involved vessels span between portions of a bilobate or a succenturiate placenta (Catanzarite, 2001).

Two other risks are conception with in vitro fertilization and second-trimester placenta previa, with or without later migra tion (Baulies, 2007; Schachter, 2003).

Compared with intrapartum diagnosis, antepartum diagnosis greatly improves the perinatal survival rate, which ranges from 97 to 100 percent (Oyelese, 2004; Rebarber, 2014; Swank, 2016). Thus, vasa previa is ideally identiied early, although this is not always possible. Clinically, an examiner is occasionally able to palpate or directly see a tubular fetal vessel in the membranes overlying the presenting part. Efective screening for vasa previa begins during scheduled midtrimester sonographic examination. In suspicious cases, transvaginal sonography is added and shows cord vessels inserting into the membranes-rather than directly into the placenta-and vessels running above the cervical internal os (Fig. 6-7). Routine color Doppler interrogation of the placental cord insertion site, particularly in cases of placenta previa or low-lying placenta, may aid its detection. With this, the vessel waveform relects the fetal heart rate. In one systematic review, the median prenatal detection rate was 93 percent (Ruiter, 2015).

Once vasa previa is identiied, subsequent imaging is reasonable because 6 to 17 percent of cases ultimately resolve (Rebarber, 2015; Swank, 2016). Bed rest apparently has no added advantage. Antenatal corticosteroids can be provided as indicated or given prophylactically at 28 to 32 weeks' gestation to cover possible urgent preterm delivery. Antenatal hospitalization may be considered at 30 to 34 weeks to permit surveillance and expedited delivery for labor, bleeding, or rupture of membranes. Data supporting is limited, and admission may best serve women with risk factors that portend early delivery (Society for Maternal-Fetal Medicine, 2015). A few cases

FIGURE 6-7 Vasa previa. Using color Doppler, an umbilical vessel (red circle) is seen overlying the internal os. At the bottom, the Doppler waveform seen with this vasa previa has the typical appearance of an umbilical artery, with a pulse rate of 141 beats per minute.

of antepartum fetoscopic surgery with vessel laser ablation are described (Hosseinzadeh, 2015; Johnston, 2014). However, current practice is early scheduled cesarean delivery. Robinson mend elective cesarean delivery at 34 to 35 weeks' gestation to balance the risks of perinatal exsanguination versus preterm birth morbidity. he Society for Maternal-Fetal Medicine (2015) considers planned cesarean delivery at 34 to 37 weeks' gestation reasonable.

At delivery, the fetus is expeditiously delivered after the hys terotomy incision in case a vessel is lacerated during uterine entry. Delayed cord clamping is not encouraged.

In all pregnancies, otherwise unexplained vaginal bleeding of vasa previa and a lacerated fetal vessel. In many cases, bleed ing is rapidly fatal, and infant salvage is not possible. With less hemorrhage, however, it may be possible to distinguish fetal ver sus maternal bleeding. Various tests may be used, and each relies on the increased resistance of fetal hemoglobin to denaturing by alkaline or acid reagents (Odunsi, 1996; Oyelese, 1999).

• Knots, Strictures, and Loops

Various mechanical abnormalities in the cord can impede blood low and sometimes cause fetal harm. Of these, true knots are found in approximately 1 percent of births. hese form from fetal movement, and associated risks include hydramnios and diabetes (Hershkovitz, 2001; Raisanen, 2013). Knots are especially common and dangerous in monoamnionic twins, which are discussed in Chapter 45 (p. 874). When true knots are associated with singleton fetuses, the stillbirth risk is increased four-to tenfold (Airas, 2002; S0rnes, 2000).

Knots can be found incidentally during antepartum sonography, and a "hanging noose" sign is suggestive (Ramon y Cajal, 2006). hree-dimensional and color Doppler aid diagnostic accuracy (Hasbun, 2007). With these knots, optimal fetal surveillance is unclear but may include umbilical artery Doppler velocimetry, nons tress testing, or subjective fetal movement monitoring (Rodriguez, 2012; Scioscia, 201l). Allowing vaginal delivery is suitable, but abnormal intrapartum fetal heart rate tracings are more often encountered. hat said, cesarean delivery rates are not increased, and cord blood acid-base values are usually normal (Airas, 2002; Maher, 1996).

In contrast,alse knots form from focal redundancy and folding of an umbilical cord vessel. hese lack clinical signiicance.

Cord strictures are focal narrowings of the diameter that usually develop near the fetal cord insertion site (Peng, 2006). Characteristic pathological features include an absence of Wharton jelly and stenosis or obliteration of cord vessels at the narrow segment (Sun, 1995). In most instances, the fetus is stillborn (French, 2005). Even less common is a cord stricture caused by an amnionic band.

Cord loops are frequently encountered and are caused by coiling around various fetal parts during movement. A cord around the neck-a nuchal cord-is common, and vaginal delivery is suitable. One loop is reported in 20 to 34 percent of deliveries; two loops in 2.5 to 5 percent; and three loops in 0.2 to 0.5 percent (Kan, 1957; S0rnes, 1995; Spellacy, 1966).

During labor, up to 20 percent of fetuses with a nuchal cord have moderate to severe variable heart rate decelerations, and these are associated with a lower umbilical artery pH (Hankins, 1987). Cords wrapped around the body can have similar efects (Kobayashi, 2015). Despite their frequency, nuchal cords are not associated with greater rates of adverse perinatal outcome (Henry, 2013; Sheiner, 2006).

Last, a unic presentation describes when the umbilical cord is the presenting part in labor. These are uncommon and most often are associated with fetal malpresentation (Kinugasa, 2007). A funic presentation in some cases is identiied with placental sonography and color low Doppler (Ezra, 2003). Overt or occult cord prolapse can complicate labor. hus, once identiied at term, cesarean delivery is typically recommended.

Cord hematomas are rare and generally follow rupture of an umbilical vessel, usually the vein, and bleeding into the Wharton jelly. Hematomas have been associated with abnormal cord length, umbilical vessel aneurysm, trauma, entanglement, umbilical vessel venipuncture, and funisitis (Gualandri, 2008). Most are identiied postpartum, but hematomas are recognized so no graphically as hypoechoic masses that lack blood low (Chou, 2003). Sequelae include stillbirth or intrapartum abnormal fetal heart rate pattern (Abraham, 2015; Barbati, 2009; Sepulveda, 2005; Towers, 2009).

Umbilical cord vessel thromboses are rare in utero events and seldom diagnosed antepartum. Approximately 70 percent are venous, 20 percent are venous and arterial, and 10 percent are arterial thromboses (Heifetz, 1988). hese all have high associated rates of stillbirth, fetal-growth restriction, and intrapartum fetal distress (Minakami, 2001; Sato, 2006; Shilling, 2014). If these are identiied antepartum as hypoechoic masses without blood low, data from case reports support consideration of prompt delivery if of viable age (Kanenishi, 2013).

n umbilical vein varix can complicate either the intraamnionic or fetal intraabdominal portion of the umbilical vein. So no graphically and complemented by color Doppler, rare intraamnionic varices show cystic dilatation of the umbilical vein that is contiguous with a normal-caliber portion. Of complications, an intraamnionic varix may compress an adjacent umbilical artery or can rupture or thrombose. In cases without these, White and colleagues (1994) recommend fetal surveillance and delivery once fetal maturity is confirmed. However, data are limited and derived from case reports.

he rare umbilical artey aneuysm is caused by congenital thinning of the vessel wall with diminished support from Wharton jelly. Indeed, most form at or near the cord placental insertion site, where this support is absent. These are associated with single umbilical artery, trisomy 18, amnionic luid volume extremes, fetal-growth restriction, and stillbirth (Hill, 2010; Vyas, 2016). At least theoretically, these aneurysms could cause fetal compromise and death by compression of the umbilical vein. These aneurysms may appear sonographically as a cyst with a hyperechoic rim. Within the aneurysm, color low and spectral Doppler interrogation demonstrate either lowvelocity or turbulent nonpulsatile flow (Olog, 2011; Sepulveda, 2003; Shen, 2007b). Although not codified, management may include fetal karyotyping, antenatal fetal surveillance, and early delivery to prevent stillbirth (Doehrman, 2014).

Abraham A, Rathore S, Gupta M, et al: Umbilical cord haematoma causing still birth-a case report. J Clin Diagn Res 9(12):QD01, 2015

Adeniran AJ, Stanek J: Amnion nodosum revisited: clinicopathologic and placental correlations. Arch Pathol Lab Med 131: 1829, 2007

Airas U, Heinonen S: Clinical signiicance of true umbilical knots: a population-based analysis. Am J PerinatoIs19:127, 2002

Al-Adnani M, Kiho L, Scheimberg I: Maternal pancreatic carcinoma metastatic to the placenta: a case report and literature review. Pediatr Dev Pathol 10:61,s2007

Alexander A, Samlowski E, Grossman D, et al: Metastatic melanoma in pregnancy: risk of transplacental metastases in the infant. J Clin Oncol 21:2179,s2003

Altshuler G. Chorangiosis: An important placental sign of neonatal morbidity and mortality. Arch Pathol Lab Med 108(1):71, 1984

Al Wattar BH, Hillman SC, Marton T, et al: Placenta chorioangioma: a rare case and systematic review of literature. J Matern Fetal Neonatal Med 27(10):1055,s2014

American Institute of Ultrasound in Medicine: AlUM practice guideline for the performance of obstetric ultrasound examinations. J Ultrasound Med 32(6):1083,s2013

Andres RL, Kuyper W, Resnik R, et al: The association of maternal floor infarction of the placenta with adverse perinatal outcome. Am J Obstet Gynecol 163:935, 1990

Avnet H, Shen 0, Mazaki E, et al: Four-vessel umbilical cord. Ultrasound Obstet Gynecol 38:604, 2011

Baergen RN, Malicki D, Behling C, et al: Morbidity, mortality, and placental pathology in excessively long umbilical cords: retrospective study. Pediatr Dev PathoIs4(2):144, 2001

Bagby C, Redline RW: Multifocal chorangiomatosis. Pediatr Dev Pathol 14(1):38,s2011

Ball RH, Ade CM, Schoenborn JA, et al: The clinical significance of ultrasonographically detected subchorionic hemorrhages. Am J Obstet Gynecol 174:996,s1996

Barbati A, Cacace MG, Fratini D, et al: Umbilical cord haematoma with altered fetal heart rate. J Obstet Gynaecol 29(2): 150, 2009

Barbieri C, Cecatti JG, Krupa F, et al: Validation study of the capacity of the reference curves of ultrasonographic measurements of the umbilical cord to identiy deviations in estimated fetal weight. Acta Obstet Gynecol Scand 87:286, 2008

Barros M, Gorgal G, Machado AP, et al: Revisiting amniotic band sequence: a wide spectrum of manifestations. Fetal Diagn Ther 35(1):51, 2014

Barzilay E, Harel Y, Haas J, et al: Prenatal diagnosis of amniotic band syndrome-risk factors and ultrasonic signs. J Matern Fetal Neonatal Med 28(3):281,s2015

Batukan C, Holzgreve W, Danzer E, et al: Large placental chorioangioma as a cause of sudden intrauterine fetal death. A case report. Fetal Diagn her 16:394, 2001

Bauer CR, Fojaco M, Bancalari E, et al: Microangiopathic hemolytic anemia and thrombocytopenia in a neonate associated with a large placental chorioangioma. Pediatrics 62(4):574, 1978

Baulies S, Maiz N, Munoz A, et al: Prenatal ultrasound diagnosis of vasa praevia and analysis of risk factors. Prenat Diagn 27:595, 2007

Bedir Findik R, Ersoy AO, Fidanci V, et al: Vitamin D deficiency and placental calciication in low-risk obstetric population: are they related? J Matern Fetal Neonatal Med 29(19):3189, 2015

Benirschke K, Burton GJ, Baergen R: Pathology of the Human Placenta, 6th ed. New York, Springer, 2012, p 908

Bonilla F Jr, Raga F, Villalaiz E, et al: Umbilical cord cysts: evaluation with different 3-dimensional sonographic modes. J Ultrasound Med 29(2):281, 2010

Catanzarite V, Maida C, Thomas W, et al: Prenatal sonographic diagnosis of vasa previa: ultrasound indings and obstetric outcome in ten cases. Ultrasound Obstet GynecoIs18:109, 2001

Chen KH, Chen LR, Lee H: Exploring the relationship berween preterm placental calciication and adverse maternal and fetal outcome. Ultrasound Obstet GynecoIs37(3):328, 2011

Chen KH, Seow M, Chen LR: The role of preterm placental calciication on assessing risks of stillbirth. Placenta 36(9): 1039, 2015

Chetty-John S, Zhang J, Chen Z, et al: Long-term physical and neurologic development in newborn infants with isolated single umbilical artery. Am J Obstet GynecoI203(4):368.el, 2010

Chisholm M, Heerema-McKenney A: Fetal thrombotic vasculopathy: signiicance in live born children using proposed society for pediatric pathology diagnostic criteria. Am J Surg PathoIs39(2):274, 2015

Chitra T, Sushanth YS, Raghavan S: Umbilical coiling index as a marker of perinatal outcome: an analytical study. Obstet Gynecol Int 2012:213689, 2012

Chou SY, Chen YR, Wu CF, et al: Spontaneous umbilical cord hematoma diagnosed antenatally with ultrasonography. Acta Obstet Gynecol Scand 82(11): 1056, 2003

Cromi A, Ghezzi F, Di Naro E, et al: Large cross-sectional area of the umbilical cord as a predictor of fetal macrosomia. Ultrasound Obstet Gynecol 30:804, 2007

Dagklis T, Deigueiredo 0, Staboulidou I, et al: Isolated single umbilical artery and fetal karyotype. Ultrasound Obstet Gynecol 36(3):291, 2010

Deans A, Jauniaux E: Prenatal diagnosis and outcome of subamniotic hematomas. Ultrasound Obstet Gynecol 11:319, 1998 de Laat MW, Franx A, Bots ML, et al: Umbilical coiling index in normal and complicated pregnancies. Obstet Gynecol 107:1049,s2006

Doehrman P, Derksen BJ, Perlow JH, et al: Umbilical artery aneurysm: a case report, literature review, and management recommendations. Obstet Gynecol Surv 69(3):159,s2014

Ebbing C, Johnsen SL, Albrechtsen S, et al: Velamentous or marginal cord insertion and the risk of spontaneous preterm birth, prelabor rupture of the membranes, and anomalous cord length, a population-based study. Acta Obstet Gynecol Scand 96(1):78, 2017

Ebbing C, Kiserud T, Johnsen SL, et al: Prevalence, risk factors and outcomes of velamentous and marginal cord insertions: a population-based study of 634,741 pregnancies. PLoS One 8(7):e70380, 2013

Ebbing C, Kiserud T, Johnsen SL, et al: Third stage of labor risks in velamentous and marginal cord insertion: a population-based study. Acta Obstet Gynecol Scand 94(8):878, 2015

EsakofTF, Cheng W, Snowden JM, et al: Velamentous cord insertion: is it associated with adverse perinatal outcomes? J Matern Fetal Neonatal Med 28(4):409,s2015

Ezra Y, Strasberg SR, Farine 0: Does cord presentation on ultrasound predict cord prolapse? Gynecol Obstet Invest 56:6, 2003

Faye-Petersen 0, Sauder A, Estrella Y, et al: Dichorionic twins discordant for massive perivillous ibrinoid deposition: report of a case and review of the literature. Int J Surg Pathol July 1, 2017 [Epub ahead of print]

Faye-Petersen OM, Heller OS, Joshi VV: Handbook of Placental Pathology, 2nd ed. London, Taylor & Francis, 2006, pp 27, 83

Fletcher S: Chirality in the umbilical cord. BJOG 100(3):234, 1993

Fox H, Sebire NJ: Pathology of the Placenta, 3rd ed. Philadelphia, Saunders, 2007, pp 99, 133, 484

French AE, Gregg VH, Newberry Y, et al: Umbilical cord stricture: a cause of recurrent fetal death. Obstet Gynecol 105: 1235,s2005

Fujikura T: Fused umbilical arteries near placental cord insertion. Am J Obstet Gynecol 188:765, 2003

Fung Y, To KF, Sahota OS, et al: Massive subchorionic thrombohematoma: a series of 10 cases. Acta Obstet Gynecol Scand 89(10):1357, 2010

Ghezzi F, Raio L, Di Naro E, et al: Single and multiple umbilical cord cysts in early gestation: two diferent entities. Ulrrasound Obstet Gynecol 21:213, 2003

Gordon Z, Eytan 0, Jafa AJ, et al: Hemodynamic analysis of Hyrtl anastomosis in human placenta. Am J Physiol Regul Integra Comp PhysioI292:R977, 2007

Grannum PA, Berkowitz RL, Hobbins JC: he ultrasonic changes in the maturing placenta and their relation to fetal pulmonic maturity. Am J Obstet Gynecol 133:915, 1979

Greenberg JA, Sorem A, Shifren JL, et al: Placenta membranacea with placenta increta: a case report and literature review. Obstet Gynecol 78:512, 1991

Gualandri G, Rivasi F, Santunione AL, et al: Spontaneous umbilical cord hematoma: an unusual cause of fetal mortality: a report of 3 cases and review of the literature. Am J Forensic Med Pathol 29(2): 185, 2008

Guschmann M, Henrich W, Entezami M, et al: Chorioangioma-new insights into a well-known problem. I. Results of a clinical and morphological study of 136 cases. J Perinat Med 31: 163, 2003

Gutvirtz G, Walisch A, Beharier 0, et al: Isolated single umbilical artery is an independent risk factor for perinatal mortality and adverse outcomes in term neonates. Arch Gynecol Obstet 294(5):931,s2016

Guzman-Huerta ME, Muro-Barragan SA, Acevedo-Gallegos S, et al: Amniotic band sequence: prenatal diagnosis, phenotype descriptions, and a proposal of a new classiication based on morphologic indings. Rev Invest Clin 65(4):300,s2013

Hankins GO, Snyder R, Hauth JC, et al: Nuchal cords and neonatal outcome. Obstet Gynecol 70:68 , 1987

Hannaford K, Reeves S, Wegner E: Umbilical cord cysts in the irst trimester: are they associated with pregnancy complications? J Ultrasound Med 32(5):801,s2013

Hasbun J, Alcalde JL, Sepulveda W: hree-dimensional power Doppler sonography in the prenatal diagnosis of a true knot of the umbilical cord: value and limitations. J Ultrasound Med 26(9):1215,s2007

Heifetz SA: Single umbilical artery: a statistical analysis of 237 autopsy cases and a review of the literature. Perspect Pediatr Pathol 8:345, 1984a

Heifetz SA: Strangulation of the umbilical cord by amniotic bands: report of 6 cases and literature review. Pediatr PathoIs2:285, 1984b

Heifetz SA: hrombosis of the umbilical cord: analysis of 52 cases and literature review. Pediatr Pathol 8:37, 1988

Heinonen S, Ryynanen M, Kirkinen P, et al: Perinatal diagnostic evaluation of velamentous umbilical cord insertion: clinical, Doppler, and ultrasonic indings. Obstet GynecoI87(l):112, 1996

Henry E, Andres L, Christensen D: Neonatal outcomes following a tight nuchal cord. J PerinatoIs33(3):231, 2013

Hershkovitz R, Silberstein T, Sheiner E, et al: Risk factors associated with true knots of the umbilical cord. Eur J Obstet Gynecol Reprod Bioi 98(1):36, 200s1

Hill AJ, Strong TH Jr, Elliott JP, et al: Umbilical artery aneurysm. Obstet Gynecol 116(Suppl 2):559, 2010

Hill LM, Breckle R, Ragozzino MW, et al: Grade 3 placentation: incidence and neonatal outcome. Obstet Gynecol 61: 728, 1983

Hoddick K, Mahony BS, Callen PW, et al: Placental thickness. J Ultrasound Med 4(9):479, 1985

Hosseinzadeh P, Shamshirsaz A, Cass DL, et al: Fetoscopic laser ablation of vasa previa for a fetus with a giant cervical lymphatic malformation. Ultrasound Obstet GynecoIs46(4):507, 2015

Hua M, Odibo AO, Macones GA, et al: Single umbilical artery and its associated indings. Obstet GynecoIs115(5):930, 2010

Huang B, Zhang P, Yuan OF, et al: Chorangiocarcinoma: a case report and clinical review. Int J Clin Exp Med 8(9): 16798, 2015

Jauniaux E, De Munter C, Vanesse M, et al: Embryonic remnants of the umbilical cord: morphologic and clinical aspects. Hum Pathol 20(5):458, 1989

Javadian P, Shamshirsaz A, Haeri S, et al: Perinatal outcome after fetoscopic release of amniotic bands: a single-center experience and review of the literature. Ultrasound Obstet GynecoIs42(4):449, 2013

Jessop FA, Lees Cc, Pathak S, et al: Umbilical cord coiling: clinical outcomes in an unselected population and systematic review. Virchows Arch 464(1):105,s2014

Johnston R, Shrivastava K, Chmait RH: Term vaginal delivery following fetoscopic laser photocoagulation of rype II vasa previa. Fetal Diagn Ther 35(1):62,s2014

Kan PS, Eastman NJ: Coiling of the umbilical cord around the foetal neck.

BJOG 64:227, 1957

Kanenishi K, Nitta E, Mashima M, et al: HDlive imaging of intra-amniotic umbilical vein varix with thrombosis. Placenta 34(11): 111 0, 2013

Kent EM, Breathnach FM, Gillan JE, et al: Placental cord insertion and birthweight discordance in twin pregnancies: results of the national prospective ESPRiT Study. Am J Obstet Gynecol 205(4):376.el, 201s1

Kim CJ, Romero R, Chaemsaithong P, et al: Acute chorioamnionitis and funisitis: deinition, pathologic features, and clinical signiicance. Am J Obstet Gynecols213(4 Suppl):S29, 2015

Kinugasa M, Sato T, Tamura M, et al: Antepartum detection of cord presentation by transvaginal ultrasonography for term breech presentation: potential prediction and prevention of cord prolapse. J Obstet Gynaecol Res 33(5):612,s2007

Klesges LM, Murray OM, Brown JE, et al: Relations of cigarette smoking and dietary antioxidants with placental calciication. Am J Epidemiol 147(2):127, 1998

Kobayashi N, Aoki S, Oba MS, et al: Efect of umbilical cord entanglement and position on pregnancy outcomes. Obstet Gynecol Int 2015:342065, 2015 Korbin CD, Benson CB, Doubilet PM: Placental implantation on the amni otic sheer: efect on pregnancy outcome. Radiology 206(3):773, 1998 Krakowiak P, Smith EN, de Bruyn G, et al: Risk factors and outcomes associated with a short umbilical cord. Obstet Gynecol 103: 119, 2004

Lacro RV, Jones KL, Benirschke K: he umbilical cord twist: origin, direction, and relevance. Am J Obstet Gynecol 157(4 Pt 1):833, 1987

Lademacher OS, Vermeulen RC, Hartens]J, et al: Circumvallate placenta and congenital malformation. Lancet 1:732, 1981

Langston C, Kaplan C, Macpherson T, et al: Practice guideline for examination of the placenta. Arch Pathol Lab Med 121 :449, 1997

Lepais L, Gaillot-Durand L, Boutitie F, et al: Fetal thrombotic vasculopathy is associated with thromboembolic events and adverse perinatal outcome but not with neurologic complications: a retrospective cohort study of 54 cases with a 3-year follow-up of children. Placenta 35(8):611,s2014

Lubusky M, Dhaifalah I, Prochazka M, et al: Single umbilical artery and its siding in the second trimester of pregnancy: relation to chromosomal defects. Prenat Diagn 27:327, 2007

Luo G, Redline RW: Peripheral insertion of umbilical cord. Pediatr Dev Pathol 16(6):399,s2013

Madu AE: Breus' mole in pregnancy.] Obstet Gynaecol 26:815, 2006

Maher ]T, Contis]A: A comparison of umbilical cord blood gas values between newborns with and without true knots. Obstet Gynecol 88:863, 1996

Mandsager NT, Bendon R, Mostello D, et al: Maternal floor infarction of the placenta: prenatal diagnosis and clinical signiicance. Obstet Gynecol 83:750, 1994

Mathis], Raio L, Baud D: Fetal laser therapy: applications in the management offetal pathologies. Prenat Diagn 35(7):623, 2015

McKenna D, Tharmaratnam S, Mahsud S, et al: Ultrasonic evidence of placental calciication at 36 weeks' gestation: maternal and fetal outcomes. Acta Obstet Gynecol Scand 84:7, 2005

Miller ME, Jones Me, Smith DW: Tension: the basis of umbilical cord growth.] Pediatr 101(5):844, 1982

Minakami H, Akahori A, Sakurai S, et al: Umbilical vein thrombosis as a possible cause of perinatal morbidity or mortality: report of two cases. ] Obstet Gynaecol Res 27(2):9 ; 2001

Montan S, Jorgensen C, Svalenius E, et al: Placental grading with ultrasound in hypertensive and normotensive pregnancies: a prospective, consecutive study. Acta Obstet Gynecol Scand 65:477, 1986

Murphy-Kaulbeck L, Dodds L, Joseph KS, et al: Single umbilical artery risk factors and pregnancy outcomes. Obstet Gynecol 116(4):843,2010

Nath ME, Kanbour A, Hu], et al: Transplantation of congenital primitive neuroectodermal tumor of fetus to the uterus of mother: application of biotinlabeled chromosome-speciic probes. lnt] Gynecol Cancer 5(6):459, 1995

Nelson LD, Grobman WA: Obstetric morbidity associated with amniotic sheets. Ultrasound Obstet Gynecol 36(3):324, 2010

Odunsi K, Bullough CH, Henzel], et al: Evaluation of chemical tests for fetal bleeding from vasa previa. Int] Gynaecol Obstet 55(3):20 , 19%

Ogino S, Redline RW: Villous capillary lesions of the placenta: distinctions between chorangioma, chorangiomatosis, and chorangiosis. Hum Pathol 31:945,s2000

Olaya-C M, Bernal ]E: Clinical associations to abnormal umbilical cord length in Latin American newbons.s] Neonatal Perinatal Med 8(3):251, 2015 Olog A, homas ]T, Petersen S, et al: Large umbilical artery aneurysm with a live healthy baby delivered at 31 weeks. Fetal Diagn Ther 29(4):331,2011 Oyelese KO, Turner M, Lees e, et al: Vasa previa: an avoidable obstetric tragedy. Obstet Gynecol Surv 54: 138, 1999

Oyelese Y, Catanzarite V, Prefumo F, et al: Vasa previa: the impact of prenatal diagnosis on outcomes. Obstet Gynecol 103:937, 2004

Papinniemi M, Keski-Nisula L, Heinonen S: Placental ratio and risk of velamentous umbilical cord insertion are increased in women with placenta previa. Ams] Perinatol 24:353, 2007

Pathak S, Hook E, Hackett G, et al: Cord coiling, umbilical cord insertion and placental shape in an unselected cohort delivering at term: relationship with common obstetric outcomes. Placenta 31 (11) :963, 2010

Peng HQ, Levitin-Smith M, Rochelson B, et al: Umbilical cord stricture and over coiling are common causes of fetal demise. Pediatr Dev Pathol 9: 14, 2006

Pereira N, Yao R, Guilfoil DS, et al: Placenta membranacea with placenta accreta: radiologic diagnosis and clinical implications. Prenat Diagn 33(13):1293,s2013

Prapas N, Liang RI, Hunter D, et al: Color Doppler imaging of placental masses: diferential diagnosis and fetal outcome. Ultrasound Obstet Gynecol 16:559,s2000

Predanic M, Perni SC, Chasen ST, et al: Ultrasound evaluation of abnormal umbilical cord coiling in second trimester of gestation in association with adverse pregnancy outcome. Am] Obstet Gynecol 193:387,2005

Proctor LK, Fitzgerald B, Whittle L, et al: Umbilical cord diameter percentile curves and their correlation to birth weight and placental pathology. Placenta 34(1):62, 2013

Puvabanditsin S, Garrow E, Bhatt M, et al: Four-vessel umbilical cord associated with multiple congenital anomalies: a case report and literature review. Fetal Pediatr Pathol 30(2):98, 2011

Raio L, Ghezzi F, Di Naro E, et al: In-utero characterization of the blood flow in the Hyrtl anastomosis. Placenta 22:597,s2001

Raio L, Ghezzi F, Di Naro E, et al: Prenatal assessment of the Hyrtl anastomosis and evaluation of its function: case report. Hum Reprod 14: 1890, 1999a

Raio L, Ghezzi F, Di Naro E, et al: Sonographic measurement of the umbilical cord and fetal anthropometric parameters. Eur ] Obstet Gynecol Reprod Bioi 83: 131, 1999b

Raio L, Ghezzi F, Di Naro E, et al: Umbilical cord morphologic characteristics and umbilical artery Doppler parameters in intrauterine growth-restricted fetuses. ] Ultrasound Med 22: 1341, 2003

Raisanen S, Georgiadis L, Harju M, et al: Risk factors and adverse pregnancy outcomes among births afected by velamentous umbilical cord insertion: a retrospective population-based register study. Eurs] Obstet Gynecol Reprod BioI 165(2):231, 2012

Raisanen S, Georgiadis L, Harju M, et al: True umbilical cord knot and obstetric outcome. Int] Gynaecol Obstet 122(1):18, 2013

Ramon y Cajal CL, Martinez RO: Four-dimensional ultrasonography of a true knot of the umbilical cord. Am] Obstet Gynecol 195:896, 2006

Ranas], Ebert GA, Kappy A: Adverse perinatal outcome in patients with an abnormal umbilical coiling index. Obstet Gynecol 85(4):573, 1995 Rayburn WF, Beynen A, Brinkman DL: Umbilical cord length and intrapartum complications. Obstet Gynecol 57(4):450, 1981

Rebarber A, Dolin e, Fox NS, et al: Natural history of vasa previa across gestation using a screening protocol.] Ultrasound Med 33(1):141, 2014 Redline RW: Inlammatory response in acute chorioamnionitis. Semin Fetal Neonatal Med 17(1):20,s2012

Redline RW: Placental pathology: a systematic approach with clinical correlations. Placenta 29(Suppl A):S86, 2008

Reif P, Hofer N, Kolovetsiou-Kreiner V, et al: Metastasis of an undiferentiated fetal soft tissue sarcoma to the maternal compartment of the placenta: maternal aspects, pathology indings and review of the literature on fetal malignancies with placenta metastases. Histopathology 65(6):933,s2014

Roberts D]: Placental pathology, a survival guide. Arch Pathol Lab Med 132(4):641, 2008

Robinson BK, Grobman WA: Efectiveness of timing strategies for delivery of individuals with vasa previa. Obstet Gynecol 117(3):542,s201s1

Rodriguez N, Angarita M, Casasbuenas A, et al: Three-dimensional highdeinition low imaging in prenatal diagnosis of a true umbilical cord knot. Ultrasound Obstet Gynecol 39(2):245, 2012

Romero R, Whitten A, Korzeniewski S], et al: Maternal Boor infarction/massive perivillous ibrin deposition: a manifestation of maternal antifetal rejection? Am] Reprod Immunol 70(4):285,s2013

Ruiter L, Kok N, Limpens ], et al: Incidence of and risk indicators for vasa praevia: a systematic review. B]OG 123(8):1278,s2016 Ruiter L, Kok N, Limpens J, et al: Systematic review of accuracy of ultrasound in the diagnosis of vasa previa. Ultrasound Obstet Gynecol 45(5):516, 2015

Salaia CM, Silberman L, Herrera NE, et al: Placental pathology at term associated with elevated midtrimester maternal serum alpha-fetoprotein concent·ation. Am ] Obstet Gynecol 158(5): 1 064, 1988

Saleemuddin A, Tantbirojn P, Sirois K, et al: Obstetric and perinatal complications in placentas with fetal thrombotic vasculopathy. Pediatr Dev Pathol 13(6):459,s2010

Sato Y, Benirschke K: Umbilical arterial thrombosis with vascular wall necrosis: clinicopathologic indings of 11 cases. Placenta 27: 15, 2006

Schachter M, Tovbin Y, Arieli S, et al: In vitro fertilization is a risk factor for vasa previa. Fertil Steril 78(3):642, 2003

Scioscia M, Fornale M, Bruni F, et al: Four-dimensional and Doppler sonography in the diagnosis and surveillance of a true cord knot. ] Clin Ultrasound 39(3):157,s2011 Sebire N]: Pathophysiological signiicance of abnormal umbilical cord coiling index. Ultrasound Obstet Gynecol 30(6):804, 2007 Sebire N], Backos M, El Gaddal S, et al: Placental pathology, antiphospholipid antibodies, and pregnancy outcome in recurrent miscarriage patients. Obstet Gynecol 10 1 :258, 2003 Sebire N], Backos M, Goldin RD, et al: Placental massive perivillous ibrin deposition associated with antiphospholipid antibody syndrome. B]OG 109:570,s2002 Sepulveda W, Aviles G, Carstens E, et al: Prenatal diagnosis of solid placental masses: the value of color Bow imaging. Ultrasound Obstet GynecoIs16:554, 2000 Sepulveda W, Corral E, Kottmann C, et al: Umbilical artery aneUlysm: prenatal identiication in three fetuses with trisomy 18. Ultrasound Obstet Gynecol 21:213, 2003 Sepulveda W, Wong AE, Gonzalez R, et al: Fetal death due to umbilical cord hematoma: a rare complication of umbilical cord cyst. ] Matern-Fetal Neonatal Med 18(6):387,s2005 Sheiner E, Abramowicz ]S, Levy A, et al: Nuchal cord is not associated with adverse perinatal outcome. Arch Gynecol Obstet 274:81, 2006 Shen 0, Golomb E, Lavie 0, et al: Placental shelf-a common, typically transient and benign inding on early second-trimester sonography. Ultrasound Obstet Gynecol 29: 192, a Shen 0, Reinus e, Baranov A, et al: Prenatal diagnosis of umbilical artery aneurysm: a potentially lethal anomaly. ] Ultrasound Med 26(2):251, 2007b Shilling e, Walsh e, Downey P, et al: Umbilical artery thrombosis is a rare but clinically important inding: a series of cases with clinical outcomes. Pediatr Dev PathoIs17(2):89, 2014

Society for Maternal-Fetal (SMFM) Publications Committee, Sinkey RG, Odibo AO, et al: Diagnosis and management of vasa previa. Am J Obstet GynecoIs213(5):615,s2015

S0nes T: Umbilical cord encirclements and fetal growth restriction. Obstet Gynecol 86:725, 1995

S0nes T: Umbilical cord knots. Acta Obstet Gynecol Scand 79: , 2000

Spellacy erN, Gravem H, Fisch RO: The umbilical cord complications of true knots, nuchal coils and cords around the body. Report from the collaborative study of cerebral palsy. Am J Obstet Gynecol 94: 1136, 1966

Stanek J: Chorangiosis of chorionic villi: what does it really mean? Arch Pathol Lab Med 140(6):58,s2016 5teemers NY, De Rop C, Van Assche A: Zonary placenta. Int J Gynaecol Obstet 51(3):251,s1995

Strong TH Jr, Jarles DL, Vega JS, et al: The umbilical coiling index. Am J ObstetsGynecols1700 Pt 1):29, 1994

Sullivan EA, Javid N, Duncombe G, et al: Vasa previa diagnosis, clinical practice, and outcomes in Australia. Obstet Gynecol 130(3):591, 2017

Sun Y, Arbuckle S, Hocking G, et al: Umbilical cord stricture and intrauterine fetal death. Pediatr Pathol Lab Med 15:723, 1995

Suzuki S: Clinical signiicance of pregnancies with circumvallate placenta. J Obstet Gynaecol Res 340):51, 2008

Swank ML, Garite TJ, Maurel K, et al: Vasa previa: diagnosis and management. Obstetrix Collaborative Research Network. Am J Obstet Gynecol 215(2):223.e1,s2016

Taniguchi H, Aoki S, Sakamaki K, et al: Circumvallate placenta: associated clinical manifestations and complications-a retrospective study. Obstet Gynecol Int 2014:986230,s2014

Towers CV, Juratsch CE, Garite TJ: The fetal heart monitor tracing in pregnancies complicated by a spontaneous umbilical cord haematoma. J Perinatol 29:517, 2009

Tuuli MG, Norman SM, Odibo AO, et al: Perinatal outcomes in women with subchorionic hematoma: a systematic review and meta-analysis. Obstet GynecoIsI17(5):1205,2011

Tuuli MG, Shanks A, Bernhard L, et al: Uterine synechiae and pregnancy complications. Obstet GynecoIs119(4):810, 2012

Vahanian SA, Lavery JA, Ananth CV, et al: Placental implantation abnormalities and risk of preterm delivery: a systematic review and metaanalysis. Am J Obstet Gynecol213(4 Suppl):S78, 2015

Vintzileos AM, Ananth CV, Smulian JC: Using ultrasound in the clinical management of placental implantation abnormalities. Am J Obstet Gynecol 213(4 Suppl):S70, 2015

Voskamp BJ, Fleurke-Rozema H, Oude-Rengerink K, et al: Relationship of isolated single umbilical artery to fetal growth, aneuploidy and perinatal mortality: systematic review and meta-analysis. Ultrasound Obstet Gynecol 42(6):622,s2013

Vyas NM, Manjeera L, Rai S, et al: Prenatal diagnosis of umbilical artery aneurysm with good fetal outcome and review of literature. J Clin Diagn Res 10(l):QDOl,s2016

White SP, Koinas A: Prenatal diagnosis and management of umbilical vein varix of the intra-amniotic portion of the umbilical vein. J Ultrasound Med 13(2):992, 1994

Whitten E, Romero R, Korzeniewski SJ, et al: Evidence of an imbalance of angiogeniclantiangiogenic factors in massive perivillous ibrin deposition (maternal Aoor infarction): a placental lesion associated with recurrent miscarriage and fetal death. Am J Obstet GynecoIs208(4):310.el, 2013

Woo GW, Rocha FG, Gaspar-Oishi M, et al: Placental mesenchymal dysplasia.

Am J Obstet Gynecol 205(6):e3, 201s1

Yamada S, Hamanishi J, Tanada S, et al: Embryogenesis of fused umbilical arteries in human embryos. Am J Obstet Gynecol 193: 1709, 2005

Yamamoto Y, Aoki S, Oba MS, et al: Relationship between short umbilical cord length and adverse pregnancy outcomes. Fetal Pediatr Pathol 35(2):81, 2016

Zalel Y, Weisz B, Gamzu R, et al: Chorioangiomas of the placenta: sonographic and Doppler low characteristics. Ultrasound Med 21 :909, 2002

Zangen R, Boldes R, Yafe H, et al: Umbilical cord cysts in the second and third trimesters: signiicance and prenatal approach. Ultrasound Obstet Gynecol 36(3):296, 2010

GESTATIONAL AGE ............................. 124

EMBRYONIC DEVELOPMENT . . . . . . . . . . . . . . . . . . . .. 125

FETAL DEVELOPMENT AND PHYSIOLOGY. . . . . . . . . .. 128

ENERGY AND . . . . . . . . . . . . . . . . . . . . . .. 137

PLACENTAL ROLE IN EMBRYOFETAL DEVELOPMENT. .. 139

Our knowledge concening the physioloy of the oetus has been markedy enriched during recent years; nevertheless, when com pared with the adult, it oers many points concening which we are but slighty inormed or prooundy ignorant.

-J. Whitridge Williams (1903)

Since these words were written by Williams in 1903, great strides in the understanding of fetal organogenesis and physiology have been gained. Contemporary obstetrics incorporates physiology and pathophysiology of the fetus, its development, and its environment. An important result is that fetal status has been elevated to that of a patient who, in large measure, can be given the same meticulous care that obstetricians provide for gravidas. In our 2yh edition, the entirety of Section 5 is dedicated to the fetal patient, as are individual chapters in other sections. Indeed, virtually every aspect of obstetrics can afect the developing fetus.

Several terms define pregnancy duration and thus fetal age (Fig. 7-1). Gestational age or menstrual age is the time elapsed since the first day of the last menstrual period (LMP), a time that actully precedes conception. This starting time, which is usually approximately 2 weeks before ovulation and fertilization and nearly 3 weeks before blastocyst implantation, has traditionally been used because most women know their approximate last period. Embryologists describe embryofetal development in ovuation age, or the time in days or weeks from ovulation. Another term is postconceptional age, which is nearly identical to ovulation age.

Until recently, clinicians customarily calculated menstrual age with term pregnancy averaging approximately 280 days, or 40 weeks between the first day of the LMP and birth. This corresponds to 9 and 113 calendar months. However, menstrual cycle length variability among women renders many of these calculations inaccurate. This realization, combined with the frequent use of first-trimester sonography, has led to more accurate gestational age determination (Duryea, 2015). Much of this change hinges on the accuracy of early sonographic measurement. As a result, the American College of Obstetricians and Gynecologists, the American Institute of Ultrasound in Medicine, and the Society for Maternal-Fetal Medicine (Reddy, 2014) together recommend the following: 1.

First-trimester sonography is the most accurate method to establish or reairm gestational age.

2.

In conceptions achieved with assisted-reproductive technology, this gestational age is used.

FIGURE 7-1 Terminology used to describe pregnancy duration.

3.

If available, the gestational ages calculated from the LMP and from first-trimester sonography are compared, and the estimated date of coninement (EDC) recorded and discussed with the patient.

4.

The best obstetrical estimate of gestational age at delivery is recorded on the birth certiicate.

he embryofetal crown-rump length in the first trimester is accurate ±5 to 7 days. hus, if sonographic assessment of gestational age difers by more than 5 days prior to 9 weeks' gestation, or by more than 7 days later in the irst trimester, the estimated delivery date is changed.

An EDC based on LMP can be quickly estimated as follows: add 7 days to the irst day of the LMP and subtract 3 months. For example, if the irst day of the LMP was October 5, the due date is 10-05 minus 3 (months) plus 7 (days) = 7-12, or July 12 of the following year. This calculation has been termed the Naegele rule. The period of gestation can also be divided into three units of approximately 14 weeks each. These three trimesters are important obstetrical milestones.

In addition to estimating the EDC with either Naegele rule or pregnancy "wheels," calculator tools in the electronic medical record and smartphone applications can provide a calculated EDC and gestational age. For example, the American College ofObstetricians and Gynecologists (2016) has developed a calculator application that incorporates sonographic criteria and the LMP or embryo transfer date. This is discussed further in Chapter 10 (p. 183).

The complexity of embryofetal development is almost beyond comprehension. Figure 7-2 shows a developmental sequence of various organ systems. New information regarding organ development continues to accrue. For example, imaging techniques help unravel the contributions of gene regulation and tissue interaction to eventual three-dimensional organ morphology (Anderson, 2016; Mohun, 2011). Others have described the sequence of gene activation that underlies cardiac development.

During the irst 2 weeks after ovulation and then fertilization, the zygote-or preembryo-develops to the blastocyst stage. The blastocyst implants 6 or 7 days following fertilization. The 58-cell blastocyst diferentiates into ive embryo-producing cells-the inner cel mass-and the remaining 53 cells form placental trophoblast. Details of implantation and early development of the blastocyst and placenta are described in Chapter 5 (p. 87).

Ears Canals,

Diaphragm Transverse septum, diaphragm

Lungs Tracheoesophageal septum, bronchi, lobes

Heart Primitive tube, great vessels, valves. chambers

Intestines Foregut, liver, pancreas, midgut gut chlea. inner ears. ossicles --Yolksac . Developing

FIGURE 7-3 Early human embryos. Ovulation ages: A. 19 days (presomite). B. 21 days (7 somites). C. 22 days (1o7 somites). (After drawings and models in the Carnegie Institute.) he conceptus is termed an embryo at the beginning of the third week after ovulation and fertilization. Primitive chorionic villi form, and this coincides with the expected day of menses. he embryonic period, during which time organogenesis takes place, lasts 6 weeks. It begins the third week from the LMP through the eighth week. The embryonic disc is well deined, and most pregnancy tests that measure human chorionic

FIGURE 7-4 Three-to four-week-old embryos. A, B. Dorsal views of embryos during 22 to 23 days of development showing 8 and 12 somites, gonadotropin (hCG) become positive by this time. As shown in Figure 7-3, the body stalk is now diferentiated. There are villous cores in which angioblastic chorionic mesoderm can be distinguished and a true intervillous space that contains maternal blood.

During the third week, fetal blood vessels in the chorionic villi appear. In the fourth week, a cardiovascular system has formed (Fig. 7-4). hereby, a true circulation is established respectively. (-E. Lateral views of embryos during 24 to 28 days, showing 16, 27, and 33 somites, respectively. (Redrawn from Moore KL: The Developing Human: Clinically Oriented Embryology, 4th ed. Philadelphia, Saunders, 1988.)

FIGURE 7-5 Embyro photographs. A. Dorsal view of an embryo at 24 to 26 days and corresponding to Figure 7-4C. B. Lateral view of an embryo at 28 days and corresponding to Figure 7-40. C. Lateral view of embryofetus at 56 days, which marks the end of the embryonic period and the beginning of the fetal period. The liver is within the white, halo circle. (From Werth B, Tsiaras A: From Conception to Birth:

A Life Unfolds. New York, Doubleday, 2002.) both within the embryo and between the embryo and the chorionic villi. Partitioning of the primitive heart begins. Also in the fourth week, the neural plate forms, and it subsequently folds to form the neural tube. By the end of the ifth menstrual week, the chorionic sac measures approximately 1 cm in diameter. he embryo is 3 mm long and can be measured sonographically. Arm and leg buds have developed, and the amnion is beginning to ensheathe the body stalk, which thereafter becomes the umbilical cord. At the end of the sixth week, the embryo measures approximately 9 mm long, and the neural tube has closed (Fig. 7-5). Cardiac motion is almost always discern able sonographically (Fig. 7-6). The cranial end of the neural tube closes by 38 days from the LMP, and the caudal end closes by 40 days. Thus, the neural tube has closed by the end of the sixth week. And by the end of the eighth week, the crownrump length approximates 22 mm. Fingers and toes are present, and the arms bend at the elbows. The upper lip is complete, and the external ears form definitive elevations on either side of the head. hree-dimensional images and videos of human embryos from the MultiDimensional Human Embryo project are found at: http://embryo.soad. umich.edu/index.html.

FIGURE 7-6 A. This image of a 6-week, 4-day embryo depicts measurement of the crown-rump length, which is 7.4 mm at this gestational age. B. Despite the early gestational age, M-mode imaging readily demonstrates embryonic cardiac activity. The heart rate in this image is 124 beats per minute.

Transition from the embryonic period to the fetal period occurs at 7 weeks after fertilization, corresponding to 9 weeks after onset of the last menses. At this time, the fetus approximates 24 mm in length, most organ systems have developed, and the fetus enters a period of growth and maturation. These phases are outlined in Figure 7-2.

The uterus usually is just palpable above the symphysis pubis. Fetal growth is rapid, and the fetal crown-rump length is 5 to 6 cm (Fig. 7-7). Centers of ossiication have appeared in most fetal bones, and the fingers and toes have become diferentiated. Skin and nails develop, and scattered rudiments of hair appear. he external genitalia are beginning to show deinitive signs of male or female gender. he fetus begins to make spontaneous movements.

Fetal growth slows at this time. The crown-rump length is 12 cm, and the fetal weight approximates 150 g (Hadlock, 1991). Practically speaing, the sonographic crown-rump length is not measured beyond 13 weeks, which corresponds to approximately 8.4 cm. Instead, biparietal diameter, head circumference, abdominal circumference, and femur length are measured. Fetal weight in the second and third trimesters is estimated from a combination of these measurements (Chap. 10, p. 184).

Eye movements begin at 16 to 18 weeks, coinciding with midbrain maturation. By 18 weeks in the female fetus, the uterus is formed and vaginal canalization begins. By 20 weeks in the male, testicles start to descend.

FIGURE 7-7 This image of a 12-week, 3-day embryo depicts measurement of the crown-rump length. The fetal profile, cranium, and a hand and foot are also visible in this image.

This is the midpoint of pregnancy as estimated from the LMP. The fetus now weighs somewhat more than 300 g, and weight increases substantially in a linear manner. From this point onward, the fetus moves approximately every minute and is active 10 to 30 percent of the day (DiPietro, 2005). Brown fat forms, and the fetal skin becomes less transparent. Downy lanugo covers its entire body, and some scalp hair can be seen. Cochlear function develops between 22 and 25 weeks, and its maturation continues for 6 months after delivery.

The fetus now weighs almost 700 g (Duryea, 2014). he skin is characteristically wrinkled, and fat deposition begins. The head is still comparatively large, and eyebrows and eyelashes are usually recognizable. By 24 weeks, the secretory type II pneumocytes have initiated surfactant secretion (Chap. 32, p. 607). The canalicular period of lung development, during which the bronchi and bronchioles enlarge and alveolar ducts develop, is nearly completed. Despite this, a fetus born at this time will attempt to breathe, but many will die because the terminal sacs, required for gas exchange, have not yet formed. The overall survival rate at 24 weeks is barely above 50 percent, and only approximately 30 percent survive without severe morbidity (Rysavy, 2015). By 26 weeks, the eyes open. Nociceptors are present over all the body, and the neural pain system is developed (Kadic, 2012). The fetal liver and spleen are important sites for hemopoiesis.

The crown-rump length approximates 25 cm, and the fetus weighs about 1100 g. The thin skin is red and covered with vernix caseosa. The pupillary membrane has just disappeared from the eyes. Isolated eye blinking peaks at 28 weeks. The bone marrow becomes the major site of hemopoiesis. he otherwise normal neonate born at this age has a 90-percent chance of survival.without physical or neurological impairment.

At 32 weeks, the fetus has attained a crown-rump length approximating 28 cm and a weight of about 1800 g. he skin surface is still red and wrinkled. In contrast, by 36 weeks, the fetal crown-rump length averages about 32 cm, and the weight approximates 2800 g (Duryea, 2014). Because of subcutaneous fat deposition, the body has become more rotund, and the previous wrinkled facies is now fuller. Normal fetuses have nearly 100-percent survival rate.

This is considered term, and the fetus is now fully developed. The average crown-rump length measures about 36 cm, and the average weight approximates 3500 g.

The cranial end of the neural tube closes by 38 days from the LMP, and the caudal end closes by 40 days. Hence, folic acid supplementation to prevent neural-tube defects must be in place before this point to be eicacious (Chap. 9, p. 169). The walls of the neural tube form the brain and spinal cord. The lumen becomes the ventricular system of the brain and the central canal of the spinal cord. During the sixth week, the cranial end of the neural tube forms three primary vesicles. In the seventh week, five secondary vesicles develop: the telencephalon-future cerebral hemispheres; diencephalon-thalami; mesencephalon-midbrain; metencephalon-pons and cerebellum; and myelencephalonmedulla. Meanwhile, lexures develop and fold the brain into its typical configuration. The end of the embryonic period signiies completion of primary and secondary neuralization.

At 3 to 4 months' gestation, neuronal proleration peaks.

As expected, disorders in this cerebral development phase profoundly worsen function (Volpe, 2008). Neuronal migration occurs almost simultaneously and peaks at 3 to 5 months. This process is characterized by movement of millions of neuronal cells from their ventricular and subventricular zones to areas of the brain in which they reside for life (Fig. 7-8). U pregulation of gene expression for neuronal migration has been described (Iruretagoyena, 2014). Noninvasive methods to study fetal neurodevelopment have also been reported (Goetzl, 2016).

As gestation progresses, the fetal brain appearance steadily changes. Thus, it is possible to identiY fetal age from its external appearance (Volpe, 2008). Neuronal proliferation and migration proceed along with gyral growth and maturation (see Fig. 7-8). Sequential maturation studies by Manganaro (2007) and Dubois (2014) and their colleagues have characterized the developing fetal brain image using magnetic resonance (MR) imaging. Other recent investigations that also used MR imaging have quantiied development of subcortical brain structures from 12 to 22 weeks (Meng, 2012).

Myelination of the ventral roots of the cerebrospinal nerves and brainstem begins at approximately 6 months, but most

A B c �. .�. ''' FIGURE 7-8 Neuronal proliferation and migration are complete at 20 to 24 weeks. During the second half of gestation, organizational events proceed with gyral formation and proliferation, diferentiation, and migration of cellular elements. Approximate gestational ages are shown. A. 20 weeks. B. 35 weeks. C.40 weeks.

myelination progresses after birth. This lack of myelin and incomplete skull ossiication permit fetal brain structure to be seen sonographically throughout gestation.

Whereas the superior two thirds of the neural tube give rise to the brain, the inferior third forms the spinal cord. In the embryo, the spinal cord extends along the entire vertebral column length, but after that it lags behind vertebral growth. Ossiication of the entire sacrum is visible sonographically by approximately 21 weeks (Chap. 10, p. 191). By 24 weeks, the spinal cord extends to SIiat birth to L3, and in the adult to LI.

Spinal cord myelination begins at midgestation and continues through the irst year of life. Synaptic function is suiciently developed by the eighth week to demonstrate flexion of the neck and trunk (Temiras, 1968). During the third trimester, integration of nervous and muscular function proceeds rapidly.

The embryology of the heart is complex. At its earliest stages of formation, the fetal heart undergoes molecular programming, and more than a hundred genes and molecular factors are integral to its morphogenesis. To summarize, the straight cardiac tube is formed by the 23rd day during an intricate morphogenetic sequence, during which each segment arises at a unique time. The tube then undergoes looping, and the chambers then fuse and form septa (Manner, 2009). The valves develop, and the aortic arch forms by vasculogenesis. For a complete description, refer to Chapter 9 in Hursts he Heart (Keller, 2013).

his unique circulation is substantially diferent from that of the adult and functions until birth, when it changes dramatically. For example, because fetal blood does not need to enter the pulmonary vasculature to be oxygenated, most of the right ventricular output bypasses the lungs. In addition, the fetal heart chambers work in parallel, not in series, which efectively supplies the brain and heart with more highly oxygenated blood than the rest of the body.

Oxygen and nutrient materials required for fetal growth and maturation are delivered from the placenta by the single umbilical vein (Fig. 7-9). The vein then divides into the ductus venosus and the portal sinus. The ductus venosus is the major branch of the umbilical vein and traverses the liver to enter the inferior vena cava directly. Because it does not supply oxygen to the intervening tissues, it carries well-oxygenated blood directly to the heart. In contrast, the portal sinus carries blood to the hepatic veins primarily on the left side of the liver, and oxygen is extracted. The relatively deoxygenated blood from the liver then lows back into the inferior vena cava, which also receives more deoxygenated blood returning from the lower body. Blood flowing to the fetal heart from the inferior vena cava, therefore, consists of an admixture of arterial-like blood that passes directly through the ductus venosus and less well-oxygenated blood that returns from most of the veins below the level of the diaphragm. The oxygen content of blood delivered to the heart from the inferior vena cava is thus lower than that leaving the placenta.

Foramen ovale Umbilical v. Hypogastricaa. Ductus Aorta _ --

FIGURE 7-9 The intricate nature of the fetal circulation is evident. The degree of blood oxygenation in various vessels differs appreciably from that in the postnatal state. aa = arteries; LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle; v = vein.

As discussed, the ventricles of the fetal heart work in parallel, not in series. Well-oxygenated blood enters the left ventricle, which supplies the heart and brain, and less oxygenated blood enters the right ventricle, which supplies the rest of the body. These two separate circulations are maintained by the right atrial structure, which efectively directs entering blood to either the left atrium or the right ventricle, depending on its oxygen content. his separation of blood according to its oxygen content is aided by the pattern of blood flow in the inferior vena cava. The well-oxygenated blood tends to course along the medial aspect of the inferior vena cava and the less oxygenated blood flows along the lateral vessel wall. This aids their shunting into opposite sides of the heart. Once this blood enters the right atrium, the configuration of the upper interatrial septum-the crista dividens-preferentially shunts the well-oxygenated blood from the medial side of the inferior vena cava and the ductus venosus through the foramen ovale into the left heart and then to the heart and brain (Dawes, 1962). After these tissues have extracted needed oxygen, the resulting less oxygenated blood returns to the right atrium through the superior vena cava.

The less oxygenated blood coursing along the lateral wall of the inferior vena cava enters the right atrium and is deflected through the tricuspid valve to the right ventricle.

The superior vena cava courses inferiorly and anteriorly as it enters the right atrium, ensuring that less well-oxygenated blood returning from the brain and upper body also will be shunted directly to the right ventricle. Similarly, the ostium of the coronary sinus lies just superior to the tricuspid valve so that less oxygenated blood from the heart also returns to the right ventricle. As a result of this blood flow pattern, blood in the right ventricle is 15 to 20 percent less saturated than blood in the left ventricle.

lmost 90 percent of blood exiting the right ventricle is shunted through the ductus arteriosus to the descending aorta. High pulmonary vascular resistance and comparatively lower resistance in the ductus arteriosus and the umbilical-placental vasculature ensure that only about 8 percent of right ventricular output goes to the lungs (Fineman, 2014). Thus, one third of the blood passing through the ductus arteriosus is delivered to the body. The remaining right ventricular output returns to the placenta through the two hypogastric arteries. These two arteries course from the level of the bladder along the abdominal wall to the umbilical ring and into the cord as the umbilical arteries. In the placenta, this blood picks up oxygen and other nutrients and is recirculated through the umbilical vein.

After birth, the umbilical vessels, ductus arteriosus, foramen ovale, and ductus venosus normally constrict or collapse. With the functional closure of the ductus arteriosus and the expansion of the lungs, blood leaving the right ventricle preferentially enters the pulmonary vasculature to become oxygenated before it returns to the left heart (Hillman, 2012). Virtually instantaneously, the ventricles, which had worked in parallel in fetal life, now efectively work in series. The more distal portions of the hypogastric arteries undergo atrophy and obliteration within 3 to 4 days after birth. hese become the umbilicaliligaments, whereas the intraabdominal remnants of the umbilical vein form the ligamentum teres. The ductus venosus constricts by 10 to 96 hours after birth and is anatomically closed by 2 to 3 weeks. This ultimately forms the ligamentum venosum (Fineman, 2014).

Although precise measurements of human fetoplacental blood volume are lacking, Usher and associates (1963) reported values in term normal newborns to average 78 mLlkg when immediate cord clamping was conducted. Gruenwald (1967) found the fetal blood volume contained in the placenta after prompt cord clamping to average 45 mLlkg of fetal weight. Thus, fetoplacental blood volume at term is approximately 125 mLlkg of fetal weight. This is important when assessing the magnitude of fetomaternal hemorrhage as discussed in Chapter 15 (p. 307).

In the early embryo, hemopoiesis is demonstrable first in the yolk sac, followed by the liver, and inally spleen and bone marrow. Both myeloid and erythroid cells are continually pro duced by progenitors that are from hematopoietic stem cells (Golub, 2013; Heinig, 2015). The first erythrocytes released into the fetal circulation are nucleated and macrocytic. The mean cell volume is at least 180 L in the embryo and decreases to 105 to 115 L at term. The erythrocytes of aneuploid fetuses mean cell volumes-130 L on average (Sipes, 1991). As fetal development progresses, more and more of the circulating erythrocytes are smaller and nonnucleated. With fetal growth, both the blood volume in the common fetoplacental circu lation and hemoglobin concentration increase. As shown in

Figure 7-10, fetal hemoglobin concentrations rise across preg nancy. The Society for Maternal-Fetal Medicine (2015) rec ommends a cutof hematocrit value of 30 percent to define anemia.

Because of their large size, fetal erythrocytes have a short life span, which progressively lengthens to approximately 90 days at term (Pearson, 1966). As a consequence, red blood cell production rises. Reticulocytes are initially present at high levels, but decrease to 4 to 5 percent of the total at term. Fetal erythrocytes difer structurally and metabolically from those in the adult (Baron, 2012). They are more deformable, which serves to ofset their higher viscosity. They also contain several enzymes with appreciably diferent activities.

Erythropoiesis is controlled primarily by fetal erythropoietin because maternal erythropoietin does not cross the placenta. Fetal hormone production is influenced by testosterone, estrogen, prostaglandins, thyroid hormone, and lipoproteins (Stockman, 1992). Serum erythropoietin levels rise with fetal maturity. Although the exact production site is disputed, the fetal liver appears to be an important source until renal production begins. There is a close correlation between the erythropoietin concentration in amnionic fluid and that in umbilical venous blood obtained by cordocentesis. After birth, erythropoietin normally may not be detectable for up to 3 months.

In contrast, platelet production reaches stable levels by midpregnancy, although there is some variation across gestation (Fig.

The fetal and neonatal platelet count is subject to various agents as discussed in Chapter 15 (p. 307).

This tetrameric protein is composed of two copies of two diferent peptide chains, which determine the type of hemoglobin produced. Normal adult hemoglobin A is made of a and 3 chains. During embryonic and fetal life, various a and 3 chain precursors are produced. This results in the serial production of several diferent embryonic hemoglobins. Genes for 3-type chains are on chromosome 11, and those for a-type chains on chromosome 16. Each of these genes is turned on and then of during fetal life, until a and 3 genes, which direct the production of adult hemoglobin A, are permanentlyiactivated.

FIGURE 7-11 Platelet counts by gestational age obtained the first day of life. Mean values and 5th and 95th percentiles are shown. (Data from Christensen RD, Henry E, Antonio DV: Thrombocytosis and thrombocytopenia in the NICU: incidence, mechanisms and treatments, J Matern Fetal Neonatal Med 2012 Oct;25 SuppIo4:15-17) • •• • •••• • • • •• •• •• • Moderateanemia • • ,• •• Mildanemia • Severeanemia•• • • 1.16 :JA12 0.84 ) 0.65 0.55 ) :;)I S

FIGURE 7-10 Relationship between fetal hemoglobin across gestational age. Blue dots indicate fetuses with hydrops. (Reproduced with permission from Mari G, Deter RL, Carpenter RL, et al: Noninvasive diagnosis by Doppler ultrasonography offetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment ofthe Blood Velocity in Anemic Fetuses (Level II-I), N Engl J Med 2000 Jan 6;342(1 ):9-14.)

The timing ofproduction ofeach ofthese earlyhemoglobins corresponds to the site of hemoglobin production. Fetal blood is first produced in the yolk sac, where hemoglobins Gower 1, Gower 2, and Portland are made. Erythropoiesis then moves to the liver, where fetal hemoglobin F is produced. When hemopoiesis finally moves to the bone marrow, adult-type hemoglobin A appears in fetal red blood cells and is present in progressively greater amounts as the fetus matures (Pataryas, 1972).

he final adult version of the . chain is produced exclusively by 6 weeks. Mter this, there are no functional alternative 400,000 /95th :J:LD 300,000 200,000 ::D)5 ) 100,000 24262830323436384042 versions. Ifan a-gene mutation or deletion occurs, no alternate a-type chain can be substituted to form functional hemoglobin. In contrast, at least two versions of the � chain-6 and ,-remain in production throughout fetal life and beyond. In the case ofa �-gene mutation or deletion, these two other versions of the � chain often continue to be produced, resulting in hemoglobin A2 or hemoglobin F, which substitute for the abnormal or missing hemoglobin.

Genes are turned of by methylation of their control region, which is discussed in Chapter 13 (p. 267). In some situations, methylation does not occur. For example, in newborns ofdiabetic women, hemoglobin F may persist due to hypomethylation of thei, gene (Perrine, 1988). With sickle cell anemia, thei, gene remains unmethylated, and large quantities of fetal hemoglobin continue to be produced. s discussed in Chapter 56 (p. 1081), elevated hemoglobin F levels are associated with fewer sickle-cell disease symptoms, and pharmacological modiication ofthese levels by hemoglobin F-inducing drugs is one approach to treatment.

As discussed on page 140, there is a functional diference between hemoglobins A and F. At any given oxygen tension and at identical pH, fetal erythrocytes that contain mostly hemoglobin F bind more oxygen than do those that contain nearly all hemoglobin A (Fig. 47-2, p. 920). his is because hemoglobin A binds 2,3-diphosphoglycerate (2,3-DPG) more avidly than does hemoglobin F, thus lowering the ainity of hemoglobin A for oxygen. During pregnancy, maternal 2,3-DPG levels are greater, and because fetal erythrocytes have lower concentrations of 2,3-DPG, the latter has increased oxygen ainity.

he amount of hemoglobin F in fetal erythrocytes begins to decrease in the last weeks of pregnancy. At term, approximately three fourths oftotal hemoglobin levels are hemoglobin F. During the irst 6 to 12 months of life, the hemoglobin F proportion continues to decline and eventually reaches the low levels found in adult erythrocytes.

With the exception of fibrinogen, there are no embryonic forms of the various hemostatic proteins. he fetus starts producing normal, adult-type procoagulant, ibrinolytic, and anticoagulant proteins by 12 weeks. Because they do not cross the placenta, their concentrations at birth are markedly below the levels that develop within a few weeks of life (Corrigan, 1992). In normal neonates, the levels of factors II, VII, IX, X, XI, and of protein S, protein C, antithrombin, and plasminogen all approximate 50 percent of adult levels. In contrast, levels of factors V, VIII, XIII, and ibrinogen are closer to adult values (Saracco, 2009). Without prophylactic treatment, the levels of vitamin K-dependent coagulation factors usually decrease even further during the irst few days after birth. his decline is ampliied in breastfed infants and may lead to newborn hemorrhage (Chap. 33, p. 626).

Fetal ibrinogen, which appears as early as 5 weeks, has the same amino acid composition as adult ibrinogen, however, it has diferent properties (Klagsbrun, 1988). It forms a less compressible clot, and the ibrin monomer has a lower degree of aggregation (Heimark, 1988). Although plasma ibrinogen levels at birth are less than those in nonpregnant adults, the protein is functionally more active than adult ibrinogen (Ignjatovic, 2011).

Levels of functional fetal factor XIII-ibrin stabilizing factor-are signiicantly reduced compared with those in adults (Henriksson, 1974). Nielsen (1969) described low levels of plasminogen and elevated ibrinolytic activity in cord plasma compared with that of maternal plasma. Platelet counts in cord blood are in the normal range for nonpregnant adults (see Fig. 7-11).

Despite this relative reduction in procoagulants, the fetus appears to be protected from hemorrhage, and fetal bleeding is rare. Even after invasive fetal procedures such as cordocentesis, excessive bleeding is uncommon. Ney and coworkers (1989) have shown that amnionic luid thromboplastins and a factor(s) in Wharton jelly combine to aid coagulation at the umbilical cord puncture site.

Various thrombophilias may cause thromboses and pregnancy complications in adults (Chap. 52, p. 1008). If the fetus inherits one of these mutations, thrombosis and infarction can develop in the placenta or fetal organs. his is usually seen with homozygous inheritance. One example is homozygous protein C mutation, which causes purpura fulminans.

Liver enzymes and other plasma proteins are produced by the fetus, and these levels do not correlate with maternal levels (Weiner, 1992). Concentrations of plasma proteins, which include albumin, lactic dehydrogenase, aspartate aminotransferase, 1-glutamyl transpeptidase, and alanine transferase, all rise. Conversely, prealbumin levels decline with gestational age (Fryer, 1993). At birth, mean total plasma protein and albumin concentrations in fetal blood are similar to maternal levels. This is important because albumin binds unconjugated bilirubin to prevent kernicterus in the newborn (Chap. 33, p. 626).

Lung maturation and biochemical indices of functional fetal lung maturity are important predictors of early neonatal outcome. Morphological or functional immaturity at birth leads to the development of the respiratoy distress syndrome (Chap. 34, p. 636). A suicient amount of surface-active materialscollectively referred to as suactant-in the amnionic fluid is evidence of fetal lung maturity. As Liggins (1994) emphasized, however, the structural and morphological maturation of fetal lung also is extraordinarily important to proper lung function.

The limits of viability appear to be determined by the usual process of pulmonary growth. Like the branching of a tree, lung development proceeds along an established timetable that apparently cannot be hastened by antenatal or neonatal therapy. Within this framework, four essential lung development stages are described by Moore (2000). First, the pseudoglandular stage entails growth of the intrasegmental bronchial tree between the 5th and 17th weeks. During this period, the lung looks microscopically like a gland. Second, during the canalicular stage, from 16 to 25 weeks, the bronchial cartilage plates extend peripherally. Each terminal bronchiole gives rise to several respiratory bronchioles, and each of these in turn divides into multiple saccular ducts. Third, the terminal sac stage begins after 25 weeks. During this stage, alveoli give rise to primitive pulmonary alveoli, that is, the terminal sacs. Simultaneously, an extracellular matrix develops from proximal to distal lung segments until term. Finally, the alveolar stage begins during the late fetal period and continues well into childhood. An extensive capillary network is built, the lymph system forms, and type II pneumocytes begin to produce surfactant. At birth, only approximately 15 percent of the adult number of alveoli is present. hus, the lung continues to grow, adding more alveoli for up to 8 years.

Various insults can upset this process, and their timing determines the sequelae. One example is fetal renal agenesis, in which amnionic luid is absent at the beginning oflung growth, and major defects occur in all four developmental stages. In another instance, the fetus with membrane rupture and subsequent oligohydramnios before 20 weeks usually exhibits nearly normal bronchial branching and cartilage development but has immature alveoli. In contrast, membrane rupture after 24 weeks may have minimal long-term efect on pulmonary structure. In another example, various growth factors are expressed abnormally in the fetus with a diaphragmatic hernia (Candilira, 2015). Finally, vitamin D is thought to be important for several aspects oflung development (Hart, 2015; Lykkedegn, 2015).

After the irst breath, the terminal sacs must remain expanded despite the pressure imparted by the tissue-to-air interface, and surfactant keeps them from collapsing. Surfactant is formed in type II pneumonocytes that line the alveoli. These cells are characterized by multivesicular bodies that produce the lamellar bodies in which surfactant is assembled. During late fetal life, at a time when the alveolus is characterized by a waterto-tissue interface, the intact lamellar bodies are secreted from the lung and swept into the amnionic fluid during respiratorylike movements that are termed fetal breathing. At birth, with the first breath, an air-to-tissue interface is established in the lung alveolus. Surfactant uncoils from the lamellar bodies and spreads to line the alveolus to prevent alveolar collapse during expiration. hus, the fetal lungs' capacity to produce surfactant establishes lung maturity.

Surfactant Composition. Gluck (1972) and Hallman (1976) and their coworkers approximated that 90 percent of surfactant's dry weight is lipid, speciically glycerophospholipids. Proteins account for the other 10 percent. Nearly 80 percent of the glycerophospholipids are phosphatidylcholines (lecithins). The principal active component that constitutes half of surfactant is a speciic lecithin, which is dipalmitoylphosphatidylcholine (DPPC or PC). Phosphatidylglycerol (PG) accounts for another 8 to 15 percent. Its precise role is unclear because newborns without PG usually do well. he other major constituent is phosphatidylinositol (PI). The relative contributions of each component are shown in Figure 7-12.

Surfactant Synthesis. Biosynthesis takes place in the type II pneumocytes. he apoproteins are produced in the endoplasmic reticulum, and the glycerophospholipids are synthesized by cooperative interactions of several cellular organelles. Phospholipid is the primary surface tension-lowering component of surfactant, whereas the apoproteins aid the forming and reforming of a surface ilm.

The major apoprotein is surfactant A (SP-A), which is a glycoprotein with a molecular weight of 28,000 to 35,000 Da (Whitsett, 1992). It is synthesized in the type II cells, and its content in amnionic fluid increases with gestational age and fetal lung maturity. SP-A gene expression is demonstrable by 29 weeks (Mendelson, 2005). Specifically, SP-Ai and SP-A2 0: : o .

15 -.a are two separate genes on chromosome 10, but their regulation is distinctive and diferent (McCormick, 1994).

Several smaller apoproteins such as SP-B and SP-C are likely important in optimizing the action of surfactant. For example, deletions.in SP-B gene are incompatible with survival despite production of large amounts of surfactant (Hallman, 2013).

Corticosteroids and Fetal Lung Maturation. Since Liggins (1969) observed accelerated lung maturation in lamb fetuses given glucocorticosteroids prior to preterm delivery, many suggested that fetal cortisol stimulates lung maturation and surfactant synthesis. It is unlikely that corticosteroids are the only stimulus for augmented surfactant formation. However, when these are administered at certain critical times, they may improve preterm fetal lung maturation. As fetal lung therapy, antenatal betamethasone and dexamethasone use and neonatal replacement surfactant therapy are discussed in Chapter 34 (p. 637).

Fetal respiratory muscles develop early, and chest wall movements are detected sonographically as early as 11 weeks (Koos, 2014). From the beginning of the fourth month, the fetus engages in respiratory movement suiciently intense to move amnionic luid in and out of the respiratory tract. Some extrauterine events have efects on fetal breathing, for example, maternal exercise stimulates it (Sussman, 2016).

After its embryogenic formation from the yolk sac as the primordial gut, the digestive system forms the intestines and various appendages. The foregut gives rise to the pharynx, lower respiratory system, esophagus, stomach, proximal duodenum, liver, pancreas, and biliary tree. The midgut gives rise to the distal duodenum, jejunum, ileum, cecum, appendix, and the right colon. The hindgut develops into the left colon, rectum, and the superior portion of the anal canal. Numerous malformations develop in these structures from improper rotation, ixation, and partitioning.

Swallowing begins at 10 to 12 weeks, coincident with the ability of the small intestine to undergo peristalsis and actively transport glucose (Koldovsky, 1965). As a correlate, neo ..A:.A : 0 of immature gut motility (Singendonk, 2014). Much of the water in swallowed luid is absorbed, and unabsorbed matter o).

::) 0-0..

.-o i:S :.=. 0 is propelled to the lower colon. Gitlin (1974) demonstrated that late in pregnancy, approximately 800 mg of soluble pro tein is ingested daily by the fetus. he stimulus for swallow :.o)B : 0 ing is unclear, but the fetal neural analogue of thirst, gastric o : 0 :.=.=t ..A emptying, and change in the amnionic fluid composition are potential factors (Boyle, 1992). The fetal taste buds may play a role because saccharin injected into amnionic fluid increases ..At 40 swallowing, whereas injection of a noxious chemical inhibits it

Gestational age (weeks) (Liley, 1972).

Fetal swallowing appears to have little efect on amnionic

FIGURE 7-12 Relationship between the levels of lecithindipalmitoyl phosphatidylcholine (PC), phosphatidylinositol (PI), and fluid volume early in pregnancy because the volume swallowed phosphatidylglycerol (PG) in amnionic fluid. is small compared with the total. However, term fetuses swallow between 200 and 760 mL per day-an amount comparable to that of the term neonate (Pritchard, 1966). hus at term, amnionic fluid volume regulation can be substantially altered by fetal swallowing. For example, as discussed in Chapter 11 (p. 227), if swallowing is inhibited, hydramnios is common.

Hydrochloric acid and some digestive enzymes are pres ent in the stomach and small intestine in minimal amounts in the early fetus. Intrinsic factor is detectable by 11 weeks, and pepsinogen by 16 weeks. The preterm neonate, depending on its gestational age, may have transient deficiencies of these enzymes (Lebenthal, 1983).

Stomach emptying appears to be stimulated primarily by volume. Movement of amnionic luid through the gastroin testinal system may enhance growth and development of the alimentary canal. That said, other regulatory factors likely are involved. For example, anencephalic fetuses, in which swallow ing is limited, often have normal amnionic fluid volume and normal-appearing gastrointestinal tract.

Fetal bowel contents consist of various products of secretion, such as glycerophospholipids from the lung, desquamated fetal cells, lanugo, scalp hair, and vernix. It also contains undigested debris from swallowed amnionic fluid. The dark greenish-black color forms from bile pigments, especially biliverdin. Meconium can pass from normal bowel peristalsis in the mature fetus or from vagal stimulation. It can also pass when hypoxia stimulates arginine vasopressin (A VP) release from the fetal pituitary gland. A VP stimulates colonic smooth muscle to contract, resulting in intraamnionic defecation (deVane, 1982; Rosenfeld, 1985). Meconium is toxic to the respiratory system, and its inhalation can result in meconium aspiration syndrome (Chap. 33, p. 620).

The hepatic diverticulum is an outgrowth of the endodermal lining of the foregut. Epithelial liver cords and primordial cells diferentiate into hepatic parenchyma. Serum liver enzyme levels increase with gestational age. Still, the fetal liver has a gestational-age-related diminished capacity for converting free unconjugated bilirubin to conjugated bilirubin (Morioka, 2015). Because of hepatic immaturity, the preterm newborn is at particular risk for hyperbilirubinemia (Chap. 33, p. 626). And because the life span of normal fetal macrocytic erythrocytes is shorter than that of the adult, relatively more unconjugated bilirubin is produced. As just noted, the fetal liver conjugates only a small fraction, and this is excreted into the intestine and ultimately oxidized to biliverdin. Most of the unconjugated bilirubin is excreted into the amnionic luid after 12 weeks and transferred across the placenta (Bashore, 1969).

Importantly, placental bilirubin transfer is bidirectional. Thus, a woman with severe hemolysis from any cause has excess unconjugated bilirubin that readily passes to the fetus and then into the amnionic fluid. Conversely, conjugated bilirubin is not exchanged to any significant degree between mother and fetus.

Most fetal cholesterol derives from hepatic synthesis, which satisies the large demand for low-density lipoprotein (LDL) cholesterol by the fetal adrenal glands. Hepatic glycogen is present in low concentration during the second trimester, but near term, levels rise rapidly and markedly to reach concentrations that are two-to threefold higher than those in the adult liver. After birth, glycogen content falls precipitously.

from the endoderm of the foregut. Gene regulation of its development was recently reviewed Qennings, 2015). Insu lin-containing granules can be identiied by 9 to 10 weeks, and insulin is detectable in fetal plasma at 12 weeks (Adam, 1969). The pancreas responds to hyperglycemia by secreting insulin (Obenshain, 1970). Glucagon has been identified in the fetal pancreas at 8 weeks. Although hypoglycemia does not cause an increase in fetal glucagon levels, similar stimuli do so by 12 hours after birth (Chez, 1975). At the same time, however, fetal pancreatic a cells do respond to L-dopa infu sions (Epstein, 1977). Therefore, unresponsiveness to hypo glycemia is likely the consequence of failed glucagon release rather than inadequate production. This is consistent with developmental expression of pancreatic genes in the fetus (Mally, 1994).

Most pancreatic enzymes are present by 16 weeks. T rypsin, chymotrypsin, phospholipase A, and lipase are found in the 14-week fetus, and their concentrations increase with gestational age (Wedin, 1992). Amylase has been identiied in amnionic luid at 14 weeks (Davis, 1986). The exocrine function of the fetal pancreas is limited. Physiologically important secretion occurs only after stimulation by a secretagogue such as acetylcholine, which is released locally after vagal stimulation (Werlin, 1992). Cholecystokinin normally is released only after protein ingestion and thus ordinarily would not be found in the fetus.

Renal development involves interaction between pluripotential stem cells, undiferentiated mesenchymal cells, and epithelial components (Fanos, 2015). Two primitive urinary systemsthe pronephros and the mesonephros-precede development of the metanephros, which forms the inal kidney (Chap. 3, p. 33). The pronephros involutes by 2 weeks, and the mesonephros produces urine at 5 weeks and degenerates by 11 to 12 weeks. Failure of these two structures either to form or to regress may result in anomalous urinary system development. Between 9 and 12 weeks, the ureteric bud and the nephrogenic blastema interact to produce the metanephros. he kidney and ureter develop from intermediate mesoderm. The bladder and urethra develop from the urogenital sinus. The bladder also develops in part from the allantois.

By week 14, the loop of Henle is functional and reabsorption occurs (Smith, 1992). New nephrons continue to be formed until 36 weeks. In preterm neonates, their formation continues after birth. Although the fetal kidneys produce urine, their ability to concentrate and modiy the pH is limited even in the mature fetus. Fetal urine is hypotonic with respect to fetal plasma and has low electrolyte concentrations.

Renal vascular resistance is high, and the filtration fraction is low compared with adult values (Smith, 1992). Fetal renal blood low and thus urine production are controlled or inluenced by the renin-angiotensin system, the sympathetic nervous system, prostaglandins, kallikrein, and atrial natriuretic peptide. The glomerular filtration rate increases with gestational age from less than 0.1 mLimin at 12 weeks to 0.3 mLi min at 20 weeks. In later gestation, the rate remains constant when corrected for fetal weight (Smith, 1992). Hemorrhage or hypoxia generally results in a decrease in renal blood flow, glomerular filtration rate, and urine output.

Urine usually is found in the bladder even in small fetuses.

The fetal kidneys start producing urine at 12 weeks. By 18 weeks, they are producing 7 to 14 mLi day, and at term, this increases to 650 mLiday (Wladimirof, 1974). Maternally administered furosemide increases fetal urine formation, whereas uteroplacental insuiciency, fetal growth restriction, and other fetal disorders can lower it. Obstruction of the urethra, bladder, ureters, or renal pelves can damage renal parenchyma and distort fetal anatomy (Muller Brochut, 2014). Kidneys are not essential for survival in utero but inluence control of amnionic luid composition and volume. hus, abnormalities that cause chronic fetal anuria are usually accompanied by oligohydramnios and pulmonary hypoplasia. Pathological correlates and prenatal therapy of urinary tract obstruction are discussed in Chapter 16 (p. 325).

The fetal endocrine system is functional for some time before the central nervous system reaches maturity (Mulchahey, 1987). he anterior pituitary gland develops from oral ectodermRathke pouch, whereas the posterior pituitary gland derives from neuroectoderm. As with other organ systems, embryonic development involves a complex and highly spatiotemporally regulated network of signaling molecules and transcription factors (Bancalari, 2012; de Moraes, 2012).

Anterior and Intermediate Lobes. The adenohypophysis, or anterior pituitary, diferentiates into five cell types that secrete six protein hormones. Of these types, lactotropes produce prolactin (PRL), somatotropes produce growth hormone (GH), corticotropes produce adrenocorticotropic hormone (ACTH), thyrotropes produce thyroid-stimulating hormone (TSH), and gonadotropes produce luteinizing hormone (LH) and folliclestimulating hormone (FSH).

ACTH is irst detected in the fetal pituitary gland at 7 weeks, and GH and LH have been identified by 13 weeks. By the end of the 17th week, the fetal pituitary gland synthesizes and stores all pituitary hormones. Moreover, the fetal pituitary is responsive to tropic hormones and is capable of secreting these early in gestation (Grumbach, 1974). he fetal pituitary secretes �-endorphin, and cord blood levels of �-endorphin and �-lipotrophin rise with fetal PC02 (Browning, 1983).

The intermediate lobe in the fetal pituitary gland is well developed. The cells of this structure begin to disappear before term and are absent from the adult pituitary. he principal secretory products of the intermediate lobe cells are .-melanocytestimulating hormone (.-MSH) and �-endorphin.

Neurohypophysis. The posterior pituitary gland or neurohypophysis is well developed by 10 to 12 weeks, and oxytocin and arginine vasopressin are demonstrable. Both hormones probably unction in the fetus to conserve water by actions directed largely at the lung and placenta rather than kidney. Vasopressin levels in umbilical cord plasma are increased strikingly compared with maternal levels (Chard, 1971).

This gland arises from the endoderm of the second pharyngeal pouch. he thyroid migrates to its inal position and the obliterated thyroglossal duct connects to the foramen cecum of the tongue. he pituitary-thyroid system is functional by the end of the first trimester. The thyroid gland is able to synthesize hormones by 10 to 12 weeks, and thyrotropin, thyroxine, and thyroid-binding globulin (TBG) have been detected in fetal serum as early as 11 weeks (Bernal, 2007). he placenta actively concentrates iodide on the fetal side, and by 12 weeks and throughout pregnancy, the fetal thyroid concentrates iodide more avidly than does the maternal thyroid. hus, maternal administration of either radioiodide or appreciable amounts of ordinary iodide is hazardous after this time (Chap. 58, p. 1121). Normal fetal levels of free thyroxine (T4), free triiodothyronine (T3)' and thyroxin-binding globulin increase steadily throughout gestation (Ballabio, 1989). Compared with adult levels, by 36 weeks, fetal serum concentrations of TSH are higher, total and free T3 concentrations are lower, and T4 is similar. This suggests that the fetal pituitary may not become sensitive to feedback until late pregnancy (horpeBeeston, 1991).

Fetal thyroid hormone plays a role in the normal development of virtually all fetal tissues, especially the brain (Forhead, 2014; Rovet, 2014). Its inluence is illustrated by congenital hyperthyroidism, which develops when maternal thyroidstimulating antibody crosses the placenta to stimulate the fetal gland to secrete thyroxine (Donnelley, 2015). These fetuses develop large goiters as shown in Figure 58-3 (p. 1121). They also display tachycardia, hepatosplenomegaly, hematological abnormalities, craniosynostosis, and growth restriction. As children, they have perceptual motor diiculties, hyperactivity, and reduced growth (Wenstrom, 1990). Fetal thyroid disease and its treatment are discussed in Chapter 16 (p. 318) . Neonatal efects of fetal thyroid deficiency are discussed in Chapter 58 (p. 1126).

The placenta prevents substantial passage of maternal thyroid hormones to the fetus by rapidly deiodinating maternal T 4 and T 3 to form reverse T 3' a relatively inactive thyroid hormone (Vulsma, 1989). Several antithyroid antibodies cross the placenta when present in high concentrations (Pelag, 2002). Those include the long-acting thyroid stimulators (LATS), LATSprotector (LATS-P), and thyroid-stimulating immunoglobulin (TSI). It was previously believed that normal fetal growth and development, which occurred despite fetal hypothyroidism, provided evidence that T 4 was not essential for fetal growth. It is now known, however, that growth proceeds normally because small quantities of maternal T4 prevent antenatal cretinism in fetuses with thyroid agenesis (Forhead, 2014; Vulsma, 1989).

The fetus with congenital hypothyroidism typically does not develop stigmata of cretinism until after birth (Abduljabbar, 2012). Because administration of thyroid hormone will prevent this, by state law, all newborns are tested for high serum levels ofTSH (Chap. 32, p. 614).

Immediately after birth, thyroid function and metabolism undergo major change. Cooling to room temperature evokes sudden and marked increase in TSH secretion. his in turn causes a progressive increase in serum T 4 levels that are maximal 24 to 36 hours after birth. here are nearly simultaneous eleva tions of serum T levels.

These glands develop from two separate tissues. The medulla derives from neural crest ectoderm, whereas the fetal and adult cortex arise from intermediate mesoderm. The gland grows rapidly through cell proliferation and angiogenesis, cellular migration, hypertrophy, and apoptosis (Ishimoto, 2011). Fetal glands are much larger in relation to total body size than in adults. he bulk is made up of the inner or fetal zone of the adrenal cortex and involutes rapidly after birth. his zone is scant to absent in rare instances in which the fetal pituitary gland is congenitally absent. he function of the fetal adrenal glands is discussed in detail in Chapter 5 (p. 104).

Infections in utero have provided an opportunity to examine mechanisms of the fetal immune response. Evidence of immunological competence has been reported as early as 13 weeks (Kohler, 1973; Stabile, 1988). In cord blood at or near term, the average level for most components is approximately half that of the adult values (Adinolfi, 1977).

B cells diferentiate from pluripotent hemopoietic stem cells that migrate to the liver (Melchers, 2015; Muzzio, 2013). Despite this, in the absence of a direct antigenic stimulus such as infection, fetal plasma immunoglobulins consist almost totally of transferred maternal immunoglobulin G (IgG). hus, antibodies in the newborn are most often relective of maternal immunological experiences (American College of Obstetricians and Gynecologists, 2017). he interaction between maternal and fetal T cells is described in detail in Chapter 5 (p. 95).

Maternal IgG transport to the fetus begins at approximately 16 weeks and increases thereafter. he bulk of IgG is acquired during the last 4 weeks of pregnancy (Gitlin, 1971). Accordingly, preterm neonates are poorly endowed with protective maternal antibodies. Newborns begin to slowly produce IgG, and adult values are not attained until age 3 years. In certain situations, the transfer of IgG antibodies from mother to fetus can be harmful rather than protective to the fetus. The classic example is hemolytic disease of the fetus and newborn resulting from Rh-antigen alloimmunization (Chap. 15, p. 301).

In the adult, production of immunoglobulin M (IgM) in response to an antigenic stimulus is superseded in a week or so predominantly by IgG production. In contrast, very little

IgM is produced by normal fetuses. With infection, the IgM response is dominant in the fetus and remains so for weeks to months in the newborn. And, because IgM is not trans ported from the mother, any IgM in the fetus or newborn is that which it produced. hus, specific IgM levels in umbilical cord blood may be useful in fetal infection diagnosis. Accord ing to the American College of Obstetricians and Gynecologists (2017), elevated levels of IgM are usually found in newborns with congenital infection such as rubella, cytomegalovirus infection, or toxoplasmosis. In infants, adult levels of IgM are normally attained by age 9 months.

mucosal protection against enteric infections. This may explain the small amount of fetal secretory IgA found in amnionic luid (Quan, 1999).

he immune system develops early, and B lymphocytes appear in fetal liver by 9 weeks and in blood and spleen by 12 weeks. T lymphocytes begin to leave the thymus at approximately 14 weeks. Despite this, the newborn responds poorly to immunization, and especially poorly to bacterial capsular polysaccharides. his immature response may stem from a deicient response of newborn B cells to polyclonal activators or from a lack of T cells that proliferate in response to specific stimuli (Hayward, 1983). In the newborn, monocytes are able to process and present antigen when tested with maternal antigen-speciic T cells. DNA methylation patterns are developmentally regulated during monocyte-macrophage diferentiation and contribute to the antiinlammatory phenotype in macro phages (Kim, 2012).

The origin of most muscles and bones is mesodermal. he skeleton arises from condensed mesenchyme-embryonic connective tissue-which eventually forms hyaline cartilage models of the bones. By the end of the embryonic period, ossification centers have developed, and bones harden by endochondral ossification. The limb buds appear by the fourth week. Most skeletal muscle derives from myogenic precursor cells in the somites.

Because of the small amount of yolk in the human ovum, growth of the embryofetus is dependent on maternal nutrients during the irst 2 months. During the first few days after implantation, blastocyst nutrition comes from the interstitial fluid of the endometrium and the surrounding maternal tissue.

Maternal adaptations to store and transfer nutrients to the fetus are discussed in Chapter 4 and summarized here. Three major maternal storage depots are the liver, muscle, and adipose tissue. These maternal depots and the storage hormone insulin are intimately involved in the metabolism of the nutrients absorbed from the gut. Maternal insulin secretion is sustained by increased serum levels of glucose and amino acids. he net efect is maternal storage of glucose as glycogen primarily in liver and muscle, retention of some amino acids as protein, and storage of the excess as fat. Storage of maternal fat peaks in the second trimester and then declines as fetal energy demands rise in the third trimester (Pipe, 1979). Interestingly, the placenta appears to act as a nutrient sensor, altering transport based on the maternal supply and environmental stimuli (Fowden, 2006; Jansson, 2006b).

During times of fasting, glucose is released from glycogen, but maternal glycogen stores cannot provide an adequate amount of glucose to meet requirements for maternal energy and fetal growth. Augmentation is provided by cleavage of triacylglycerols, stored in adipose tissue, which result in free fatty acids and activation of lipolysis.

Although dependent on the mother for nutrition, the fetus also actively participates in providing its own nutrition. At midpregnancy, fetal glucose concentration is independent of maternallevels and may exceed them (Bozzetti, 1988). Glucose is the major nutrient for fetal growth and energy. Logically, mechanisms exist during pregnancy to minimize maternal glucose use so that the limited maternal supply is available to the fetus. Human placental lactogen (hPL), a hormone normally abundant in the mother bur not the fetus, has an insulin antagonist efect. It blocks the peripheral uptake and use of glucose, while promoting mobilization and use of free fatty acids by maternal tissues (Chap. 5, p. 100). his hormone is also diabetogenic as discussed in Chapter 57 (p. 1107).

he transfer of D-glucose across cell membranes is accomplished by a carrier-mediated, stereospecific, nonconcentrating process of facilitated difusion. There are 14 glucose transport proteins (GLUTs) encoded by the SLC2A gene family and characterized by tissue-speciic distribution (Leonce, 2006). GLUT-1 and GLUT -3 primarily facilitate glucose uptake by the placenta and are located in the plasma membrane of the syncytiotrophoblast microvilli (Acosta, 2015). DNA methylation regulates expression of placental GLUT genes, with epigenetic modiication across gestation (Novakovic, 2013). It increases as pregnancy advances and is induced by almost all growth factors (Frolova, 2011). GLUT-3 expression is up regulated with fetal growth restriction a anzen, 2013).

Lactate is a product of glucose metabolism and transported across the placenta also by facilitated difusion. By way of cotransport with hydrogen ions, lactate is probably transported as lactic acid.

The precise biomolecular events in the pathophysiology of fetal macrosomia are not deined. Nonetheless, fetal hyperinsulinemia is clearly one driving force (Luo, 2012). As discussed in Chapter 44 (p. 845), insulin-like growth factor, fibroblast growth factor, and corticotropin-releasing hormone (CRH) and are important regulators of placental development and function (Gao, 2012; Giudice, 1995). Maternal obesity begets fetal macrosomia (Chap. 44, p. 857). In addition, it is hypothesized that maternal obesity afects fetal cardiomyocyte growth that may result in fetal cardiomyopathy or even congenital heart disease (Roberts, 2015).

This polypeptide hormone was originally identified as a product of adipocytes and a regulator of energy homeostasis by curbing appetite. It also contributes to angiogenesis, hemopoiesis, osteogenesis, pulmonary maturation, and neuroendocrine, immune, and reproductive functions (Brifa, 2015; Maymo, 2009). Leptin is produced by the mother, fetus, and placenta. It is expressed in syncytiotrophoblast and fetal vascular endothelial cells. Of placental production, 5 percent enters the fetal circulation, whereas 95 percent is transferred to the mother (Hauguel-de vlouzon, 2006). Leptin concentrations peak in amnionic fluid at midpregnancy (Scott-Finley, 2015).

Fetalileptin levels begin rising at approximately 34 weeks and are correlated with fetal weight. This hormone is involved in the development and maturation of the heart, brain, kidneys, and pancreas, and its levels are decreased with fetal growth restriction (Brifa, 2015). Abnormal levels have been associated with fetal growth disorders, gestational diabetes, and preeclampsia (Fasshauer, 2014). Postpartum, leptin levels decline in both the newborn and mother. Perinatal leptin is associated with the development of metabolic syndromes later in life (Brifa, 2015; Granado, 2012).

The newborn has a large proportion of fat, which averages 15 percent of body weight (Kimura, 1991). Thus, late in pregnancy, a substantial part of the substrate transferred to the human fetus is stored as fat. Although maternal obesity raises placental fatty acid uptake and fetal fat deposition, it does not appear to afect fetal organ growth (Dube, 2012). Neutral fat in the form of triglycerides does not cross the placenta, but glycerol does. Despite this, evidence supports that abnormal maternal concentrations of triglycerides-both low and high levels-are associated with major congenital anomalies (Nederlof, 2015).

There is preferential placental-fetal transfer of long-chain polyunsaturated fatty acids (Gil-Sanchez, 2012). Lipoprotein lipase is present on the maternal but not on the fetal side of the placenta. his arrangement favors hydrolysis of triacylglycerols in the maternal intervillous space yet preserves these neutral lipids in fetal blood. Fatty acids transferred to the fetus can be converted to triglycerides in the fetal liver.

The placental uptake and use ofLDL is an alternative mechanism for fetal assimilation of essential fatty acids and amino acids (Chap. 5, p. 103). LDL binds to specific receptors in the coated-pit regions of the syncytiotrophoblast microvilli. The large LDL particle, measuring about 250,000 Da, is taken up by a process of receptor-mediated endocytosis. The apoprotein and cholesterol esters of LD L are hydrolyzed by lysosomal enzymes in the syncytium to yield: (1) cholesterol for progesterone synthesis; (2) free amino acids, including essential amino acids; and (3) essential fatty acids, primarily linoleic acid.

he placenta concentrates many amino acids in the syncytiotrophoblast, which are then transferred to the fetal side by difusion. Based on data from cordocentesis blood samples, the amino acid concentration in umbilical cord plasma is greater than in maternal venous or arterial plasma (Morriss, 1994) . Transport system activity is influenced by gestational age and environmental factors. hese include heat stress, hypoxia, under-and overnutrition, and hormones such as glucocorticoids, growth hormone, and leptin (Brifa, 2015; Fowden, 2006). Trophoblastic mammalian target of rapamycin complex 1 (mTORC1) regulates placental amino acid transporters and modulates transfer across the placenta Qansson, 2012). In vivo studies suggest an upregulation of transport for certain amino acids and a greater delivery rate of these to the fetuses of women with gestational diabetes associated with fetal overgrowth Oansson, 2006a).

Placental transfer of larger proteins is limited, but there are exceptions. IgG crosses the placenta in large amounts via endocytosis and trophoblast Fc receptors. IgG transfer depends on maternal levels of total IgG, gestational age, placental integrity, IgG subclass, and antigenic potential (Palmeira, 2012). Conversely, the larger immunoglobulins-IgA and IgM-of maternal origin are efectively excluded from the fetus.

Calcium and phosphorus are actively transported from mother to fetus. Calcium is transferred for fetal skeletal mineralization (Olausson, 2012). A calcium-binding protein is produced in placenta. Parathyroid hormone-related protein (PTH-rP), as the name implies, acts as a surrogate PTH in many systems (Chap. 5, p. 102). PTH is not found in fetal plasma, but PTHrP is present, suggesting that PTH-rP is the fetal parathormone. The expression of PTH-rP in cytotrophoblasts is modulated by the extracellular concentration of Ca2+ (Hellman, 1992). It seems possible, therefore, that PTH-rP synthesized in decidua, placenta, and other fetal tissues is important in fetal Cai+ transfer and homeostasis.

Iodide transport is clearly attributable to a carrier-mediated, energy-requiring active process. And indeed, the placenta concentrates iodide. he concentrations of zinc in the fetal plasma also are greater than those in maternal plasma. Conversely, copper levels in fetal plasma are less than those in maternal plasma. his fact is of particular interest because important copperrequiring enzymes are necessary for fetal development.

Placental Sequestration of Heavy Metals he heavy metal-binding protein metallothionein-1 is expressed in human syncytiotrophoblast. his protein binds and sequesters a host of heavy metals, including zinc, copper, lead, and cadmium. Despite this, fetal exposure is variable (Caserta, 2013). For example, lead enters the fetal environment at a level 90 percent of maternal concentrations. In contrast, placental transfer of cadmium is limited (Kopp, 2012). he most common source of environmental cadmium is cigarette smoke.

Metallothionein also binds and sequesters copper (Cu2+) in placental tissue. This accounts for the low levels of Cu2+ in cord blood (Iyengar, 2001). It is possible that cadmium provokes metallothionein synthesis in the amnion. his may cause Cu2+ sequestration, a pseudo-copper deficiency, and in turn, diminished tensile strength of the amnion.

he concentration of vitamin A (retinol) is greater in fetal than in maternal plasma and is bound to retinol-binding protein and to prealbumin. Retinol-binding protein is transferred from the maternal compartment across the syncytiotrophoblast. The transport of vitamin C-ascorbic acid-from mother to fetus is accomplished by an energy-dependent, carrier-mediated process. Levels of principal vitamin D metabolites, including 1,25-dihydroxycholecalciferol, are greater in maternal plasma than in fetal plasma. The 1 3-hydroxylation of 25-hydroxyvitamin D3 is known to take place in placenta and in decidua.

The placenta is the organ of transfer between mother and fetus.

Within this maternal-fetal interface, oxygen and nutrients transfer from the mother to the fetus, whereas CO2 and meta bolic wastes are directed from fetus to mother. Fetal blood, which is contained in the fetal capillaries of the chorionic villi, has no direct contact with maternal blood, which remains in the intervillous space. Instead, bidirectional transfer depends on processes that allow or aid the transport through the syncy tiotrophoblast that lines chorionic villi.

Over the past few years, it has become apparent that breaks in the chorionic villi permit escape of fetal cells and other bloodborne material into the maternal circulation. This leakage is the mechanism by which some D-negative women become sensitized by the erythrocytes of their D-positive fetus (Chap. 15, p. 301). In fact, after 10 weeks, 10 to 15 percent of cell-free DNA (cDNA) in maternal plasma is placental in origin, that is, trophoblastic DNA (Norton, 2012). he escape of fetal cells can also lead to fetal microchimerism from entrance of allogeneic fetal cells, including trophoblast, into maternal blood and other organs (Rijnik, 2015). Volumes are estimated to range from 1 to 6 cells/ mL at midpregnancy. Some fetal cells become "immortal" in that they persist in the maternal circulation and organs following pregnancy. As discussed in Chapter 59 (p. 1139), the clinical corollary is that some maternal autoimmune diseases may be provoked by such microchimerism.

• The Intervillous Space vIaternal blood within the intervillous space is the primary source of maternal-fetal transfer. Blood from the maternal spiral arteries directly bathes the trophoblast layer that surrounds the villi. Substances transferred from mother to fetus irst enter the intervillous space and are then transported to the syncytiotrophoblast. As such, the chorionic villi and intervillous space function together as the fetal lung, gastrointestinal tract, and kidney.

Circulation within the intervillous space is described in Chapter 5 (p. 94). Intervillous and uteroplacental blood flow increases throughout the irst trimester of normal pregnancies (Merce, 2009). At term, the residual volume of the intervillous space approximates 140 mL. Moreover, utero placental blood flow near term is estimated to be 700 to 900 mLl min, and most of this blood apparently goes to the intervillous space (Pates, 2010).

Active labor contractions reduce blood low into the intervillous space to a degree that depends on contraction intensity. Blood pressure within the intervillous space is significantly less than uterine arterial pressure, but somewhat greater than venous pressure. he latter, in turn, varies depending on several factors, including maternal position (Nelson, 2015). When supine, for example, pressure in the lower part of the inferior vena cava is elevated, and consequently, pressure in the uterine and ovarian veins, and in turn in the intervillous space, is increased.

Substances that pass from maternal to fetal blood must irst traverse the syncytiotrophoblast, the attenuated cytotrophoblast layer, the villous stroma, and inally, the fetal capillary wall. Although this histological barrier separates maternal and fetal circulations, it is not a simple physical barrier. First, throughout pregnancy, syncytiotrophoblast actively or passively permits, facilitates, and adjusts the amount and rate of substance transfer to the fetus. The maternal-facing syncytiotrophoblast surface is characterized by a complex microvillous structure. he fetal-facing basal cell membrane is the site of transfer to the intravillous space. Finally, the villous capillaries are an additional site for transport from the intravillous space into fetal blood, or vice versa. In determining the efectiveness of the human placenta as an organ of transfer, several variables are important and shown in Table

Zhao and coworkers (2014) have provided a review of the pharmacology of these interactions.

Mechanisms of Transfer

Most substances with a molecular mass <500 Da pass readily through placental tissue by simple difusion. These include

TABLE 7-1. Variables of Maternal-Fetal Substance binding of the substance

Maternal blood flow rate through the intervillous space Trophoblast surface area size available for exchange Physical trophoblast properties to permit simple difusion Trophoblast biochemical machinery for active transport Substance metabolism by the placenta during transfer Fetal intervillous capillary surface area size for exchange Fetal blood concentration of the substance

Specific binding or carrier proteins in the fetal or maternal ci rcu lation oxygen, CO2, water, most electrolytes, and anesthetic gases (Carter, 2009). Some low-molecular-weight compounds undergo transfer facilitated by syncytiotrophoblast. These are usually those that have low concentrations in maternal plasma but are essential for normal fetal development.

Insulin, steroid hormones, and thyroid hormones cross the placenta, but very slowly. he hormones synthesized in situ in the syncytiotrophoblast enter both the maternal and fetal circulations, but not equally (Chap. 5, p. 98). Examples are hCG and hPL concentrations, which are much lower in fetal plasma than in maternal plasma. High-molecularweight substances usually do not traverse the placenta, but there are important exceptions. One is immunoglobulin G-molecular weight 160,000 Da-which is transferred by way of a speciic trophoblast receptor-mediated mechanism (Stach, 2014).

Transfer of Oxygen and Carbon Dioxide

Placental oxygen transfer is blood flow limited. Using estimated uteroplacental blood low, Longo (1991) calculated oxygen delivery to be approximately 8 mL 02/min/kg of fetal weight. Normal values for oxygen and CO2 are presented in Figure 7-13. Because of the continuous passage of oxygen from maternal blood in the intervillous space to the fetus, its oxygen saturation resembles that in maternal capillaries. The average oxygen saturation of intervillous blood is estimated to be 65 to 75 percent, with a partial pressure (P02) of 30 to 35 mm Hg.

;: 50 .N 30 . 2010 n = 58 1 mm Hg approx. = 0.•133 kPa

FIGURE 7-13 Umbilical venous cordocentesis samples obtained in fetuses being evaluated for possible intrauterine infections or hemolysis, but who were found to be healthy. A. Oxygen pressure (PoJ B. Carbon dioxide pressure (Pco2). Shaded areas represent 5th to 95th percentiles. (Modified from Ramsey, MM: Normal Values in Pregnancy. Ramsay MM, James OK, Steer PJ, et al (eds). London, Elsevier, 1996, p 106.)

The oxygen saturation of umbilical vein blood is similar but has a somewhat lower oxygen partial pressure. Fetal hemoglobin has a higher oxygen ainity than adult hemoglobin. This is illustrated by the oxyhemoglobin disassociation curve, which is described in Chapter 47 (p. 920).

he placenta is highly permeable to CO2, which traverses the chorionic villus by diusion more rapidly than oxygen. Near term, the partial pressure of carbon dioxide (PC02) in the umbilical arteries averages 50 mm Hg, which is approximately 5 mm Hg higher than in the maternal intervillous blood. Fetal blood has less ainity for CO2 than does maternal blood, thereby favoring CO2 transfer from fetus to mother. Also, mild maternal hyperventilation results in a fall in Pc02ilevels, favoring a transfer of CO2 from the fetal compartment to maternal blood.

Although simple difusion is an important method of placental transfer, the trophoblast and chorionic villus unit demonstrate enormous selectivity in transfer. his results in diferent metabolite concentrations on the two sides of the villus. Importantly, the levels of many substances that are not synthesized by the fetus are several times higher in fetal than in maternal blood. Ascorbic acid is one example. his relatively low-molecularweight substance might be expected to traverse the placenta by simple difusion. he concentration of ascorbic acid, however, is two to four times higher in fetal plasma than in maternal plasma (Morriss, 1994). Another example is the unidirectional transfer of iron. Typically, maternal plasma iron concentration is much lower than that in her fetus. Even with severe maternal iron-deficiency anemia, the fetal hemoglobin mass is normal.

Abduljabbar MS, ii M: Congenital hypothyroidism. ] Pediatr Endocrinol Metab 25(102)13, 2012

Acosta 0, Ramirez I, Lager S, et al: Increased glucose and placental GLUT-1 in large infants of obese nondiabetic mothers. Am ] Obstet Gynecol 212(2):227.e1,s2015

Adam PA, Teramo K, Raiha N, et al: Human fetal insulin metabolism early in gestation: response to acute elevation of the fetal glucose concentration and placental transfer of human insulin-I-13l. Diabetes 18:409,s1969

Adinoli M: Human complement: onset and site of synthesis during fetal life.

Am] Dis Child 131:1015,s1977

American College of Obstetricians and Gynecologists: CytOmegalovirus, parvovirus B 19, varicella zoster, and tOxoplasmosis in pregnancy. Practice Bulletin No. 151,] une 2015, Reairmed 2017

American College of Obstetricians and Gynecologists: ACOG reinvents the pregnancy wheel. 2016. Available at: http://www.acog.org/About-ACOG/ N ews-Room/N ews-Releasesl20 161 ACOG-Reinven ts-the-PregnancyWheel. Accessed April 8, 2016

Anderson RH, Brown NA, Mohun T]: Insights regarding the normal and abnormal formation of the atrial and ventricular septal structures. Clin Anat 29(3):290,s2016

Ballabio M, Nicolini U, Jowett T, et al: Maturation of thyroid function in normal human foetuses. Clin Endocrinol 31 :565, 1989

Bancalari E, Gregory LC, McCabe M], et al: Pituitary gland development: an update. Endocr Dev 23:1,s2012

Baron MH, Isern ], Fraser ST: The embryonic origins of erythropoiesis in mammals. Blood 119(21):4828,s2012

Bashore A, Smith F, Schenker S: Placental transfer and disposition of bilirubin in the pregnant monkey. Am] Obstet Gynecols103:950, 1969

Bernal ]: hyroid hormone receptors in brain development and function. Nat Clin Pract Endocrinol Metab 3:249, 2007

Boyle ]T: Motility of the upper gastrointestinal tract in the fetus and neonate.

In Polin A, Fox WW (eds): Fetal and Neonatal Physiology. Philadelphia, Saunders, 1992, p 1028

Bozzetti P, Ferrari MM, Marconi M, et al: The relationship of maternal and fetal glucose concentrations in the human from midgestation until term. Metabolism 37:358, 1988

Brifa ]F, McAinch AG, Romano T, et al: Leptin in pregnancy and development: a contributOr to adulthood disease? Am ] Physiol Endocrinol Metab 308:E335,s2015

Browning A]F, Butt WR, Lynch SS, et al: Maternal plasma concentrations of 3-lipotropin, 3-endorphin and �-lipotropin throughout pregnancy. B]OG 90: 1147, 1983

Candilira V, Bouche C, Schleef K, et al: Lung growth factOrs in the amniotic luid of normal pregnancies and with congenital diaphragmatic hernia. ] Matern Fetal Neonatal Med 3:1, 2015

Carter M: Evolution of factors afecting placental oxygen transfer. Placenta 30(Suppl A):19, 2009

Caserta 0, Graziano A, Lo Monte G, et al: Heavy metals and placental fetalmaternal barrier: a mini-review on the major concerns. Eur Rev Med Phar macol Sci 17(16):198,s2013

Chard T, Hudson CN, Edwards CR, et al: Release of oxytocin and vasopressin by the human foetus during labour. Narure 234:352, 1971

Chez A, Mintz DH, Reynolds WA, et al: Maternal-fetal plasma glucose relationships in late monkey pregnancy. Am ] Obstet Gynecol 121 :938, 1975

Christensen RD, Henry E, Antonio DV: hrombocytOsis and thrombocytOpenia in the NICU: incidence, mechanisms and treatments. ] Matern Fetal Neonat Med 25(54):15, 2012

Corrigans]] ]r: Normal hemostasis in the fetus and newborn: Coagulation. In Polin A, Fox WW (eds): Fetal and Neonatal Physiology. Philadelphia, Saunders, 1992, p 1368

Davis MM, Hodes ME, Munsick A, et al: Pancreatic amylase expression in human pancreatic development. Hybridoma 5:137, 1986

Dawes GS: The umbilical circulation. Am] Obstet Gynecol 84: 1634, 1962 de Moraes DC, Vaisman M, Conceidio FL, et al: Pituitary development: a complex, temporal regulated process dependent on speciic transcriptional factors.s] EndocrinoIs215(2):239, 2012 deVane GW, Naden RP, Porter ]C, et al: Mechanism of arginine vasopressin release in the sheep fetus. Pediatr Res 16:504, 1982

DiPietro ]A: Neurobehavioral assessment before birth. MRDD Res Rev 11 :4, 2005

Donnelley MA, Wood C, Casey B, et al: Early severe fetal Graves disease in a mother after thyroid ablation and thyroidectomy. Obstet Gynecol 125(5):1059,s2015

Dube E, Gravel A, Martin C, et al: Modulation of fatty acid transport and metabolism by maternal obesity in the human full-term placenta. BioI Reprod 87(1):14, 2012

Dubois ], Dehaene-Lambertz G, Kulilova S, et al: he early development of brain white matter: a review of imaging studies in fetuses, newborns and infants. Neuroscience 12:276,s2014

Duryea EL, Hawkins ]S, McIntire DO, et al: A revised birth weight reference for the United States. Obstet GynecoIs124(1):16, 2014

Duryea EL, McIntire DO, Leveno K]: The rate of preterm birth in the United States is afected by the method of gestational age assignment. Am ] Obstet GynecoIs213:331.e1,2015

Epstein M, Chez A, Oakes GK, et al: Fetal pancreatic glucagon responses in glucose-intOlerant nonhuman primate pregnancy. Ams] Obstet Gynecol 127:268, 1977

Fanos V, Loddo C, Puddu M, et al: From ureteric bud to the irst glomeruli: genes, mediators, kidney alterations. Int U rol Nephrol 47(1): 109, 20s15

Fasshauer M, Bliiher M, Stumvoll M: Adipolines in gestational diabetes. Lancet Diabetes EndocrinoIs2(6):488, 2014

Fineman ]R, Clyman R: Fetal cardiovascular physiology. In Resnik R, Creasy RK, lams ]0, et al (eds): Creasy and Resnik's Maternal-Fetal Medicine:

Principles and Practice, 7th ed. Philadelphia, Saunders, 2014, p 147 Forhead A], Fowden L: Thyroid hormones in fetal growth and prepartum maturation.s] EndocrinoIs221(3):R87, 2014

Fowden AL, Ward ]W, Wooding FP, et al: Programming placental nutrient transport capacity. ] Physiol 572(1):5, 2006

Frolova AI, Moley KH: Quantitative analysis of glucose transporter mNAs in endometrial stromal cells reveals critical role of GLUT1 in uterine receptivity. Endocrinology 152(5):2123, 2011

Fryer A, Jones P, Strange R, et al: Plasma protein levels in normal human fetuses: 13-41 weeks' gestation. B]OG 100:850, 1993

Gao L, Lv C, Xu C, et al: Diferential regulation of glucose transporters mediated by CRH receptor type 1 and type 2 in human placental trophoblasts. Endocrinology 153:1464,s2012

Gil-Sanchez A, Koletzko B, Larque E: Current understanding of placental fatty acid transport. Curr Opin Clin Nutr Metab Care 15(3):265,s2012

Gitlin D: Development and metabolism of the immune globulins. In Kaga BM, Stiehm ER (eds): Immunologic Incompetence. Chicago, Year Book, 1971

Gitlin D: Protein transport across the placenta and protein turnover between amnionic fluid, maternal and fetal circulation. In Moghissi KS, Hafez ESE (eds): he Placenta. Springfield, Thomas, 19

Giudice LC, de-Zegher F, Gargosky SE, et al: Insulin-like growth factors and their binding proteins in the term and preterm human fetus and neonate with normal and extremes of intrauterine growth. J Clin Endocrinol Metab 80:1548, 1995

Gluck L, Kulovich MV, Eidelman AI, et a1: Biochemical development of surface activity in mammalian lung. 4. Pulmonary lecithin synthesis in the human fetus and newborn and etiology of [he respiratory distress syndrome. Pediatr Res 6:81, 1972

Goetzl L, Darbinian N, Goetzl EJ: Probing early human neural development through fetal exosomes in maternal blood. Abstract No. Ill. Am J Obstet 7,s2016

Golub R, Cumano A: Embryonic hematopoiesis. Blood Cells Mol Dis 51(4):226,s2013

Granado M, Fuente-Martin E, Garcia-Caceres C, et al: Leptin in early life: a key factor for the development of the adult metabolic proile. Obes Facts 5(1):138,s2012

Gtuenwald P: Growth of the human foetus. In McLaren A (ed): Advances in Reproductive Physiology. New York, Academic Press, 1967

Grumbach MM, Kaplan SL: Fetal pituitary hormones and the maturation of central nervous system regulation of anterior pituitary function. In Gluck L (ed): Modern Perinatal Medicine. Chicago, Year Book, 1974

Hadlock FP, Harrist RB, Martinez-Poyer J: In urero analysis of fetal growth: a sonographic weight standard. Radiology 181(1):129,s1991

Hallman M: The surfactant system protects both fetus and newborn. Neonatology 103(4):320,s2013

Hallman M, Kulovich MV, Kirkpatrick E, et al: Phosphatidylinositol and phosphatidylglycerol in amniotic luid: indices of lung maturity. Am J Obstet Gynecol 125:613, 1976

Hart PH, Lucas RM, Walsh JP, et al: Vitamin D in fetal development: indings from a birth cohort study. Pediatrics 135(1):eI67, 2015

Hauguel-de Mouzon S, Lepercq J, Catalano P: The known and unknown of leptin in pregnancy. Am J Obstet GynecoIs193(6):1537, 2006

Hayward AR: The human fetus and newborn: development of the immune response. Birth Defects 19:289, 1983

Heimark R, Schwartz S: Cellular organization of blood vessels in development and disease. In Ryan U (ed): Endothelial Cells, Vol II. Boca Raton, CRC Press, 1988, p 103

Heinig K, Sage F, Robin C, et al: Development and traicking function ofhaematopoietic stem cells and myeloid cells during fetal ontogeny. Cardiovasc Res 10 (3):352,s2015

Hellman P, Ridefelt P, Juhlin C, et al: Parathyroid-like regulation of parathyroid hormone related protein release and cytoplasmic calcium in cytotrophoblast cells of human placenta. Arch Biochem Biophys 293: 1 4, 1992

Henriksson P, Hedner V, Nilsson 1M, et al: Fibrin-stabilization factor XIII in the fetus and the newborn infant. Pediatr Res 8:789, 1974

Hillman NH, Kallapur SG, Jobe AH: Physiology of transition from intrauterine to extrauterine life. Clin PerinatoI39(4):769, 2012

Ignjatovic V, I1han A, Monagle P: Evidence for age-related diferences in human ibrinogen. Blood Coagul Fibrinolysis 22(2): 11 0, 2011

Iruretagoyena JL, Davis W, Bird C, et a1: Diferential changes in gene expression in human brain during late irst trimester and early second trimester of pregnancy. Prenat Diagn 34(5) :431, 2014

Ishimoto H, Jafe RB: Development and function of the human fetal adrenal cortex: a key component in the feto-placental unit. Endocr Rev 32(3):317, 2011

Iyengar GV, Rapp A: Human placenta as a "dual" biomarker for monitoring fetal and maternal environment with special reference to potentially toxic trace elements. Part 3: Toxic trace elements in placenta and placenta as a biomarker for these elements. Sci Total Environ 280:221, 2001

Jansson T, Aye IL, Goberdhan DC: The emerging role of mTORCl signaling in placental nutrient-sensing. Placenta 33(Suppl 2):e23, 2012

Jansson T, Cetin I, Powell TL, et al: Placental transport and metabolism in fetal overgrowth-a workshop report. Placenta 27:109, 2006a

Jansson T, Powell TL: Human placental transport in altered fetal growth: does the placenta function as a nutrient sensor? A review. Placenta 27:S91, 2006b

Janzen C, Lei MY, Cho J, et a1: Placental glucose transporter 3(GLUT3) is up-regulated in human pregnancies complicated by late-onset intrauterine growth restriction. Placenta 34(11): 2, 2013

Jennings E, Berry A, Strutt JP, et al: Human pancreas development 142(18):3126,s2015

Kadic AS, Predojevic M: Fetal neurophysiology according to gestational age.

Semin Fetal Neonatal Med 17(5):256, 2012

Keller BB, Hoying JB, Markwald RR: Molecular development of the heart. In Fuster V, Walsh A, Harrington A, et al (eds): Hurst's he Heart, 13th ed. New York, McGraw-Hill, 2013, p 1

Kim ST, Romero R, Tarca L: Methylome of fetal and maternal monocytes and macro phages at the feto-maternal interface. Am J Reprod Immunol 68(1):8,s2012

Kimura E: Lipid metabolism in the fetal-placental unit. In Cowett RM (ed):

Principles of Perinatal-Neonatal Metabolism. New York, Springer, 1991, p 291

K1agsbrun M: Angiogenesis factors. In Ryan U (ed): Endothelial Cells, Vol II.

Boca Raton, CRC Press, 1988, p 37

Kohler PF: Maturation of the human complement system. J Clin Invest 52:671, 1973

Koldovsky 0, Heringova A, Jirsova U, et a1: Transport of glucose against a concentration gradient in everted sacs of jejunum and ileum of human fetuses. Gastroenterology 48:185, 1965

Koos BJ, Rajaee A: Fetal breathing movements and changes at birth. Adv Exp Med BioI 814:89, 2014

Kopp RS, Kumbarrski M, Harth V, et al: Partition of metals in the maternal/fetal unit and lead-associated decreases of fetal iron and manganese: an observational biomonitoring approach. Arch Toxicol 1,2012

Lebenthal E, Lee PC: Interactions of determinants of the ontogeny of the gastrointestinal tract: a uniied concept. Pediatr Res 1: 19, 1983

Leonce J, Brockton N, Robinson S, et a1: Glucose production in the human placenta. Placenta :S103, 2006

Liggins GC: Fetal lung maturation. Aust N Z J Obstet Gynaecol 34:247, 1994 Liggins GC: Premature delivery of fetal lambs infused with glucocorticoids. J EndocrinoIs45:515,s1%9

Liley AW: Disorders of amniotic fluid. In Assali NS (ed): Pathophysiology of Gestation. New York, Academic Press, 1972

Longo LD: Respiration in the fetal-placental unit. In Cowett RM (ed): Principles of Perinatal-Neonatal Metabolism. New York, Springer, 1991, P 304

Luo ZC, Nuyt AM, Delvin E, et al: Maternal and fetal IGF-I and IGF-II levels, fetal growth, and gestational diabetes. J Clin Endocrinol Metab 97(5): 1720, 2012

Lykkedegn S, Sorensen GL, Beck-Nielsen SS, et al: he impact of vitamin D on fetal and neonatal lung maturation. A systematic review. Am J Physiol Lung Cell Mol Physiol 308(7):L587, 2015

Mally MI, Otonkoski T, Lopez AD, et al: Developmental gene expression in the human fetal pancreas. Pediatr Res 36:537, 1994

Manganaro L, Perrone A, Savelli S, et al: Evaluation of normal brain development by prenatal MR imaging. Radiol Med 112:444, 2007

Manner J: he anatomy of cardiac looping: a step towards the understanding of the morphogenesis of several forms of congenital cardiac malformations. Clin nat 22(1):21,s2009

Mari G, Deter L, Carpenter L, et al: Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell a1loimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses (Level II-I). N Engl J Med 342:9, 2000

Maymo JL, Perez Perez A, Sanchez-Margalet V, et al: Up-regulation of placental leptin by human chorionic gonadotropin. Endocrinology 150(1):304, 2009

McCormick SM, Mendelson CR: Human SP-Al and SP-A2 genes are differentially regulated during development and by cAMP and glucocorticoids. Am J Physiol 266:367, 1994

Melchers F: Checkpoints that control B cell development. J Clin Invest 125(6):2203,s2015

Mendelson CR, Condon JC: New insights into the molecular endocrinology of parturition. J Steroid Biochem Mol BioI 93: 113, 2005

Meng H, Zhang Z, Geng H, et a1: Development of the subcortical brain structures in the second trimester: assessment with 7.0-T MRI. Neuroradiology 54(10):1153,s2012

Merce LT, Barco MJ, Alcazar JL, et al: Intervillous and utero placental circulation in normal early pregnancy and early pregnancy loss assessed by 3-dimensional power Doppler angiography. Am J Obstet Gynecol 200(3):315.el,s2009

Mohun TJ, Weninger WJ: Imaging heart development using high resolution episcopic microscopy. Curr Opin Genet Dev 21(5):573,s2011

Moore L: he Developing Human: Clinically Oriented Embryology, 4th ed.

Philadelphia, Saunders, 1988

Moore L, Persaud N, Shiota K: Color Atlas of Clinical Embryology, 2nd ed. Philadelphia, Saunders, 2000, p 150

Morioka I, Iwatani S, Koda T, et al: Disorders of bilirubin binding to albumin and bilirubin-induced neurologic dysfunction. Semin Fetal Neonatal Med 20(1):31,s2015

Morriss FH ]r, Boyd RD, Manhendren 0: Placental transport. In Knobil E, Neills] (eds): The Physiology of Reproduction, Vol II. New York, Raven, 1994, p 813

Mulchahey JJ, DiBlasio AM, Martin MC, et al: Hormone production and peptide regulation of the human fetal pituitary gland. Endocr Rev 8:406, 1987

M.iller Brochut AC, homann 0, Kluwe W, et al: Fetal megacystis: experience of a single tertiary center in Switzerland over 20 years. Fetal Diagn Ther 36(3):215,s2014

Muzzio 0, Zenclussen AC, Jensen F: The role ofB cells in pregnancy: the good and the bad. Am] Reprod Immunol 69(4):408, 2013

Nederlof M, de Walle HE, van Poppel MN, et a1: Deviant early pregnancy matenal triglyceride levels and increased risk of congenital anomalies: a prospective community-based cohon study. B]OG 122:1176,s2015

Nelson DB, Stewart RD, Matulevicius SA, et al: The efects of matenal position and habitus on maternal cardiovascular parameters as measured by cardiac magnetic resonance. Ams] PerinatoIs32(14):1318, 2015

Ney]A, Fee Sc, Dooley SL, et al: Factors inluencing hemostasis after umbilical vein puncture in vitro. Am] Obstet Gynecol 160:424, 1989

Nielsen NC: Coagulation and ibrinolysin in normal women immediately postpartum and in newborn infants. Acta Obstet Gynecol Scand 48:371, 1969 Norton ME, ]acobsson B, Swamy GK, et al: Cell-free DNA analysis for nonin vasive examination of trisomy. N Engl] Med 2(17):1589,2015

Novakovic B, Gordon L, Robinson WP, et a1: Glucose as a fetal nutrient: dynamic regulation of several glucose transporter genes by DNA methylation in the human placenta across gestation.] Nutr Biochem 24(1):282, 2013

Obenshain SS, Adam PAl, King KC, et al: Human fetal insulin response to sustained maternal hyperglycemia. N Engls] Med 283:566, 1970 Olausson H, Goldberg GR, Laskey A, et al: Calcium economy in human pregnancy and lactation. Nutr Res Rev 25(1):40,2012

Palmeira P, Quinello C, Silveira-Lessa AL, et al: IgG placental transfer in health and pathological pregnancies. C1in Dev Immunol 2012:985646, 2012

Pataryas HA, Stamatoyannopoulos G: Hemoglobins in human fetuses: evidel1Ce for adult hemoglobin production after the 11 th gestational week. Blood 39:688, 1972

Pates ]A, Hatab MR, McIntire DO, et al: Determining uterine blood low in pregnancy with magnetic resonance imaging. Magn Reson Imaging 28(4):507,s2010

Pearson HA: Recent advances in hematology. ] Pediatr 69:466, 1966

Pelag 0, Cada S, Peleg A, et al: he relationship berween matenal serum thyroid-stimulating immunoglobulin and fetal and neonatal thyrotoxicosis. Obstet Gynecol 99: 1040, 2002

Perrine SP, Greene MF, Cohen A, et al: A physiological delay in human fetal hemoglobin switching is associated with speciic globin DNA hypo methylation. FEBS Lett 228: 139, 1988

Pipe NG], Smith T, Halliday 0, et al: Changes in fat, fat-free mass and body water in human normal pregnancy. B]OG 86:929, 1979

Pritchard ]A: Fetal swallowing and amniotic fluid volume. Obstet Gynecol 28:606, 1966 Quan CP, Forestier F, Bouvet ]P: Immunoglobulins of the human amniotic luid. Am] Reprod Immunol 42:219, 1999

Ramsay MM, James OK, Steer P], et al (eds): Normal Values in Pregnancy.

London, Elsevier, 1996, p 106

Reddy UM, Abuhamad AZ, Levine 0, et al: Fetal imaging: executive summary of a joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Institute of Ultrasound in Medicine, American College of Obstetricians and Gynecologists, American College of Radiology, Society for Pediatric Radiology, and Society of Radiologists in Ultrasound Fetal Imaging workshop. Obstet GynecoIs123(5):1070, 2014

Rijnink EC, Penning ME, Wolterbeek R, et al: Tissue microchimerism is increased during pregnancy: a human autopsy study. Mol Hum Reprod Aug 24,s2015

Roberts VH], Frias AE, Grove KL: Impact of maternal obesity on fetal programming of cardiovascular disease. Physiology 30:224, 2015

Rosenfeld CR, Poner JC: Arginine vasopressin in the developing fetus. In Albrecht ED, Pepe GJ (eds): Research in Perinatal Medicine, Vol 4. Perinatal Endocrinology. Ithaca, Perinatology Press, 1985, p 91

Rovet JF: The role of thyroid hormones for brain development and cognitive function. Endocr Dev 26:26, 2014

Rysavy MA, Li L, Bell EF, et al: Berween-hospital variation in treatment and outcomes in extremely preterm infants. N Engl J Med 372(19):1801,s2015

Saracco P, Parodi E, Fabris C, et al: Management and investigation of neonatal thromboembolic events: genetic and acquired risk factors. Thromb Res 123(6):805,s2009

Scott-Finley M, Woo JG, Habli M, et a1: Standardization of amniotic luid leptin levels and utility in matenal overweight and fetal undergrowth.J Perinatol ,2015

Singendonk MM, Rommel N, Omari TI, et al: Upper gastrointestinal motility: prenatal development and problems in infancy. Nat Rev Gastroenterol Hepatol 11(9):545,s2014

Sipes SL, Weiner CP, Wenstrom KD, et al: The association between fetal karyotype and mean corpuscular volume. Am] Obstet Gynecol 165:1371, 1991

Smith FG, Nakamura KT, Segar JL, et al: In Polin A, Fox W (eds): Fetal and Neonatal Physiology, Vol 2, Chap 114. Philadelphia, Saunders, 1992, p 1187

Society for Matenal-Fetal Medicine, Mari G, Norton ME, et al: Society for Matenal-Fetal Medicine (SMFM) Clinical Guidelines #8: the fetus at risk for anemia-diagnosis and management. Am] Obstet Gynecol 212(6):697, 2015

Stabile I, Nicolaides KH, Bach A, et al: Complement factors in fetal and maternal blood and amniotic luid during the second trimester of normal pregnancy. BJOG 95:281, 1988

Stach Sc, Brizot Mde L, Liao AW, et al: Transplacental total IgG transfer in rwin pregnancies. Am J Reprod Immunol 72(6):555, 2014

Stockman JA III, deAlarcon PA: Hematopoiesis and granulopoiesis. In Polin A, Fox WW (eds): Fetal and Neonatal Physiology. Philadelphia, Saunders, 1992, p 1327

Sussman 0, Lye S], Wells GO: Impact of matenal physical activity on fetal breathing and body movement-a review. Early Hum Dev 94:53, 2016

Temiras PS, Vernadakis A, Sherwood NM: Development and plasticiry of the nervous system. In AssaJi NS (ed): Biology of Gestation, Vol VII. he Fetus and Neonate .. New York, Academic Press, 1968

Thorpe-Beeston JG, Nicolaides KH, Felton CV, et al: Maturation of the secretion of thyroid hormone and thyroid-stimulating hormone in the fetus. N Engl J Med 324:532,s1991

Usher R, Shephard M, Lind ]: he blood volume of the newbon infant and placental transfusion. Acta Paediatr 52:497, 1963 Volpe JJ: Neurology of the Newborn, 5th ed. Saunders, Philadelphia, 2008, p 85

Vulsma T, Gons MH, De Vijlder JJ: Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organi6cation defect or thyroid agenesis. N Engl] Med 321:13, 1989

Weiner CP, Sipes SL, Wenstrom K: The efect of fetal age upon normal fetal laboratory values and venous pressure. Obstet Gynecol 79:713, 1992 Wenstrom KO, Weiner CP, Williamson A, et al: Prenatal diagnosis of fetal hyperthyroidism using funipuncture. Obstet Gynecol 76:513, 1990 Werlin SL: Exocrine pancreas. In Polin A, Fox WW (eds): Fetal and Neonatal Physiology. Philadelphia, Saunders, 1992, p 1047

Werth B, Tsiaras A: From Conception to Birth: A Life Unfolds. New York, Doubleday, 2002

Whitsett JA: Composition of pulmonary surfactant lipids and proteins. In Polin A, Fox W (eds): Fetal and Neonatal Physiology. Philadelphia, Saunders, 1992, p 941

Wladimirof ]W, Campbell S: Fetal urine-production rates in normal and complicated pregnancy. Lancet 1:151, 1974

Zhao Y, Hebert MF, Venkataramanan R: Basic obstetric pharmacology. Semin 5,s2014

COUNSELING SESSION . . . . . . . . . . . . . . . . . . . . . . . . .. 147

MEDICAL HISTORY. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 147

GENETIC DISEASES ............................. 149

REPRODUCTIVE HISTORY ........................ 151

PARENTAL AGE ................................ 151

SOCIAL HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 SCREENING TESTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 153

Pregnancy may be associated with certain diseases that existed bore the inception of pregnancy. As a rule, all diseases which subject the organism to a considerable strain are much more serious when occurring in a pregnant woman.

-J. Whitridge Williams (1903) he Centers for Disease Control and Prevention (CDC) (2015) defines preconceptional care as "a set of interventions that aim to identiy and modiy biomedical, behavioral, and social risks to a woman's health or pregnancy outcome through prevention and management." To achieve this goal, the CDC has developed an action plan for preconceptional health care in the United States Qohnson, 2006). The American College of Obstetricians and Gynecologists (2017 e) and the Society for Maternal-Fetali1vIedicine (2014) also reairm the importance of preconceptional care, and the following objectives have been established for advancing it: 1. Improve knowledge, attitudes, and behaviors of men and women related to preconceptional health 2.

Assure that all childbearing-aged women receive preconceptional care services-including evidence-based risk screening, health promotion, and interventions-that will enable them to enter pregnancy in optimal health 3.

Reduce risks indicated by a previous adverse pregnancy outcome through interconceptional interventions to prevent or minimize recurrent adverse outcomes 4.

Reduce the disparities in adverse pregnancy outcomes

To illustrate potentilly modifiable conditions, data that describe the health status of women who delivered liveborn neonates in the United States in 2004 are reviewed. Table 8-1 demonstrates the high prevalence of many conditions that may be amenable to intervention during the preconceptional and interpregnancy periods. To be successul, however, strategies that mitigate these potential pregnancy risks must be provided before conception. By the time most women realize they are pregnantusually 1 to 2 weeks ater the first missed period-the embryo has already begun to form. hus, many preventive steps-for example, folic acid to avoid neural-tube defects-will be inefective if initiated at this time. Importantly, up to half of all pregnancies in the United States in 2008 were unplanned according to the Guttmacher Institute (2015), and oten these are at greatest risk.

Few randomized trials evaluate preconceptional counseling eicacy, in part because withholding such counseling would be unethical. Also, pregnancy outcomes are dependent on the interaction of various maternal, fetal, and environmental factors. hus, ascribing a salutary outcome to a specific intervention is diicult (Moos, 2004; Temel, 2014). However, prospective observational and case-control studies have demonstrated the successes of preconceptional counseling (American College of Obstetrics and Gynecologists, 2016b). \100s and coworkers (1996) assessed the efectiveness of a preconceptional counseling program administered during routine health care provision to reduce unintended pregnancies. he 456 counseled women had a 50-percent greater likelihood of subsequent pregnancies that they considered "intended" compared with 309 uncounseled

TABLE 8-1. Prevalence of Prepregnancy Maternal Behaviors, Experiences, Health Conditions, and Previous Poor Birth Outcomesa aln the United States in 2004.

bAmong women who were not trying to become pregnant.

Data from D'Angelo D, Williams L, Morrow 8, et al: Precon ception and interconception health status of women who recently gave birth to a live-born infant-Pregnancy Risk

Assessment Monitoring System (PRAMS), United States, 26 reporting areas, 2004. MMWR 56(1l0):1,l2007.

women. Moreover, compared with another group of women who had no health care before pregnancy, the counseled group had a 65-percent higher rate of intended pregnancy. Interesting ethical aspects of paternal lifestyle modification were reviewed by van der Zee and associates (2013).

Gynecologists, internists, family practitioners, and pediatricians have the best opportunity to provide preventive counseling during periodic health maintenance examinations. The occasion of a negative pregnancy test is also an excellent time for education. Jack and colleagues (1995) administered a comprehensive preconceptional risk survey to 136 such women, and almost 95 percent reported at least one problem that could afect a uture pregnancy. These included medical or reproductive problems-52 percent; family history of genetic disease-50 percent; increased risk of human immunodeiciency virus infection-30 percent; increased risk of hepatitis B and illegal substance abuse-25 percent; alcohol use-17 percent; and nutritional risks-54 percent. Counselors should be knowledgeable regarding relevant medical diseases, prior surgery, reproductive disorders, or genetic conditions and must be able to interpret data and recommendations provided by other specialists (Simpson, 2014). If the practitioner is uncomfortable providing guidance, the woman or couple should be referred to an appropriate counselor.

Women presenting specifically for preconceptional evaluation should be advised that information collection may be time consuming, depending on the number and complexity of factors that require assessment. he intake evaluation includes a thorough review of the medical, obstetrical, social, and family histories. Useul information is more likely to be obtained by asking specific questions regarding each of these histories and each family member than by asking general, open-ended questions. Some important information can be obtained by questionnaires that address these topics. Answers are reviewed with the couple to ensure appropriate follow-up, including obtaining relevant medical records.

With specific medical conditions, general points include how pregnancy will afect maternl health and how a high-risk condition might afect the fetus. terward, advice for improving outcome is provided. Some chronic conditions that may ffect pregnancy outcomes include treated or active cancer, prior peripartum cardiomyopathy, and systemic lupus erythematosus (mant, 2015; Buyon, 2015; McNamara, 2015). Importantly, psychological health should be considered (Lassi, 2014). Detailed preconceptional information regarding a few exemplary conditions is found in the next sections and in the other topic-speciic chapters of this text.

Because maternal and fetal pathology associated with hyperglycemia is well known, diabetes is the protoype of a condition for which preconceptional counseling is beneficial. Diabetesassociated risks to both mother and fetus are discussed in detail in Chapter 57 (p. 1099). Many of these complications can be avoided if glucose control is optimized before conception. Another important aspect of counseling pertains to the frequent use of teratogenic angiotensin-converting enzyme inhibitors in this population (Podymow, 2015).

The American College of Obstetricians and Gynecologists (2016a) has concluded that preconceptional counseling for women with pregestational diabetes is both beneicial and costefective and should be encouraged. The American Diabetes Association has promulgated consensus recommendations for preconceptional care for diabetic women (Kitzmiller, 2008). hese guidelines advise obtaining a thorough inventory of disease duration and related complications and completing a clinical and laboratory examination for end-organ damage. Perhaps most essential, they encourage a preconceptional goal of the lowest hemoglobin Ale level possible without undue hypoglycemic risk to the mother. In addition to assessing diabetic control during the preceding 6 weeks, hemoglobin Ale measurement can also be used to estimate risks for major anomalies as shown in Figure lthough these data are from women with severe overt diabetes, the incidence of fetal anomalies in women who have gestational diabetes with fasting hyperglycemia is increased fourfold compared with that in normal women (Sheield, 2002).

Such counseling in diabetic women has been shown to be efective. Leguizam6n and associates (2007) identiied 12 studies that included more than 3200 pregnancies in women with insulin-dependent diabetes. Of the 1618 women without precon o..Ac) 'uE ..

4.6-7.6 7.7-8.6 8.7-9.9 10-10.5 >10.6

FIGURE 8-1 Relationship between first-trimester glycosylated hemoglobin values and risk for major congenital malformations in 320 women with insulin-dependent diabetes. (Data from Kitzmiller JL, Gavin LA, Gin GO, et al: Preconception care of diabetics. JAMA 265:731, 1991.) ceptional counseling, 8.3 percent had a fetus with a major congenital anomaly, and this compared with a rate of 2.7 percent in the 1599 women who did have counseling. Tripathi and coworkers (2010) compared outcomes in 588 women with pregestational diabetes in whom approximately half had preconceptional counseling. hose women who received counseling had improved glycemic control before pregnancy and in the first trimester. his group also had higher folate intake rates preconceptionally, and they experienced lower rates of adverse outcomes-deined as a perinatal death or major congenital anomaly. hese cited beneits are accompanied by reduced helth-care costs in diabetic women. From their review, Reece and Homko (2007) found that each $1 expended for a preconceptional care program saved between $1.86 and $5.19 in averted medical costs. Despite such beneits, the proportion of diabetic women receiving preconceptional care is suboptimal. In their study of approximately 300 diabetic women in a managed-care plan, Kim and colleagues (2005) found that only approximately one half had preconceptional counseling. Counseling rates are undoubtedly much lower among uninsured and indigent women.

Compared with unafected women, those with a seizure disorder carry an undisputed augmented risk of having neonates with structural anomalies (Chap. 12, p. 240). Some early reports indicated that epilepsy conferred an elevated a priori risk for congenital malformations that was independent of anticonvulsant treatment efects. Although more recent publications have largely failed to conirm this increased risk in untreated women, it is diicult to refute entirely because women who are controlled without medication generally have less severe disease (Cassina, 2013; Vajda, 2015). Fried and associates (2004) conducted a metaanalysis of studies comparing epileptic women, both treated and untreated, with controls. In this study, greater malformation rates could only be demonstrated in the ofspring of women who had been exposed to anticonvulsant therapy. Veiby and coworkers (2009) used the Medical Birth Registry of Norway and identiied an increased malformation risk only in women who were exposed to valproic acid (5.6 percent) or poly therapy (6.1 percent). Untreated women had anomaly rates that were similar to those of nonepileptic controls. Risks for miscarriage and stillbirths in exposed epileptic women do not appear elevated (Aghajanian, 2015; Bech, 2014).

Ideally, seizure control is optimized preconceptionlly. For example, Vajda and colleagues (2008) nalyzed data from the Australian Register of Antiepileptic Drugs in Pregnancy. hey found the seizure risk during pregnancy was 50-to 70-percent lower in women without a seizure in the year preceding pregnancy compared with a group experiencing seizures in this preceding year. No urther advantages accrued if the seizure-free period exceeded a year.

Treatment goals attempt to achieve seizure control with monotherapy and with medications considered less teratogenic (Aguglia, 2009; Tomson, 2009). As discussed in detail in Chapter 60 (p. 1159) and shown in Table 8-2, some one-drug regimens are more teratogenic than others. Valproic acid, in particular, is avoided if possible, as this medication has consistently been associated with a greater risk for major congenital malformations than other antiepileptic drugs Qentink, 2010; Vajda, 2015). Trimethadione is contraindicated (Aghajanian, 2015). he American Academy of Neurology recommends consideration of antiseizure medication discontinuation before pregnancy in suitable candidates Qeha, 2005). hese include women who satisy the following criteria: (1) have been seizure-free for 2 to 5 years, (2) display a single seizure type, (3) have a normal neurological examination and normal intelligence, and (4) showeelectroencephalogram results that have normalized with treatment.

Epileptic women should be advised to daily take a 4-mg folic acid supplement. Even so, it is not entirely clear that folate supplementation reduces the fetal malformation risk in pregnant women taking anticonvulsant therapy. In one case-control study, Kjer and associates (2008) reported that the congenital abnormality risk was reduced by maternal folate supplementation in fetuses exposed to carbamazepine, phenobarbitl, phenytoin, and primidone. Conversely, from the United Kingdom Epilepsy and

TABLE 8-2. First-Trimester .ntiepileptic Monotherapy and the Associated Major Malformation Risk

Unexposed controls (442) 1.1 Reference

Lamotrigine (1 562) 2.0 1.8 (0.7-4.6)

Carbamazepine (1 033) 3.0 2.7 (1 .0-7.0)

Phenytoin (4 16) 2.9 2.6 (0.9-7.4)

Levetiracetam (450) 2.4 2.2 (0.8-6.4)

Topiramate (359) 4.2 3.8 (1 .4-10.6)

Valproate (323) 9.3 9.0 (3.4-23.3)

Phenobarbital (1 99) 5.5 5.1 (1 .8-1 4.9) Oxcarbazepine (1 82) 2.2 2.0 (0.5-7.4)

Gabapentin (1 45) 0.6 (0.07-5.2)

Clonazepam (64) 3.1 2.8 (0.5-14.8) aRisk compared with that of the unexposed reference population of nonepileptic women.

n =number of exposed infants.

Data from Hernandez-Oraz 5, Smith CR, Shen A., et al: Comparative safety of antiepileptic drugs during pregnancy. Neurology 78:1692, 2012.

Pregnancy Register, Morrow and coworkers (2009) compared fetal outcomes of women who received preconceptional folic acid with those who did not receive it until later in pregnancy or not at all. In this study, a paradoxical increse in the number of major congenital malformations was observed in the group who received preconceptional folate. hese investigators concluded that folate metabolism may be only a part of the mechanism by which malformations are induced in women taking these medications.

Preconceptional counseling includes assessment of immunity against common pathogens. Also, depending on health status, travel plans, and time of year, other immunizations may be indicated as discussed in Chapter 9 (Table 9-7, p. 172). Vac cines that contain toxoids such as tetanus are suitable before or during gestation. Also, those containing killed bacteria or viruses-such as inluenza, pneumococcus, hepatitis B, menin gococcus, and rabies vaccines-are not associated with adverse fetal outcomes and are not contraindicated preconceptionally or during pregnancy. Conversely, live-virus vaccines are not recommended during pregnancy. Examples are vaccines against varicella-zoster, measles, mumps, rubella, polio, chickenpox, and yellow fever. Moreover, 1 month or longer should ideally pass between vaccination and conception attempts. That said, inadvertent administration of measles, mumps, rubella (MMR) considered indications for pregnancy termination. Most reports indicate that the fetal risk is only theoretical. Immunization to smallpox, anthrax, and other bioterrorism diseases should be discussed if clinically appropriate (Chap. 64, p. 1228).

With some infections, vaccines are unavailable. One recent example is the Zika virus (Brasil, 2016). For this virus, the CDC has issued travel advisories for pregnant women (Petersen, 2016; Schuler-Faccini, 2016).

he CDC (20e16) estimates that 3 percent of neonates born each year in the United States will have at least one birth defect. Importantly, such defects are the leading cause of infant mortality and account for 20 percent of deaths. The benefits of preconceptional counseling usually are measured by comparing the incidence of new cases before and after initiation of a counseling program. Congenital conditions that clearly beneit from patient education include neural-tube defects, phenylketonuria, thalassemias, and other genetic diseases more common in individuals of Eastern European Jewish descent.

Pedigree construction using the symbols shown in Figure 8-2 is the most thorough method for obtaining a family history as a part of genetic screening. he health and reproductive status of each "blood relative" should be individually reviewed for medical illnesses, mental retardation, birth defects, infertility, and pregnancy loss. Certain racial, ethnic, or religious backgrounds may indicate elevated risk for specific recessive disorders.

Although most women can provide some information regarding their history, their understanding may be limited. For example, several studies have shown that pregnant women often fail to report a birth defect in the family or they report it incorrectly. hus, any disclosed defect or genetic disease should be conirmed by reviewing pertinent medical records or by contacting afected relatives for additional information.

he incidence of neural-tube defects (NTDs) is 0.9 per 1000 live births, and they are second only to cardiac anomalies as the most frequent structural fetal malformation (Chap. 13, p. 270). Some NTDs, as well as congenital heart defects, are associated with speciic mutations. One example is the 677C -+=T substitution in the gene that encodes methylene tetrahydrofolate reductase. For this and similar gene defects, the trial conducted by the Medical Research Council Vitamin Study Research Group (1991) showed that preconceptional folic acid therapy significantly reduced the risk for a recurrent NTD by 72 percent. More importantly, because more than 90 percent of neonates with NTDs are born to women at low risk, Czeizel and Dudas (1e992) showed that supplementation reduced the a priori risk of a irst NTD occurrence. It is currently recommended, therefore, that all women who may become pregnant take daily 400 to 800 j1g of folic acid orally before conception and through the irst trimester (U.S Preventive Services Task Force, 2009). Folate fortiication of cereal grains has been mandatory in the United States since 1998, and this practice has also resulted in decreased neural-tube defect rates (Williams, 2015). Despite the demonstrated benefits of folate supplementation, only half of women have taken folic acid supplementation periconceptionally (de Jong-van den Berg, 2005; Goldberg, 2006). The strongest predictor of use appears to be consultation with a health-care provider before conception.

More than 600 mutations have been identified in the phenylalanine hydroxylase gene. The inherited defect in phenylalanine metabolism exempliies diseases in which the fetus may not be at risk to inherit the disorder but may be damaged by maternal disease. Specifically, mothers with phenylketonuria (PKU) who eat an unrestricted diet have abnormally high blood phenylalanine levels. his amino acid readily crosses the placenta and can damage developing fetal organs, especially neural and cardiac tissues (Table 8-3).

TABLE 8-3. Frequency of Complications in the Offspring of Women with Untreated Phenylketonuria

Data from American Academy of Pediatrics: Matenal phenylketonuria, Pediatrics 2008 \ug;122(2):445-449.

No offspring II Proband is II -2

Adopted out of a family

FIGURE 8-2 Symbols used for pedigree construction. (Modified with permission from Thompson MW, Mcinnes RR, Huntington FW (eds):

Number of children of sex indicated

Carrier of X-linked recessive trait

Twins of unknown zygosity

Genetics in Medicine, 5th ed. Philadelphia, Saunders, 1991o.)

With appropriate preconceptional counseling and adherence to a phenylalanine-restricted diet before pregnancy, the incidence of fetal malformations is dramatically reduced (Camp, 2014; Vockley, 2014). Therefore, the phenylalanine concentration is ideally normalized 3 months before conception and then maintained throughout pregnancy (American College of Obstetricians and Gynecologists, 2017b). The target phenylalanine blood concentration is 120 to 360 �mol/L (Camp, 2014).

hese disorders of globin-chain synthesis are the most common single-gene disorders worldwide (Forget, 2013; Vichinsky, 2013). As many as 200 million people carry a gene for one of these hemoglobinopathies, and hundreds of mutations are known to cause thalassemia syndromes (Chap. 56, p. 1084). In endemic areas such as Mediterranean and Southeast Asian countries, counseling and other prevention strategies have reduced the incidence of new cases by up to 80 percent (Cao, 2013).

The American College of Obstetricians and Gynecologists (2015a) recommends that individuals of high-risk ancestry be ofered carrier screening to allow them informed decision making regarding reproduction and prenatal diagnosis. One method of early prenatal diagnosis is preimplantation genetic diagnosis (PGD), which is coupled with assisted reproductive technologies. Described in Chapter 14 (p. 295), PGD is available for patients at risk for certain thalassemia syndromes (Kuliev, 2011).

• Individuals of Eastern European Jewish Descent

Most individuals of Jewish ancestry in North America are descended from Ashkenazi Jewish communities and are at increased risk for having ofspring with one of several autosomal recessive disorders. These include Tay-Sachs disease, Gaucher disease, cystic ibrosis, Canavan disease, familial dysautonomia, mucolipidosis IV, Niemann-Pick disease type A, Fanconi anemia group C, and Bloom syndrome. The American College ofObstetricians and Gynecologists (20 16c, 2017a) recommends preconceptional counseling and screening for these in this population. Carrier frequency and features of these conditions are discussed in Chapter 14 (p. 290).

During preconceptional screening, information is sought regarding infertility; abnormal pregnancy outcomes that may include miscarriage, ectopic pregnancy, and recurrent pregnancy loss; and obstetrical complications such as cesarean delivery, preeclampsia, placental abruption, and preterm delivery (Stubblefield, 2008). As discussed in Chapter 35 (p. 646), details involving a prior stillbirth are especially important. For example, Korteweg and associates (2008) identiied chromosomal abnormalities in 13 percent ofstillborns who underwent karyotyping. Reddy and colleagues (2012) confirmed that chromosomal microarray analysis (CMA) yielded better detection of genetic abnormalities than did standard karyotyping, primarily because nonviable tissue can be used for the analysis. CMA is described and illustrated in Chapter 13 (p. 271). Identiication of a genetic abnormality in a stillborn can help determine the recurrence risk and aid in the preconceptional or prenatal management in subsequent pregnancies.

Women at both ends of the reproductive-age spectrum have unique outcomes to be considered. First, according to the CDC, in 2010,i3.4 percent ofbirths in the United Stateswerein women between the ages of 15 and 19 years (Martin, 2012). These adolescents are at increased risk for anemia, preterm delivery, and preeclampsia compared with women aged 20 to 35 years (Usta, 2008). he incidence of sexually transmitted diseases-common in adolescents-is even higher during pregnancy (Niccolai, 2003). Unfortunately, because most of their pregnancies are unplanned, adolescents rarely seek preconceptional counseling.

Conceptions after age 35 currently comprise approximately 15 percent ofpregnancies in the United Stares (Martin, 2012). By contrast, these older women are more likely to request preconceptional counseling, either because of postponed pregnancy with a desire to optimize outcomes or because of plans to undergo infertility treatment. Some studies-including data from Parland Hospital presented in Figure 8-3 indicate that ater age 35, the risks for obstetrical complications and for perinatal morbidity and mortality rise (Cunningham, 1995; Waldenstrom, 2015). he older woman who has a chronic illness or who is in poor physical condition usually has readily apparent risks. For rhe physicallyfit woman without medical problems, however, the risks are much lower than previously reported.

Overall, the maternal mortality rate is higher in women aged 35 and older. Compared wirh women in rheir 20s, women aged 35 to 39 are 2.5 times more likely and women aged 40 or older are 5.3 times more likely to sufer pregnancy-related mortality (Geller, 2006). Creanga and coworkers (2015) analyzed pregnancy-related deaths in the United States for 2006 through 2010. Although women older than 35 years contributed less than 15 percent of all live births, they constituted 27 percent ofmaternal deaths. For the fetus, maternal age-related risks primarily stem from: (1) indicated preterm delivery for maternal complications such as hypertension and diabetes, (2) spontaneous preterm birth, (3) fetal growth disorders related to chronic maternal disease or multifetal gestation, (4) fetal aneuploidy, and (5) pregnancies resulting from assisted reproductive technology.

Recall that older women have subfertility problems. And although the incidence of dizygotic twinning increases with maternal age, the more important cause of multifetal gestation in older women follows the use ofassisted reproductive technology (ART) and ovulation induction. Indeed, according to the CDC, 30 to 40 percent ofall multifetal gestations in the United States in 2012 were conceived with the use ofART (Sunderan, 2015). Morbidity and mortality with multifetal pregnancies stem from preterm delivery. Other obstetrical morbidities, such as placenta previa, abruption, and preeclampsia, are also risks associated with these conceptions (Lukes, 2017; Qin, 2016).

Finally, experience has accrued that links ART to higher major congenital malformation rates. Davies and colleagues (2012) reported that of 308,974 births in South Australia, 8.3 percent ofneonates conceived byART had major birth defects.

In this analysis, after adjustment for maternal age and other risk factors, intracytoplasmic injection continued to be associated with a signiicantly elevated risk for malformations, but in vitro fertilization did not.

Parental history and experiences-paternal and maternal-can exert efects through epigenomic information not contained in the DNA sequence. Examples include variations in sperm and oocyte cytosine methylation and other mechanisms (Cedars, 2015; Lane, 2014). Perhaps one example is the possible link between increasing paternal age and complex neuropsychiatric conditions (Malaspina, 2015). Finally, the incidence of genetic diseases in ofspring caused by new autosomal-dominant mutations in older men is increased. Still, the incidence is low (Chap. 13, p. 265). Accordingly, targeted sonographic examination performed solely for advanced maternal or paternal age is controversial.

Fetal risks associated with alcohol, marijuana, cocaine, amphetamines, and heroin are discussed in Chapter 12 (p. 239). he first step in preventing drug-related fetal risk is an honest assessment of use by the patient (American College of Obstetricians and Gynecologists, 2017 c) . Toward this end, questioning should be nonjudgmental. Screening for at-risk drinking can be accomplished using several validated tools. One is the wellstudied T ACE questions (American College of Obstetricians and Gynecologists, 2013). This is a series of four questions concerning .olerance to alcohol, being 4nnoyed by comments about their drinking, attempts to fut down, and a history of drinking early in the morning-the fye opener.

In a Canadian study of more than 1000 postpartum patients, Tough and coworkers (2006) found that a high percentage of women reported alcohol use concurrent with conception attempts. Specifically, nearly half of those planning for pregnancy reported a mean of 2.2 drinks daily during early gestation and before they recognized their pregnancy. Of note, Bailey and associates (2008) found that rates of binge drinking and marijuana use by men were unafected by their partner's pregnancy. The frequency and pattern of such behaviors clearly underscore the opportunity for preconceptional counseling.

Currently 20 million women in the United States smoke cigarettes (Centers for Disease Control and Prevention, 2014). Smoking in pregnancy has been consistently associated with numerous adverse perinatal outcomes, listed in Chapter 12 (p. 249). These risks are largely mitigated by cessation before pregnancy, highlighting the importance of screening for tobacco use in the preconceptional period and during prenatal care as outlined in Chapter 9 (p. 161).

Contact with environmental substances is inescapable. Thus, it is fortunate that only a few agents have been shown to cause adverse pregnancy outcomes (Windham, 2008). Exposures to infectious diseases have myriad deleterious efects, and these are detailed in Chapters 64 and 65. Likewise, contact with some chemicals may impart signiicant maternal and fetal risks. As discussed in Chapters 9 and 12 (pp. 170 and 244), excess exposure to methyl mercury or lead is associated with neurodevelopmental disorders.

In the past, some concerns were raised over common everyday exposure to electromagnetic iels such as those emanated by high-voltage power lines, electric blankets, microwave ovens, and cellular phones. Fortunately, no human or animal evidence links these and adverse fetal outcomes (Robert, 1999). he efects of electrical shock are discussed in Chapter 47 (p. 930).

Pica is the craving for and consuming of ice, laundry starch, clay, dirt, or other nonfood items. It should be discouraged due to its inherent replacement of healthul food with nutritionally empty products (Chap. 9, p. 174). In some cases, it may represent an unusual physiological response to iron deficiency. Many vegetarian diets are protein deficient but can be corrected by increasing egg and cheese consumption. Anorexia and bulimia increase maternal risks of nutritional deiciencies, electrolte disturbances, cardiac arrhythmias, and gastrointestinal pathology (Becker, 1999). s discussed in Chapter 61 (p. 1180), pregnancy-related complications with these disorders include greater risks of low birthweight, smaller head circumference, microcephaly, and small-for-gestational-age newborns (Kouba, 2005).

In contrast to these perinatal morbidities, obesiy is linked with several maternal complications. As discussed in Chapter 48 (p. 939), these include preeclampsia, gestational diabetes, labor abnormalities, cesarean delivery, and operative complications (American College of Obstetricians and Gynecologists, 2015b). Obesity also appears to be associated with a range of structural fetal anomalies (Stothard, 2009).

Conditioned pregnant women usually can continue to exercise throughout gestation (American College of Obstetricians and Gynecologists, 2017d). As discussed in Chapter 9 (p. 170), no data suggest that exercise is harmful during pregnancy. One caveat is that as pregnancy progresses, balance problems and joint relaxation may predispose to orthopedic injury. A woman is advised not to exercise to exhaustion, and she should augment heat dissipation and fluid replacement. Further avoidances include prolonged supine position, activities requiring good balance, and extreme weather conditions.

Pregnancy can exacerbate interpersonal problems and is a time of elevated risk from an abusive partner. According to the American College of Obstetricians and Gynecologists (2012), approximately 324,000 pregnant women are abused each year. As discussed in Chapter 47 (p. 925), intimate partner violence has been associated with greater risk for several pregnancy-related complications, including hypertension, vaginal bleeding, hyperemesis, preterm delivery, and low-birthweight neonates (Silverman, 2006). Because domestic violence can escalate during pregnancy, even to the point of homicide, the preconceptional period provides an ideal time for screening and if indicated, intervention (Cheng, 2010). s detailed in Chapter 9 (p. 162), the American College of Obstetricians and Gynecologists (2012) provides recommendations and resources for screening both pregnant and nonpregnant women for domestic violence.

Certain laboratory tests may help assess the risk for and prevent some pregnancy complications. hese include basic tests that are usually performed during prenatal care and are enumerated in Chapter 9. More speciic tests may assist evaluation of women with certain chronic medical diseases. Examples of some chronic diseases that ideally would be assessed before conception are highlighted in Table 8-4. With several of these, optimizing maternal condition before conception will improve pregnancy outcomes. Cox and coworkers (1e992) reviewed pregnancy outcomes in 1075 high-risk women who received such evaluation. hey reported that the 240 women with hypertension, asthma, or renal, thyroid, or cardiac disease had better outcomes compared with the outcomes from their prior pregnancies.

TABLE 8-4. Selected Preconceptional

Methyl mercury: Avoid shark, swordfish, king mackerel, and tile fish. Ingest no more than 12 ounces or 2 servings of canned tuna and no more than 6 ounces of albacore per week.

Lead: Blood lead testing if a risk factor is identified; treat if indicated according to recommendations.

Calculate BMI yearly from Figure 48-1, p. 937

BMI .25 kglm2: Counsel on diet. Test for diabetes and metabolic syndrome if indicated. Consider weight 105s prior to conception.

BMI � 78.5 kglm2: Assess for eating disorder.

Counsel on cardiac risks during pregnancy; discuss situations in which pregnancy is contraindicated.

cardiac function. Discuss medication teratogenicity (warfarin, ACE inh'bitor, ARB) and, if possible, switch to less dangerous agent when conception planned. Ofer genetic counseling to those with congenital cardiac anomalies (Table 49-4, p. 953).

Counsel on specific risks during pregnancy. Assess those with long-standing HTN for ventricular hypertrophy, retinopathy, and rena! disease. Optimize blood pressure co trol. If medications indicated, select or switch to an agent appropriate for pregnancy.

Counsel on asthma risks during pregnancy. Optimize pulmonary function preconceptionally. Treat women with pharmacologica l step therapy for chronic asthma.

Question for personal or family history of thrombotic events or recurrent poor pregnancy outcomes. If a thrombopbilia is found or known, counsel and offer appropriate anticoagulation regimen.

Counsel on specific risks during pregnancy. Optimize blood pressure control before conception. Counsel women taking ACE inhibitors and ARBs abolJt teratogenicity and the need to switch agents before pregnancy.

Inlammatory bowel disease: Counsel afected women on subfertility risks and risks of adverse pregnancy outcomes. Discuss teratogenicity of methotrexate and the other imnunomodulators. Offer effective contraception during their use and switch agents, if possible, before conception.

Hepatitis B: Vaccinate all high-risk women before conception (Table 9-7, p. 1l72).

Counsel chronic carriers on transmission prevention to partners and fetus. Treat if indicated.

Hepatitis C: Screen high-risk women. Counsel affected ,fomen on risks of disease and transmission. If treatment indicated, discuss ramifications and appropriateness of pregnancy.

Iron-deficiency anemia: Iron supplementation.

Sickle-cell disease: Screen all black women. Counsel those with trait or disease. Test partner if desired. Thalassemias: Screen women of Southeast Asian or Mediterranean ancestry.

Renal d:sease

Chap. 9, p. 170

Chap. 12, p. 244

Chap.l48,lp.l936

Chap. 61A, p. 1180

Chap. 49, p. 951

Chap. 12, pp. 241,

Chap. 50, p. 976

Chap. 51, p. 988

Chap.l52,lp.ll006

Chap. 53, p. 1025

Chap. 12, p. 241

Chap. 54, p. 1050

Chap. 12, pp. 242,

Chap. 55, p. 1064

Chap.l56,lp.ll075

TABLE 8-4. Continued

Diabetes Chap. 57, p. 1104 Optimize glycemic control to minimize teratogenicity of hyperglycemia. Evaluate for end-organ damage such as retinopathy, nephropathy, hypertension, and others. Discontinue ACE inhibitors.

Thyroid disease Chap. 58, p. 1118 Screen those with thyroid disease symptoms. Ensure diet.

Treat overt hyper-or hypothyroidism. Counsel on risks to pregnancy outcome.

Connective Chap. 59, p. 11l38 RA: Counsel on flare risk after pregnancy. Discuss methotrexate and leflunomide tissue disease Chap. 12, p. 241 teratogenicity, as well as possible effects of other immunomodulators.

Switch these agents before conception. Stop NSAIDs by 27 weeks' gestation.

SLE: Counsel on risks during pregnancy. Optimize disease before conception.

Discuss mycophenolate mofetil and cyclophosphamide teratogenicity as well as possible effects of newer immunomodulators. Switch these agents before conception.

Psych iatric Cha p. 61, p. 11 75 Depression: Screen for symptoms of depression. Counsel on risks of treatment and disorders of untreated illness and the high risk of exacerbation during pregnancy and the puerperium.

Neurological Chap. 60, p. 11l59 Seizure disorder: Optimize seizure control using monotherapy if possible. disorders Dermatological Chap. 12, p. 245 Discuss isotretinoin and etretinate teratogenicity and effective contraception disease during their use; switch agents before conception.

Cancer Chap. 63, p. 11l92 Counsel on fertility preservation options before cancer therapy and on decreased fertility following certain agents. Discuss appropriateness of pregnancy balanced with need for ongoing cancer therapy and prognosis of the disease state.

Infectious Chap. 64, p. 1209 Influenza: Vaccinate all women who will be pregnant during flu season. Vaccinate diseases high-risk women prior to flu season.

Malaria: Counsel to avoid travel to endemic areas during conception. If unable, offer effective contraception during travel or provide chemoprophylaxis for those planning pregnancy.

Zika virus: See travel restrictions by CDC.

Rubella: Screen for rubella immunity. If nonimmune, vaccinate and counsel on the need for effective contraception during the subsequent month.

Tdap: tetanus, diphtheria, pertussis: Update vaccination in all reproductive-aged women.

Varicella: Question regarding immunity. If nonimmune, STDs Chap.l65,lp.l1235 Gonorrhea, syphilis, chlamydial infection: Screen high-risk women and treat as indicated.

HIV: Screen at-risk women. Counsel afected women on risks during pregnancy and on perinatal transmission. Discuss initiation of treatment before pregnancy to decrease transmission risk. Offer effective contraception to those not desiring conception.

HPV' Provide Pap smear screening per guidelines (Chap. 63, p. 1193). Vaccinate candidate patients.

HSV: Provide serological screening to asymptomatic women with affected partners. Counsel affected women on risks of perinatal transmission and on preventative measures during the third trimester and labor.

ACE = angiotensin-converting enzyme; ACOG = American College of Obstetricians and Gynecologists; ARB = angiotensinreceptor blocker; BMI = body mass index; CDC = Centers for Disease Control and Prevention; HIV = human immunodeficiency virus; HPV = human papillomavirus; HSV = herpes simplex virus; HTN = hypertension; NSAID = nonsteroidal antiinflammatory drug; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; STD = sexually transmitted disease. Data from Jack BW, Atrash H, Coonrod DV, et al: The clinical content of preconception care: an and preparation of this supplement, Am J Obstet Gynecol. 2008 Dec;199(6 Suppl 2):5266-S279.

Aghajanian P, Gupta M: Helping your epileptic patient. Contemp OB/GYN 60:10,s2015

Aguglia U, Barboni G, Battino 0, et al: Italian consensus conference on epilepsy and pregnancy, labor and puerperium. Epilepsia 50:7, 2009

Amant F, Vandenbroucke T, Verheecke M, et a1: Pediatric outcome after maternal cancer diagnosed during pregnancy. N Engl J Med 3(19): 1824, 2015 American Academy of Pediatrics: Maternal phenylketonuria. Pediatrics 122: 445, 2008

American College of Obstetricians and Gynecologists: Intimate partner violence. Committee Opinion No. 518, 2012

American College of Obstetricians and Gynecologists: At-risk drinking and alcohol dependence: obstetric and gynecologic implications. Committee Opinion No. 496, August 2011, Reairmed 2013

American College of Obstetricians and Gynecologists: Hemoglobinopathies in pregnancy. Practice Bulletin No. 78, January 2007, Reairmed 2015a American College of Obstetricians and Gynecologists: Obesiry in pregnancy.

Committee Opinion No. 549, January 2013, Reairmed 2015b

American College of Obstetricians and Gynecologists: Pregestational diabetes mellitus. Practice Bulletin No. 60, March 2005, Reairmed 2016a American College ofsObstetricians and Gynecologists: Reproductive life plan nll1g to reduce unIntended pregnancy. Committee Opinion No. 654, February 2016b

American College of Obstetricians and Gynecologists: Screening for fetal aneuploidy. Practice Bulletin No. 163, March 2016c

America� Coll�g� of Obstetricians and Gynecologists: Carrier screening for genetIc condltlons. Committee Opinion No. 691, March 2017a

Ame:ican College of Obstetricians and Gynecologists: Management of women WIth phenylketonuria. Committee Opinion No. 636, June 2015, Reaffirmed 2017b

American College of Obstetricians and Gynecologists: Marijuana use during pregnancy and lactation. Committee Opinion No. 722, July 2015, Reaffirmed 2017c

American Col�ege of Obstetricians and Gynecologists: Physical activiry and exerCIse dunng pregnancy and postpartum period. Committee Opinion No. 650, December 2015, Reairmed 2017 d

American College of Obstetricians and Gynecologists: The importance of preconception care in the continuum of women's health care. Committee Opinion No. 313, September 2005, Reairmed 2017e

Bailey]A, Hill KG, Hawkins ]0, et al: Men's and women's patterns of substance use around pregnancy. Birth 35:1, 2008

Be:h BH, Kjaersgaard MI, Pedersen HS, et al: Use of antiepileptic drugs durIl1g pregnancy and risk of spontaneous abortion and stillbirth: population based cohort study. BM] 349:g5159, 2014

Becker AE, Grinspoon SK, Klibanski A, et al: Eating disorders. N Engl ] Med 340: 14, 1999

Brasil P, Pereira JP, Gabaglia CR, et al: Zika virus infection in pregnant women in Rio de Janeiro-preliminary report. N Engl J Vied 375(24): 2321,s2016

Buyon ]P, Kim MY, Guerra Mvl, et al: Predictors of pregnancy outcomes in patients with lupus: a cohort study. Ann Intern Med 163(3): 153, 2015

Camp M, Paris A, Acosta PB, et al: Phenylketonuria scientific review conference: state of the science and future research needs. Mol Genet Metab 112(2):87,s2014

Cao A, Kan W: he prevention of thalassemia. Cold Spring Harb Perspect Med 3(2):aOll775, 2013

Cassina M, Dilaghi A, Di Gianantonio E, et al: Pregnancy outcome in women exposed to antiepileptic drugs: teratogenic role of maternal epilepsy and its pharmacologic treatment. Reprod ToxicoI39:50, 2013

Cedars MI: Introduction: childhood implications of parental aging. Fertil Steril 103(6):1379,s2015

Center� for Disease Control and Prevention: Women and smoking. 2014.

AvaIlable at: http://www.cdc.gov/ tobaccol data_statisticsl sgrl50th-anniversary/pdfs/fs_women_smokin�508.pdf. Accessed April 5, 2016

Centers for Disease Control and Prevention: Preconception health and health care. 2015. Available at: http://www.cdc.gov/preconception/index.html. Accessed April 5,s2016

Centers for Disease Control and Prevention: Birth defects. 2016. Available at: http://www.cdc.gov/ncbddd/birthdefects/data.html. Accessed April 5, 2016 Cheng 0, Horon IL: Intimate-partner homicide among pregnant and postpar tum women. Obstet GynecoIsI15(6):1l81, 2010

Cox M, Whittle M], Byrne A, et al: Prep regnancy counseling: experience from 10 5 cases. B]OG 99:873, 1992 Creanga A, Berg CJ, Syverson C, et al: Pregnancy-related mortaliry in the United States, 2006-2010. Obstet Gynecol 125:5,s2015

Cunningham FG, Leveno KJ: Childbearing among older women-the message is cautiously optimistic. N Engl J Med 333:953, 1995 Czeize1 AE, Dudas I: �rev�ntion of the irst occurrence of neural-tube defects by penconceptIonal vltamll1 supplementation. N Engl J Med 327:1832, 1992

D'Angelo 0, Williams L, Morrow B, et al: Preconception and interconception health st�tus of women who recently gave birth to a live-born infant-Pregnancy Risk Assessment Monitoring System (PRAMS), United States, 26 reporting areas, 2004.

IMWR 56(10): 1,s2007

Davies M], Moore VM, Willson KJ, et al: Reproductive technologies and the risk of birth defects. N Engl ] Med 366(19): 1803, 2012 de Jong-van den Berg LT, Hernandez-Diaz S, Weder MM, et al: Trends and predictors of folic acid awareness and periconceptional use in pregnant women. Am] Obstet Gynecolsl92:121, 2005

Forget BG, Bunn HF: Classiication of the disorders of hemoglobin. Cold Spring Harb Perspect Med 3(2):aOI1684, 2013

Fried S, Kozer E, Nulman I, et al: Malformation rates in children of women with untreated epilepsy: a meta-analysis. Drug Saf 27(3): 197, 2004

Geller SE, C?X SM, Callaghan WM, et al: Morbidiry and mortaliry in pregnancy: layll1g the groundwork for safe motherhood. Womens Health Issues 16: 176, 2006

Gold?erg BB, Alvarado 5, Chavez C, et al: Prevalence of periconceptional folic aCId use a�d perceived barriers to the postgestation continuance of supple mental folIc aCId: survey results from a Teratogen Information Service. Birth Defects Res Part A Clin Mol Teratol 76:193, 2006

Guttmacher Institute: State facts about unintended pregnancies. 2015. Available at: https:llwww.guttmacher.org/fact-sheet/ state-facts-abou t-unin tendedpregnancy. Accessed April 5, 2016

Hernandez-Dlaz 5, Smith CR, Shen A, et al: Comparative safery of antiepileptic drugs during pregnancy. Neurology 78: 1692,s2012

Jack BW, Arrash H, Coonrod DV, et al: he clinical content of preconception care: an overview and preparation of this supplement. Ams] Obstet Gynecol 199(6 Suppl 2):5266, 2008

Jack BW, Campanile C, McQuade W, et al: he negative pregnancy test. An opportuniry for preconception care. Arch Fam Med 4:340, 1995 ]eha LE, Morris HH: Optimizing outcomes in pregnant women with epilepsy.

Cleve Clin J Med 72:928, 2005

Jentink], Loane MA, Dolk H, et al: Valproic acid mono therapy in pregnancy and major congenital malformations. N Engl] Med 362(23):2185, 2010

Johnson KsPosner SF, Biermann J, et al: Recommendations to improve pre conception health and health care-United States. A report of the CDCI ATSDR Preconception Care Work Group and the Select Panel on Preconception Care. MMWR 55(6):1,2006

Kim C, Ferrara A, McEwen LN, et al: Preconception care in managed care: the translating research into action for diabetes study. Am J Obstet Gynecol 192:227,s2005

Kitzmiller JL, Block JM, Brown FH, et al: Managing preexisting diabetes for pregnancy: summary of evidence and consensus recommendations for care. Diabetes Care 31(5):1060,s2008

Kitzmiller JL, Gavin A, Gin GO, et al: Preconception care of diabetics. JAMA 265:731, 1991

Kjer 0, Horvath-Puh6 E, Christensens], et a1: Antiepileptic drug use, folic acid supplementation, and congenital abnormalities: a population-based case-control study. 115(1):98,s2008

Korteweg FJ, Bouman K, Erwich n, et al: Cytogenetic analysis after evaluation of 750 fetal deaths: proposal for diagnostic workup. Obstet Gynecol III (4):865, 2008

Kouba 5, Hallstrom T, Lindholm C, et al: Pregnancy and neonatal outcomes in women with eating disorders. Obstet Gynecol 105:255,s2005

Kuliev A, Pakhalchuk T, Verlinsky 0, et al: Preimplantation genetic for hemoglobinopathies. Hemoglobin 35(5-6):547, 201s1

Lane M, Robker RL, Robertson SA: Parenting from before conception. Science 345(6198):756,s2014

Lassi ZS, Imam AM, Dean SV, et al: Preconception care: screening and management of chronic disease and promoting psychological health. Reprod Health 26:11, 2014

Leguizam6n G, Igarzabal ML, Reece EA: Periconceptional care of women with diabetes mellitus. Obstet Gynecol C1in North Am 34:225, 200

Luke B: Pregnancy and birth outcomes in couples with infertility and with and without assisted reproductive technology: with an emphasis on US population-based studies. Am J Obstet Gynecol 217:270, 2017

Maillot F, �ook P, Lilburn M, et al: A practical approach to maternal phenylketonufla management. J Inherit Metab Dis 30: 198, 2007

Malaspina 0, Gilman C, Kranz TM: Paternal age and mental health of ofspring. Ferti! Steril 103(6):1392,s2015

Martin ]A, Hamilton BE, Ventura 5], et al: Births: inal data for 2010. Nat!

Vital Stat Rep 61(1):1, 2012

McNamara OM, Elkayam U, Alharethi R, et al: Clinical outcomes for peripartum cardiomyopathy in North America: results of the IPAC study (investigations of pregnancy-associated cardiomyopathy). J Am ColI CardioIe66(8): 905,e2015

Medical Research Council Vitamin Study Research Group: Prevention of neural tube defects: results of the Medical Research Council vitamin study. Lancet 338:131, 1991

Moos MK: Preconceptional health promotion: progress in changing a prevention paradigm. J Perinat Neonatal Nurs 18:2,e2004

Moos MK, Bangdiwala SI, Meibohm R, et al: he impact of a preconceptional health promotion program on intendedness of pregnancy. Am J PerinatoIe13:103, 1996

Morrow JI, Hunt SJ, Russell AJ, et al: Folic acid use and major congenital malformations in ofspring of women with epilepsy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 80(5):506, 2009

Niccolai LM, Ethier A, Kershaw TS, et al: Pregnant adolescents at risk: sexual behaviors and sexually transmitted disease prevalence. Am J Obstet Gynecol 188:63,e2003

Petersen EE, Staples JE, Meaney-Delman 0, et al: Interim guidelines for pregnant women during a Zika virus outbreak-United States, 2016. MMWR 65(2):30,e2016

Podymow T, Joseph G: Preconception and pregnancy management of women with diabetic nephropathy on angiotensin converting enzyme inhibitors. Clin NephroIe83(2):73, 2015

Qin J, Liu X, Sheng X, et al: Assisted reproductive technology and the risk of pregnancy-related complications and adverse pregnancy outcomes in Singleton pregnancies: a meta-analysis of cohort studies. Fertil Steril 105(1):73, 2016

Reddy UM, Page GP, Saade GR, et al: Karyotype versus microarray testing for genetic abnormalities ater stillbirth. N Engl J Med 367(23):2185,2012

Reece EA, Homko CJ: Prepregnancy care and the prevention of fetal malformations in the pregnancy complicated by diabetes. Clin Obstet Gynecol 50:990, 2007

Robert E: Intrauterine efects of electromagnetiC ields (low frequency, midfrequency F, and microwave): review of epidemiologic studies. Teratology 59:292, 1999

Schuler-Faccini L, Ribeiro EM, Feitosa 1M, et al: Possible association between Zika virus infection and microcephaly-Brazil, 2015. MMWR 65(3):59, 20e16 Sheield JS, Butler-Koster EL, Casey BM, et al: Maternal diabetes mellitus and infant malformations. Obstet Gynecolel00:925, 2002 Silverman JG, Decker MR, Reed E, et al: Intimate partner violence victimization prior to and during pregnancy among women residing in 26 U.S. States: associations with maternal and neonatal health. Am J Obstet Gynecol 195:140,e2006

Simpson LL: Preconception considerations. Semin Perinatol 38(5):236, 2014

Society for Maternal-Fetal Medicine (SMFM), Sciscione A, Berghella V, et al: Society for Maternal-Fetal Medicine (SMFM) special report: the maternal-fetal medicine subspecialists' role within a health care system. Am J Obstet Gynecole211 (6):607,e2014

Stothard KJ, Tennant PW, Bell R, et al: Maternal oveweight and obesity and the risk of congenital anomalies: a systematic review and meta-analysis. JAMA 301:636,e2009

Stubbleield PG, Coonrod DV, Reddy UM, et al: he clinical content of preconception care: reproductive history. Am J Obstet Gynecol 199(6 Suppl 2):S373, 2008

Sunderan S, Kissin OM, Crawford SB, et al: Assisted reproduction technology suveillance-United States, 20e12. MMWR 64:e1,e20e15

Temel S, Van Voorst SF, Jack BW, et al: Evidence-based preconceptionalelifestyle interventions. Epidemiol Rev 36:19,e2014 hompson MW, McInnes R, Huntington FW (eds): Genetics in Medicine, 5th ed. Philadelphia, Saunders, 1991

Tomson T, Battino 0: Pregnancy and epilepsy: what should we tell our patients? J Neurol 256(6):856, 2009

Tough S, ToHemire K, Clarke M, et al: Do women change their drinking behaviors while trying to conceive? n opportunity for preconception counseling. Clin Med Res 4:97, 2006

Tripathi A, Rankin J, Aarvold J, et al: Preconception counseling in women with diabetes: a population-based study in the North of England. Diabetes Care 33(3):586,e2010

U.S. Preventive Services Task Force: Final update summary: folic acid to prevent neural tube defects. 2009. Available at: http://ww.uspreventiveservicestaskfo rce. 0rg/Pagel Documen t/U pdateS ummary F inall folic-acidto-prevent-neural-tube-defects-preventive-medication. Accessed April 5, 2016

Usta 1M, Zoorob 0, Abu-Musa A, et al: Obstetric outcome of teenage pregnancies compared with adult pregnancies. Acta Obstet Gynecol 87: 178, 2008 Vajda FJ, Hitchcock A, Graham J, et al: Seizure control in antiepileptic drug treated pregnancy. Epilepsia 49: 172, 2008 Vajda FJ, O'Brien TJ, Graham J, et al: he outcomes of pregnancy in women with untreated epilepsy. Seizure 24: 7, 2015

Van der Zee B, de Wert G, Steegers A, et al: Ethical aspects of paternal preconception lifestyle modiication. Am J Obstet Gynecol 209(1): 11, 2013 Veiby G, Daltveit AK, Engelsen BA, et al: Pregnancy, delivery, and outcome for the child in maternal epilepsy. Epilepsia 50(9):2130, 2009

Vichinsky EP: Clinical manifestations of a-thalassemia. Cold Spring Harb Perspect Med 3(5):aOI1742, 2013

Vockley J, Andersson HC, Antshel KM, et al: Phenylalanine hydroxylase deiciency: diagnosis and management guideline. American College of Medical Genetics and Genomics Therapeutics Committee 16:356,2014

Waldenstrom U, Cnattingius S, Norman M, et al: Advanced maternal age and stillbirth risk in nulliparous and parous women. Obstet Gynecol 126(2): 355, 2015

Williams J, Mai CT, Mulinare J, et al: Updated estimates of neural tube defects prevention by mandatory folic acid fortiication-United States, 1995-2011. MMWR 64(1):1, 2015

Windham G, Fenster L: Environmental contaminants and pregnancy outcomes. Fertil Steril 89:e Ill, 2008

DIAGNOSIS OF PREGNANCY. . . . . . . . . . . . . . . . . . . . .. 158 INITIAL PRENATAL EVALUATION .e. .e..... .e.. .e.. ...e. 159

SUBSEQUENT PRENATAL VISITS .... .e. .e......... .e. 164 ..NUTRITIONAL COUNSELING. . . . . . . . . . . . . . . . . . . . .. 165 COMMON CONCERNS . . . . . . . . . . . . . . . . . . . . . . . . . .. 170

The borderline between health and disease is less distincty marked during gestation, and therore, it accordingy becomes necessary to keep pregnant patients under strict supervision, and to be constanty on the alert or the appearance of untoward symptoms.

-J. Whitridge Williams (1903) s emphasized above by Williams, prenatal care is important. According to the merican Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017) a comprehensive antepartum program is deined as: "a coordinated approach to medical care, continuous risk assessment, and psychological support that optimally begins before conception and extends throughout the postpartum period and interconceptional period."

Almost a century after its introduction, prenatal care has become one of the most frequently used health services in the United States. In 2001, there were approximately 50 million prenatal visits. The median was 12.3 visits per pregnancy, and many women had 17 or more visits. Still, as seen from

Figure 9-1, 6 to 7 percent of women in this country have late or no prenatal care. In 2014, the percentages of non-Hispanic white, Hispanic, and African-American women who received inadequate or no prenatal care were 4.3, 7.5, and 9.7, respec tively (Child Trends, 2015).

he Centers for Disease Control and Prevention (CDC) (2000) analyzed birth certificate data and found that half of women with delayed or no prenatal care wanted to begin care earlier. Barriers to care varied by social and ethnic group, age, and payment method. he most common reason cited was late recognition of pregnancy by the patient. The second most commonly cited obstacle was lack of money or insurance. he third was inability to obtain an appointment.

Care designed during the early 1900s focused on lowering the extremely high maternal mortality rate. Prenatal care undoubtedly contributed to the dramatic decline in this mortality rate from 690 deaths per 100,000 births in 1920 to 50 per 100,000 •• Births in all states Births in states using the 1989 birth certificate/revision • Births in states using the 2003 birth certificate/revision

FIGURE 9-1 Percentage of births to mothers who received late or no prenatal care-United States, 1990-2014. (Data from Trends, 2015.) by 1955 (Loudon, 1992). And, the low current maternal mortality rate of 10 to 15 per 100,000 is likely associated with the high utilization of this care (Xu, 2010). Indeed, data from 1998 to 2005 from the Pregnancy \10rtality Surveillance System identified a ivefold increased risk for maternal death in women who received no prenatal care (Berg, 2010).

Other reports also attest to prenatal care eicacy. In a study of almost 29 million births, the risk for preterm birth, stillbirth, early and late neonatal death, and infant death rose linearly with decreasing prenatal care (Partridge, 2012). Similarly, Leveno and associates (2009) found that a significant decline in preterm births at Parkland Hospital correlated closely with increased use of prenatal care by medically indigent women. Moreover, National Center for Health Statistics data showed that women with prenatal care had an overall stillbirth rate of 2.7 per 1000 compared with 14.1 per 1000 for women without this care (Vintzileos, 2002).

Evaluating the format of care, Ickovics and coworkers (2016) compared individual prenatal care and group prenatal care. he latter provided traditional pregnancy surveillance in a group setting with special focus on support, education, and active healthcare participation. Women enrolled in group prenatal care had significantly better pregnancy outcomes. Carter and colleagues (2016) cited similar results. Childbirth education classes are also reported to result in better pregnancy outcomes (Afshar, 2017). Adolescent pregnancies carry special risk, and guidelines have been developed that focus on this subgroup (Fleming, 2015). Few data are available to recommend the practice of ofering tangible incentives to improve prenatal care attendance (Till, 2015).

Pregnancy is usually identified when a woman presents with symptoms and possibly a positive home urine pregnancy test result. Typically, these women receive conirmatory testing of urine or blood for human chorionic gonadotropin (hCG). Further, presumptive signs or diagnostic indings of pregnancy may be found during examination. Sonography is often used, particularly if miscarriage or ectopic pregnancy is a concern.

100,000 50,000

E 10,000

Amenorrhea in a healthy reproductive-aged woman who previously has experienced spontaneous, cyclical, predictable menses is highly suggestive of pregnancy. Menstrual cycles vary appreciably in length among women and even in the same woman (Chap. 5, p. 81). hus, amenorrhea is not a reliable pregnancy indicator until 10 days or more after expected menses have passed. Occasionally, uterine bleeding that mimics menstruation is noted after conception. During the irst month of pregnancy, these episodes are likely the consequence of blastocyst implantation. Still, irst-trimester bleeding should generally prompt evaluation for an abnormal pregnancy.

Of other symptoms, maternal perception of fetal movement depends on factors such as parity and habitus. In general, after a irst successful pregnancy, a woman may irst perceive fetal movements between 16 and 18 weeks' gestation. A primigravida may not appreciate fetal movements until approximately 2 weeks later. At about 20 weeks, depending on maternal habitus, an examiner can begin to detect fetal movements.

Of pregnancy signs, changes in the lower reproductive tract, uterus, and breasts develop early. These are described in detail in Chapter 4 (p. 49).

Detection of hCG in maternal blood and urine is the basis for endocrine assays of pregnancy. Syncytiotrophoblast produces hCG in amounts that increase exponentially during the irst trimester following implantation. A main function of hCG is to prevent involution of the corpus luteum, which is the principal site of progesterone formation during the irst 6 weeks of pregnancy.

With a sensitive test, the hormone can be detected in maternal serum or urine by 8 to 9 days after ovulation. he doubling time of serum hCG concentration is 1.4 to 2.0 days. As shown in Figure 9-2, serum levels range widely and increase from the day of implantation. They reach peak levels at 60 to 70 days. Thereafter, the concentration declines slowly until a plateau is reached at approximately 16 weeks' gestation.

Measurement of hCG his hormone is a glycoprotein with high carbohydrate content. he general structure of hCG is a heterodimer composed of two dissimilar subunits, designated a and �, which are non covalently linked. The a-subunit is identical to those of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH), but the �-subunit is structurally distinct among these. hus, antibodies were developed with high speciicity for the hCG �-subunit.

FIGURE 9-2 Mean concentration (95% CI) of human chorionic gonadotropin (hCG) in serum of This speciicity allows its detecwomen throughout normal pregnancy. tion, and numerous commercial immunoassays are available for measuring serum and urine hCG levels. Although each immunoassay detects a slightly diferent mixture of hCG variants, its free subunits, or its metabolites, all are appropriate for pregnancy testing (Braunstein, 2014).

Depending on the assay used, the sensitivity for the laboratory detection limit of hCG in serum is 1.0 mIU/mL or even lower (Wilcox, 2001).

False-positive hCG test results are rare (Braunstein, 2002).

erroneously with the test antibody directed to hCG in a given assay. The most common factors are heterophilic antibodies.

hese are produced by an individual and bind to the animal derived test antibodies used in a given immunoassay. Thus, women who have worked closely with animals are more likely to develop these antibodies, and alternative laboratory tech niques are available (American College of Obstetricians and

Gynecologists, 2017a). Elevated hCG levels may also reflect molar pregnancy and its associated cancers (Chap. 20, p. 391).

Other rare causes of positive assays without pregnancy are: (1) exogenous hCG injection used for weight loss, (2) renal fail ure with impaired hCG clearance, (3) physiological pituitary hCG, and (4) hCG-producing tumors that most commonly originate from gastrointestinal sites, ovary, bladder, or lung (Montagnana, 2011).

Over-the-counter pregnancy test kits have been available since the early 1970s, and millions are sold annually in the United States. More than 60 such tests are available in this country (Grenache, 2015). Unfortunately, many of these are not as accurate as advertised Gohnson, 2015). For example, Cole and associates (201i1) found that a detection limit of 12.5 mIU/mL would be required to diagnose 95 percent of pregnancies at the time of missed menses, but they reported that only one brand had this degree of sensitivity. Two other brands gave false-positive or invalid results. In fact, with an hCG concentration of 100 mIU/mL, clearly positive results were displayed by only 44 percent of brands. Accordingly, only about 15 percent of pregnancies could be diagnosed at the time of the missed menses. Some manufacturers of even newer home urine assays claim >99-percent accuracy of tests done on the day of-and some up to 4 days before-the expected day of menses. Again, careful analysis suggests that these assays are often not as sensitive as advertised Gohnson, 2015).

• Sonographic Recognition of Pregnancy

Transvaginal sonography has revolutionized early pregnancy imaging and is commonly used to accurately establish gestational age and conirm pregnancy location. A gestational sac-a small anechoic luid collection within the endometrial cavityis the irst sonographic evidence of pregnancy. It may be seen with transvaginal sonography by 4 to 5 weeks' gestation. A luid collection, however, can also be seen within the endometrial cavity with an ectopic pregnancy and is termed a pseudogestational sac or pseudosac (Fig. 19-4, p. 375). Thus, further evaluation may be warranted if this is the only sonographic inding, particularly in a woman with pain or bleeding. A normal

FIGURE 9-3 Transvaginal sonogram of a first-trimester intrauterine pregnancy. The double decidual sign is noted surrounding the gestational sac and is defined by the decidua parietalis (white asterisk) and the decidua capsularis (yellow asterisk). The arrow notes the yolk sac, and the crown-rump length of the embryo is marked with measuring calipers. (Used with permission from Dr. Elysia Moschos.) gestational sac implants eccentrically in the endometrium, whereas a pseudosac is seen in the midline of the endometrial cavity. Other potential indicators of early intrauterine pregnancy are an anechoic center surrounded by a single echogenic rim-the intradecidual sign-or two concentric echogenic rings surrounding the gestational sac-the double decidual sin shown in Figure 9-3. If sonography yields equivocal indings, the term pregnancy of unknown location (PUL) is applied. In these cases, serial serum hCG levels and transvaginal sonograms can help diferentiate a normal intrauterine pregnancy from an extrauterine pregnancy or an early miscarriage (Chap. 19, p. 373).

If the yolk sac-a brightly echogenic ring with an anechoic center-is seen within the gestational sac, an intrauterine location for the pregnancy is confirmed. The yolk sac can normally be seen by the middle of the ifth week. As shown in Figure 9-3, after 6 weeks, an embryo is seen as a linear structure immediately adjacent to the yolk sac. Cardiac motion is typically noted at this point. Up to 12 weeks' gestation, the crown-rump length is predictive of gestational age within 4 days (Chap. 10, p. 183).

Prenatal care is ideally initiated early. Major goals are to: (1) deine the health status of the mother and fetus, (2) estimate the gestational age, and (3) initiate a plan for continued obstetrical care. Typical components of the initial visit are summarized in Table

Subsequent care may range from relatively infrequent routine visits to prompt hospitalization because of serious maternal or fetal disease.

Use of a standardized record within a perinatal health-care system greatly aids antepartum and intrapartum management.

TABLE 9-1 . Typical Components of Routine Prenatal Care

Chap. 9, p. 161

Chap. 9, p. 163

Chap. 40, p. 71l1

Chap. 9, p. 165

Chap. 9, p. 163

Chap. 9, p. 164

Chap. 9, p. 165

Chap. 56, p. 1075

Chap. 15, p. 301

Chap. 15, p. 301

Chap. 63, p. 1193

Chap. 57, p. 1108

Chap. 14, p. 278

Chap. 14, p. 283

Chap. 14, p. 289

Chap. 4, p. 66

Chap. 53, p. 1026

Chap. 64, p. 1215

Chap. 65, p. 1l237

Chap. 65, p. 1239

Chap. 65, p. 1240

Chap. 55, p. 1064

Chap. 65, p. 1247

Chap. 64, p. 1220

Chap. 51, p. 996 aFirst-trimester aneuploidy screening may be ofered between 11 and 14 weeks. A Performed at 28 weeks, if indicated.

8 Test should be ofered.

C High-risk women should be retested at the beginning of the third trimester.

o High-risk women should be screened at the first prenatal visit and again in the third trimester.

culture should be between 35 and 37 weeks.

HIV human immunodeficiency virus.

Standardizing documentation allows communication and care continuity between providers and enables objective measures of care quality to be evaluated over time and across diferent clinical settings (Gregory, 2006). A prototype is provided by the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017) in their Guidelines or Perinatal Care, 8th edition.

Several deinitions are pertinent to establishment of an accurate prenatal record.

1. Nulligravida-a woman who currently is not pregnant and has never been pregnant.

2.

Gravida-a woman who currently is pregnant or has been in the past, irrespective of the pregnancy outcome. With the establishment of the first pregnancy, she becomes a primigravida, and with successive pregnancies, a multigravida.

3.

Nullpara-a woman who has never completed a pregnancy beyond 20 weeks' gestation. She may not have been pregnant or may have had a spontaneous or elective abortion(s) or an ectopic pregnancy.

4.

Primipara-a woman who has been delivered only once of a fetus or fetuses born alive or dead with an estimated length of gestation of 20 or more weeks. In the past, a 500-g birthweight threshold was used to define parity. his threshold is now controversial because many states still use this weight to diferentiate a stillborn fetus from an abortus (Chap. 1, p. 3). However, the survival of neonates with birthweights < 500 g is no longer uncommon.

5. Multpara-a woman who has completed two or more pregnancies to 20 weeks' gestation or more. Parity is determined by the number of pregnancies reaching 20 weeks. It is not increased to a higher number if multiples are delivered in a given pregnancy. Moreover, stillbirth does not lower this number. In some locales, the obstetrical history is summarized by a series of digits connected by dashes. hese refer to the number of term infants, preterm infants, abortuses younger than 20 weeks, and children currently alive. For example, a woman who is para 2-1-0-3 has had two term deliveries, one preterm delivery, no abortuses, and has three living children. Because these are nonconventional, it is helpful to speciy the outcome of any pregnancy that did not end normally.

The normal duration of pregnancy calculated from the irst day of the last normal menstrual period is very close to 280 days or 40 weeks. In a study of 427,581 singleton pregnancies from the Swedish Birth Registry, Bergsj0 and coworkers (1990) found that the mean pregnancy duration was 281 days with a standard deviation of 13 days. However, menstrual cycle length varies among women and renders many of these calculations inaccurate. This, combined with the frequent use of irst-trimester sonography, has changed the method of determining an accurate gestational age (Duryea, 2015).

he American College of Obstetricians and Gynecologists (2017e), the American Institute of Ultrasound in Medicine, and the Society for Maternal-Fetal Medicine have concluded that irst-trimester ultrasound is the most accurate method to establish or reairm gestational age. For pregnancies conceived by assisted reproductive technology, embryo age or transfer date is used to assign gestational age. If available, the gestational ages calculated from the last menstrual period and from irst-trimester ultrasound are compared, and this estimated date of delivery is recorded. his is discussed in further detail in Chapter 7 (p. 124) and in Table 10-1 (p. 183).

A quick estimate of a pregnancy due date based on menstrual data can be made as follows: add 7 days to the irst day of the last period and subtract 3 months. For example, if the irst day of the last menses was October 5, the due date is 10-05 minus 3 (months) plus 7 (days) = 7-12, or July 12 of the following year. his calculation is the Naegele rule (American College of Obstetricians and Gynecologists, 2017 e).

It has become customary to divide pregnancy into three equal epochs or trimesters of approximately 3 calendar months. Historically, the irst trimester extends through completion of 14 weeks, the second through 28 weeks, and the third includes the 29th through 42nd weeks of pregnancy. Thus, there are three periods of 14 weeks each. Certain major obstetrical problems tend to cluster in each of these time periods. For example, most spontaneous abortions take place during the irst trimester, whereas most women with hypertensive disorders due to preg nancy are diagnosed during the third trimester.

In modern obstetrics, the clinical use of trimesters to describe a speciic pregnancy is imprecise. For example, it is inappropriate in cases of uterine hemorrhage to categorize the problem temporally as "third-trimester bleeding." Appropriate management for the mother and her fetus will vary remark ably depending on whether bleeding begins early or late in the third trimester (Chap. 41, p. 757). Because precise knowledge of fetal age is imperative for ideal obstetrical management, the clinically appropriate unit is weeks of gestation complete. And more recently, clinicians designate gestational age using com pleted weeks and days, for example, 334/7 weeks or 33 + 4, for 33 completed weeks and 4 days.

As elsewhere in medicine, history taking begins with queries concerning medical or surgical disorders. Also, detailed information regarding previous pregnancies is essential as many obstetrical complications tend to recur in subsequent pregnancies. The menstrual and contraceptive histories are also important. Gestational or menstrual age is the number of weeks since the onset of the last menstrual period in women with menstrual cycles lasting 28 to 30 days. For those with irregular menses, sonography in early pregnancy will clariy gestational age. Last, some methods of birth control favor ectopic implantation following method failure (Chap. 38, pp. 683 and 689).

Psychosocial Screening. The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017) define psychosocial issues as nonbiomedical factors that afect mental and physical well-being. Women should be screened regardless of social status, education level, race, or ethnicity. Such screening should seek barriers to care, communication obstacles, nutritional status, unstable housing, desire for pregnancy, safety concerns that include intimate-partner violence, depression, stress, and use of substances such as tobacco, alcohol, and illicit drugs. his screening is performed on a regular basis, at least once per trimester, to identiy important issues and reduce adverse pregnancy outcomes. Coker and colleagues (2012) compared pregnancy outcomes in women before and after implementation of a universal psychosocial screening program and found that screened women were less likely to have preterm or low-birthweight newborns, as well as other adverse outcomes. Speciic screens for depression are presented in Chapter 61 (p. 1174).

Cigarette Smoking. Data on this practice have been included on the birth certiicate since 1989. The number of pregnant women who smoke continues to decline. From 2000 to 2010, the prevalences were 12 to 13 percent (Tong, 2013). Based on the Pregnancy Risk Assessment Monitoring System, these women were more likely younger, had less education, and were either Alaska Natives or American Indians (Centers for Disease Control and Prevention, 20 13a).

Numerous adverse outcomes have been linked to smoking during pregnancy (U.S. Department of Health and Human Services, 2000). Potential teratogenic efects are reviewed in

TABLE 9-2. Five A's of Smoking Cessation

ASK about smoking at the first and subsequent prenatal visits.

ADVISE with clear, strong statements that explain the risks of continued smoking to the woman, fetus, and newborn. ASSESS the patient's willingness to attempt cessation. ASSIST with pregnancy-specific, self-help smoking cessation materials. Ofer a direct referral to the smoker's quit line (1-800-QUIT NOW) to provide ongoing counseling and support. ARRANGE to track smoking progress at subsequent visits.

Adapted from Fiore, 2008.

Chapter 12 (p. 249). Notable among these are greater rates of miscarriage, stillbirth, low birthweight, and preterm delivery (Man, 2006; Tong, 2013). here is also a twofold risk of placenta previa, placental abruption, and premature membrane rupture compared with nonsmokers. hus, the U.S. Preventive Services Task Force recommends that clinicians ofer counseling and efective intervention options to pregnant smokers at the irst and subsequent prenatal visits (Siu, 2015). Although beneits are greatest if smoking ceases early in pregnancy or preferably preconceptionally, quitting at any stage of pregnancy can improve perinatal outcomes (Fiore, 2008).

Person-to-person psychosocial interventions are signiicantly more successful in achieving smoking abstinence in pregnancy than is simply advising the woman to quit (Fiore, 2008). One example is a brief counseling session covering the "5As" of smoking cessation (Table 9-2). This approach can be accomplished in 15 minutes or less and is efective when initiated by health-care providers (American College of Obstetricians and Gynecologists, 20 17i).

Behavioral interventions and nicotine replacement products are successful in reducing smoking rates (Patnode, 2015). hat said, nicotine replacement has not been suiciently evaluated to determine its efectiveness and safety in pregnancy. Trials evaluating such therapy have yielded conflicting evidence (Coleman, 2015; Pollak, 2007; Spindel, 2016). Two recent randomized trials also produced nonconclusive results. In the Smoking and Nicotine in Pregnancy (SNAP) trial, Cooper and associates (2014) reported a temporary cessation of smoking that may have been associated with improved infant development. In the Study of Nicotine Patch in Pregnancy (SNIPP) trial, Berlin and coworkers (2014) found no diferences in smoking cessation rates or birthweights.

Because of limited available evidence to support pharmacotherapy for smoking cessation in pregnancy, the American College of Obstetricians and Gynecologists (2017i) has recommended that if nicotine replacement therapy is used, it should be done with close supervision and after careful consideration of the risks of smoking versus nicotine replacement.

Alcohol. Ethyl acohol or ethanol is a potent teratogen that causes a etal syndrome characterized by growth restriction, acial abnormalities, and central nervous system dyunction. s discussed in Chapter 12 (p. 239), women who are pregnant or considering pregnancy should abstain from using any alcoholic beverages. The CDC analyzed data from the Behavioral isk Factor Surveillance System from 2011 to 2013 and estimated that 10 percent of pregnant women used alcohol. It is estimated that 3.3 million women are at risk for such exposure (Green, 2016). he American College of Obstetricians and Gynecologists (2016b) in collaboration with the CDC has developed the Fetal Acohol Spectrum Disorders (FASD) Prevention Program, which provides resources for providers and is available at: http://www. acog.org/ alcohol.

Illicit Drugs. It is estimated that 10 percent of fetuses are exposed to one or more illicit drugs. Agents may include heroin and other opiates, cocaine, amphetamines, barbiturates, and marijuana (American Academy of Pediatrics, 2017; merican College of Obstetricians and Gynecologists, 20 15a, 2017 d). As discussed in Chapter 12 (p. 247), chronic use of most of these in large quantities is harmful to the fetus (Metz, 2015). Well-documented sequelae include fetal-growth restriction, low birthweight, and drug withdrawal soon ater birth. Adverse efects of marijuana are less convincing. Women who use such drugs frequently do not seek prenatal care, which in itself is associated with risks for preterm and low-birthweight newborns (EI-Mohandes, 2003; Eriksen, 2016).

For women who abuse heroin, methadone maintenance can be initiated within a registered methadone treatment program to reduce complications of illicit opioid use and narcotic withdrawal, to encourage prenatal care, and to avoid drug culture risks (American College of Obstetricians and Gynecologists, 2017£). Available programs can be found through the treatment locator of the Substance Abuse and Mental Health Services Administration at ww.samhsa.gov. Methadone dosages usually are initiated at 10 to 30 mg daily and titrated as needed. In some women, careful methadone taper may be an appropriate option (Stewart, 2013). Although less commonly used, buprenorphine alone or in combination with naloxone may also be ofered and managed by physicians with specific credentialing.

Intimate-Partner Violence. his term refers to a pattern of assault and coercive behavior that may include physical injury, psychological abuse, sexual assault, progressive isolation, stalking, deprivation, intimidation, and reproductive coercion (American College of Obstetricians and Gynecologists, 2012). Such violence has been recognized as a major public health problem. Unfortunately, most abused women continue to be victimized during pregnancy. With the possible exception of preeclampsia, domestic violence is more prevalent than any major medical condition detectable through routine prenatal screening (American Academy of Pediatrics and the Ameri can College of Obstetricians and Gynecologists, 2017). The prevalence during pregnancy is estimated to range between 4 and 8 percent. Intimate-partner violence is associated with an increased risk of several adverse perinatal outcomes including preterm delivery, fetal-growth restriction, and perinatal death (Chap. 47, p. 925).

The American College of Obstetricians and Gynecologists (2012) has provided methods for domestic violence screening and recommends their use at the irst prenatal visit, then again at least once per trimester, and again at the postpartum visit. Such screening should be done privately and away from family members and friends. Patient self-administered or computerized screenings appear to be as efective for disclosure as clinician-directed interviews (Ahmad, 2009; Chen, 2007). Physicians should be familiar with state laws that may require reporting of intimate-partner violence. Coordination with social services can be invaluable in these cases. The National Domestic Violence Hotline (l-800-799-SAFE [7233]) is a nonprofit telephone referral service that provides individualized information regarding city-speciic shelter locations, counseling resources, and legal advocacy.

A thorough, general physical examination should be completed at the initial prenatal encounter. Pelvic examination is performed as part of this evaluation. he cervix is visualized employing a speculum lubricated with warm water or waterbased lubricant gel. Bluish-red passive hyperemia of the cervix is characteristic, but not of itself diagnostic, of pregnancy. Dilated, occluded cervical glands bulging beneath the ectocervical mucosa-nabothian cysts-may be prominent. he cervix is not normally dilated except at the external os. To identiy cytological abnormalities, a Pap test is performed according to current guidelines noted in Chapter 63 (p. 1193). Specimens for identiication of Chlamydia trachomatis and Neisseria gonorrhoeae are also obtained when indicated.

Bimanual examination is completed by palpation, with special attention given to the consistency, length, and dilatation of the cervix; to uterine and adnexal size; to the bony pelvic architecture; and to any vaginal or perineal anomalies. Later in pregnancy, fetal presentation often can also be determined. Lesions of the cevix, vagina, or vulva are further evaluated as needed by colposcopy, biopsy, culture, or dark-field examination. The perianal region is visualized, and digital rectal examination performed as required for complaints of rectal pain, bleeding, or mass.

Precise knowledge of gestational age is one of the most important aspects of prenatal care because several pregnancy complications may develop for which optimal treatment will depend on fetal age. As discussed earlier and in Chapter 7 (p. 124), irst-trimester sonographic assessment is best correlated with menstrual history. That said, gestational age can also be estimated with considerable precision by carefully performed clinical uterine size examination that is coupled with knowledge of the last menses. Uterine size similar to a small orange roughly correlates with a 6-week gestation; a large orange, with an 8-week pregnancy; and a grapefruit, with one at 12 weeks (Margulies, 2001).

Recommended routine tests at the first prenatal encounter are listed in Table 9-1. Initial blood tests include a complete blood count, a determination of blood type with h status, and an antibody screen. The Institute of Medicine recommends universal human immunodeiciency virus (HIV) testing, with patient notiication and right of refusal, as a routine part of prenatal care. The CDC (Branson, 2006) as well as the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (20 16f, 2017) continue to support this practice. If a woman declines testing, this is recorded in the prenatal record. All pregnant women are also screened for hepatitis B virus infection, syphilis, and immunity to rubella at the initial visit. Based on their prospective investigation of 1000 women, Murray and coworkers (2002) concluded that in the absence of hypertension, routine urinalysis beyond the irst prenatal visit was not necessary. A urine culture is recommended by most because treating bacteruria signiicantly reduces the likelihood of developing symptomatic urinary tract infections in pregnancy (Chap. 53, p. 1026).

Chlamydia trachomatis is isolated from the cervix in 2 to 13 percent of pregnant women. he American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017) recommend that all women be screened for chlamydia during the irst prenatal visit, with additional third-trimester testing for those at increased risk. Risk factors include unmarried status, recent change in sexual partner or multiple concurrent partners, age younger than 25 years, inner-city residence, history or presence of other sexually transmitted diseases, and little or no prenatal care. For those testing positive, treatment described in Chapter 65 (p. 1240) is followed by a second testing-a test of cure-3 to 4 weeks after treatment completion.

Neisseria gonorrhoeae typically causes lower genital tract infection in pregnancy. It also may cause septic arthritis (Bleich, 2012). Risk factors for gonorrhea are similar to those for chlamydial infection. The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017) recommend that pregnant women with risk factors or those living in an area of high N gonorrhoeae prevalence be screened at the initial prenatal visit and again in the third trimester. Treatment is given for gonorrhea and simultaneously for possible coexisting chlamydial infection (Chap. 65, p. 1240). Test of cure is also recommended following treatment.

Many factors can adversely afect maternal and fetal well-being. Some are evident at conception, but many become apparent during the course of pregnancy. The designation of "high-risk pregnancy" is overly vague for an individual woman and probably is best avoided if a more specific diagnosis can be assigned.

TABLE 9-3. Conditions for Which Maternal-Fetal Medicine Consultation May Be Beneficial

Cardiac disease-moderate to severe disorders

Diabetes mellitus with evidence of end-organ damage or uncontroiled hyperglycemia Family or personal history of genetic abnormalities

Renal insuficiency if associated with significant proteinuria (::500 mg/24 hour), serum creatininel::1.5 mg/dL, or hypertension Pulmonary disease if severe restrictive or obstructive, including severe asthma Human immunodeficiency virus infection Prior embolus or deep-vein thrombosis Severe systemic disease, including autoimmune conditions Bariatric surgery Epilepsy if poorly controlled or requires more than one anticonvulsant Cancer, especially if treatment is indicated in pregnancy

CDE (Rh) or other blood group alloimmunization (excluding ABO, Lewis) Prior or current fetal structural or chromosomal abnormality

Periconceptional exposure to known teratogens

Infection with or exposure to organisms that cause congenital infection Higher-order multifetal gestation

Severe disorders of amnionic fluid volume

Some common risk factors for which consultation is recommended by the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017) are shown in Table 9-3. Some conditions may require the involvement of a maternal-fetal medicine subspecialist, geneticist, pediatrician, anesthesiologist, or other medical specialist in the evaluation, counseling, and care of the woman and her fetus.

hese are traditionally scheduled at 4-week intervals until 28 weeks, then every 2 weeks until 36 weeks, and weekly thereafter. Women with complicated pregnancies-for example, with twins or diabetes-often require return visits at 1-to 2-week intervals (Luke, 2003; Power, 2013). In 1986, the Department of Health and Human Services convened an expert panel to review the content of prenatal care. his report was subsequently reevaluated and revised in 2005 (Gregory, 2006). he panel recommended, among other things, early and continuing risk assessment that is patient speciic. It also endorsed lexibility in clinical visit spacing; health promotion and education, including preconceptional care; medical and psychosocial interventions; standardized documentation; and expanded prenatal care objectives-to include family health up to 1 year after birth.

he World Health Organization conducted a multicenter randomized trial with almost 25,000 women comparing routine prenatal care with an experimental model designed to minimize visits (Villar, 2001). In the new model, women were seen once in the irst trimester and screened for certain risks. hose without anticipated complications-80 percent of those screened-were seen again at 26, 32, and 38 weeks. Compared with routine prenatal care, which required a median of eight visits, the new model required a median of only ive. No disadvantages were attributed to the regimen with fewer visits, and these indings were consistent with other randomized trials (Clement, 1999; McDuie, 1996).

At each return visit, the well-being of mother and fetus are assessed (see Table 9-1). Fetal heart rate, growth, and activity and amnionic fluid volume are evaluated. Maternal blood pressure and weight and their extent of change are examined. Symptoms such as headache, altered vision, abdominal pain, nausea and vomiting, bleeding, vaginal luid leakage, and dysuria are sought. Mter 20 weeks' gestation, uterine examination measures size from the symphysis to the fundus. In late pregnancy, vaginal examination often provides valuable information that includes conirmation of the presenting part and its station, clinical estimation of pelvic capacity and configuration, amnionic luid volume adequacy, and cervical consistency, efacement, and dilatation (Chap. 22, p. 435).

Between 20 and 34 weeks' gestation, the height of the uterine fundus measured in centimeters correlates closely with gestational age in weeks Gimenez, 1983). his measurement is used to monitor fetal growth and amnionic fluid volume. It is measured along the abdominal wall from the top of the symphysis pubis to the top of the fundus. Importantly, the bladder must be emptied before fundal measurement (Worthen, 1980). Obesity or the presence of uterine masses such as leiomyomas may also limit fundal height accuracy. Moreover, using fundal height alone, fetal-growth restriction may be undiagnosed in up to a third of cases (American College of Obstetricians and Gynecologists, 2015b; Haragan, 2015).

Instruments incorporating Doppler ultrasound are often used to easily detect fetal heart action, and in the absence of maternal obesity, heart sounds are almost always detectable by 10 weeks with such instruments (Chap. 10, p. 213). he fetal heart rate ranges from 11e0 to 160 beats per minute and is typically heard as a double sound. Using a standard nonampliied stethoscope, the fetal heart is audible by 20 weeks in 80 percent of women, and by 22 weeks, heart sounds are expected to be heard in all (Herbert, 1987). Because the fetus moves freely in amni onic fluid, the site on the maternal abdomen where fetal heart sounds can be heard best will vary.

Additionally, with ultrasonic auscultation, one may hear the unic soule, which is a sharp, whistling sound that is syn chronous with the fetal pulse. It is caused by the rush of blood through the umbilical arteries and may not be heard consistently.

In contrast, the uterine soule is a soft, blowing sound that is synchronous with the maternal pulse. It is produced by the pas sage of blood through the dilated uterine vessels and is heard most distinctly near the lower portion of the uterus.

Sonography provides invaluable information regarding fetal anatomy, growth, and well-being, and most women in the United States have at least one prenatal sonographic examination during pregnancy (American College of Obstetricians and Gynecologists, 2016h). Continuing trends suggest that the number of these examinations performed per pregnancy is increasing. Siddique and associates (2009) reported that the average number rose from 1.5 in 1995 through 1997 to 2.7 almost 10 years later. his trend was noted in both high-and low-risk pregnancies. he actual clinical utility of this increased use in pregnancy has not been demonstrated, and it is unclear that the cost-benefit ratio is justified (Washington State Health Care Authority, 2010). The American College of Obstetricians and Gynecologists (20e16h) has concluded that sonography should be performed only when there is a valid medical indication and under the lowest possible ultrasound exposure setting. The College further states that a physician is not obligated to perform sonography without a specific indication in a low-risk patient, but that if she requests sonographic screening, it is reasonable to honor her request.

If initial results were normal, most tests need not be repeated. Hematocrit or hemoglobin determination, along with serology for syphilis if it is prevalent in the population, is repeated at 28 to 32 weeks (Hollier, 2003; Kiss, 2004). For women at increased risk for HIV acquisition during pregnancy, repeat testing is recommended in the third trimester, preferably before 36 weeks (American College of Obstetricians and Gynecologists, 20 16). Similarly, women who engage in behaviors that place them at high risk for hepatitis B virus infection are retested at the time of hospitalization for delivery. Women who are D (h) negative and are unsensitized should have an antibody screening test repeated at 28 to 29 weeks, and anti-D immunoglobulin is given if they remain unsensitized (Chap. 15, p. 305).

he CDC (20e1e0b) recommends that vaginal and rectal group B streptococcal (GBS) cultures be obtained in all women between 35 and 37 weeks' gestation, and the American College of Obstetricians and Gynecologists (20e1e6g) has endorsed this recommendation. Intrapartum antimicrobial prophylaxis is provided to those whose culture results are positive. Women with GBS bacteriuria or a previous infant with invasive disease are given empirical intrapartum prophylaxis. Trials are in progress to test an investigational vaccine (Donders, 2016; Schrag, 2016). hese infections are described further in Chapter 64 (p. 1220).

All pregnant women are screened for gestational diabetes mellitus, whether by history, clinical factors, or routine laboratory testing. Although laboratory testing between 24 and 28 weeks' gestation is the most sensitive approach, there may be pregnant women at low risk who are less likely to beneit from testing (American College of Obstetricians and Gynecologists, 2017c). Gestational diabetes is discussed in Chapter 57 (p. 11 07).

Serum screening for neural-tube defects is ofered at 15 to 20 weeks. Fetal aneuploidy screening may be performed at 11 to 14 weeks' gestation and/or at 15 to 20 weeks, depending on the protocol selected (Rink, 2016). Additionally, screening for certain genetic abnormalities is ofered to women at increased risk based on family history, ethnic or racial background, or age (American College of Obstetricians and Gynecologists, 20 17h). These are discussed in greater detail in Chapter 14 (p. 277). Some examples include testing for Tay-Sachs disease for persons of Eastern European Jewish or French Canadian ancestry; �-thalassemia for those of Mediterranean, Southeast Asian, Indian, Pakistani, or Mrican ancestry; a-thalassemia for individuals of Southeast Asian or Mrican ancestry; sickle-cell anemia for people of African, Mediterranean, Middle Eastern, Caribbean, Latin American, or Indian descent; and trisomy 21 for those with advanced maternal age.

In 2009, the Institute of Medicine and National Research Council revised guidelines for weight gain in pregnancy and continued to stratiy suggested weight gain ranges based on prepregnancy body mass index (BMI) (Table 9-4). The new guidelines included a specific, relatively narrow range of recommended weight gains for obese women. Also, the same recommendations apply to adolescents, short women, and women of

TABLE 9-4. Recommendations for Total and Rate of Weight Gain During Pregnancy

Underweight 28-40 1 (1l-1l.3) «1l8.5)

Normal weight 25-35 1 (0.8-1) (1l8.5-24.9)

Overweight 15-25 0.6 (0.5-0.7) (25.0-29.9)

Obese (::30.0) 11l-20 0.5 (0.4-0.6) aEmpirical recommendations for weight gain in twin pregnancies include: normal BMI, 37-54 Ib; overweight women, 31-50 Ib; and obese women, 25-42 lb. BMI = body mass index. Modified from the Institute of Medicine and National Research Council, 2009.

all racial and ethnic groups. The American College of Obstetricians and Gynecologists (2016i) has endorsed these measures.

When the Institute of Medicine guidelines were formulated, concern focused on low-birthweight newborns, however, current emphasis is directed to the obesity epidemic (Catalano, 2007). This explains renewed interest in lower weight gains during pregnancy. Obesity is associated with significantly greater risks for gestational hypertension, preeclampsia, gestational diabetes, macrosomia, cesarean delivery, and other complications (Chap. 48, p. 939). he risk appears "dose related" to prenatal weight gain. In a population-based cohort of more than 120,000 obese pregnant women, those who gained <15 lb had the lowest rates of preeclampsia, large-for-gestational age neonates, and cesarean delivery (Kiel, 2007). Among 100,000 women with normal prepregnancy BMI, De Vader and colleagues (2007) found that those who gained <25 Ib during pregnancy had a lower risk for preeclampsia, failed induction, cephalopelvic disproportion, cesarean delivery, and large-for-gestational age neonates. his cohort, however, had an increased risk for smallfor-gestational age newborns. Lifestyle intervention during pregnancy can result in less weight gain (Sagedal, 2017).

There is irrefutable evidence that maternal weight gain during pregnancy inluences birthweight. Martin and coworkers (2009) studied this using birth certificate data for 2006. Approximately 60 percent of women gained 26 Ib or more during pregnancy, and maternal weight gain positively correlated with birthweight. Nloreover, women with the greatest risk14 percent-for delivering a newborn weighing <2500 g were those with weight gain < 16 lb. Nearly 20 percent of births to women with such low weight gains were preterm.

Meaningful studies of nutrition in human pregnancy are exceedingly diicult to design because experimental dietary deficiency is not ethical. In those instances in which severe nutritional deiciencies have been induced as a consequence of social, economic, or political disaster, coincidental events have oten created many variables, the efects of which are not amenable to quantiication. Some past experiences suggest, however, that in otherwise healthy women, a state of near starvation is required to establish clear diferences in pregnancy outcome.

During the severe European winter of 1944 to 1945, nutritional deprivation of known intensity prevailed in a wellcircumscribed area of The Netherlands occupied by the German military (Kyle, 2006). At the lowest point during this Dutch Hunger Winter, rations reached 450 kcal/d, with generalized rather than selective malnutrition. Smith (1947) analyzed the outcomes of pregnancies that were in progress during this 6-month famine. Median neonatal birthweights declined approximately 250 g and rose again ater food became available. This indicated that birthweight can be inluenced significantly by starvation during later pregnancy. he perinatal mortality rate, however, was not altered. Moreover, the incidence of fetal malformations or preeclampsia did not rise signiicantly. Parenthetically, weight loss in obese women during pregnancy is also associated with an increased risk for low-birthweight neonates (Cox Bauer, 2016).

Evidence of impaired brain development has been obtained in some animal fetuses whose mothers had been subjected to intense dietary deprivation. Subsequent intellectual development was studied by Stein and associates (1972) in young male adults whose mothers had been starved during pregnancy in the aforementioned Hunger Winter. The comprehensive study was made possible because all males at age 19 underwent compulsory examination for military service. It was concluded that severe dietary deprivation during pregnancy caused no detectable efects on subsequent mental performance.

Several studies of the long-term consequences to this cohort of children born to nutritionally deprived women have been performed and have been reviewed by Kyle and Pichard (2006).

Progeny deprived in mid to late pregnancy were lighter, shorter, and thinner at birth, and they had a higher incidences of sub sequent hypertension, reactive airway disease, dyslipidemia, diminished glucose tolerance, and coronary artery disease. Early pregnancy deprivation was associated with greater obesity rates in adult women but not men. Early starvation was also linked to higher rates of central nervous system anomalies, schizophre nia, and schizophrenia-spectrum personality disorders.

hese observations and others have led to the concept of etal programming by which adult morbidity and mortality are related to fetal health. Known widely as the Barker hypothesis, as promulgated by Barker and colleagues (1989), this concept is discussed in Chapter 44 (p. 848).

Not all the weight gained during pregnancy is lost during and immediately after delivery. Schauberger and coworkers (1992) studied prenatal and postpartum weights in 795 women. Their average weight gain was 28.6 Ib or 12.9 kg. As shown in Figure 9-4, most maternal weight loss was at deliveryapproximately 12 lb or 5.4 kg-and in the ensuing 2 weeksapproximately 9 Ib or 4 kg. An additional 5.5 lb or 2.5 kg was lost between 2 weeks and 6 months postpartum. Thus, average retained pregnancy weight was 2.1 Ib or 1 kg. Excessive weight gain is manifest by accrual of fat and may be partially retained as long-term fat (Berggren, 2016; Widen, 2015). Overall, the more weight that was gained during pregnancy, the more that was lost postpartum. Interestingly, there is no relationship between pre pregnancy BMI or prenatal weight gain and weight retention.

Periodically, the Institute of Medicine (2006, 2011) publishes recommended dietary allowances, including those for pregnant aRecommendations measured as adequate intake.

Calories are necessary for energy. Whenever caloric intake is inadequate, protein is metabolized rather than being spared for its vital role in fetal growth and development. Total physiologiWeeks of pregnancy cal requirements during pregnancy are not necessarily the sum or lactating women. The latest recommendations are summarized in Table 9-5. Certain prenatal vitamin-mineral supplements may lead to intakes well in excess of the recommended allowances. Moreover, the use of excessive supplements, which often are self-prescribed, has led to concern regarding nutrient toxicities during pregnancy. Those with potentialy toxic fects include iron, zinc, selenium, and vitamins A, B6, C, and D.

As shown in Figure 9-5, pregnancy requires an additional 80,000 kcal, mostly during the last 20 weeks. To meet this demand, a caloric increase of 100 to 300 kcal/d is recommended during pregnancy (American Academy of Pediatrics and the American College of Obstetricians and Gynecologists, 2017). This greater intake, however, should not be divided equally during the course of pregnancy. The Institute ofMedicine (2006) recommends adding 0, 340, and 452 kcal/d to the estimated nonpregnantenergy requirements in the irst, second, and third trimesters, respectively. he addition of 1000 kcal/d or more results in fat accrual Qebeile, 2015).

From the Institute of Medicine, 2006, 2011.

pregnancy may be compensated in whole or in part by reduced physical activity (Hytten, 1991).

Protein requirements rise to meet the demands for growth and remodeling of the fetus, placenta, uterus, and breasts, and for 80,000 70,000 60,000 Maintenance ) 50,000 � 40,000 30,000 20,000 10,000

FIGURE 9-4 Cumulative weight loss from last antepartum visit to 6 months postpartum. *Significantly different from 2-week weight loss; **Significantly different from 6-week weight loss. (Redrawn from Schauberger CW, Rooney BL, Brimer LM: Factors that influence weight loss in the puerperium. Obstet Gynecol 79:424, 1992.)

FIGURE 9-5 Cumulative kilocalories required for pregnancy. (Redrawn of ordinary nonpregnant requirements plus those speciic to from Chamberlain G, Broughton-Pipkin F (eds): Clinical Physiology in pregnancy. For example, the additional energy required during Obstetrics, 3rd ed. Oxford, Blackwell Science, 1998.) increased maternal blood volume (Chap. 4, p. 55). During the second half of pregnancy, approximately 1000 g of protein are deposited, amounting to 5 to 6 g/d (Hytten, 1971). To accomplish this, protein intake that approximates 1 g/kg/ d is recommended (see Table 9-5). Data suggest this should be doubled in late gestation (Stephens, 2015). Most amino-acid levels in maternal plasma fall markedly, including ornithine, glycine, taurine, and proline (Hytten, 1991). Exceptions during pregnancy are glutamic acid and alanine, the concentrations of which rise.

Preferably, most protein is supplied from animal sources, such as meat, milk, eggs, cheese, poultry, and fish. hese furnish amino acids in optimal combinations. Milk and dairy products are considered nearly ideal sources of nutrients, especially protein and calcium, for pregnant or lactating women. Ingestion of specific ish and potential methylmercury toxicity are discussed on page 170.

The intakes recommended by the Institute of Medicine (2006) for various minerals are listed in Table 9-5. With the exception of iron and iodine, practically all diets that supply suicient calories for appropriate weight gain will contain enough minerals to prevent deiciency.

Iron requirements are greatly increased during pregnancy, and reasons for this are discussed in Chapter 4 (p. 58). Of the approximately 300 mg of iron transferred to the fetus and placenta and the 500 mg incorporated into the expanding maternal hemoglobin mass, nearly all is used after midpregnancy. During that time, iron requirements imposed by pregnancy and maternal excretion total approximately 7 mg/ d (Pritchard, 1970). Few women have suicient iron stores or dietary intake to supply this amount. Thus, the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (20e17) endorse the recommendation by the National Academy of Sciences that at least 27 mg of elemental iron be supplemented daily to pregnant women. his amount is contained in most prenatal vitamins.

Scott and coworkers (1970) established that as little as 30 mg of elemental iron, supplied as ferrous gluconate, sulfate, or fumarate and taken daily throughout the latter half of pregnancy, provides suicient iron to meet pregnancy requirements and protect preexisting iron stores. his amount will also provide for iron requirements of lactation. he pregnant woman may benefit from 60 to 100 mg of elemental iron per day if she is large, has a multifetal gestation, begins supplementation late in pregnancy, takes iron irregularly, or has a somewhat depressed hemoglobin level. he woman who is overtly anemic from iron deficiency responds well to oral supplementation with iron salts. In response, serum ferritin levels rise more than the hemoglobin concentration (Daru, 2016).

Iodine is also needed, and the recommended iodine allowance is 220 Lg/d (see Table 9-5). The use of iodized salt and bread products is recommended during pregnancy to ofset the increased fetal requirements and maternal renal losses of iodine. Despite this, iodine intake has declined substantially in the past 15 years, and in some areas it is probably inadequate (Casey, 2017). Severe maternal iodine deficiency predisposes ofspring to endemic cretinism, which is characterized by multiple severe neurological defects. In parts of China and Africa where this condition is common, iodide supplementation very early in pregnancy prevents some cretinism cases (Cao, 1994). To obviate this, many prenatal supplements now contain various quantities of iodine.

Cacium is retained by the pregnant woman during gestation and approximates 30 g. Most of this is deposited in the fetus late in pregnancy (Pitkin, 1985). his amount of calcium represents only approximately 2.5 percent of total maternal calcium, most of which is in bone and can readily be mobilized for fetal growth. s another potential use, routine calcium supplementation to prevent preeclampsia has not proved efective (Chap. 40, p. 727).

Zinc deficiency if severe may lead to poor appetite, suboptimal growth, and impaired wound healing. During pregnancy, the recommended daily intake approximates 12 mg. But, the safe level of zinc supplementation for pregnant women has not been clearly established. Vegetarians have lower zinc intakes (Foster, 2015). he bulk of studies support zinc supplementation only in zinc-deficient women in poor-resource countries (Nossier, 2015; Ota, 2015).

Manesium deficiency as a consequence of pregnancy has not been recognized. Undoubtedly, during prolonged illness with no magnesium intake, the plasma level might become critically low, as it would in the absence of pregnancy. We have observed magnesium deiciency during pregnancies in some with previous intestinal bypass surgery. As a preventive agent, Sibai and coworkers (1989) randomly assigned 400 normotensive primigravid women to 365-mg elemental magnesium supplementation or placebo tablets from 13 to 24 weeks' gestation. Supplementation did not improve any measures of pregnancy outcome.

Trace metals include copper, selenium, chromium, and manganese, which all have important roles in certain enzyme functions. In general, most are provided by an average diet. Selenium deficiency is manifested by a frequently fatal cardiomyopathy in young children and reproductive-aged women. Conversely, selenium toxicity resulting from oversupplementation also has been observed. Selenium supplementation is not needed in American women.

Potassium concentrations in maternal plasma decline by approximately 0.5 mEq/L by midpregnancy (Brown, 1986). Potassium deficiency develops in the same circumstances as in nonpregnant individuals-a common example is hyperemesis gravidarum.

Fluoride metabolism is not altered appreciably during pregnancy (Maheshwari, 1983). Horowitz and Heifetz (1967) concluded that no additional ofspring beneits accrued from maternal ingestion of luoridated water if the newborn ingested such water from birth. Sa Roriz Fonteles and associates (2005) studied microdrill biopsies of deciduous teeth and concluded that antenatal luoride provided no additional fluoride uptake compared with postnatal fluoride alone. Finally, supplemental luoride ingested by lactating women does not raise the luoride concentration in breast milk (Ekstrand, 1981).

he increased requirements for most vitamins during pregnancy shown in Table 9-5 usually are supplied by any general diet that provides adequate calories and protein. he excep tion is folic acid during times of unusual requirements, such as pregnancy complicated by protracted vomiting, hemo lytic anemia, or multiple fetuses. hat said, in impoverished countries, routine multivitamin supplementation reduced the incidence of low-birthweight and growth-restricted fetuses, (Fawzi, 2007).

neural-tube defect risks (Chap. 13, p. 270). Namely, the CDC (2004) estimated that the number of afected pregnancies had decreased from 4000 pregnancies per year to approximately 3000 per year after mandatory fortiication of cereal products with folic acid in 1998. Perhaps more than half of all neural tube defects can be prevented with daily intake of 400 �g of folic acid throughout the periconceptional period. Evidence development (Ars, 2016). Putting 140 �g of folic acid into each 100 g of grain products may increase the folic acid intake of the average American woman of childbearing age by 1 00 �g/ d.

Because nutritional sources alone are insuicient, however, folic acid supplementation is still recommended (American

College of Obstetricians and Gynecologists, 20 16e). Likewise, the U.S. Preventive Services Task Force (2009) recommends that all women planning or capable of pregnancy take a daily supplement containing 400 to 800 �g of folic acid.

A woman with a prior child with a neural-tube defect can reduce the 2-to 5-percent recurrence risk by more than 70 percent with a daily 4-mg folic acid supplement taken during the month before conception and during the first trimester. As emphasized by the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017), this dose should be consumed as a separate supplement and not as multivitamin tablets. This practice avoids excessive intake of fat-soluble vitamins.

Vitamin A, although essential, has been associated with congeni tal malformations when taken in high doses (> 10,000 IU / d) during pregnancy. These malformations are similar to those produced by the vitamin A derivative isotretinoin (Accutane), which is a potent teratogen (Chap. 12, p. 245). Beta-carotene, the precursor of vitamin A found in fruits and vegetables, has not been shown to produce vitamin A toxicity. Most prenatal vitamins contain vitamin A in doses considerably below the teratogenic threshold. Dietary intake of vitamin A in the United States appears to be adequate, and additional supplementation is not routinely recommended. In contrast, vitamin A deiciency is an endemic nutritional problem in the developing world (McCauley, 2015). Vitamin A deficiency, whether overt or subclinical, is associated with night blindness and with an increased risk of maternal anemia and spontaneous preterm birth (West, 2003).

Vitamin BJ2 plasma levels drop in normal pregnancy, mostly as a result of reduced plasma levels of their carrier proteinstranscobalamins. Vitamin BJ2 occurs naturally only in foods of animal origin, and strict vegetarians may give birth to neonates whose BI2 stores are low. Likewise, because breast milk of a vegetarian mother contains little vitamin B12, the deiciency may become profound in the breastfed infant (Higginbottom, 1978). Excessive ingestion of vitamin C also can lead to a functional deiciency of vitamin B12. Although its role is still controversial, vitamin BI2 deiciency preconceptionally, similar to folate, may elevate the risk of neural-tube defects (Molloy, 2009).

Vitamin B6, which is pyridoxine, does not require supple mentation in most gravidas (Salam, 2015). For women at high risk for inadequate nutrition, a daily 2-mg supplement is rec ommended. As discussed on page 174, vitamin B6, when com bined with the antihistamine doxylamine, is helpful in many cases of nausea and vomiting of pregnancy.

Vitamin C allowances during pregnancy are 80 to 85 mg/ d

Table 9-5). A reasonable diet should readily provide this amount, and supplementation is not necessary (Rumbold, 2015). Maternal plasma levels decline during pregnancy, whereas cord-blood levels are higher, a phenomenon observed with most water-soluble vitamins.

Vitamin D is a fat-soluble vitamin. After being metabolized to its active form, it boosts the eiciency of intestinal calcium absorption and promotes bone mineralization and growth. Unlike most vitamins that are obtained exclusively from dietary intake, vitamin D is also synthesized endogenously with exposure to sunlight. Vitamin D deiciency is common during pregnancy. his is especially true in high-risk groups such as women with limited sun exposure, vegetarians, and ethnic minoritiesparticularly those with darker skin (Bodnar, 2007). Maternal deiciency can cause disordered skeletal homeostasis, congenital rickets, and fractures in the newborn (American College of Obstetricians and Gynecologists, 2017k). Vitamin D supplementation to women with asthma may decrease the likelihood of childhood asthma in their fetuses (Litonjua, 2016). The Food and Nutrition Board of the Institute of Medicine (2011) established that an adequate intake of vitamin D during pregnancy and lactation was 15 �g/d (600 IU/d). In women suspected of having vitamin D deficiency, serum levels of 25-hydroxyvitamin D can be obtained. Even then, the optimal levels in pregnancy have not been established (De-Regil, 2016).

Although researchers continue to study the ideal nutritional regimen for the pregnant woman and her fetus, basic tenets for the clinician include: 1.

Advise the pregnant woman to eat food types she wants in reasonable amounts and salted to taste.

2.

Ensure that food is amply available for socioeconomically deprived women.

3.

Monitor weight gain, with a goal of approximately 25 to 35elb in women with a normal BMI.

4.

Explore food intake by dietary recall periodically to discover the occasional nutritionally errant diet.

5.

Give tablets of simple iron salts that provide at least 27 mg of elemental iron daily. Give folate supplementation before and in the early weeks of pregnancy. Provide iodine supplementation in areas of known dietary insuiciency.

6.

Recheck the hematocrit or hemoglobin concentration at 28 to 32 weeks' gestation to detect signiicant anemia.

TABLE 9-6. Some Contraindications to Exercise During Pregnancy

Significant cardiovascular or pulmonary disease Significant risk for preterm labor: cerclage, multifetal gestation, significant bleeding, threatened preterm labor, prematurely ruptured membranes Obstetrical complications: preeclampsia, placenta previa, poorly controlled diabetes or epilepsy, morbid obesity,

Summarized from American College of Obstetricians and Gynecologists, 2017g.

More than half of the children in the United States are born to working mothers. Federal law prohibits employers from excluding women from job categories on the basis that they are or might become pregnant. he Family and Medical Leave Act of 1993 requires that covered employers must grant up to 12 work weeks of unpaid leave to an employee for the birth and care of a newborn child Qackson, 2015). In the absence of complications, most women can continue to work until the onset of labor (American Academy of Pediatrics and the American College of Obstetricians and Gynecologists, 2017).

Some types of work, however, may increase pregnancy complication risks. Mozurkewich and colleagues (2000) reviewed 29 studies that involved more than 160,000 pregnancies. With physically demanding work, women had 20-to 60-percent higher rates of preterm birth, fetal-growth restriction, or gestational hypertension. In a prospective study of more than 900 healthy nulliparas, women who worked had a ivefold risk of preeclampsia (Higgins, 2002). Newman and coworkers (2001) reported outcomes in more than 2900 women with singleton pregnancies. Occupational fatigue-estimated by the number of hours standing, intensity of physical and mental demands, and environmental stressors-was associated with an increased risk of preterm premature membrane rupture. For women reporting the highest degrees of fatigue, the risk was 7.4 percent.

Thus, any occupation that subjects the gravida to severe physical strain should be avoided. Ideally, no work or play is continued to the extent that undue fatigue develops. Adequate periods of rest should be provided. It seems prudent to advise women with prior pregnancy complications that commonly recur to minimize physical work.

In general, pregnant women do not need to limit exercise, provided they do not become excessively fatigued or risk injury (Davenport, 2016). Clapp and associates (2000) reported that both placental size and birthweight were signiicantly greater in women who exercised. Duncombe and coworkers (2006) reported similar findings in 148 women. In contrast, vfagann and colleagues (2002) prospectively analyzed exercise behavior in 750 healthy women and found that working women who exercised had smaller infants and more dysfunctional labors.

The American College of Obstetricians and Gynecologists (2017 g) advises a thorough clinical evaluation before recommending an exercise program. In the absence of contraindications listed in Table 9-6, pregnant women are encouraged to engage in regular, moderate-intensity physical activity for at least 150 minutes each week. Each activity should be reviewed individually for its potential risk. Examples of safe activities are walking, running, swimming, stationary cycling, and low-impact aerobics. However, they should refrain from activities with a high risk of falling or abdominal trauma. Similarly, scuba diving is avoided because the fetus is at increased risk for decompression sickness.

In the setting of certain pregnancy complications, it is wise to abstain from exercise and even limit physical activity. For example, some women with pregnancy-associated hypertensive disorders, preterm labor, placenta previa, or severe cardiac or pulmonary disease may gain from being sedentary. Also, those with multiple or suspected growth-restricted fetuses may be served by greater rest.

Fish are an excellent source of protein, are low in saturated fats, and contain omega-3 fatty acids. The Avon Longitudinal Study of Parents and Children reported beneicial efects on pregnancy outcomes in women who consumed 340 g or more of seafood weekly (Hibbeln, 2007). Because nearly all fish and shellish contain trace amounts of mercury, pregnant and lactating women are advised to avoid specific types of ish with potentially high methylmercury levels. These include shark, swordfish, king mackerel, and tile fish. It is further recommended that pregnant women ingest 8 to 12 ounces of fish weely, but no more than 6 ounces of albacore or "white" tuna (U.S. Environmental Protection Agency, 2014). If the mercury content oflocally caught fish is unknown, then overall fish consumption should be limited to 6 ounces per week (American Academy of Pediatrics and the American College of Obstetricians and Gynecologists, 2017) .

Maternal lead exposure has been associated with several adverse maternal and fetal outcomes across a range of maternal blood lead levels (Taylor, 2015). These include gestational hypertension, miscarriage, low birthweight, and neurodevelopmental impairments in exposed pregnancies (American College of Obstetricians and Gynecologists, 2016c). The levels at which these risks rise remains unclear. However, recognizing that such exposure remains a significant health issue for reproductive-aged women, the CDC (201 Oa) has issued guidance for screening and managing exposed pregnant and lactating women. These guidelines, which have been endorsed by the American College of Obstetricians and Gynecologists (2016c), recommend blood lead testing only if a risk factor is identified. If the levels are > 5 /Lg1 dL, then counseling is completed, and the lead source is sought and removed. Subsequent blood levels are obtained. Blood lead levels >45 Lg/dL are consistent with lead poisoning, and women in this group may be candidates for chelation therapy. Afected pregnancies are best managed in consultation with lead poisoning treatment experts. National and state resources are available at the CDC website: ww.cdc.gov/ncehllead/.

Pregnant women are encouraged to wear properly positioned three-point restraints as protection against automobile crash injury (Chap. 47, p. 927). The lap portion of the restraining belt is placed under the abdomen and across her upper thighs. The belt should be comfortably snug. The shoulder belt also is irmly positioned between the breasts. Airbags should not be disabled for the pregnant woman.

In general, air travel in a properly pressurized aircraft has no harmful efect on pregnancy (Aerospace Medical Association, 2003). Thus, in the absence of obstetrical or medical complications, the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (20 16a, 2017) have concluded that pregnant women can safely ly up to 36 weeks' gestation. It is recommended that pregnant women observe the same precautions for air travel as the general population. Seatbelts are used while seated. Periodic lower extremity movement and at least hourly ambulation help lower the venous thromboembolism threat. Signiicant risks with travel, especially international travel, are infectious disease acquisition and development of complications remote from adequate healthcare resources (Ryan, 2002).

In healthy pregnant women, sexual intercourse usually is not harmul. Whenever miscarriage, placenta previa, or preterm labor threatens, however, coitus is avoided. Nearly 10,000 women enrolled in a prospective investigation by the Vaginal Infection and Prematurity Study Group were interviewed regarding sexual activity (Read, 1993). hey reported a decreased frequency of coitus with advancing gestation. By 36 weeks, 72 percent had intercourse less than once weekly. The decline is attributed to lower desire and fear of harming the pregnancy (Bartellas, 2000; Staruch, 2016).

Intercourse speciically late in pregnancy is not harmful. Grudzinskas and coworkers (1979) noted no association between gestational age at delivery and coital frequency during the last 4 weeks of pregnancy. Sayle and colleagues (2001) reported no increased-and actually a decreased-risk of delivery within 2 weeks of intercourse. Tan and associates (2007) studied women scheduled for non urgent labor induction and found that spontaneous labor ensued at equal rates in groups either participating in or abstaining from intercourse.

Oral-vaginal intercourse is occasionally hazardous. Aronson and Nelson (1967) described a fatal air embolism late in pregnancy as a result of air blown into the vagina during cunnilingus. Other near-fatal cases have been described (Bernhardt, 1988).

Examination of the teeth is included in the prenatal examination, and good dental hygiene is encouraged. Indeed, periodontal disease has been linked to preterm labor. Unfortunately, although its treatment improves dental health, it does not prevent preterm birth (Michalowicz, 2006). Dental caries are not aggravated by pregnancy. Importantly, pregnancy is not a contraindication to dental treatment including dental radiographs (Giglio, 2009) .

Current recommendations for immunization during pregnancy are summarized in Table 9-7. Well-publicized concerns regarding a causal link between childhood exposure to the thimerosal preservative in some vaccines and neuropsychological disorders have led to some parents to vaccine prohibition. Although controversy continues, these associations have proven groundless (Sugarman, 2007; Thompson, 2007; Tozzi, 2009). Thus, many vaccines may be used in pregnancy. The American College of Obstetricians and Gynecologists (20 16b) stresses the importance of integrating an efective vaccine strategy into the care of both obstetrical and gynecological patients. The College further emphasizes that information on the safety of vaccines given during pregnancy is subject to change, and recommendations can be found on the CDC website at ww.cdc.gov/vaccines.

he frequency of pertussis infection has substantially risen in the United States. Young infants are at increased risk for death from pertussis and are entirely dependent on passive immunization from maternal antibodies until the infant vaccine series is initiated at age 2 months. For this reason, a three-agent tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (T dap) vaccine is recommended and is safe for pregnant women (Centers for Disease Control and Prevention, 2013b, 2016; Morgan, 2015). However, as demonstrated by Healy and coworkers (2013), maternal antipertussis antibodies are relatively shortlived, and T dap administration before pregnancy-or even in the first half of the current pregnancy-is not likely to provide a high level of newborn antibody protection. Thus, to maximize passive antibody transfer to the fetus, a dose of T dap is ideally given to gravidas between 27 and 36 weeks' gestation (American College of Obstetricians and Gynecologists, 2017j; Centers for Disease Control and Prevention, 2013b, 2016).

All women who will be pregnant during inluenza season should be ofered vaccination, regardless of gestational age. hose with underlying medical conditions that increase the risk for influenza complications are provided the vaccine before lu season starts. In addition to maternal protection against infection, prenatal maternal vaccination in one study reduced the infant influenza incidence in the irst 6 months of life by 63 percent (Zaman, 2008). Moreover, it reduced all febrile respiratory illnesses in these infants by a third.

Women who are susceptible to rubella during pregnancy should receive measles, mumps, rubella (MMR) vaccination postpartum. Although this vaccine is not recommended during

TABLE 9-7. Continued

Rabies Postexposure prophylaxis Half dose at injury site, half dose in Used in conjunction with rabies deltoid killed-virus vaccine

Tetanus Postexposure prophylaxis One dose 1M Used in conjunction with tetanus

Varicella Should be considered for One dose 1M within 96 hours of Indicated also for newborns or exposed pregnant women exposure women who developed varicella to protect against maternal, within 4 days before delivery or not congenital, infection 2 days following delivery

Hepatitis A: Postexposure prophylaxis and 0.02 mUkg 1M in one dose Immune globulin should be given Hepatitis A those at high risk as soon as possible and within virus vaccine 2 weeks of exposure; infants should be used born to women who are with hepatitis A incubating the virus or are immune globulin acutely ill at delivery should receive one dose of0.5 mL as soon as possible after birth 'Two doses necessary for students entering institutions of higher education, newly hired medical personnel, and travel abroad. blnactlvated polio vaccine recommended for nonimmunized adults at increased risk.

10 = intradermally; 1M = intramuscularly; MMR = measles, mumps, rubella; PO = orally; SC = subcutaneously. From the Centers for Disease Control and Prevention, 201 1; Kim, 201 6.

pregnancy, congenital rubella syndrome has never resulted from its inadvertent use. Breastfeeding is compatible with MMR vaccination (Centers for Disease Control and Prevention, 201l).

Whether adverse pregnancy outcomes are related to cafeine consumption is somewhat controversial. As summarized from Chapter 18 (p. 348), heavy intake of cofee each day-about five cups or 500 mg of cafeine-slightly raises the miscarriage risk. Studies of "moderate" intake-less than 200 mg dailydid not find a higher risk.

It is unclear if cafeine consumption is associated with preterm birth or impaired fetal growth. Clausson and coworkers (2002) found no association between moderate cafeine consumption of less than 500 mg/d and low birthweight, fetalgrowth restriction, or preterm delivery. Bech and associates (2007) randomly assigned more than 1200 pregnant women who drank at least three cups of cofee per day to cafeinated versus decafeinated cofee. They found no diference in birthweight or gestational age at delivery between groups. The CARE Study Group (2008), however, evaluated 2635 lowrisk pregnancies and reported a l.4-fold risk for fetal-growth restriction among those whose daily cafeine consumption was >200 mg/d compared with those who consumed <100 mg/d. he American College of Obstetricians and Gynecologists (20e1e6d) concludes that moderate consumption of caffeine-less than 200 mg/ d-does not appear to be associated with miscarriage or preterm birth, but that the relationship between cafeine consumption and fetal-growth restriction remains unsettled. The American Dietetic Association (2008) recommends that cafeine intake during pregnancy be limited to less than 300 mg/d, which approximates three 5-oz cups of percolated cofee.

Nausea and vomiting are common complaints during the first half of pregnancy. These vary in severity and usually commence between the first and second missed menstrual period and continue until 14 to 16 weeks' gestation. Although nausea and vomiting tend to be worse in the morning-thus erroneously termed morning sickness-both symptoms frequently continue throughout the day. Lacroix and coworkers (2000) found that nausea and vomiting were reported by three fourths of pregnant women and lasted an average of35 days. Halfhad reliefby 14 weeks, and 90 percent by 22 weeks. In 80 percent of these women, nausea lasted all day.

Treatment of pregnancy-associated nausea and vomiting seldom provides complete relief, but symptoms can be minimized. Eating small meals at frequent intervals is valuable. One systematic literature search reported that the herbal remedy ginger was likely efective (Borrelli, 2005). Mild symptoms usually respond to vitamin BG given along with doxylamine, but some women require phenothiazine or HI-receptor blocking antiemetics (American College of Obstetricians and Gynecologists, 2015c). In some with hyperemesis gravidarum, vomiting is so severe that dehydration, electrolyte and acid-base disturbances, and starvation ketosis become serious problems.

Heartburn is another common complaint of gravidas and is caused by gastric content reflux into the lower esophagus. The greater frequency of regurgitation during pregnancy most likely results from upward displacement and compression of the stomach by the uterus, combined with relaxation of the lower esophageal sphincter. Avoiding bending over or lying flat is preventive. In most pregnant women, symptoms are mild and relieved by a regimen of more frequent but smaller meals. Antacids may provide considerable relief (Phupong, 2015). Specifically, aluminum hydroxide, magnesium trisilicate, or magnesium hydroxide is given alone or in combination. Management of heartburn or nausea that does not respond to simple measures is discussed in Chapter 54 (p. 1045).

The craving of pregnant women for strange foods is termed pica. Worldwide, its prevalence is estimated to be 30 percent (Fawcett, 2016). At times, nonfoods such as ice-pagophagia, starch-amylophagia, or clay-geophagia may predominate. This desire is considered by some to be triggered by severe iron deficiency. Although such cravings usually abate after deficiency correction, not all pregnant women with pica are iron deficient. Indeed, if strange "foods" dominate the diet, iron deficiency will be aggravated or will develop eventually.

Patel and coworkers (2004) prospectively completed a dietary inventory on more than 3000 women during the second trimester. The prevalence of pica was 4 percent. The most common nonfood items ingested were starch in 64 percent, dirt in 14 percent, sourdough in 9 percent, and ice in 5 percent. he prevalence of anemia was 15 percent in women with pica compared with 6 percent in those without it. Interestingly, the rate of spontaneous preterm birth before 35 weeks was twice as high in women with pica.

Women during pregnancy are occasionally distressed by profuse salivation-pyalism. Although usually unexplained, ptyalism sometimes appears to follow salivary gland stimulation by the ingestion of starch.

At least 5 percent of pregnancies are estimated to be complicated by new-onset or new-type headache (Spierings, 2016). Common headaches are virtually universal. Acetaminophen is suitable for most of these, and an in-depth discussion is found in Chapter 60 (p. 1057).

Low back pain to some extent is reported by nearly 70 percent of gravidas (Liddle, 2015; Wang, 2004). Minor degrees follow excessive strain or significant bending, lifting, or walking. It can be reduced by squatting rather than bending when reaching down, by using a back-support pillow when sitting, and by avoiding high-heeled shoes. Back pain complaints increase with progressing gestation and are more prevalent in obese women and those with a history of low back pain. In some cases, troublesome pain may persist for years after the pregnancy (Noren, 2002).

Severe back pain should not be attributed simply to pregnancy until a thorough orthopedic examination has been conducted. Severe pain has other uncommon causes that include pregnancy-associated osteoporosis, disc disease, vertebral osteoarthritis, or septic arthritis (Smith, 2008). More commonly, muscular spasm and tenderness are classiied clinically as acute strain or ibrositis. Although evidence-based clinical research directing care in pregnancy is limited, low back pain usually responds well to analgesics, heat, and rest. Acetaminophen may be used chronically as needed. Nonsteroidal antiinlammatory drugs may also be beneicial but are used only in short courses to avoid fetal efects (Chap. 12, p. 241). Muscle relaxants that include cyclobenzaprine or baclofen may be added when needed. Once acute pain is improved, stabilizing and strengthening exercises provided by physical therapy help improve spine and hip stability, which is essential for the increased load of pregnancy. For some, a support belt that stabilizes the sacroiliac joint may be helpful (Gutke, 2015).

Venous leg varicosities have a congenital predisposition and accrue with advancing age. They can be aggravated by factors that raise lower extremity venous pressures, such as an enlarging uterus. Femoral venous pressures in the supine gravida rise from 8 mm Hg in early pregnancy to 24 mm Hg at term. Thus, leg varicosities typically worsen as pregnancy advances, especially with prolonged standing. Symptoms vary from cosmetic blemishes and mild discomfort at the end of the day to severe discomfort that requires prolonged rest with feet elevation. Treatment is generally limited to periodic rest with leg elevation, elastic stockings, or both. Surgical correction during pregnancy generally is not advised, although rarely the symptoms may be so severe that injection, ligation, or even stripping of the veins is necessary.

Vulvar varicosities frequently coexist with leg varicosities, but they may appear without other venous pathology. Uncommonly, they become massive and almost incapacitating. If these large varicosities rupture, blood loss can be severe. Treatment is with specially itted pantyhose that will also minimize lower extremity varicosities. With particularly bothersome vulvar varicosities, a foam rubber pad suspended across the vulva by a belt can be used to exert pressure on the dilated veins.

Hemorrhoids are rectal vein varicosities and may irst appear during pregnancy as pelvic venous pressures rise. Commonly, they are recurrences of previously encountered hemorrhoids. Up to 40 percent of pregnant women develop these (Poskus, 2014). Pain and swelling usually are relieved by topically applied anesthetics, warm soaks, and stool-softening agents. With thrombosis of an external hemorrhoid, pain can be considerable. This may be relieved by incision and removal of the clot following injection of a local anesthetic.

Beginning early in pregnancy, many women experience fatigue and need greater amounts of sleep. his likely is due to the soporiic efect of progesterone but may be compounded in the irst trimester by nausea and vomiting. In the latter stages, general discomforts, urinary frequency, and dyspnea can be additive. Sleep duration may be related to obesity and gestational weight gain (Facco, 2016; Lockhart, 2015). Moreover, sleep eiciency appears to progressively diminish as pregnancy advances. Wilson and associates (201i1) performed overnight polysomnography and observed that women in the third trimester had poorer sleep eiciency, more awakenings, and less of both stage 4 (deep) and rapid-eye movement sleep. Women in the irst trimester were also afected, but to a lesser extent. Daytime naps and mild sedatives at bedtime such as diphenhydramine (Benadryl) can be helpful.

Since the irst successful cord blood transplantation in 1988, more than 25,000 umbilical cord blood transplantations have been performed to treat hemopoietic cancers and various genetic conditions (Butler, 2011). There are two types of cord blood banks. Public banks promote allogeneic donation, for use by a related or unrelated recipient, similar to blood product donation (Armson, 2015). Private banks were initially developed to store stem cells for future autologous use and charged fees for initial processing and annual storage. The American College of Obstetricians and Gynecologists (20 15d) has concluded that if a woman requests information on umbilical cord banking, information regarding advantages and disadvantages of public versus private banking should be explained. Some states have passed laws that require physicians to inform patients about cord blood banking options. Importantly, few transplants have been performed by using cord blood stored in the absence of a known indication in the recipient (Screnci, 2016). The likelihood that cord blood would be used for the child or family member of the donor couple is considered remote, and it is recommended that directed donation be considered when an immediate family member carries the diagnosis of a speciic condition known to be treatable by hemopoietic transplantation (Chap. 56, p. 1075).

Aerospace Medical Association, Medical Guidelines Task Force: Medical guidelines for airline travel, 2nd ed. Aviat Space Environ Med 74:5, 2003 Afshar Y, Wang ET, Mei J, et al: Childbirth education class and birth plans are associated with a vaginal delivery. Birth 44(1):29, 2017

Ahmad F, Hogg-Johnson S, Stewart 0,et al: Computer-assisted screening for intimate parmer violence and control. Ann Intern Med 151 (2):94, 2009

American Academy of Pediarrics, American College of Obstetricians and Gynecologists: Guidelines for perinatal care, 8th ed. Elk Grove Village, AAP, 2017

American College of Obstetricians and Gynecologists: Intimate partner violence. Committee Opinion No. 518, February 2012

American College of Obstetricians and Gynecologists: Alcohol abuse and other substance use disorders: ethical issues in obsterric and gynecologic practice. Committee Opinion No. 633, June 2015a

American College of Obsterricians and Gynecologists: Fetal growth restriction.

Practice Bulletin No. 134, May 2013, Reairmed 2015b

American College of Obstetricians and Gynecologists: Nausea and vomiting of pregnancy. Practice Bulletin No. 153, September 2015c

American College of Obstetricians and Gynecologists: Umbilical cord blood banking. Committee Opinion No. 648, December 201s5d

American College of Obstetricians and Gynecologists: Air travel during pregnancy. Committee Opinion No. 443, October 2009, Reairmed 2016a American College of Obstetricians and Gynecologists: Integrating immuniza tion into practice. Committee Opinion No. 661, April 2016b

American College of Obstetricians and Gynecologists: Lead screening during pregnancy and lactation. Committee Opinion No. 533, August 2012, Reafirmed 2016c

American College of Obstetricians and Gynecologists: Moderate cafeine consumption during pregnancy. Committee Opinion No. 462, August 2010, Reairmed 2016d

American College of Obstetricians and Gynecologists: Neural tube defects.

Practice Bulletin No. 44, July 2003, Reairmed 2016e

American College of Obstetricians and Gynecologists: Prenatal and perinatal human immunodeficiency virus testing: expanded recommendations. Committee Opinion No. 635, June 2015, Reairmed 2016f

American College of Obstetricians and Gynecologists: Prevention of early onset group B streptococcal disease in newborns. Committee Opinion No. 485, April 20e11e, Reairmed 20e16g

American College of Obstetricians and Gynecologists: Ultrasound in pregnancy. Practice Bulletin No. 175, December 2016h

American College of Obstetricians and Gynecologists: Weight gain during pregnancy. Committee Opinion No. 548, January 2013, Reairmed 2016i American College of Obstetricians and Gynecologists: Avoiding inappropriate clinical decisions based on false-positive human chorionic gonadotropin test results. Committee Opinion No. 278, November 2002, Reairmed 20e17a

American College of Obstetricians and Gynecologists: Fetal alcohol spectrum disorders (FASD) prevention program. 2017b. Available at: http://www. acog.org/alcohol. Accessed October 23,e2017

American College of Obstetricians and Gynecologists: Gestational diabetes mellitus. Practice Bulletin No. 180, July 2017c

American College of Obstetricians and Gynecologists: Marijuana use during pregnancy and lactation. Committee Opinion No. 722, October 20e17d American College of Obstetricians and Gynecologists: Method for estimating the due date. Committee Opinion No. 700, May 2017e

American College of Obstetricians and Gynecologists: Opioid use and opioid use disorder in pregnancy. Committee Opinion No. 711, August 2017f

American College of Obstetricians and Gynecologists: Physical activity and exercise during pregnancy and the postpartum period. Committee Opinion No. 650, December 2015, Reairmed 2017g

American College of Obstetricians and Gynecologists: Carrier screening for genetic conditions. Committee Opinion No. 691, March 2017h

American College of Obstetricians and Gynecologists: Smoking cessation during pregnancy. Committee Opinion No. 721, October 2017i

American College of Obstetricians and Gynecologists: Update on immunization and pregnancy: tetanus, diphtheria, and pertussis vaccination. Committee Opinion No. 718, September 2017j

American College of Obstetricians and Gynecologists: Vitamin 0: screening and supplementation during pregnancy. Committee Opinion No. 495, July 201e1, Reairmed 2017k

American Dietetic Association: Position of the American Dietetic Association: nutrition and lifestyle for a healthy pregnancy outcome. J Am Diet Assoc 108:553,e2008

Armson BA, Allan OS, Casper F, et al: Umbilical cord blood: counseling, collection, and banking. J Obstet Gynaecol Can 37:832, 2015

Aronson ME, Nelson PK: Fatal air embolism in pregnancy resulting from an unusual sex act. Obstet Gynecol 30: 127, 1967

Ars CL, Nijs 1M, Marroun HE, et al: Prenatal folate, homocysteine and vitamin B12 levels and child brain volumes, cognitive development and psychological functioning: the Generation R Study. Br J Nutr 22: 1, 20e16 Barker OJ, Osmond C, Law CM: he intrauterine and early postnatal origins of cardiovascular disease and chronic bronchitis. J Epidemiol Community Health 43:237, 1989 Bartellas E, Crane JM, Daley M, et al: Sexuality and sexual activity in pregnancy. BJOG 107:964,e2000 Bech BH, Obel C, Henriksen TB, et al: Efect of reducing cafeine intake on birth weight and length of gestation: randomized controlled trial. BMJ 335:409,e2007 Berg q, Callaghan M, Syverson C, et al: Pregnancy-related mortality in the United States, 1998 to 2005. Obstet GynecoIe1l6(6):1302, 2010 Berggren EK, Groh-Wargo S, Presley L, et al: Maternal fat, but not lean, mass is increased among overweight/obese women with excess gestational weight gain. Am J Obstet GynecoIe214(6):745.e1, 2016 Bergsj0 P, Denman OW III, Hofman HJ, et al: Duration of human singleton pregnancy. A population-based study. Acta Obstet Gynecol Scand 69: 197, 1990 Berlin 1, Grange G, Jacob N, et al: Nicotine patches in pregnant smokers: randomized, placebo controlled, multicentre trial of eicacy. BMJ 348:g1622, 20e14 Bernhardt TL, Goldmann RW, Thombs PA, et al: Hyperbaric oxygen treatment of cerebral air embolism from orogenital sex during pregnancy. Crit Care Med 16:729, 1988 Bleich AT, Sheield JS, Wendel GO Jr, et al: Disseminated gonococcal infection in women. Obstet GynecoIe119(3):597, 2012 Bodnar LM, Simhan HN, Powers RW, et al: High prevalence of vitamin 0 insuiciency in black and white pregnant women residing in the northern United States and their neonates. J Nutr 137(2)e:447, 2007

Borrelli F, Capasso R, Aviello G, et al: Efectiveness and safety of ginger in the treatment of pregnancy-induced nausea and vomiting. Obstet Gynecol 105:849,e2005

Branson BM, Handsfield HH, Lampe A, et al: Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR 55(RR-14):1, 2006

Braunstein GO: False-positive serum human chorionic gonadotropin results: causes, characteristics, and recognition. Am J Obstet Gynecol 187:217, 2002

Braunstein GO: he long gestation of the modern home pregnancy test. Clin Chen 60(1):18, 2014

Brown A, Sinosich MJ, Saunders OM, et al: Potassium regulation and progesterone-aldosterone interrelationships in human pregnancy: a prospective study. Am J Obstet Gynecol 155:349, 1986

Butler MG, Menitove JE: Umbilical cord blood banking: an update. J Assist Reprod Genet 28:669,e2011

Cao XY, Jiang XM, Dou ZH, et al: Timing of vulnerability of the brain to iodine deiciency in endemic cretinism. N Engl J Med 331: 1739, 1994

CARE Study Group: Maternal cafeine intake during pregnancy and risk of fetal growth restriction: a large prospective observational study. BMJ 337:a2332,e2008

Carter EB, Temming A, Akin J, et al: Group prenatal care compared with traditional prenatal care: a systematic review and meta-analysis. Obstet GynecoIe128(3):551,e2016

Casey BM, hon A, Peaceman M, et al: Treatment of subclinical hypothyroidism or hypothyroxinemia in pregnancy. N Engl J Med 376(9):815, 20e17

Catalano PM: Increasing maternal obesity and weight gain during pregnancy: the obstetric problems of plentitude. Obstet Gynecol 110:743,e2007 Centers for Disease Control and Prevention: Entry into prenatal care-United States, 1989-1997. MMWR 49:393,e2000

Centers for Disease Control and Prevention: Spina biida and anencephly before and ater folic acid mandate-United States, 1995-1996 and 19992000. MMWR 53(17):362, 2004

Centers for Disease Control and Prevention: Guidelines for the identiication and management of lead exposure in pregnant and lactating women. November 2010a. Available at: http://www.cdc.gov/nceh/lead/publications/ leadandpregnancy2010.pd. Accessed September 19, 2016

Centers for Disease Control and Prevention: Prevention of perinatal group B streptococcal disease: revised guidelines from CDC, 2010. MMWR 59(10): 1, 2010b Centers for Disease Control and Prevention: General recommendations on immunization-recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 60(2):1,e2011

Centers for Disease Control and Prevention: PMS and smoking. 2013a. Available at: http://www.cdc.gov/prams/TobaccoandPrams.htm. Accessed September 18,e2016

Centers for Disease Control and Prevention: Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) in pregnant women-Advisory Committee on Immunization Practices (ACIP), 2012. MMWR 62(7):131, 2013b

Centers for Disease Control and Prevention: Guidelines for vaccinating pregnant women. 2016. Available at: http://www.cdc.gov/vaccines/pubs/ downloads/b_pre-guide. pdf. Accessed September 18, 2016

Chamberlain G, Broughton-Pipkin F (eds): Clinical Physiology in Obstetrics, 3rd ed. Oxford, Blackwell Science, 1998

Chen PH, Rovi S, Washington J, et al: Randomized comparison of 3 methods to screen for domestic violence in family practice. Ann Fam Med 5(5):430, 2007

Child Trends: Databank: late or no prenatal care. 2015. Available at: http://www. childtrends.org/?indicators=late-or-no-prenatal-care. Accessed September 19, 20e16

Clapp JF III, Kim H, Burciu B, et al: Beginning regular exercise in early pregnancy: efect on fetoplacental growth. Am J Obstet Gynecol 183: 1484, 2000

Clausson B, Granath F, Ekbom A, et al: Efect of cafeine exposure during pregnancy on birth weight and gestational age. Am J Epidemiol 155:429, 2002

Clement S, Candy B, Sikorski J, et al: Does reducing the frequency of routine antenatal visits have long term efects? Follow up of participants in a randomised controlled trial. BJOG 106:367, 1999

Coker L, Garcia LS, Williams CM, et al: Universal psychosocial screening and adverse pregnancy outcomes in an academic obstetric clinic. Obstet GynecoIe1l9(6):1180,e2012

Cole A: he utility of six over-the-counter (home) pregnancy tests. Clin Chen Lab Med 49(8): 1317,e2011

Coleman T, Chamberlain C, Davey MA, et al: Pharmacological interventions for promoting smoking cessation during pregnancy. Cochrane Database Syst Rev 12:CD010078, 2015

Cooper S, Taggar J, Lewis S, et al: Efect of nicotine patches in pregnancy on infant and maternal outcomes at 2 years: follow-up from the randomized, double-blind, placebo-controlled SNAP trial. Lancet Respir Med 2(9):728, 20e14

Cox Bauer CM, Bernhard A, Greer OM, et al: Maternal and neonatal outcomes in obese women who lose weight during pregnancy. J Perinatol 36(4):278,e2016

Daru K, Cooper NA, Khan KS: Systematic review of randomized trials of the efect of iron supplementation on iron stores and oxygen carrying capacity in pregnancy. Acta Obstet Gynecol Scand 95(3):270, 2016

Davenport MH, Skow RJ, Steinback CD: Maternal responses to aerobic exercise in pregnancy. Clin Obstet Gynecol 59(3):541, 2016

De-Regil LM, Palacios C, Lombardo LK, et al: Vitamin 0 supplementation for women during pregnancy. Cochrane Database Syst Rev 1 :CD008873, 20e16

DeVader SR, Neeley HL, Myles TO, et al: Evaluation of gestational weight gain guidelines for women with normal prep regnancy body mass index. Obstet Gynecole110:745, 2007

Donders GG, Halperin SA, Devligger R, et al: Maternal immunization with an investigational trivalent Group B streptococcal vaccine. Obstet Gynecol 127(2):213,e2016

Duncombe 0, Skouteris H, Wertheim EH, et al: Vigorous exercise and birth outcomes in a sample of recreational exercisers: a prospective study across pregnancy. Aust N Z J Obstet Gynaecol 46:288, 2006

Duryea EL, McIntire DO, Leveno KJ: The rate of preterm birth in the United States is afected by the method of gestational age assignment. Am J Obstet GynecoIe213:331, el, 2015

Ekstrand J, Boreus LO, de Chateau P: No evidence of transfer of luoride from plasma to breast milk. BMJ (Clin Res Ed) 61, 1981

EI-Mohandes A, Herman AA, Kl-Khorazaty MN, et al: Prenatal care reduces the impact of illicit drug use on perinatal outcomes. J Perinatol 23:354, 2003

Eriksen JLK, Pilliod A, Caughey AB: Impact oflate initiation of prenatal care on pregnancy outcomes among women who use drugs. Abstract No. 732. Am J Obstet Gynecol 214:S384, 2016

Facco F, Reid K, Grobman W, et al: Short and long sleep duration are associated with extremes of gestational weight gain. Abstract No. 33. Am J Obstet GynecoIe214:S24,e2016

Fawcett EJ, Fawcett JM, Mazmanian 0: A meta-analysis of the worldwide prevalence of pica during pregnancy and the postpartum period. Int J Gynaecol Obsrer 133(3):277,e2016

Fawzi W, Msamanga GI, Urassa W, et al: Vitamins and perinatal outcomes among HIV-negative women in Tanzania. N Engl J Med 356: 14, 2007

Fiore MC, Jaen CR, Baker TB, et al: Treating tobacco use and dependence: 2008 update. Clinical practice guideline. 2008. Available at: http://ww. ncbi.nlm.nih.gov/books/NBK63952/. Accessed September 19, 2016

Fleming N, O'Driscoll T, Becker G, et al: Adolescent pregnancy guidelines.

J Obstet Gynaecol Can 37(8):740,e2015

Foster M, Herulah UNPrasad A, et al: Zinc status of vegetarians during pregnancy: a systematic review of observational studies and meta-analysis of zinc intake. Nutrients 7(6):4512, 2015

Giglio JA, Lanni SM, Laskin OM, et al: Oral health care for the pregnant patient. J Can Dent 5(1):43, 2009

Green PP, McKnight-Eily LR, Tan CH, et al: Vital signs: alcohol-exposed pregnancies-United States, 201e1-2013. MMWR 65(4):91,e2016

Gregory KD, Johnson CT, Johnson TR, et al: The content of prenatal care.

Women's Health Issues 16:198,e2006

Grenache DG: Variable accuracy of home pregnancy tests: truth in advertising?

Clin Chen Lab Med 53(3):339, 2015

Grudzinskas JG, Watson C, Chard T: Does sexual intercourse cause fetal distress?

Lancet 2:692, 1979

Gutke A, Betten C, Degerskar K, et al: Treatments for pregnancy-related lumbopelvic pain: a systematic review of physiotherapy modalities. Acta Obstet Gynecol Scand 94(1e1): 1156, 2015

Haragan AF, Hulsey TC, Hawk AF, et al: Diagnostic accuracy of fundal height and handheld ultrasound-measured abdominal circumference to screen for fetal growth abnormalities. Am J Obstet Gynecol 212(6):820. e1,e2015

Healy CM, Rench A, Baker CJ: Importance of timing of maternal combined tetanus, diphtheria, and acellular pertussis (Tdap) immunization and protection of young infants. Clin Infect Dis 56(4):539, 2013

Herbert WNP, Bruninghaus HM, Barefoot AB, et al: Clinical aspects of fetal heart auscultation. Obstet GynecoIe69:574, 198

Hibbeln JR, Davis JM, Steer C, et al: Maternal seafood consumption in pregnancy and neurodevelopmental outcomes in childhood (LSPAC study): an observation cohort study. Lancet 369:578, 2007

Higginbottom MC, Sweetman L, Nyhan L: A syndrome of methylmalonic aciduria, homocystinuria, megaloblastic anemia and neurologic abnormalities in a vitamin B 12-deicient breast-fed infant of a strict vegetarian. N Engl J Med 299:317, 1978

Higgins JR, Walshee]], Conroy M, et al: The relation between maternal work, ambulatory blood pressure, and pregnancy hypertension. J Epidemiol Community Health 56:389, 2002

Hollier LM, Hill J, Sheield JS, et al: State laws regarding prenatal syphilis screening in the United States. Am J Obstet Gynecol 189: 1178, 2003 Horowitz HS, Heifetz SB: Efects of prenatal exposure to fluoridation on dental caries. Public Health Rep 82:297, 1967

Hytten FE, Chamberlain G (eds): Clinical Physiology in Obstetrics, 2nd ed.

Oxford, Blackwell, 1991

Hytten FE, Leitch I: The Physiology of Human Pregnancy, 2nd ed. Oxford, Blackwell, 1971

Ickovics JR, Earnshaw V, Lewis JB, et al: Cluster randomized controlled trial of group prenatal care: perinatal outcomes among adolescents in New York City health centers. Am J Public Health 106(2):359,e2016

Institute of Medicine: Dietary Reference Intakes: The Essential Guide to Nutrient Requirements. Washington, The National Academies Press, 2006 Institute of Medicine: DRI Dietary Reference Intakes for Calcium and Vitamin

D. Washington, The National Academies Press, 20e11

Institute of Medicine and National Research Council: Weight Gain During Pregnancy: Reexamining the Guidelines. Washington, The National Academic Press, 2009

Jackson A, Gardner S, Torres LN, et al: My obstetrician got me fired: how work notes can harm pregnant patients and what to do about it. Obstet Gynecol 126(2):250, 2015

Jebeile H, Mijatovic J, Louie JC, et al: A systematic review and meta-analysis of energy intake and weight gain in pregnancy. Am J Obstet Gynecol 214(4): 465,e2015

Jimenez JM, Tyson JE, Reisch JS: Clinical measures of gestational age in normal pregnancies. Obstet Gynecol 61 :438, 1983

Johnson S, Cushion M, Bond S, et al: Comparison of analytical sensitivity and women's interpretation of home pregnancy tests. Clin Chen Lab Med 53(3):391,e2015

Kiel OW, Dodson EA, Artal R, et al: Gestational weight gain and pregnancy outcomes in obese women: how much is enough. Obstet Gynecol 110:752, 2007

Kim OK, Bridges CB, Harriman KH, et al: Advisory Committee on Immunization Practices recommended immunization schedule for adults aged 19 years or older-United States, 2016. MMWR 65(4):88,e2016

Kiss H, Widham A, Geusau A, et al: Universal antenatal screening for syphilis: is it still justified economically? A 10-year retrospective analysis. Eur J Obstet Gynecol Reprod Bioi 112:24,e2004

Kyle UG, Pichard C: The Dutch Famine of 1944-1945: a pathophysiological model of long-term consequences of wasting disease. Curr Opin Clin Nutr Metab Care 9:388, 2006

Lacroix R, Eason E, Melzack R: Nausea and vomiting during pregnancy: a prospective study of its frequency, intensity, and patterns of change. Am J Obstet Gynecol 182:931, 2000

Leveno KJ, McIntire DO, Bloom SL, et al: Decreased preterm births in an inner-city public hospital. Obstet Gynecol 113(3):578, 2009

Liddle SO, Pennick V: Interventions for preventing and treating low-back and pelvic pain during pregnancy. Cochrane Database Syst Rev 9:CDOO 1139, 20e15

Litonjua AA, Carey VJ, Laranjo N, et al: Efect of prenatal supplementation with vitamin 0 on asthma or recurrent wheezing in ofspring by age 3 years: the VDAART randomized clinical trial. JAviA 315(4):362,e2016

Lockhart EM, Ben Abdallah M, Tuuli MG, et al: Obstructive sleep apnea in pregnancy: assessment of current screening tools. Obstet Gynecol 126(1): 93, 2015

Loudon I: Death in Childbirth. New York, Oxford University Press, 1992

Luke B, Brown MB, Misiunas R, et al: Specialized prenatal care and maternal and infant outcomes in twin pregnancy. Am J Obstet Gynecol 934, 2003

Magann EF, Evans SF, Weitz B, et al: Antepartum, intrapartum, and neonatal significance of exercise on healthy low-risk pregnant working women. Obstet Gynecol 99:466, 2002

Maheshwari UR, King JC, Leybin L, et al: Fluoride balances during early and late pregnancy. J Occup Med 25:587, 1983

Man LX, Chang B: Maternal cigarette smoking during pregnancy increases the risk of having a child with a congenital digital anomaly. Plast Reconstr Surg :301,e2006

Margulies R, Miller L: Fruit size as a model for teaching irst trimester uterine sizing in bimanual examination. Obstet Gynecol 98(2):341, 2001 Martin ]A, Hamilton BE, Sutton PO, et al: Births: inal data for 2006. Natl Vital Stat Rep (7): 1, 2009

McCauley ME, van den Broek N, Dou L, et al: Vitamin A supplementation during pregnancy for maternal and newborn outcomes. Cochrane Database Syst Rev 1O:CD008666, 2015

McDuie RS ] r, Beck A, Bischof K, et al: Efect of frequency of prenatal care visits on perinatal outcome among low-risk women. A randomized controlled trial. ]AMA 275:847, 1996

Metz TO, Stickrath EH: Marijuana use in pregnancy and lactation: a review of the evidence. Am] Obstet Gynecol 213(6): 61,2015 Michalowicz BS, Hodges ]S, DiAngelis A], et al: Treatment of periodontal disease and the risk of preterm birth. N Engl] Med 355:1885, 2006

Molloy AM, Kirke PN, Troendle ]F, et al: Matenal vitamin BI2 status and risk of neural tube defects in a population with high neural tube defect prevalence and no folic acid fortiication. Pediatrics 123(3):917,s2009

Montagnana M, Trenti T, Aloe R, et al: Human chorionic gonadotropin in pregnancy diagnostics. Clin Chim Acta 412(17-18):1515,s2011

Morgan ]L, Baggari SR, McIntire DO, et al: Pregnancy outcomes after antepartum tetanus, diphtheria, and acellular pertussis vaccine. Obstet Gynecol 125(6): 1433,s2015

Mozurkewich EL, Luke B, Avni M, et al: Working conditions and adverse pregnancy outcome: a meta-analysis. Obstet Gynecol 95:623, 2000 Murray N, Homer CS, Davis GK, et al: he clinical utility of routine urinalysis in pregnancy: a prospective study. Meds] Aust ,s2002

Newman RB, Goldenberg RL, Moawad AH, et al: Occupational fatigue and preterm premature rupture of membranes. Am ] Obstet Gynecol 184:438, 2001 Noren L, bstgaard S, Johansson G, et al: Lumbar back and posterior pelvic pain during pregnancy: a 3-year follow-up. Eur Spines] 11 :267, 2002

Nossier SA, Naeim NE, EI-Sayed NA, et al: he efect of zinc supplementation on pregnancy outcomes: a double-blind, randomized cotrolled trial, Egypt. Br] Nutr 114(2):274,s2015

Ota E, Mori R, Middleton P, et al: Zinc supplementation for improving pregnancy and infant outcome. Cochrane Database Syst Rev 2:CD000230, 2015 Patel MV, Nuthalapaty FS, Ramsey PS, et al: Pica: a neglected risk factor for preterm birth. Obstet Gynecol 103:68S, 2004 Patnode CD, Henderson ]T, hompson ]H, et al: Behavioral counseling and pharmacotherapy interventions for tobacco cessation in adults, including pregnant women: a review of reviews for the U.S. Preventive Services Task Force. Ann Intern Med 163(8):608,s2015 Partridge S, Balayla], Holcroft CA, et al: Inadequate prenatal care utilization and risks of infant mortality and poor birth outcome: a retrospective analysis of28,729,765 U.S. deliveries over 8 years. Am] Perinatol 29(10):787, 2012 Phupong V, Hanprasertpong T: Interventions for heartburn in pregnancy. Coch rane Database Syst Rev 9 :CDO 113 79, 2015 Pitkin M: Calcium metabolism in pregnancy and the perinatal period: a review. Am] Obstet Gynecol 151:99, 1985 Pollak KT, Oncken CA, Lipkus 1M, et al: Nicotine replacement and behavioral therapy for smoking cessation in pregnancy. Am ] Prev Med 33(4):297, 200 Poskus T, Buzinskiene 0, Drasutiene G, et al: Haemorrhoids and anal issures during pregnancy and after childbirth: a prospective cohort study. B]OG 121(13):1666,s2014 Power ML, Wilson EK, Hogan SO, et al: Patterns of preconception, prenatal and postnatal care for diabetic women by obstetrician-gynecologists. ] Reprod Med 58(1-2):7, 2013 Pritchard ]A, Scott DE: Iron demands during pregnancy. In Hallberg L, Harwerth HG, Vannotti A (eds): Iron Deficiency: Pathogenesis, Clinical Aspects, Therapy. New York, Academic Press, 1970 Read ]S, lebanof A: Sexual intercourse during pregnancy and preterm delivery: efects of vaginal microorganisms. Am ] Obstet Gynecol 168:514, 1993 Rink BD, Norton ME: Screening for fetal aneuploidy. Semin Perinatol 40(1): 35,s2016 Rumbold A, Ota E, Nagata C, et al: Vitamin C supplementation in pregnancy. Cochrane Database Syst Rev 9:CD0040 2,2015 Ryan ET, Wilson ME, Kain KC: Illness after international travel. N Engl ] Med 347:505, 2002 Sa Roriz Fonteles C, Zero DT, Moss ME, et al: Fluoride concentrations in enamel and dentin of primary teeth after pre-and postnatal luoride exposure. Caries Res 39:505, 2005 Sagedal LR, Overby NC, Bere E, et al: Lifestyle intervention to limit gestational weight gain: the Norwegian Fit for Delivery randomized controlled trial. B]OG 1240):97,s2017

Salam A, Zuberi NF, Bhutta ZA: Pyridoxine (vitamin BG) supplementation during pregnancy or labour for maternal and neonatal outcomes. Cochrane Database Syst Rev 6:CD0001 9,2015

Sayle AE, Savitz DA, Thorps]M ]r, et al: Sexual activity during late pregnancy and risk of preterm delivery. Obstet Gynecol 97:283, 2001

Schau berger CW, Rooney BL, Brimer LM: Factors that inluence weight loss in the puerperium. Obstet Gynecol 9:424, 1992

Schrag S]: Maternal immunization to prevent neonatal group B streptococcal disease. Obstet Gynecol 127(2):199,s2016

Scott DE, Pritchard ]A, Satin AS, et al: Iron deficiency during pregnancy. In Hallberg L, Harwerth HG, Vannotti A (eds): Iron Deiciency: Pathogenesis, Clinical Aspects, Therapy. New York, Academic Press, 19

Screnci M, Murgi E, Valle V, et al: Sibling cord blood donor program for hematopoietic cell transplantation: the 20-year experience in the Rome Cord Blood Bank. Blood Cells Mol Dis 57:71, 2016

Sibai BM, Villar MA, Bray E: Magnesium supplementation dring pregnancy: a double-blind randomized controlled clinical trial. Ams] Obstet Gynecol 161:115,s1989

Siddique ], Lauderdale OS, VanderWeele T], et al: Trends in prenatal ultrasound use in the United States. Med Care 47:1129,2009

Siu AL, U.S. Preventive Services Task Force: Behavioral and pharmacotherapy interventions for tobacco smoking cessation in adults, including pregnant women: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 163(8):622,s2015

Smith CA: Efects of maternal under nutrition upon the newborn infant in Holland 0944-1945). Am] Obstet GynecoI30:229, 1947

Smith MW, Marcus PS, Wurtz LD: Orthopedic issues in pregnancy. Obstet Gynecol Surv 63: 103, 2008

Spierings EL, Sabin TO: De novo headache during pregnancy and puerperium.

Neurologist 21(1):1,s2016

Spindel ER, McEvoy CT: The role of nicotine in the efects of maternal smoking during pregnancy on lung development and childhood respiratory disease: implications for dangers of E-cigarettes. Am ] Respir Crit Care Med 193(5):486,s2016

Staruch M, Kucharcyzk A, Zawadzka K, et al: Sexual activity during pregnancy.

0):53,s2016

Stein Z, Susser M, Saenger G, et al: Nutrition and mental performance. Science 178:708, 1972

Stephens TV, Payne M, Ball Ro, et al: Protein requirements of healthy pregnancy women during early and late gestation are higher than current recommendations. J Nutr 3,s2015

Stewart RD, Nelson DB, Adhikari EH, et al: he obstetrical and neonatal impact of maternal opioid detoxiication in pregnancy. Ams] Obstet Gynecol 209:267.e1, 2013

Sugarman SO: Cases in vaccine court-legal battles over vaccines and autism.

N Engl] Med 257:1275, 200

Tan Pc, Yow CM, Omar SZ: Efect of coital activity on onset of labor in women scheduled for labor induction. Obstet Gynecol 110:820,s200

Taylor CM, Golding ], Emond AM: Adverse efects of maternal lead levels on birth outcomes in the ALSPAC study: a prospective birth cohort study. B]OG 122(3):322,s2015 hompson W, Price C, Goodson B, et al: Early thimerosal exposure and neuropsychological outcomes at 7 to 10 years. N Engl ] Med 257:1281, 2007

Till SR, Everetts 0, Haas OM: Incentives for increasing prenatal care use by women in order to improve maternal and neonatal outcomes. Cochrane Database Syst Rev 12:CD009916, 2015

Tong T, Dietz PM, Morrow B, et al: Trends in smoking before, during, and after pregnancy-pregnancy risk assessment monitoring system, United States, 40 sites, 2000-2010. MMWR 62(6):1,s2013

Tozzi AE, Bisiacchi P, Tarantino V, et al: Neuropsychological performance 10 years after immunization in infancy with thimerosal-containing vaccines. Pediatrics 123(2):475, 2009

U.S.

Department of Health and Human Services: Reducing tobacco use: a report of the Surgeon General. Atlanta, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Oice on Smoking and Health, 2000

U.S.

Environmental Protection Agency: Fish: what pregnant women and parents need to know. 2014. Available at: http://www.fda.gov/Food/FoodborneIllnessContaminants/Metals/ucm393070.htm. Accessed September 19, 2016

U.S.

Preventive Services Task Force: Recommendation statement: clinical guidelines: folic acid for the prevention of neural tube defects. Ann Intern Med 150:626, 2009

Villar], Baaqeel H, Piaggio G, et al: WHO atenatal care randomised trial for the evaluation of a new model of routine antenatal care. Lancet 357:1551, 2001

Vintzileos M, Ananth CV, Smulian JC, et al: Prenatal care and black-white fetal death disparity in the United States: heterogeneity by high-risk conditions. Obstet Gynecol 99:483, 2002

Wang SM, Dezinno P, Maranets I, et al: Low back pain during pregnancy: prevalence, risk facrors, and outcomes. Obstet Gynecol 104:65, 2004

Washington State Health Care Authority: Ultrasonography (ultrasound) in pregnancy: a health technology assessmenr. 2010. Available at: http://www. hta.hca. wa.gov/ documen ts/i naLreporcul trasound. pdf. Accessed September 19,r2016

West KP: Vitamin A deiciency disorders in children and women. Food Nun Bull 24:578, 2003

Widen EM, Whyatt vl, Hoepner A, et al: Excessive gestational weight gain is associated with long-term body fat and weight retention at 7 y postpartum in African American and Dominican mothers with underweight, normal, and overweight prepregnancy BM!. Am J Clin NLltr 102(6):1460, 2015 Wilcox AJ, Baird DD, Dunson D, et al: Natural limits of pregnancy testing in relation to the expected menstrual period. JAMA 286: 1759, 2001

Wilson DL, Barnes M, Ellett L, et al: Decreased sleep eiciency, increased wake after sleep onset and increased cortical arousals in late pregnancy. Aust N Z J Obstet Gynaecol 51(1):38, 2011

Worthen N, Bustillo M: Efect of urinary bladder fullness on fundal height measurements. Am J Obstet Gynecol 138:759, 1980

XU J, Kochanek KD, Murphy SL: Deaths: inal data for 2007. Nat Stat Vit Rep 58(19):1, 2010

Zaman K, Roy E, Arifeen SE, et al: Efectiveness of maternal inluenza immunization in mothers and infants. N Engl J vIed 359(15): 1555, 2008

SONOGRAPHY IN OBSTETRICSe. . . . . . . . . . . . . . . . . . .. 182

TECHNOLOGY AND SAFETYe. . . . . . . . . . . . . . . . . . . . . . 182

GESTATIONAL AGE ASSESSMENT . . . . . . . . . . . . . . . .. 183

FIRST-TRIMESTER SONOGRAPHY ....e.....e...e...... 185

SECOND-AND THIRD-TRIMESTER SONOGRAPHY .... 186

CERVICAL LENGTH ASSESSMENT. . . . . . . . . . . . . . . .. 189

NORMAL AND ABNORMAL FETAL ANATOMY. ....... 191

DOPPLER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

MAGNETIC RESONANCE IMAGING ....e...e.......... 215

After discovey of the Roentgen ray and the demonstration of the various uses to which it might be put, it was thought possible that it might also aord a valuable method ofinvestigating the shape and size of the pelvis.

-]. Whitridge Williams (1903)

X-ray techniques were just on the horizon when the first edition of this textbook was published. he first application focused on the maternal pelvis without attention to the fetus. hus, congenital abnormalities were routinely not discovered until birth. Subsequent radiographic eforts to evaluate the fetus were later replaced by ultrasonography and more recently by magnetic resonance (MR) imaging, techniques which have become increasingly sophisticated. he subspecialty of fetal medicine has developed only because of these advances, and today's practitioner can hardly imagine obstetrical care without them.

Prenatal sonography can be used to accurately assess gestational age, fetal number, viability, and placental location, and it can aid diagnosis of many fetal abnormalities. With improvements in resolution and image display, anomalies are increasingly detected in the irst trimester, and Doppler is used to manage pregnancies complicated by growth impairment or anemia. he American College of Obstetricians and Gynecologists (2016) recommends that prenatal sonography be performed in all pregnancies and considers it an important part of obstetrical care in the United States.

The real-time image on the ultrasound screen is produced by sound waves that are relected back from fluid and tissue interfaces of the fetus, amnionic fluid, and placenta. Sector array transducers contain groups of piezoelectric crystals working simultaneously in arrays. These crystals convert electrical energy into sound waves, which are emitted in synchronized pulses. Sound waves pass through tissue layers and are reflected back to the transducer when they encounter an interface between tissues of diferent densities. Dense tissue such as bone produces high-velocity reflected waves, which are displayed as bright echoes on the screen. Conversely, luid generates few relected waves and appears dark. Digital images generated at 50 to more than 100 frames per second undergo postprocessing that yields the appearance of real-time imaging.

Ultrasound refers to sound waves traveling at a frequency above 20,000 hertz (cycles per second). Higher-frequency transducers yield better image resolution, whereas lower frequencies penetrate tissue more efectively. Transducers use wide-bandwidth technology to perform within a range of frequencies. In early pregnancy, a 5-to 10-megahertz (MHz) transvaginal transducer usually provides excellent resolution, because the early fetus is close to the transducer. And, in the first and second trimesters, a 4-to 6-MHz transabdominal transducer is similarly close enough to the fetus to yield precise images. By the third trimester, however, a lower frequency 2-to 5-MHz transducer may be needed for tissue penetration-particularly in obese patients-and this can lead to compromised resolution.

cation, using the lowest possible exposure setting to gain neces sary information-the AAA principle-as low as reasonably 4chievable. Examinations are performed only by those trained pathology, using techniques to avoid ultrasound exposure beyond what is considered safe for the fetus (American College of Obstetricians and Gynecologists, 2016; American Institute of Ultrasound in Medicine, 2013b). No causal relationship has ognized adverse efect in human pregnancy. The International

Society of Ultrasound in Obstetrics and Gynecology (2016) further concludes that there is no scientifically proven associa tion between ultrasound exposure in the first or second trimes ters and autism spectrum disorder or its severity.

All sonography machines are required to display two indices: the thermal index and the mechanical index. The thermal index is a measure of the relative probability that the examination may raise the temperature, potentially high enough to induce injury. That said, fetal damage resulting from commercially available ultrasound equipment in routine practice is extremely unlikely. The potential for temperature elevation is higher with longer examination time and is greater near bone than in soft tissue. heoretical risks are higher during organogenesis than later in gestation. The thermal index for soft tissue, Tis, is used before 10 weeks' gestation, and that for bone, ib, is used at or beyond 10 weeks' (American Institute of Ultrasound in Medicine, 2013b). The thermal index is higher with pulsed Doppler applications than with routine B-mode scanning (p. 213). In the first trimester, if pulsed Doppler is clinically indicated, the thermal index should be ;0.7, and the exposure time should be as brief as possible (American Institute of Ultrasound in Medicine, 2016) . To document the embryonic or fetal heart rate, motion-mode (M-mode) imaging is used instead of pulsed Doppler imaging.

The mechanical index is a measure of the likelihood of adverse efects related to rarefactional pressure, such as cavi tationwhich is relevant only in tissues that contain air. Microbubble ultrasound contrast agents are not used in pregnancy for this reason. In mammalian tissues that do not contain gas bodies, no adverse efects have been reported over the range of diagnostically relevant exposures. Because fetuses cannot contain gas bodies, they are not considered at risk.

The use of sonography for any nonmedical purpose, such as "keepsake fetal imaging," is considered contray to responsible medical practice and is not condoned by the Food and Drug Administration (2014), the American Institute of Ultrasound in Medicine (2012, 2013b), or the American College ofObstetricians and Gynecologists (2016).

The reported prevalence of work-related musculoskeletal discomfort or injury among sonographers approximates 70 percent Ganga, 2012; Roll, 2012). The main risk factors for injury during transabdominal ultrasound examinations are awkward posture, sustained static forces, and various pinch grips used while maneuvering the transducer (Centers for Disease Control and Prevention, 2006). Maternal habitus can be contributory because more force is oten employed when imaging obese patients.

The following guidelines may help avert injury: 1. Position the patient close to you on the examination table.

As a result, your elbow is close to your body, shoulder abduction is less than 30 degrees, and your thumb is facing up.

2.

Adjust the table or chair height so that your forearm is parallel to the floor.

3.

If seated, use a chair with back support, support your feet, and keep ankles in neutral position. Do not lean toward the patient or monitor.

4.

Face the monitor squarely and position it so that it is viewed at a neutral angle, such as 15 degrees downward.

5.

Avoid reaching, bending, or twisting while scanning.

6.

Frequent breaks may prevent muscle strain. Stretching and strengthening exercises can be helpful.

The earlier that sonography is performed, the more accurate the gestational age assessment. Specific criteria for "re-dating" a pregnancy, that is, reassigning the gestational age and estimated date of delivery using initial sonogram findings, are shown in Table 1 0-1. The only exception to revising the gestational age based on early sonography is if the pregnancy resulted from assisted reproductive technology, in which case accuracy of gestational age assessment is presumed.

Sonographic measurement of the crown-rump length (CRL) is the most accurate method to establish or conirm gestational

TABLE 10-1. Sonographic Gestational Age Assessment

Gestational Age Parameter(s) to Revisea 9 to <14 wks CRL 14 to <16 wks BPO, HC AC FL 16 to <22 wks BPO, HC AC FL >10 d 22 to <28 wks BPO, HC AC FL >14d :28 weeks BPOt HC AC FL >21 d aSonographic gestational age should be used when the LMP-derived gestational age differs from that obtained with sonography by the threshold value.

abdominal circumference; BPO biparietal diameter; CRL = crown-rump length; FL = femur length; HC = head circumference; LMP = last menstrual period. Modified from American College of Obstetricians and Gynecologists,l2017b.

FIGURE 10-1 The measured crown-rump length in this 12-week 3-day fetus approximates 6 cm.

age (Appendix, p. 1263). As noted, transvaginal imaging typi cally yields higher resolution images. The CL is measured in the midsagittaleplane with the embryo or fetus in a neutral, nonlexed position so that its length can be measured in a straight line (Fig.

The measurement should include neither the yolk sac nor a limb bud. The mean of three discrete measurements is used. Until 136/7 weeks' gestation, the CL is accurate to within 5 to 7 days (American College of Obstetricians and Gynecologists, 201 7b).

Starting at 14°/ weeks, equipment software formulas calculate estimated gestational age and fetal weight from measurements of the biparietal diameter, head and abdominal circumference, and femur length (Fig. 10-2). The estimates are most accurate when multiple parameters are used but may over-or underestimate fetal weight by up to 20 percent (American College of Obstetricians and Gynecologists, 2016). Various nomograms for other fetal structures, including the cerebellar diameter, ear length, ocular distances, thoracic circumference, and lengths of kidney, long bones, and feet, may be used to address speciic questions regarding organ system abnormalities or syndromes (Appendix, p. 1266).

The biparietal diameter (BPD) most accurately reflects gestational age, with a variation of 7 to 10 days in the second trimester. The BPD is measured perpendicular to the midline falx in the transthalamic view, at the level of the thalami and cavum septum pellucidum (CSP) (see Fig. 10-2A). Calipers are placed from the outer edge of the skull in the near ield to the inner edge of the skull in the far field. he head circumference (HC) is also measured in the trans thalamic view. An ellipse is

FIGURE 10-2 Fetal biometry. A. Transthalamic view. A transverse (axial) image of the head is obtained at the level of the cavum septum pellucidum (arrows) and thalami (asterisks). The biparietal diameter is measured perpendicular to the sagittal midline, from the outer edge of the skull in the near field to the inner edge of the skull in the far field. By convention, the near field is that which is closer to the sonographic transducer. The head circumference is measured circumferentially around the outer border of the skull. B. Femur length. The femur is measured perpendiCUlar to the femoral shaft, from each diaphyseal end, excluding the epiphysis. C. Abdominal circumference. This is a transverse measurement at the level of the stomach (5). The J-shaped structure (arrowheads) indicates the confluence of the umbilical vein and the right portal vein. Ideally, only one rib is visible on each side of the abdomen, indicating that the image was not taken at an oblique angle.

placed around the outer edge of the skull or the circumference is calculated using BPD and occipital-frontal diameter (OFD) values. he cephalic index, which is the BPD divided by the OFD, is normally 70 to 86 percent.

If the head shape is lattened-dolichocephay, or roundedbrachycephay, the HC is more reliable than the BPD. hese head shape variants may be normal or can be secondary to fetal position or oligohydramnios. But, dolichocephaly can occur with neural-tube defects, and brachycephaly may be seen in fetuses with Down syndrome. lso, with abnormal skull shape, craniosynostosis and other craniofacial abnormalities are a consideration.

he femur length (FL) correlates well with both BPD and gestational age. It is measured with the beam perpendicular to the long axis of the shat. Calipers are placed at each end of the calcified diaphysis and exclude the epiphysis. For gestational age estimation, it has a variation of 7 to 11 days in the second trimester (see Fig. 1O-2B). A femur measurement that is <2.5th percentile for gestational age or that is shortened to :;90 percent of that expected based on the measured BPD is a minor marker for Down syndrome (Chap. 14, p.287). he normal range for the FL to abdominal circumference (AC) ratio is generally 20 to 24 percent. A dramatically foreshortened FL or a FL-to-AC ratio below 18 percent prompts evaluation for a skeletal dysplasia (p. 210).

Of biometric parameters, AC is most afected by fetal growth. Thus, for gestational age estimation, AC has the greatest variation, which can reach 2 to 3 weeks in the second trimester. To measure the AC, a circle is placed outside the fetal skin in a transverse image that contains the stomach and the confluence of the umbilical vein with the portal sinus (see Fig. 10-2C). The image should appear as round as possible and ideally contains no more than 1 rib on each side of the abdomen. he kidneys should not be visible in the image.

Variability of the sonographic gestationl age estimate increases with advancing gestation. Accordingly, pregnancies not imaged prior to 22 weeks to conirm or revise gestational age are considered suboptimaly ated (American College of Obstetricians and Gynecologists, 2017a). Although the estimate is improved by averaging multiple parameters, if one parameter difers

TABLE 10-2. Some Indications for First-Trimester Ultrasound Examination

Define the cause of vaginal bleeding

Assist chorionic villus sampling, embryo transfer, and

Assess for certain fetal anomalies, such as anencephaly, in a bnormaIities Measure nuchal translucency /hen part of a screening

Modified from the American Institute of Ultrasound in significantly from the others, consideration should be given to excluding it from the calculation. he outlier may result from poor visibility, but it could also indicate a fetal abnormality or growth problem. Reference tables such as the one in the Appendix (p. 1264) may be used to estimate fetal weight percentiles.

Indications for sonography before 14 weeks' gestation are listed in Table 10-2. Early pregnancy can be evaluated using transabdominal or transvaginal sonography, or both. he components listed in Table 10-3 should be assessed. First-trimester sonography can reliably diagnose anembryonic gestation, embryonic demise, ectopic pregnancy, and gestational trophoblastic disease. he irst trimester is also the ideal time to evaluate the uterus, adnexa, and cul-de-sac. Determination of

TABLE 10-3. Components of Standard Ultrasound Examination by Trimester

Gestational sac size, location, and number Embryo and/or yolk sac identification Crown-rump length Fetal number, including amnionicity and chorionicity of the first rimester Evaluation of the maternal uterus, adnexa, and cul-de-sac Evaluat"on of the fetal nuchal region, with consideration of fetal :chal translucenry assessment

Fetal number, including amnionicity and chorionicity of multifetal gestations

Placental location, appearance, and relationship to tie internal cervical os, with documentation of placental cord insertion site when technically possible

Fetal anatomical survey, including documentation of technical limitations

Evaluation of the maternal uterus, adnexa, and cervix when

Modified from the American Institute of Ultrasound in Medicine, 2013a.

chorionicity in a multifetal gestation is most accurate in the first trimester (Chap. 45, p. 868).

n intrauterine gestational sac is reliably visualized with transvaginal sonography by 5 weeks, and an embryo with cardiac activity by 6 weeks (Fig. 10-3). The embryo should be visible transvaginally once the mean sac diameter has reached 25 mm-otherwise the gestation is anembyonic. Cardiac motion is usually visible with transvaginal imaging when the embryo length reaches 5 mm. In embryos <7 mm without cardiac activity, subsequent examination may be needed to determine viability (American College of Obstetricians and Gynecologists, 2016). At Parkland hospital, first-trimester demise is diagnosed if the embryo has reached 10 mm and lacks cardiac motion. Other criteria for this diagnosis are found in Chapter 18 (Table 18-3, p. 350).

Nuchal translucency (NT) evaluation is a component of first-trimester aneuploidy screening, discussed in Chapter 14 (p. 281). It represents the maximum thickness of the subcutaneous translucent area between the skin and soft tissue overlying the fetal spine at the back of the neck. NT is measured in the sagittal plane between 11 and 14 weeks' gestation using precise criteria (Table 10-4). When the NT measurement is increased, the risk for fetal aneuploidy and various structural anomalies-in particular heart defects-is signiicantly elevated.

Assessment for selected fetal abnormalities in an at-risk pregnancy is done with irst-trimester sonography (see Table 10-2). Research in this area has focused on anatomy visible at 11 to 14 weeks' gestation, to coincide with sonography performed as part of aneuploidy screening. ith current technoloy, it is not realistic to expect that all major abnomalities detectable in the second trimester may be visualized in the irst trimester. Thus, irst-trimester scanning should not replace second-trimester anatomical evaluation (American College of Obstetricians and Gynecologists, 2016).

FIGURE 10-3 A. The measured crown-rump length is approximately 7 mm in this 6-week embryo. B. M-mode demonstrates embryonic cardiac activity and a heart rate of 124 beats per minute.

As examples, in one study of more than 40,000 pregnancies undergoing sonographic aneuploidy screening between 11 and 14 weeks, basic anatomical evaluation yielded a detection rate of approximately 40 percent for structural abnormalities (Syngelaki, 2011). Bromley and colleagues (2014) similarly found that late irst-trimester sonography identiied major abnormalities in 0.5 percent of pregnancies, representing approximately 40 percent of pregnancies with anomalies detected prenatally. Detection rates are very high for anencephaly, alobar holoprosencephaly, and ventral wall defects. But, in one analysis of more than 60,000 pregnancies with these early scans, only a third of major cardiac anomalies were identiied, and no cases of microcephaly, agenesis of the corpus callosum, cerebellar abnormalities, congenital pulmonary airway malformations, or bowel obstruction were detected (Syngelaki, 2011). In another study of low-risk or unselected pregnancies, 32 percent of anomalies were detected, whereas in pregnancies described as high-risk, anomaly detection exceeded 60 percent (Karim, 2017).

It is recommended that sonography be routinely ofered to all pregnant women between 18 and 22 weeks' gestation (American

TABLE 10-4. Guidelines for Nuchal Translucency (NT) Measurement

The margins of NT edges must be clear enough for proper caliper placement The fetus must be in the midsagittal plane

The image must be magnified so that it is filled by the fetal head, neck, and upper thorax The fetal neck must be in a neutral position, not flexed and not hyperextended

The amnion must be seen as separate from the NT line

Electronic calipers must be used to perform the measurement The + calipers must be placed on the inner borders of the nuchal space with none of the horizontal crossbar itself protruding into the space The calipers must be placed perpendicular to the long axis of the fetus The measurement must be obtained at the widest space of the NT

From the American Institute of Ultrasound in Medicine, 20 13a, with permission.

TABLE 10-5. Some Indications for Second-or ThirdTrimester Ultrasound Examination

Preterm premature rupture of membranes and/or preterm labor

Adjunct to cervical cerclage

Adjunct to amniocentesis or other procedure

Adjunct to external cephalic version

Assessment for findings that raise the aneuploidy risk

Follow-up evaluation of a fetal anomaly

History of congenital anomaly in prior pregnancy

Adapted from the American Institute of Ultrasound in Medicine,l201l3a.

College of Obstetricians and Gynecologists, 2016). This time interval permits accurate assessment of gestational age, fetal anatomy, placental location, and cervical length. Recognizing that the gestational age at which abnormalities are identified may afect pregnancy management options, providers may opt to perform the examination prior to 20 weeks. The many additional indications for second-and third-trimester sonography are listed in Table 10-5. The three examination types are standard, specialized-which includes targeted sonography, and limited.

The standard sonogram includes evaluation of fetal number and presentation, cardiac activity, amnionic fluid volume, placental position, fetal biometry, and fetal anatomy (American Institute of Ultrasound in Medicine, 2013b). When technically feasible, the maternal cervix and adnexa are examined as clinically appropriate. Components are found in Table 10-3, and the fetal anatomical structures that should be evaluated are listed in Table 10-6. With twins or other multiples, documentation also includes the number of chorions and amnions, comparison of fetal sizes, estimation of amnionic luid volume within each sac, and fetal sex determination (Chap. 45, p. 868).

he targeted sonogram is a type of specialized examination. It is performed when the risk for a fetal anatomical or genetic abnor mality is elevated because of history, screening test result, or abnor mal inding during standard examination (Table 10-7) . Targeted sonograms include a detailed anatomical survey, the components of which are shown in Table 10-6. Because it carries the CPT code 76811, this sonogram is colloquilly called the "76811 examina tion." It is intended to be indication-driven and should not be repeated later in the absence of an extenuating circumstance.

have expertise in fetal imaging, through both training and ongo ing experience (Wax, 2014). For many of the targeted examina tion components, the physician determines on a case-by-case basis whether assessment is needed (American College of Obstetricians and Gynecologists, 2016). Other types of specilized examinations include fetal echocardiography, Doppler evaluation, and the bio physical proile, which is described in Chapter 17 (p. 337).

A limited sonogram is performed to address a speciic clini cal question. Examples include evaluation of fetal presentation, viability, amnionic luid volume, or placental location. In the absence of an emergency, a limited examination is only per formed if a standard sonogram has already been completed.

Otherwise, provided that the gestational age is at least 18 weeks, a standard sonogram is recommended.

With current advances in imaging technology, approximately 50 percent of major fetal abnormalities overall are detected with standard sonography (Rydberg, 2017). he sensitivity of sonography for detecting fetal anomalies varies according to factors such as gestational age, maternal habitus, fetal position, equipment features, examination type, operator skill, and the speciic abnormality in question. For example, maternal obesity has been associated with a 20-percent reduction in the anomaly detection rate (Dashe, 2009).

Detection also varies considerably according to the abnormality.

For example, population-based data from 18 registries comprise the EUROCAT network. Between 2011 and 2015, EUROCAT (2017) prenatal detection rates for selected fetal anomaliesexcluding genetic conditions-were as follows: anencephaly, 99 percent; spina bifida, 89 percent; hydrocephaly, 78 percent; clet lip/palate, 68 percent; hypoplastic let heart, 87 percent; transposition of the great vessels, 64 percent; diaphragmatic hernia, 74 percent; gastroschisis, 94 percent; omphalocele, 92 percent; bilateral renal agenesis, 94 percent; posterior urethral valves, 79 percent; limb-reduction defects, 57 percent; and clubfoot, 57 percent.

Importantly, however, the overall anomaly detection rate, excluding aneuploidy, was below 40 percent. his relects inclusion of anomalies with minimal or no sonographic detection in the second trimester, such as microcephaly, choanal atresia, cleft palate, Hirschsprung disease, anal atresia, and congenital skin disorders. hese are mentioned because clinicians tend to focus on abnormalities amenable to sonographic detection, whereas those not readily detectable may be equally devastating to families. Therore, evey sonographic examination should include a frank discussion of examination limitations.

Most anomalous neonates are born to women whose pregnancies are otherwise considered low-risk, that is, without an

TABLE 10-6. Components of Standard and Targeted Fetal Anatomic Surveys

Head, face, and neck Lateral cerebral ventricles Choroid plexus Midline falx Cavum septum pellucidum Cerebellum Cistena magna Upper lip Consideration of nuchal skin fold measurement at 15-20 weeks

Four-chamber view of the heart Left ventricular outflow tract Right ventricular outflow tract

Stomach: presence, size, and situs

Cervical, thoracic, lumbar, and sacral spine

Head, face, and neck Integrity and shape of cranium Third ventriclea Fourth ventriclea Corpus callosuma Cerebellar lobes, vermis Brain parenchyma Profile Coronal nose, lips, lensa Palatea, maxilla, mandible, and tonguea Ear pOSition and sizea Orbitsa Neck

Integrity of diaphragm

Abdomen Small and large bowela Adrenal glandsa Gallbladdera Liver Renal arteriesa Spleen° Integrity of abdominal wall

Integrity of spine and overlying soft tissue

Architecture, position, number Hands

Digitsa: number, position aWhen medically indicated (determined on case-by-case basis).

Modified from the American Institute of Ultrasound in Medicine, 2013a; Wax, 2014.

indication for targeted sonography. hus, for standard sonographic examinations, accurate documentation and quality assurance are essential to optimize detection rates. Practice guidelines and standards established by organizations such as the American Institute of Ultrasound in Medicine (2013b) and the Internationl Society of Ultrasound in Obstetrics and Gynecology (Salomon, 2011) have undoubtedly contributed to improvements in anomaly detection rates. Ultrasound practice accreditation is a process ofered by the American Institute of Ultrasound in Medicine and the American College of Radiology that was developed to improve imaging quality and adherence to guidelines. It includes review of images and their storage, ultrasound equipment, report generation, and the qualifications of physicians and sonographers. The Society for Maternal-Fetal Medicine (2013) recommends that whenever possible, obstetrical ultrasound examinations by maternal-fetal medicine sub specialists be performed by accredited practices.

Evaluation of amnionic luid volume is a component of every second-or third-trimester sonogram, and volumes vary with

TABLE 10-7. Indications for Targeted Fetal Anatomical Ultrasound Examination

Prior fetus or neonate with a structural or genetic/chromosomal abnormality

Current pregnancy with known or suspected fetal abnormality or confirmed growth abnormality

Maternal diabetes diagnosed before 24 weeks' gestation Assisted repr0ductive technology to achieve conception Matenal prepregnancy body mass index >30 kg/m2 Multifetal gestation (Chap. 45, p. 864)

Nuchal translucency measurement ::3.0 mm

Parental carriage of genetic/chromosomal abnormality

Maternal age ::35 at delivery

Nuchal translucency measurement ::3.0 mm

Other condition affecting the fetus

Congenital infection (Chaps. 64 and 65)

Alloimmunization (Chap. 15, p. 301)

Amnionic fluid abnormality (Chap. 11l, p. 227)

Modified from Jax, 2014, 2015.

gestational age. Oligohydramnios indicates an amnionic fluid volume below normal range, and subjective crowding of the fetus is often noted. Hydramnios-also calledpoyhydramniosdefines a volume above a given normal threshold. Amnionic luid volume is usually assessed semiquantitatively. Measurements include either the single deepest vertical luid pocket or the sum of the deepest vertical pockets from each of four equal uterine quadrants-the amnionic luid index (Phelan, 1987). Reference ranges have been established for both measurements from 16 weeks' gestation onward. he single deepest vertical pocket is normally between 2 and 8 cm, and the amnionic luid index normally ranges between 8 and 24 cm. A further discussion and images are provided in Chapter 11 (p. 227).

Evaluation of the relationship between the placenta and the internal cervical os is an essential component of the standard sonogram. Abnormalities of the placenta and umbilical cord are reviewed in Chapter 6 (p. 111). Although the cervix may be imaged transabdominally (Fig. 10-4), this is often limited

FIGURE 10-4 A. Transabdominal image of the cervix depicting the internal os and external as. B. Transvaginal imaging a more accurate evaluation of the cervix and should be used for medical decision-making. In this image, arrowheads mark the endocervical canal. (Used with permission from Dr. Emily Adhikari.)

TABLE 10-8. Criteria for Transvaginal Evaluation of the Cervix

Imaging the Cervix

Maternal bladder should be empty.

Transducer is inserted under real-time observation, identiying midsagittal intenal os, and then extenal os, while keeping the internal os in view.

Internal os, external os, and entire endocervical canal should be visible. The internal os may appear as a small triangular indentation at the junction of the amnionic cavity and endocervical canal.

Image is enlarged so that the cervix fills approximately 75% of the screen.

Anterior and posterior width of the cervix should be approximately equal.

Transducer is pulled back slightly until the image begins to blur, ensuring that pressure is not placed on the cervix, then inserted only enough to restore a clear image.

and without fundal or suprapubic pressure, to assess for dynamic change-or shortening on real-time imaging.

Measuring the Cervix

Calipers are placed where anterior and posterior walls of cervix meet.

Endocervical canal appears as a faint, linear echodensity.

If canal has a curved contour, a straight line between the internal and external os will deviate from the path of the endocervical canal.

If midpoint of the line between the internal and external canal deviates by �3 mm from the endocervical canal, measure the cervical length in two linear segments.

Funneling, sludge (debris), or dynamic change is noted.

At least three separate images are measured during a period of at least 3 minutes to allow for dynamic change.

Visualization of cervical shortening on real-time imaging, with or without fundal or suprapubic pressure, raises preterm birth risks.

Shortest cervical length image that meets all criteria should be used.

Modified from lams, 2013.

by technical factors that include maternal habitus, cervical position, or shadowing by the fetal presenting part. In addition, the maternal bladder or pressure from the transducer may artificially elongate the appearance of the cervix. As a result, values from transabdominal or transvaginal measurement of the cervix can difer significantly.

If the cervix appears shortened or if it cannot be adequately visualized during transabdominal evaluation, transvaginal assessment is considered (American Institute of Ultrasound in Medicine, 2013b). Only cervical length measurements obtained transvaginally at or beyond 16 weeks' gestation are considered sufficiently accurate for clinical decision-making (see Fig. 10-4). A foreshortened cervix is associated with an elevated risk for preterm birth, particularly in the setting of prior preterm birth, and the degree of risk rises proportionally with the degree of cervical shortening (Chap. 42, p. 815).

To measure the cervix transvaginally, the imaging criteria shown in Table 10-8 are followed. he endocervical canal should be visible in its entirety, and images ideally are obtained over several minutes to allow for dynamic change. During examination, visible funneling or debris is sought. Funneling is a protrusion of amnionic membranes into a portion of the endocervical canal that has dilated (Fig. 10-5). Funneling is not an independent predictor of preterm birth, however, it is associated with cervical shortening, and transvaginal assessment is recommended if a funnel is suspected transabdominally. The cervical length is measured distal to the funnel, because the base of the funnel becomes the functional internal os. If the cervix is dilated, as with cervical insuiciency, the membranes may prolapse through the endocervical canal and into the vagina, producing an

FIGURE 10-5 Transvaginal image depicting a foreshortened cervix with funneling. Funneling is a protrusion of amnionic membranes into a portion of the endocervical canal that has dilated. The distal protruding edge of the funnel becomes the functional internal os (left arrow). Thus, the measured cervical length, which lies between the arrows, should not include the funnel. (Used with permission from Dr. Emily Adhikari.)

FIGURE 10-7 Transcerebellar view of the posterior fossa, demonstrating measurement of the cerebellum (+), cisterna magna (x), and nuchal fold thickness (backet). Care is taken not to angle obliquely down the spine, which may artificially increase the nuchal fold measurement.

FIGURE 10-6 The transventricular view depicts the lateral ventricles, which contain the echogenic choroid plexus (CP). The lateral ventricle is measured at the atrium (arrows), which is the confluence of the temporal and occipital horns. A normal measurement is between 5 and 10 mm throughout the second and third trimesters. The atria measured 6 mm in this 21-week fetus.

hourglass appearance. Sludge or debris represents an aggregate of particulate matter within the amnionic sac, close to the internal os. In pregnancies at risk for preterm birth, sludge is associated with a further increased risk.

Many fetal anomalies and syndromes may be characterized with targeted sonography, and selected abnormalities are discussed subsequently. This list is not intended to be comprehensive but covers abnormalities commonly detected with standard sonography and those that are potentially amenable to fetal therapy. Sonographic features of chromosomal abnormalities are reviewed in Chapters 13 and 14, and fetal therapy is discussed in Chapter 16.

Standard sonographic evaluation of the fetal brain includes three transverse (axial) views. The transthalamic view is used to measure the BPD and HC and includes the midline falx, cavum septum pellucidum (CSP), and thalami (see Fig. 10-IA). The CSP is the space between the two laminae that separate the frontal horns of the lateral ventricles. Inability to visualize a normal CSP may indicate a midline brain abnormality such as agenesis of the corpus callosum, lobar holoprosencephaly, or septo-optic dysplasia (de Morsier syndrome). The transventricular view includes the lateral ventricles, which contain the echogenic choroid plexus (Fig. 10-6). The ventricles are measured at their atrium, which is the confluence of the temporal and occipital horns. The transcerebellar view is obtained by angling the transducer back through the posterior fossa (Fig. 10-7). In this view, the cerebellum and cisterna magna are measured, and between 15 and about 20 weeks, the nuchal skinfold thickness may also be measured. From 15 until 22 weeks' gestation, the cerebellar diameter in millimeters is roughly equivalent to the gestational age in weeks (Goldstein, 1987). The cisterna magna normally measures between 2 and 10 mm. Efacement of the cisterna magna is present in the Chiari II maormation, discussed later (p. 193).

Imaging of the spine includes evaluation of the cervical, thoracic, lumbar, and sacral regions (Fig. 10-8). Representative spinal images for record keeping are often obtained in the sagittal or coronal plane, but real-time imaging of each spinal segment in the transverse plane is more sensitive for anomaly detection. Transverse images demonstrate three ossification centers. The anterior ossiication center is the vertebral body, and the posterior paired ossification centers represent the

FIGURE 10-8 Normal fetal spine. In this sagittal image of a 21-week fetus, the cervical (, thoracic (, lumbar (, and sacral spine (5) are depicted. Arrows denote the parallel rows of paired posterior ossification centers-representing the junction of vertebralolamina and pedicles.

FIGURE 10-9 Anencephaly/acrania. A. Acrania. This ll-week fetus has absence of the cranium, with protrusion of a disorganized mass of brain tissue that resembles a "shower cap" (arrows) and a characteristic triangular facial appearance. B. Anencephaly. This sagittal image shows the absence of forebrain and cranium above the skull base and orbit. The long white arrow points to the fetal orbit, and the short white arrow indicates the nose.

junction of vertebral laminae and pedicles. Ossiication of the spine proceeds in a cranial-caudal fashion, such that ossification of the upper sacrum (51-52) is not generally visible sonographically before 16 weeks' gestation, and ossification of the entire sacrum may not be visible until 21 weeks (De Biasio, 2003). Thus, detection of some spinal abnormalities can be challenging in the early second trimester.

If a brain or spinal abnormality is identified, targeted sonography is indicated. he International Society of Ultrasound in Obstetrics and Gynecology (2007) has published guidelines for a "fetal neurosonogram." Fetal MR imaging may also be helpful (p. 217).

hese defects include anencephaly, myelomeningocele (also called spina bifida), cephalocele, and other rare spinal fusion (or schisis) abnormalities. hey result from incomplete closure of the neural tube by the embryonic age of 26 to 28 days. heir birth prevalence is 0.9 in 1000 in the United States and most of Europe and 1.3 in 1000 in the United Kingdom (Cragan, 2009; Dolk, 2010). Many neural-tube defects can be prevented with folic acid supplementation. When isolated, neural-tube defect inheritance is multifactorial, and the recurrence risk without periconceptional folic acid supplementation is 3 to 5 percent (Chap. 13, p. 270).

Screening for neural-tube defects with maternal serum alpha-fetoprotein (MSAFP) has been ofered routinely as part of prenatal care since the 1980s (Chap. 14, p. 283). Women currently have the option of neural-tube defect screening with MSAFP, sonography, or both (American College of Obstetricians and Gynecologists, 2016). Serum screening is generally performed between 15 and 20 weeks' gestation. And, if using an upper threshold of 2.5 multiples of the median (MoM), the anticipated detection rate is at least 90 percent for fetal anencephaly and 80 percent for myelomeningocele. Targeted sonography is the preferred diagnostic test, and in addition to characterizing the neural-tube defect, it may identiy other abnormalities or conditions that also result in MSAFP elevation (Table 14-6, p. 283).

Anencephay is characterized by absence of the cranium and telencephalic structures above the level of the skull base and orbits (Fig. 10-9). Acrania is absence of the cranium with protrusion of disorganized brain tissue. Both are uniformly lethal and are generally considered together, with anencephaly as the final stage of acrania (Bronshtein, 1991). These anomalies are often diagnosed in the late first trimester, and with adequate visualization, virtually all cases may be diagnosed in the second trimester. Inability to image the BPD raises suspicion. The face often appears triangular, and sagittal images readily demonstrate absence of the ossified cranium. Hydramnios from impaired fetal swallowing is common in the third trimester.

Cphaocee is the herniation of meninges through a cranial defect, tpically located in the midline occipital region (Fig. 10-10).

FIGURE 10-10 Encephalocele. This transverse image depicts a large defect in the occipital region of the cranium (arrows) through which meninges and brain tissue have herniated.

FIGURE 10-1 1 Myelomeningocele, In this sagittal image of a lumbosacral myelomeningocele, the arrowheads indicate nerve roots within the anechoic herniated sac. The overlying skin is visible above the level of the spinal defect but abruptly stops at the defect (arrow),

When brain tissue herniates through the skull defect, the anomaly is termed an encephaocee. Herniation of the cerebellum and other posterior fossa structures constitutes a Chiari II maomaion. Associated hydrocephalus and microcephaly are common, and survivors have a high incidence of neurological deficits and intellectual disability. Cephalocele is an important feature of the autosomal recessive Meckel-Guber syndrome, which includes cystic renal dysplasia and polydactyly. A cephalocele not located in the occipital midline rises suspicion for amnionic-band sequence (Chap. 6, p. 116).

Spina bia is a defect in the vertebrae, typically the dorsal arches, with exposure of the meninges and spinal cord. The birth prevalence approximates 1 in 2000 (Cragan, 2009; Dolk, 2010). Most cases are open spina bia-the defect includes the skin and sot tissues. Herniation of a meningeal sac containing neural elements is termed a myelomeningocele (Fig. 10-1i1). When only a meningeal sac is present, the defect is a meningocele. Although the sac may be easier to image in the sagittal plane, transverse images more readily demonstrate separation or splaying of the laterl processes.

Detection of spina bifida is aided by two characteristic cranial findings (Nicolaides, 1986). Scalloping of the frontal bones is termed the lemon sign, and anterior curvature of the cerebellum with efacement of the cisterna magna is the banana sign (Fig. 10-12). These indings are manifestations of the Chiari II malformation, also called the Arnold-Chiari maormation. This develops when downward displacement of the spinal cord pulls a portion of the cerebellum through the foramen magnum and into the upper cervical canal. Ventriculomegay is another frequent associated sonographic finding, particularly after midgestation. More than 80 percent of infants with open spina bifida require ventriculoperitoneal shunt placement. A small BPD is often present as well. Children with spina biida require multidisciplinary care to address problems related to the defect, therapeutic shunting, and deicits in swallowing, bladder and bowel function, and ambulation. Fetal myelomeningocele surgery is discussed

Chapter 16 (p. 319).

Characterized by distention of the cerebral ventricles by cerebrospinal luid (CSF), this finding is a nonspecific marker of abnormal brain development (Pilu, 2011). The atrium normally measures between 5 and 10 mm from 15 weeks' gestation until term (see Fig. 10-6). Mild ventriculomegaly is diagnosed when the atrial width measures 10 to 15 mm (Fig. 10-13), and overt or severe ventriculomegaly when it exceeds 15 mm. The larger the atrium, the greater the likelihood of an abnormal outcome (Gaglioti, 2009; J06, 2008). CSF is produced within the ventricles by the choroid plexus, which is composed of loose connective tissue surrounding an epithelium-lined capillary core. he choroid plexus often appears to dangle within the ventricle when severe ventriculomegaly is present.

Ventriculomegaly may be caused by various genetic and environmental insults. It may be due to other central nervous system (CNS) abnormalities-such as Dandy-Walker malformation or holoprosencephaly, to an obstructive process-such as aqueductal stenosis, or to a destructive process-such as porencephaly or an intracranial teratoma. Initial evaluation includes a targeted examination of fetal anatomy, testing for congenital infections such as cytomegalovirus and toxoplasmosis, and chromosomal microarray analysis, which is described in Chapter 13 (p. 271). Fetal MR imaging should be considered to assess for associated abnormalities that may not be detectable sonographically.

FIGURE 10-12 Cranial findings in myelomeningocele, A. Image of a fetal head at the level of the lateral ventricles demonstrates inward bowing or scalloping of the frontal bones (arrows)-the lemon sign. B. Image of a fetal head at the level of the posterior fossa shows anterior curvature of the cerebellum (arrows) with effacement of the cisterna magna-the banana sign.

FIGURE 10-13 Ventriculomegaly. In this transverse view of the cranium, the white line depicts measurement of the atrium of the lateral ventricle, which measured 12 mm, consistent with mild ventriculomegaly.

Prognosis is generally determined by etiology, severity, and rate of progression. However, even with mild-appearing and isolated ventriculomegaly, prognosis can vary widely. In a systematic review of nearly 1500 mild-to-moderate cases, 1 to 2 percent were associated with congenital infection, 5 percent with aneuploidy, and 12 percent with neurological abnormality (Devaseelan, 2010). A neurological abnormality was significantly more common if ventriculomegly progressed with advancing gestation.

Agenesis of the Corpus Callosum

The corpus callosum is the major iber bundle connecting reciprocal regions of the cerebral hemispheres. With complete agenesis of the corpus callosum, a normal cavum septum pellucidum cannot be visualized sonographically. Also, the frontal horns are displaced laterally, and the atria show mild enlargement posteriorly-such that the ventricle has a characteristic "teardrop" appearance (Fig. 10-14). Callosal dysgenesis involves only the caudal portions-the body and splenium-and consequently may be more diicult to detect prenatally.

In population-based studies, agenesis of the corpus callosum has a prevalence of 1 in 5000 births (Glass, 2008; Szabo, 2011). In a review of apparently isolated cases, fetal MR imaging identiied additional brain abnormalities in more than 20 percent (Sotiriadis, 2012). If the anomaly was still considered isolated following MR imaging, normal developmental outcome was reported in 75 percent of cases, but severe disability occurred in 12 percent. Agenesis of the corpus callosum is associated with other anomalies, aneuploidy, and more than 200 genetic syndromes. Thus, genetic counseling can be challenging.

FIGURE 10-14 Agenesis of the corpus callosum. This image demonstrates a "teardrop" shaped ventricle with mild ventriculomegaly (dotted line) and laterally displaced frontal horns (arrow). A normal cavum septum pellucidum cannot be visualized.

In early normal brain development, the prosencephalon or forebrain divides as it becomes the telencephalon and diencephalon. With holoprosencephaly, the prosencephalon fails to divide completely into two separate cerebral hemispheres and underlying paired diencephalic structures. Main forms of holoprosencephaly are a continuum that contains, with decreasing severity, alobar, semilobar, and lobar types. In the most severe form-alobar holoprosencephay-a single monoventricle, with or without a covering mantle of cortex, surrounds fused central thalami (Fig. 10-15). In semilobar holoprosencephay, partial separation of the hemispheres occurs. Lobar holoprosencephay is characterized by a variable degree of fusion of frontal structures and should be considered when a normal CSP cannot be seen.

Diferentiation into two cerebral hemispheres is induced by prechordal mesenchyme, which is also responsible for diferentiation of the midline face. Thus, holoprosencephaly may be associated with anomalies of the orbits and eyeshypotelorism, cyclopia, or micro-ophthalmia; lips-median cleft; or nose-ethmocephaly, cebocephaly, or arhinia with proboscis (see Fig. 10-15).

The birth prevalence of holoprosencephaly is only 1 in 10,000 to 15,000. However, the abnormality has been identiied in nearly 1 in 250 early abortuses, which attests to the extremely high in-utero lethality (Orioli, 2010; Yamada, 2004). The alobar form accounts for 40 to 75 percent of cases, and 30 to 40 percent have a numerical chromosomal abnormality, particularly trisomy 13 (Orioli, 2010; Solomon, 2010). Conversely, two thirds of trisomy 13 cases are found to have holoprosencephaly. Fetal karyotype or chromosomal microarray analysis should be ofered when this anomaly is identiied.

This posterior fossa abnormality is characterized by agenesis of the cerebellar vermis, posterior fossa enlargement, and elevation of the tentorium. Sonographically, luid in the enlarged

FIGURE 10-15 Alobar holoprosencephaly. A. Transverse cranial image of a fetus with alobar holoprosencephaly, depicting fused thalami (Th) encircled by a monoventricle () with a covering mantle (M) of cortex. The midline falx is absent. (Reproduced with permission from Rafael Levy, ROMS.) B. In this profile view of the face, a soft tissue mass-a proboscis (arrow), protrudes from the region of the forehead.

cisterna magna visibly communicates with the fourth ventricle through the cerebellar vermis defect, with visible separation of the cerebellar hemispheres (Fig. 10-16). The birth prevalence approximates 1 in 12,000 (Long, 2006). Associated anomalies and aneuploidy are common. These include ventriculomegaly in 30 to 40 percent, other anomalies in approximately 50 percent, and aneuploidy in 40 percent (Ecker, 2000; Long, 2006). Dandy-Walker malformation is also associated with numerous genetic and sporadic syndromes, congenital viral infections, and teratogen exposure, all of which greatly afect the prognosis. Thus, the initial evaluation mirrors that for ventriculomegaly (p. 193).

Inerior vermian agenesis, also called Dandy-Walker variant, is a term used when only the inferior portion of the vermis is absent. But, even when vermian agenesis appears to be partial and relatively subtle, the prevalence of associated anomalies and aneuploidy is still high, and the prognosis is often poor (Ecker, 2000; Long, 2006).

Schizencephaly is a rare brain abnormality characterized by clefts in one or both cerebral hemispheres, typically involving the perisylvian fissure. The cleft is lined by heterotopic gray matter and communicates with the ventricle, extending through the cortex to the pial surface (Fig. 10-17). Schizencephaly is believed to be an abnormality of neuronal migration, which explains its typically delayed recognition until after midpregnancy (Howe, 2012). It is associated with absence of the cavum septum pellucidum, resulting in the frontal horn communication shown in the image below.

FIGURE 10-16 Dandy-Walker malformation. This transcerebellar image demonstrates agenesis of the cerebellar vermis. The cerebellar hemispheres (+) are widely separated by a fluid collection that connects the 4th ventricle (asterisk) to the enlarged cisterna magna (eM).

FIGURE 10-17 Schizencephaly. This transverse image ofthe fetal head shows a large cleft that extends from the right lateral ventricle through the cortex. Because the borders of the cleft are sepa rate, the defect is termed open-lipped. (Used with permission from

Michael Davidson, ROMS.)

FIGURE 10-19 Midline face. This view demonstrates the integrity of the upper lip.

FIGURE 10-18 Sacrococcygeal teratoma. Sonographically, this tumor appears as a solid and/or cystic mass that arises from the anterior sacrum and tends to extend inferiorly and externally as it grows. In this image, a 7 x 6 cm inhomogeneous solid mass is visible below the normal-appearing sacrum. There is also an internal component to the tumor.

In contrast, porencephaly is a cystic space within the brain that is lined by white matter and mayior may not communicate with the ventricular system. It is generally considered to be a destructive lesion and may develop following intracranial hemorrhage in the setting of neonatal alloimmune thrombocytopenia or following death of a monochorionic co-twin (Fig. 45-20, p. 878). Fetal MR imaging should be considered when either of these CNS anomalies is identiied.

his germ cell tumor is one of the most common tumors in neonates, with a birth prevalence of approximately 1 in 28,000 (Derikx, 2006; Swamy, 2008). It is thought to arise from the totipotent cells along Hensen node, anterior to the coccyx. Classification of sacrococcygeal teratoma (SCT) includes four types (Altman, 1974). Type 1 is predominantly external with a minimal presacral component; type 2 is predominantly external but with a significant intrapelvic component; type 3 is predominantly internal but with abdominal extension; and type 4 is entirely internal with no external component. he tumor histological type may be mature, immature, or malignant.

Sonographiclly, SCT appears as a solid and/or cystic mass that arises rom the anterior sacrum and usually extends inferiorly and externally as it grows (Fig. 10-18). Solid components oten have varying echogenicity, appear disorganized, and may enlarge rapidly with advancing gestation. Internal pelvic components may be more challenging to visualize, and fetal MR imaging should be considered. Hydramnios is frequent, and hydrops may develop from high-output cardiac failure, either as a consequence of tumor vascularity or secondary to bleeding within the tumor and resultant anemia. Mentioned throughout this chapter, hydrops is more ully described in Chapter 15 (p. 309). Fetuses with tumors >5 cm oten require cesarean delivery, and classical hysterotomy may be needed (Gucciardo, 2011). s shown in Figure 16-3 (p. 320), fetal surgery is suitable for some SCT cases.

his rare anomaly is characterized by absence of the sacral spine and often portions of the lumbar spine. It is approximately 25 times more common in diabetic pregnancies (Garne, 2012). Sonographic indings include a spine that appears abnormally short, lacks normal lumbosacral curvature, and terminates abruptly above the level of the iliac wings. Because the sacrum does not lie between the iliac wings, they are abnormally close together and may appear "shield-like." here may also be abnormal positioning of the lower extremities and lack of normal local soft tissue development. Caudal regression should be diferentiated from sirenomelia, which is a rare anomaly characterized by a single fused lower extremity that occupies the midline.

Normal fetal lips and nose are shown in Figure 10-19. A fetal profile is not a required component of standard examination but may be helpful in identiying cases of micrognathia-an abnormally small jaw (Fig. 10-20). Micrognathia should be considered in the evaluation of hydramnios (Chap. 11, p. 227). Use of the ex-utero intrapartum treatment (EI) procedure for severe micrognathia is discussed in Chapter 16 (p. 327).

here are three main types of clefts. he irst type, clt lip and palate, always involves the lip, may also involve the hard palate, can be unilateral or bilateral, and has a birth prevalence that approximates 1 in 1000 (Cragan, 2009; Dolk, 2010). If isolated, the inheritance is multifactorial-with a recurrence risk of 3 to 5 percent for one prior afected child. If a cleft is visible in the upper lip, a transverse image at the level of the alveolar ridge may demonstrate that the defect also involves the primary palate (Fig. 10-21).

In one systematic review of low-risk pregnancies, cleft lip was identiied so no graphically in only about half of cases

FIGURE 10-20 Fetal profile. A. This image depicts a normal fetal profile. B. This fetus has severe micrognathia, which creates a severely recessed chin.

(Maarse, 2010). Approximately 40 percent of those detected in prenatal series are associated with other anomalies or syndromes, and aneuploidy is common (Maarse, 2011; Oferdal, 2008). The rate of associated anomalies is highest for bilateral defects that involve the palate. Using data from the Utah Birth Defect Network, Walker and associates (2001) identified aneuploidy in 1 percent with cleft lip alone, 5 percent with unilateral cleft lip and palate, and 13 percent with bilateral cleft lip and palate. It is reasonable to ofer fetal chromosomal microarray analysis when a cleft is identiied.

he second type of cleft is isolated clt palate. I t begins at the uvula, may involve the soft palate, and occasionally involves the hard palate-but does not involve the lip. The birth prevalence approximates 1 in 2000 (Dolk, 2010). Identiication of isolated cleft palate has been described using specialized 2-and 3-dimensional sonography (Ramos, 2010; Wilhelm, 2010). However, it is not expected to be visualized during a standard sonographic examination (Maarse, 2011; Oferdal, 2008).

A third type of cleft is median clt lp, which is found in association with several conditions. hese include agenesis of the primary palate, hypotelorism, and holoprosencephaly.

FIGURE 10-21 Cleft lip/palate. A. This fetus has a prominent unilateral (left-sided) cleft lip. B. Transverse view of the palate in the same fetus demonstrates a defect in the alveolar ridge (arrow), The tongue ) is also visible.

Median clefts may also be associated with hypertelorism and frontonasal hyperplasia, formerly called the median clt ace syndrome.

This venolymphatic malformation is characterized by luidilled sacs that extend from the posterior neck (Fig. 10-22). Cystic hygromas may be diagnosed as early as the irst trimester and vary widely in size. They are believed to develop when lymph from the head fails to drain into the jugular vein and accumulates instead in jugular lymphatic sacs. Their birth prevalence approximates 1 in 5000. But, reflecting the high in-utero lethality of the condition, the first-trimester incidence exceeds 1 in 300 (Malone, 2005).

Up to 70 percent of cystic hygromas are associated with aneuploidy. When cystic hygromas are diagnosed in the irst trimester, trisomy 21 is the most common aneuploidy, followed by 45,X and trisomy 18 (Kharrat, 2006; Malone, 2005). Firsttrimester fetuses with cystic hygromas are ive times more likely to be aneuploid than fetuses with a thickened nuchal translucency. When cystic hygromas are diagnosed in the second trimester, approximately 75 percent of aneuploid cases are 45,X-Turner syndrome Gohnson, 1993; Shulman, 1992).

Even in the absence of aneuploidy, cystic hygromas confer a significantly greater risk for other anomalies, particularly cardiac anomalies that are flow-related. These include hypoplastic let heart and coarctation of the aorta. Cystic hygromas also may be part of a genetic syndrome. One is Noonan yndrome, an autosomal dominant disorder that shares several features with Turner syndrome, including short stature, lymphedema, high-arched palate, and oten pulmonary valve stenosis.

Large cystic hygromas are usually associated with hydrops fetalis, rarely resolve,

FIGURE 10-22 Cystic hygromas. A. This 9-week fetus with a cystic hygroma (arrow) was later found to have Noonan syndrome. B. Massive multiseptated hygromas (arrowheads) in the setting of hydrops fetalis at 15 weeks' gestation.

and carry a poor prognosis. Small hygromas may undergo spontaneous resolution, and provided that fetal karyotype and echocardiography results are normal, the prognosis may be good. The likelihood of a nonanomalous liveborn neonate with normal karyotype following identiication of first-trimester hygroma is approximately 1 in 6 (Kharrat, 2006; Malone, 2005).

he lungs appear homogeneous and surround the heart. In the four-chamber view of the heart, they comprise approximately two thirds of the area, with the heart occupying the remaining third. The thoracic circumference is measured at the skin line in a transverse plane at the level of the four-chamber view. In cases of suspected pulmonary hypoplasia secondary to a small thorax, such as with severe skeletal dysplasia, comparison with a reference table may be helpul (Appendix, p. 1266). Various abnormalities may appear so no graphically as cystic or solid space-occupying lesions or as an efusion outlining the heart or lung(s). Fetal therapy for thoracic abnormalities is discussed in Chapter 16 (p. 324).

This is a defect in the diaphragm through which abdominal organs herniate into the thorax. It is let-sided in approximately 75 percent of cases, right-sided in 20 percent, and bilateral in 5 percent (Gallot, 2007). he prevalence of congenital diaphragmatic hernia (CDH) is 1 in 3000 to 4000 births (Cragan, 2009; Dolk, 2010). Associated anomalies and aneuploidy are found in 40 percent of cases (Gallot, 2007; Stege, 2003). With suspected CDH, targeted sonography and fetal echo cardiography should be performed, and fetal chromosomal microarray analysis should be ofered. In population-based series, the presence of an associated abnormality reduces the overall survival rate of neonates with CDH from approximately 50 percent to about 20 percent (Colvin, 2005; Gallot, 2007). If there are no associated abnormalities, the major causes of neonatal mortality are pulmonary hypoplasia and pulmonary hypertension.

Sonographically, left-sided CDH typically shows dextroposition of the heart toward the right side of the thorax and a cardiac axis pointing toward the midline (Fig. 10-23). Associated findings include the stomach bubble or bowel peristalsis in the chest and a wedge-shaped mass-the liver-located anteriorly in the left hemithorax. Liver herniation complicates at least 50 percent of cases and is associated with a 30-percent reduction in the survival rate (Mullassery, 2010). With large lesions, impaired swallowing and mediastinal shift may result in hydramnios and hydrops, respectively.

Eforts to reduce neonatal mortality rates and need for extracorporeal membrane oxygenation (ECMO) have focused on indicators such as the sonographic lung-to-head ratio, MR imaging measurements of lung volume, and the degree of liver herniation Gani, 2012; Oluyomi-Obi, 2016; Worley, 2009). These and fetal therapy for CDH are reviewed in Chapter 16 (p. 323).

FIGURE 10-23 Congenital diaphragmatic hernia. In this transverse view of the thorax, the heart is shifted to the far right side of the chest by a let-sided diaphragmatic hernia containing stomach (5), liver (, and bowel (B).

This abnormality represents a hamartomatous overgrowth of terminal bronchioles that communicates with the tracheobronchial tree. It is also called congenital pulmonay airway maormation (CPM), based on an understanding that not all histopathological types are cystic or adenomatoid (Azizkhan, 2008; Stocker, 1977, 2002). The estimated prevalence is 1 in 6000 to 8000 births, and this rate is rising because of improved sonographic detection of milder cases (Burge, 2010; Duncombe, 2002).

Sonographically, congenital cystic adenomatoid malformation (CCAM) is a well-circumscribed thoracic mass that may appear solid and echogenic or may have one or multiple variably sized cysts (Fig. 10-24). It usually involves one lobe, has blood supply from the pulmonary artery, and drains into the pulmonary veins. Lesions with cysts :5 mm are generally

FIGURE 10-24 Transverse (A) and sagittal (8) images of a 26-week fetus with a very large left-sided microcystic congenital cystic adenomatoid malformation (CCAM). The mass () fills the thorax and has shifted the heart to the far right side of the chest, with development of ascites (asterisks). Fortunately, the mass did not continue to grow, the ascites resolved, and the neonate was delivered at term and did well following resection.

termed macrocystic, and lesions with cysts <5 mm are termed microcystic (Adzick, 1985).

In a review of 645 CCM cases, the overall survival rate exceeded 95 percent, and 30 percent of cases demonstrated apparent prenatal resolution. The other 5 percent of cases typically very large lesions with associated mediastinal shift were complicated by hydrops, and the prognosis was poor (Cavoretto, 2008). CCAMs often become less conspicuous with advancing gestation. However, a subset of CCAMs dem onstrates rapid growth between 18 and 26 weeks' gestation.

lesions to forestall growth and potentially ameliorate hydrops (Curran, 2010; Peranteau, 2016). If a large dominant cyst is present, thoracoamnionic shunt placement may lead to hydrops resolution. Fetal therapy for CCAM is discussed in Chapter 16 (p.i324).

Also called a bronchopulmonary sequestration, this abnormal ity is an accessory lung bud "sequestered" from the tracheo bronchial tree, that is, a mass of nonfunctioning lung tissue.

Most cases diagnosed prenatally are extralobar, which means they are enveloped in their own pleura. Overall, however, most sequestrations present in adulthood and are intralobar-within the pleura of another lobe. Extralobar pulmonary sequestra tion is considered significantly less common than CCAM, and no precise prevalence has been reported. Lesions have a left sided predominance and most often involve the left lower lobe.

Of cases, 10 to 20 percent are located below the diaphragm, 10 percent of cases (Yildirim, 2008).

Sonographically, pulmonary sequestration presents as a homogeneous, echogenic thoracic mass (Fig. 10-25A). Thus, it may resemble a microcystic CCAM. However, the blood supply is from the systemic circulation-from the aorta rather than the pulmonary artery (see Fig. 10-25B). In 5 to 10 percent with pulmonary sequestration, a large ipsilateral pleural efusion develops, and without treatment, this may result in pulmonary hypoplasia or hydrops (see Fig. 1 0-25C,D). Therapeutic thoracoamnionic shunting of efusions is discussed in Chapter 16 (p. 324). Hydrops may also result from mediastinal shift or high-output cardiac failure due to the left-toright shunt imposed by the mass. In the absence of a pleural efusion, the reported survival rate exceeds 95 percent, and 40 percent of cases demonstrate apparent prenatal resolution (Cavoretto, 2008).

This rare anomaly usually results from laryngeal or tracheal atresia. The normal egress of lung fluid is obstructed, and the tracheobronchial tree and lungs become massively distended. Sonographically, the lungs appear brightly echogenic, the bronchi are dilated, the diaphragm is flattened or everted, and the heart is compressed (Fig. 10-26). Venous return is impaired and ascites develops, typically followed by hydrops. In one review of 118 cases, associated anomalies were identiied in more than 50 percent (Sanford, 2012). Congenital high airway obstruction sequence (CHAOS) is a feature of the autosomal recessive Fraser syndrome and has been associated with the 22q 11.2 deletion syndrome. In some cases, the obstructed airway spontaneously perforates, which potentially confers a better prognosis. he EIT procedure has significantly improved outcome in selected cases (Chap. 16, p. 327).

FIGURE 10-25 Pulmonary sequestration. A. This transverse image at the level of the 4-chamber view of the heart depicts a pulmonary sequestration involving the left lower lobe in a 25-week fetus. Mass effect leads to dextroposition of the heart to the right side of the chest.

B. A sagittal image shows the pulmonary sequestration supplied by a branch of the abdominal aorta. C. Over the next 3 weeks, a large ipsilateral pleural effusion develops (asterisk), resulting in mediastinal shift and dextroposition of the heart to the far right thorax. D. Following placement of a double-pigtail shunt through the chest wall and into the effusion, the effusion drained and the lung significantly reexpanded. Arrows points to coils of the pigtail shunt. (Used with permission from Dr. Elaine Duryea.)

FIGURE 10-26 Congenital high airway obstruction sequence (CHAOS). The lungs appear brightly echogenic, and one is marked by an "L." The bronchi, one of which is noted by an arrow, are dilated with fluid. Flattening and eversion of the diaphragm is common, as is ascites (asterisks).

Cardiac malformations are the most common class of congenital anomalies, and their overall prevalence is 8 in 1000 births (Cragan, 2009). Almost 90 percent of cardiac defects are multifactorial or polygenic in origin, another 1 to 2 percent result from a single-gene disorder or gene-deletion syndrome, and 1 to 2 percent stem from exposure to a teratogen such as isotretinoin, hydantoin, or maternal diabetes. Based on data from population-based registries, approximately 1 in 8 liveborn and stillborn neonates with a congenital heart defect has a chromosomal abnormality (Dolk, 2010; Hartman, 201l). Of chromosomal abnormalities associated with cardiac anomalies, trisomy 21 accounts for more than 50 percent of cases. Others are trisomy 18, 22q 11.2 deletion, trisomy 13, and monosomy X (Hartman, 2011). Of these aneuploid fetuses, 50 to 70 percent also have extracardiac anomalies. Chromo defects are found.

Traditionally, detection of congenital cardiac anomalies is more challenging than for anomalies of other organ systems.

40 percent of those with major cardiac anomalies before 22 weeks' gestation, and specialized sonography may identiy 80 percent (Romosan, 2009; Trivedi, 2012). For selected anoma lies, prenatal detection may improve neonatal survival. his requiring prostaglandin infusion after birth to keep the duc tus arteriosus open (Franklin, 2002; Mahle, 2001; Tworetzky, 2001).

Standard cardiac assessment includes a four-chamber view, evaluation of rate and rhythm, and evaluation of the left and right ventricular outlow tracts (Figs. 10-27 and 10-28A-C).

Examination of the cardiac outflow tracts aids detection of abnormalities that might not be appreciated in the four-cham ber view. hese include tetralogy of Fallot, transposition of the great vessels, and truncus arteriosus.

heour-chamber view is a transverse image of the fetal tho rax at a level immediately above the diaphragm. It allows evalu ation of cardiac size, position in the thorax, cardiac axis, atria and ventricles, foramen ovale, atrial septum primum, interven tricular septum, and atrioventricular valves (see Fig. 10-27).

he atria and ventricles should be similar in size, and the apex of the heart should form a 45-degree angle with the left anterior chest wall. Abnormalities of cardiac axis are frequently encoun tered with structural cardiac anomalies and occur in more than a third (Shipp, 1995).

The lt ventricular oulow tract view is a transverse image just above the diaphragm and demonstrates that the ascending aorta arises entirely from the left ventricle. The inteventricular septum is shown to be in continuity with the anterior wall of the aorta, and the mitral valve in continuity with the posterior wall of the aorta (see Fig. 10-28B). Ventricular septal defects and outflow tract abnormalities are often visible in this view (Fig. 10-29).

The right ventricular oulow tract view shows the right ventricle giving rise to the pulmonary artery (see Fig. 10-28C). Together, the left and right outflow tract views demonstrate the normal perpendicular orientation of the aorta and pulmonary artery, and the comparable size of these great arteries. Structures visible in the right ventricular outlow tract view include the right ventricle and the main pulmonary artery, which subsequently branches into the right and left pulmonary arteries. hese structures are also visible in the short axis view, shown in Figure 10-28E.

This is a specialized examination of fetal cardiac structure and function designed to identiy and characterize abnormalities. Guidelines for its performance have been developed collaboratively by the American Institute of Ultrasound in Medicine,

FIGURE 10-27 The four-chamber view. A. Diagram demonstrat ing measurement of the cardiac axis from the four-chamber view of the fetal heart. B. Sonogram of the four-chamber view at 22 weeks' gestation shows the normal symmetry of the atria and ventricles, normal position of the mitral and triscuspid valves, pulmonary veins entering the left atrium, and descending aorta (Ao). L = left; LA = left atrium; LV = left ventricle; R = right; RA = right atrium; RV = right ventricle.

American College of Obstetricians and Gynecologists, Society for Maternal-Fetal .Medicine, American Society of Echocardiography, and American College of Radiology. Echocardiography indications include suspected fetal cardiac anomaly, extracardiac anomaly, or chromosomal abnormality; fetal arrhythmia; hydrops; thick nuchal translucency; monochorionic twin gestation; irst-degree relative to the fetus with a congenital cardiac defect; in vitro fertilization; maternal antiRo or anti-La antibodies; exposure to a medication associated with cardiac defects; and maternal metabolic disease associated with cardiac defects-such as pregestational diabetes or phenylketonuria (American Institute of Ultrasound in Medicine, 2013a). Components of the examination are listed in

TABLE 10-9. Components of Fetal Echocardiography

EvaIuation of atria Evaluation of ventricles Evaluation of great vessels Cardiac and visceral situs Atrioventricular junctions Ventriculoarterial junctions

Scanning planes, gray scale

Right ventricular outflow tract Three-vessel and trachea view Short-axis view, low (ventricles) Short-axis view, high (outflow tracts) Aortic arch aPulsed-wave Doppler sonography should be used as an adjunct to evaluate these structures.

Cardiac biometry and functional assessment are optional but should be considered for suspected structural/ functional abnormalities.

Adapted from the American Institute of Ultrasound in Medicine,l201l3b.

FIGURE 10-30 Endocardial cushion defect. A. During ventricular systole, the lateral leaflets of the mitral and triscuspid valves come together in the midline. But the atrioventricular valve plane is abnormal, a common atrium (A) is observed, and there is a visible defect (arrow) in the interventricular septum. B. During diastolic filling, opening of the atrioventricular valves more clearly demonstrates the absence of their medial leaflets.

Table 10-9, and examples of nine required gray-scale imaging views are shown in Figure 10-28. Examples of selected cardiac anomalies are reviewed below.

Ventricular Septal Defect. This is the most common congenital cardiac anomaly and is found in approximately 1 in 300 births (Cragan, 2009; Dolk, 2010). Even with adequate visualization, the prenatal detection rate of ventricular septal defect (VSD) is low. A defect may be appreciated in the membranous or muscular portion of the interventricular septum in the four-chamber view, and color Doppler demonstrates flow through the defect. Imaging of the left ventricular outflow tract may show discontinuity of the interventricular septum as it becomes the wall of the aorta (see Fig. 10-29). Fetal VSD is associated with other abnormalities and aneuploidy, and chromosomal microarray analysis should be ofered. hat said, the prognosis for an isolated defect is good. More than a third of prenatally diagnosed VSDs close in utero, and another third close in the irst year of life (Axt-Fliedner, 2006; Paladini, 2002).

Endocardial Cushion Defect. This is also called an atrioventricular (A ) septal dect or A V canal dect. It has a prevalence of approximately 1 in 2500 births and is associated with trisomy 21 in more than half of cases (Christensen, 2013; Cragan, 2009; Dolk, 2010). The endocardial cushions are the crux of the heart, and defects jointly involve the atrial septum primum, interventricular septum, and medial leaflets of the mitral and tricuspid valves (Fig. 10-30). Approximately 6 percent of cases occur with heterotaxy syndromes, that is, those in which the heart and/or abdominal organs are on the incorrect side. Endocardial cushion defects associated with heterotaxy can have comorbid conduction system abnormalities resulting in third-degree AV block, which confers a poor prognosis (Chap. 16, p. 316).

Hypoplastic Let Heart Syndrome. This anomaly is found in approximately 1 in 4000 births (Cragan, 2009; Dolk, 2010). Sonographically, the let side of the heart may appear "illed-in" or the let ventricle may be so small and attenuated that a ventricular chamber is diicult to appreciate (Fig. 10-31). There may be no visible let ventricular inlow or outflow, and reversal of low may be documented in the aortic arch.

Although this anomaly was once considered a lethal prognosis, 70 percent of afected infants may now survive to adulthood (Feinstein, 2012). Postnatal treatment consists of a three-stage palliative repair or cardiac transplantation. Still, morbidity remains high, and developmental delays are common (Lloyd, 2017; Paladini, 2017). This is a ductal-dependent lesion for which neonatal administration of prostaglandin therapy is essential. Fetal therapy for hypoplastic left heart is discussed in Chapter 16 (p. 326).

FIGURE 10-28 Fetal echocardiography gray-scale imaging planes. A. Four-chamber view. B. Left ventricular outflow tract view. The white arrow illustrates the mitral valve becoming the wall of the aorta. The arrow with asterisk marks the interventricular septum becoming the opposing aortic wall. C. Right ventricular outflow tract view. D. Three vessel and trachea view. E. High short-axis view (outflow tracts). F. Low short-axis view (ventricles). G. Aortic arch view. H. Ductal arch view. I. Superior and inferior vena cavae views. Ao = aorta; IVC = inferior vena cava; LA = left atrium; LV = left ventricle; PA = pulmonary artery; RA = right atrium; RV = right ventricle; SVC = superior vena cava.

branous) portion of the interventricular septum.

B.The left-ventricular outflow tract view of the same fetus demonstrates a break (arrow) in continuity between the interventricular septum and the anterior wall of the aorta.

FIGURE 10-29 Ventricular septal defect. A.oln this four-chamber view of a 22-week fetus, a defect (arrow) is noted in the superior (mem

Tetralogy of Fallot. This anomaly occurs in approximately 1 in 3000 births (Cragan, 2009; Dolk, 2010; Nelson, 2016). It includes a ventricular septal defect; an overriding aorta; a pulmonary valve abnormality, typically stenosis; and right ventricular hypertrophy (Fig. 10-32). he last does not present before birth. Due to the location of the ventricular septal defect, the four-chamber view may appear normal.

Following postnatal repair, the 20-year survival rates exceed 95 percent (Knott-Craig, 1998). However, cases with pulmonay atresia have a more complicated course. There is also a variant in which the pulmonary valve is absent. These afected fetuses are at risk for hydrops and for tracheomalacia from compression of the trachea by an enlarged pulmonary artery.

Cardiac Rhabdomyoma. his is the most common cardiac tumor. Approximately 50 percent of cases are associated with tuberous sclerosis, an autosomal dominant disease with multiorgan system manifestations. Tuberous sclerosis is caused by mutations in the hamartin (TSCl) and tuberin (TSC2) genes.

Cardiac rhabdomyomas appear as well-circumscribed echo genic masses, pler depicts flow from the right atrium to the right ventricle only, and left ventricular filling is usually within the ventricles or out not visible. C. The left ventricular outflow tract view demonstrates marked narrowing of the aorta (Ao). RV = right ventricle; LA = low tracts. They may be single or is the hypoplastic aortic root. (Used with permission from Rafael Levy, ROMS.) multiple; may grow in size during gestation; and occasionally, may lead to inlow or outflow obstruction. In cases without obstruction or large tumor size, the prognosis is relatively good from a cardiac standpoint, because the tumors tend to regress after the neonatal period. Because extracardiac findings of tuberous sclerosis may not be apparent with prenatal sonography, MR imaging may be considered to evaluate fetal CNS anatomy (p. 217).

Motion-mode or M-mode imaging is a linear display of cardiac cycle events, with time on the x-axis and motion on the y-axis. It is often used to measure embryonic or fetal heart rate (Fig. 10-33). If an abnormality of heart rate or rhythm is identiied, M-mode imaging permits separate evaluation of atrial and ventricular waveforms. Thus, it is particularly useful for characterizing arrhythmias and their response to treatment (Chap. 16, p. 316). M-mode can also be used to assess ventricular function and atrial and ventricular outputs.

Premature Atrial Contractions. Also called atrial extrasystoles, these are the most common fetal arrhythmia and a frequent

FIGURE 10-31 Hypoplastic left heart syndrome. A. In this 4-chamber view at 16 weeks, the let ventricle (L) appears "filled in" and is Significantly smaller than the right ventricle (R). The tricuspid valve () is open, whereas the mitral valve appears closed (asterisk). B. Color Dop let atrium. D. The tiny circle (arrow) in this short axis view

FIGURE 10-32 Tetralogy of Fallot. This image shows a ventricular septal defect with an overriding aorta in a fetus with tetralogy of Fallot. The arrow points to the aortic valve. The left ventricle (LV)and right ventricle (R) are labeled.

FIGURE 10-33 M-mode, or motion mode, is a linear display of the events of the cardiac cycle, with time on the x-axis and motion on the y-axis. M-mode is used commonly to measure the fetal heart rate, as in this 12-week fetus.

finding. They represent cardiac conduction system immaturity and typically resolve later in gestation or in the neonatal period. Premature atrial contractions (PACs) may be conducted and thus sound like an extra beat. However, they are more commonly blocked, and with handheld Doppler they sound like a dropped beat. As shown in Figure 10-34, the dropped beat may be demonstrated with M-mode evaluation as a compensatory

FIGURE 10-34 M-mode. In this image, there is normal concordance between atrial (A) and ventricular contractions (). Movement of the tricuspid valve en is also shown. There is also a premature atrial contraction (arrow) and a subsequent early ventricular contraction, followed by a compensatory pause.

pause that follows the premature contraction.

P ACs sometimes occur with an atrial septal aneurysm but are not associated with major structural cardiac abnormalities. Older case reports describe an association with maternal cafeine consumption and with hydralazine (Lodeiro, 1989; Oei, 1989). In approximately 2 percent of cases, afected fetuses are later identified to have a supraventricular tachycardia (S) that requires urgent treatment (Copel, 2000). Accordingly, pregnancies with fetal PACs are often followed with fetal heart rate assessment as often as every 1 to 2 weeks until ectopy resolves. T reatment of fetal SVT and other arrhythmias is discussed in Chapter 16 (p. 316) .

he integrity of the abdominal wall is assessed at the level of the cord insertion during the standard examination (Fig. 10-35).

Ventral wall defects include gastroschisis, omphalocele, and body stalk anomaly.

Gastroschisis is a full-thickness abdominal wall defect located to the right of the umbilical cord insertion. Bowel herniates through the defect into the amnionic cavity (Fig. 10-36). he prevalence is approximately 1 in 2000 births Oones, 2016; Nelson, 2015). Gastroschisis is the one major anomaly more common in fetuses of younger mothers, and the average maternal age is 20 years (Santiago-Munoz, 2007). Coexisting bowel abnormalities such as jjunal atresia are found in approximately 15 percent of cases (Nelson, 2015; Overcash, 2014). Gastroschisis is not associated with aneuploidy, and the survival rate is 90 to 95 percent (Kitchanan, 2000; Nelson, 2015; Nembhard, 2001).

Fetal-growth restriction complicates gastroschisis in 15 to 40 percent of cases (Overcash, 2014; Santiago-Munoz, 2007). Growth restriction does not appear to be associated with adverse outcomes such as longer hospitalization or higher mortality rate (Nelson, 2015; Overcash, 2014). However, earlier gestational age at delivery does pose a risk for adverse outcome with gastroschisis, and planned delivery at 36 to 37 weeks does not confer neonatal benefit (Al-Kaf, 2016; Overcash, 2014; South, 2013).

Omphalocele complicates 1 in 3000 to 5000 pregnancies (Canield, 2006; Dolk, 2010). It forms when the lateral ectomesodermal folds fail to meet in the midline. This leaves the abdominal contents covered only by a two-layered sac of amnion and peritoneum into which the umbilical cord inserts (Fig. 10-37). More than half of cases are associated with other major anomalies or aneuploidy. Omphalocele also is a component of syndromes such as Beckwith-Wiedemann, cloacal exstrophy, and pentaloy of Cantrell. Smaller defects confer greater risk for aneuploidy (De Veciana, 1994). Chromosomal microarray analysis should be ofered in all cases of omphalocele.

FIGURE 10-35 Normal ventral wall. Transverse view of the abdomen in a second-trimester fetus with an intact anterior abdominal wall and normal cord insertion.

Body stalk anomay, also known as limb-body-wall complex or cyllosoma, is a rare, lethal anomaly characterized by abnormal formation of the body wall. Typically, no abdominal wall is visible, and the abdominal organs extrude into the extraamnionic coelom. here is close approximation or fusion of the body to the placenta, and the umbilical cord is extremely short. Acute-angle scoliosis is another feature. Amnionic bands are often identified.

FIGURE 10-36 Gastroschisis. This 18-week fetus has a fullthickness ventral wall defect to the right of the cord insertion (arrowhea), through which multiple small bowel loops (B) have herniated into the amnionic cavity.

FIGURE 10-37 Omphalocele. Transverse view of the abdomen showing an omphalocele as a large abdominal wall defect with exteriorized liver covered by a thin membrane.

he stomach is visible in nearly all fetuses after 14 weeks' gestation. If the stomach is not seen during initial evaluation, the examination is repeated, and targeted sonography should be considered. Nonvisualization of the stomach may be secondary to impaired swallowing in the setting of oligohydramnios or to underlying causes such as esophageal atresia, a craniofacial anomaly, or a CNS or musculoskeletal abnormality. Fetuses with hydrops may also have impaired swallowing.

he bowel, liver, gallbladder, and spleen can be identiied in many second-and third-trimester fetuses. Bowel appearance changes with fetal maturation. Occasionally, it may be bright or echogenic, which may indicate small amounts of swallowed intraamnionic blood, especially with comorbid MSAFP elevation. Bowel that appears as bright as fetal bone confers a slightly greater risk for underlying gastrointestinal malformations, for cystic ibrosis, for trisomy 21, and for congenital infection such as cytomegalovirus (Fig. 14-3, p. 287).

Bowel atresia is characterized by obstruction and proximal bowel dilation. In general, the more proximal the obstruction, the more likely it is to lead to hydramnios. At times, hydramnios from proximal small-bowel obstruction can be suiciently severe to result in maternal respiratory compromise or preterm labor and may necessitate amnioreduction (Chap. 11, p. 230).

Esophageal atresia occurs in approximately 1 in 4000 births (Cragan, 2009; Pedersen, 2012). It may be suspected when the stomach cannot be visualized and hydramnios is present. hat said, in up to 90 percent of cases, a concomitant tracheoesophageal istula allows luid to enter the stomach, such that prenatal detection is problematic. More than half have associated anomalies or genetic syndromes. Multiple malformations are present in 30 percent of cases, and aneuploidy such as trisom) 18 or 21, in 10 percent (Pedersen, 2012). Cardiac, urinary tract, and other gastrointestinal abnormalities are the most frequently associated anomalies. Approximately 10 percent of

FIGURE 10-38 Duodenal atresia. The double-bubble sign represents distension of the stomach (5) and the first part of the duodenum (0), as seen on this axial abdominal image. Demonstrating continuity between the stomach and proximal duodenum confirms that the second "bubble" is the proximal duodenum.

cases of esophageal atresia occur as part of the V ACTERL asso ciation, which is yertebral defects, !nal atresia, £ardiac defects, !racheo�sophageal istula, renal anomalies, and limb abnormali ties (Pedersen, 2012).

Duodenal atresia is found in approximately 1 in 10,000 births (Best, 2012; Dolk, 2010). It is characterized by the sonographic double-bubble sin, which represents distention of the stomach and the irst part of the duodenum (Fig. 10-38). This finding is usually not present before 22 to 24 weeks' gestation. Demonstrating continuity between the stomach and proximal duodenum confirms that the second "bubble" is the proximal duodenum. Approximately 30 percent of afected fetuses have an associated chromosomal abnormality or genetic syndrome, particularly trisomy 21. Of cases without a genetic abnormality, a third have associated anomalies, most commonly cardiac defects and other gastrointestinal abnormalities (Best, 2012). Obstructions in the more distal small bowel usually result in multiple dilated loops that may have enhanced peristaltic activity.

Large-bowel obstructions and anal atresia are less readily diagnosed by sonography, because hydramnios is not a typical feature and the bowel may not be signiicantly dilated. A transverse view through the pelvis may show an enlarged rectum as an anechoic structure between the bladder and the sacrum.

The fetal kidneys are visible adjacent to the spine, frequently in the first trimester and routinely by 18 weeks' gestation (Fig. 10-39). he length of the kidney approximates 20 mm at 20 weeks and grows by about 1.1 mm each week thereafter (Chitty, 2003). With advancing gestation, the kidneys become relatively less echogenic, and a rim of perinephric fat aids visualization of their margins.

he fetal bladder is readily visible in the second trimester as a round, anechoic structure in the anterior midline of the

FIGURE 10-39 Normal fetal kidneys. The kidneys are visible adjacent to the fetal spine in this 29-week fetus. With advancing gestation, a rim of perinephric fat aids visualization of the kidney margins. A physiological amount of urine is visible in the renal pelves and is marked in one kidney by an arrow.

pelvis. With application of Doppler, the bladder is outlined by the two superior vesical arteries as they become the umbilical arteries of the umbilical cord (Fig. 10-40 and Chap. 6, p. 1i17). The fetal ureters and urethra are not visible sonographically unless abnormally dilated.

The placenta and membranes are the major sources of amnionic fluid early in pregnancy. However, after 18 weeks' gestation, most of the luid is produced by the kidneys (Chap. 11, p. 225). Fetal urine production rises from 5 mLlhr at 20 weeks to approximately 50 mLlhr at term (Rabinowitz, 1989). Normal amnionic luid volume in the second half of pregnancy suggests urinary tract patency with at least one functioning kidney. But, unexplained oligohydramnios suggests a urinary tract defect or placental perfusion abnormality.

FIGURE 10-40 Normal fetal bladder. The normal fetal bladder is readily visible as a round, fluid-filled structure in the anterior pelvis, outlined by the two superior vesical arteries as they become the umbilical arteries of the umbilical cord.

FIGURE 10-41 Renal pelvis dilatation. This common finding is identified in 1 to 5 percent of pregnancies. A.oln this 34-week fetus with mild renal pelvis dilatation, the anterior-posterior diameter of the renal pelvis measured 7 mm in the transverse plane. B. Sagittal image of the kidney in a 32-week fetus with severe renal pelvis dilatation secondary to ureteropelvic junction obstruction. The arrow points to one of the rounded calyces.

This finding is present in 1 to 5 percent of fetuses. It is also called urinary tract dilatation or hydronephrosis. In 40 to 90 percent of cases, it is transient or physiological and does not represent an underlying abnormality (Ismaili, 2003; Nguyen, 2010). In approximately a third of cases, a urinary tract abnormality is conirmed in the neonatal period. Of these, ureteropelvic junction (UP]) obstruction and vesicoureteral relux UR) are the most frequent.

he fetal renal pelvis is measured anterior to posterior in a transverse plane, and calipers are placed on the inner border of the fluid collection (Fig. 10-41). Although various thresholds have been deined, the pelvis is typically considered dilated if it exceeds 4 mm in the second trimester or 7 mm at approximately 32 weeks' gestation (Reddy, 2014). Typically, the second-trimester threshold is used to identiy pregnancies that warrant subsequent third-trimester evaluation.

he Society for Fetal Urology categorized renal pelvis dilatation based on a metaanalysis of more than 100,000 screened pregnancies (Table 10-10) (Lee, 2006; Nguyen, 2010). he degree of dilatation correlates with the likelihood of an underlying abnormality. Other suggestive indings of pathology

TABLE 10-10. Risk for Postnatal Urinary Abnormality According to Degree of Renal Pelvis Dilatationa

Second Third Postnatal Dilatation Trimester Abnormality 4 to <7 mm 7 to <9 mm

Moderate 7 to �1 0 mm 9 to �15 mm 45% aSociety for Fetal Urology Classification. Modified from Lee, 2006; Nguyen, 2010.

include calyceal dilatation, cortical thinning, or dilatation elsewhere along the urinary tract. Mild pyelectasis in the second trimester is associated with a slightly greater risk for Down syndrome and is considered a soft marker for this (Fig. 14-3, p.i287).

Ureteropelvic Junction Obstruction. This condition is the most common abnormality associated with renal pelvis dilatation. The birth prevalence is 1 in 1000 to 2000, and males are afected three times more often than females (Williams, 2007; Woodward, 2002). Obstruction is generally functional rather than anatomical, and it is bilateral in up to a fourth of cases. he likelihood of ureteropelvic junction obstruction rises from 5 percent with mild renal pelvis dilatation to more than 50 percent with severe dilatation (Lee, 2006).

Duplicated Renal Collecting System. In this anatomical anomaly, the upper and lower poles of the kidney-called moieties-are each drained b) a separate ureter (Fig. 10-42). Duplication is found in approximately 1 in 4000 pregnancies, is more common in females, and is bilateral in 15 to 20 percent of cases (James, 1998; Vergani, 1998; Whitten, 2001). Sonographically, an intervening tissue band separates two distinct renal pelves. Development of hydronephrosis or ureteral dilatation may occur due to abnormal implantation of one or both ureters within the bladder-a relationship that reflects the anatomical Weigert-Meyer rule. The upper pole ureter may develop obstruction from a ureterocele within the bladder, whereas the lower pole ureter has a shortened intravesical segment that predisposes to vesicoureteral reflux (see Fig. 10-42B). Thus, both moieties may become dilated from diferent etiologies, and both are at risk for loss of function.

The prevalence of bilateral renal agenesis is approximately in 8000 births, whereas that of unilateral renal agenesis is 1 in

FIGURE 10-42 Duplicated renal collecting system. The upper and lower moieties of the kidney are each drained by a separate ureter.

A. Renal pelvis dilatation is visible in both the upper (U) and lower (L) pole moieties, which are separated by an intervening band of renal tissue (arrowhead). B.The bladder, encircled by the highlighted umbilical arteries, contains a ureterocele (arrowhead).

1000 births (Cragan, 2009; Dolk, 2010; Sheih, 1989; Wiesel, 2005). When a kidney is absent, color Doppler imaging of the descending aorta demonstrates absence of the ipsilateral renal artery (Fig. 10-43). In addition, the ipsilateral adrenal gland typically enlarges to ill the renal fossa, termed the ying down adrenal sin (Hofman, 1992). As with other fetal anomalies, amniocentesis for chromosomal microarray analysis should be considered.

If renal agenesis is bilateral, no urine is produced, and the resulting anhydramnios leads to pulmonary hypoplasia, limb contractures, and a distinctively compressed face. When this combination results from renal agenesis, it is called Poter syndrome, after Dr. Edith Potter, who described it in 1946. When these abnormalities result from severely decreased amnionic luid volume from another etiology, such as bilateral multicystic dysplastic kidney or autosomal recessive polycystic kidney disease, it is called Poter sequence. he prognosis for these abnormalities is extremely poor.

This severe form of renal dysplasia results in a nonfunctioning kidney. The nephrons and collecting ducts do not form normally, such that primitive ducts are surrounded by ibromuscular tissue, and the ureter is atretic (Hains, 2009). Sonographically, the kidney contains numerous smooth-walled cysts of varying size that do not communicate with the renal pelvis and are surrounded by echogenic cortex (Fig. 10-44).

Unilateral multicystic dysplastic kidney (MCDK) has a prevalence of 1 in 4000 births. Contralateral renal abnormalities are present in 30 to 40 percent-most frequently vesicoureteral relux or ureteropelvic junction obstruction (Schreuder, 2009). Nonrenal anomalies have been reported in 25 percent of cases, and cystic dysplasia may occur as a component of many genetic syndromes (Lazebnik, 1999; Schreuder, 2009). If MCDK is isolated and unilateral, the prognosis is generally good.

FIGURE 10-43 Renal agenesis. A.oln this coronal image of the fetal abdomen, color Doppler shows the course of the abdominal aorta. The ultrasound beam is perpendicular to the aorta, demonstrating absence of the renal arteries bilaterally. B. This coronal image of a fetus with unilateral renal agenesis shows the adrenal gland (arrowheads) filling the renal fossa, termed the "lying-down" adrenal sign. The adrenal gland has a hypoechoic cortex and hyperechoic medulla.

FIGURE 10-44 Multicystic dysplastic kidneys. Coronal view of the fetal abdomen demonstrates markedly enlarged kidneys containing multiple cysts of varying sizes that do not communicate with a renal pelvis.

FIGURE 10-45 Posterior urethral valve. In this 19-week fetus with severe bladder outlet obstruction, the bladder is dilated and thickwalled, with dilatation of the proximal urethra that resembles a "keyhole." Adjacent to the bladder is an enlarged kidney with evidence of cystic dysplasia, conferring a poor prognosis.

Bilateral MCDK is found in approximately 1 in 12,000 births. It is associated with severely decreased amnionic luid volume starting early in gestation. his leads to Potter sequence and a poor prognosis (Lazebnik, 1999).

Of the hereditary polycystic diseases, only the infantile form of autosomal recessive poyystic kidney disease (APD) may be reliably diagnosed prenatally. ARPKD is a chronic, progressive disease of the kidneys and liver that results in cystic dilatation of the renal collecting ducts and in congenital hepatic ibrosis (Turkbey, 2009). he carrier frequency of a disease-causing mutation in the PHDI gene approximates 1 in 70, and the disease prevalence is 1 in 20,000 (Zerres, 1998). he phenotypic variability of ARPKD ranges from lethal pulmonary hypoplasia at birth to presentation in late childhood or even adulthood with predominantly hepatic manifestations. Sonographically, infantile ARPKD displays abnormally large kidneys that ill and distend the fetal abdomen and have a solid, ground-glass texture. Severe oligohydramnios confers a poor prognosis.

Autosomal dominant poyystic kidney disease ADPD), which is far more common, usually does not manifest until adulthood (Chap. 53, p. 1031). Even so, some fetuses with AD PKD have mild renal enlargement and enhanced renal echogenicity in the setting of normal amnionic luid volume. he diferential diagnosis for these findings includes several genetic syndromes, aneuploidy, or normal variant.

Distal obstruction of the urinary tract is more frequent in male fetuses, and the most common etiology is posterior urethral valves. Characteristically, the bladder and proximal urethra are dilated, termed the "keyhole" sign, and the bladder wall is thick (Fig. 10-45). Oligohydramnios, particularly before midpregnancy, portends a poor prognosis because of pulmonary hypoplasia. Unfortunately, the outcome may be poor even with normal amnionic fluid volume. Evaluation includes a careful search for associated anomalies, which may occur in 40 percent of cases, and for aneuploidy, which has been reported in 5 to 8 percent (Hayden, 1988; Hobbins, 1984; Mann, 2010). If neither are present, afected male fetuses with severe oligohydramnios who have fetal urinary electrolytes suggesting a potentially favorable prognosis may be fetal therapy candidates. Evaluation and treatment of fetal bladder outlet obstruction is discussed in Chapter 16 (p. 325).

The 2015 revision of the Nosology and Classification of Genetic Skeletal Disorders includes an impressive 436 skeletal anomalies in 42 groups, characterized by genetic abnormalities, phenotypic features, or radiographic criteria (Bonafe, 2015). he two types of skeletal dysplasias are osteochondrodyspasiasthe generalized abnormal development of bone and/or cartilage, and dysostoses-which are abnormalities of individual bones, for example, poydacyy. In addition to these maormations, skeletal abnormalities include dormations, as with some cases of clubfoot, and disruptions such as limb-reduction defects.

The prevalence of skeletal dysplasias approximates 3 in 10,000 births. Two groups account for more than half of all cases: the ibroblast growth octor 3 (FGF3) chondrodysplasia group and the osteogenesis impeecta and decreased bone density group. Each occurs in 0.8 in 10,000 births (Stevenson, 2012).

Evaluation of a pregnancy with suspected skeletal dysplasia includes a survey of every long bone, as well as the hands and feet, skull size and shape, clavicles, scapulae, thorax, and spine. Reference tables are used to determine which long bones are afected and ascertain the degree of shortening (Appendix, p. 1267). Involvement of all long bones is termed micromelia, whereas predominant involvement of only the proximal, intermediate, or distal long bone segments is termed rhizomelia, meso melia, and acromelia, respectively. he degree of ossiication should be noted, as should presence of bowing or fractures. Each of these may provide clues to narrow the diferential diagnosis and occasionally suggest a specific skeletal dysplasia. Many, if not most, skeletal dysplasias have a genetic component, and knowledge of specific mutations has advanced dramatically (Bonafe, 2015).

nosis, it is frequently possible to determine whether a skeletal dysplasia is lethal. Lethal dysplasias show profound long bone shortening, with measurements <5th percentile, and display cent (Nelson, 2014; Rahemtullah, 1997; Ramus, 1998). Gen erally, other sonographic abnormalities are evident. Pulmonary hypoplasia is suggested by a thoracic circumference < 80 per cent of the abdominal circumference value, by a thoracic cir cumference <2.5th percentile, and a cardiac circumference > 50 percent of the thoracic circumference value (Appendix, p. 1266). Afected pregnancies also may develop hydramnios and/or hydrops (Nelson, 2014).

he FGFR3 chondrodysplasias include achondroplasia and thanatophoric dysplasia. Achondroplasia, also called heterozygous achondroplasia, is the most common nonlethal skeletal dysplasia. An impressive 98 percent of cases are due to a speciic point mutation in the FGFJ gene. It has an autosomal dominant inheritance, and 80 percent of cases result from a new mutation. Achondroplasia is characterized by long bone shortening that is predominantly rhizomelic, an enlarged head with frontal bossing, depressed nasal bridge, exaggerated lumbar lordosis, and a trident configuration of the hands. Intelligence is typically normal. Sonographically, the femur and humerus measurements may not lie below the 5th percentile until the early third trimester. hus, this condition is usually not diagnosed until late in pregnancy. In homozygotes, which represent 25 percent of the ofspring of heterozygous parents, the condition is characterized by greater long bone shortening and is lethal.

he other major class of FGFR3 dysplasias, thanatophoric dysplasia, is the most common lethal skeletal disorder. It is characterized by severe micromelia, and afected fetuses-particularly those with type II-may develop a characteristic cloverleaf skull deformity (Kleeblattschade) due to craniosynostosis. More than 99 percent of cases may be con firmed with genetic testing.

Osteogenesis impeecta represents a group of skeletal dysplasias typiied by hypomineralization. here are multiple types, and more than 90 percent of cases are characterized by a mutation in the COLIAI or COLIA2 gene. Type IIa, also called the perinatal form, is lethal. It displays a profound lack of skull ossification, such that gentle pressure on the maternal abdomen from the ultrasound transducer results in visible skull deformation 10-46).

FIGURE 10-46 Osteogenesis imperfecta. Type Ila, which is lethal, is characterized by such profound lack of skull ossification that gentle pressure on the maternal abdomen from the ultrasound transducer results in visible deformation (flattening) of the skull (arrowheads).

Other features include multiple in-utero fractures and ribs that appear "beaded." Inheritance is autosomal dominant, such that all cases result from either new mutations or gonadal mosaicism (Chap. 13, p. 264). Another skeletal dysplasia that results in severe hypomineralization is hypophosphatasia, which has an autosomal recessive inheritance.

his disorder is notable for a deformed talus and shortened Achilles tendon. he afected foot is abnormally fixed and positioned with equinus (downward pointing), varus (inward rotation), and forefoot adduction. Most cases are considered malformations, with a multifactorial genetic component. However, an association with environmental factors and with early amniocentesis suggests that deformation also plays a role (T redwell, 2001). Sonographically, the footprint is visible in the same plane as the tibia and ibula (Fig. 10-47).

he prevalence of clubfoot approximates 1 in 1000 births, and the male:female ratio is 2:1 (Carey, 2003; Pavone, 2012). Clubfoot is bilateral in approximately 50 percent of afected individuals, and associated anomalies are present in at least 50 percent of all cases (lvfammen, 2004; Sharma, 201i1). Frequently associated anomalies include neuraltube defects, arthrogryposis, and myotonic dystrophy and other genetic syndromes. In cases with associated anomalies, aneuploidy is found in approximately 30 percent. In contrast, the rate is <4 percent when clubfoot appears isolated (Lauson, 2010; Sharma, 2011). hus, a careful search for associated structural abnormalities is warranted, and chromosomal microarray analysis may be considered.

FIGURE 10-47 Foot position. A. Normal fetal lower leg, demonstrating normal position of the foot. B. With talipes equinovarus, the foot "print" is visible in the same plane as the tibia and fibula.

Documentation of the arms and legs is a component of the standard examination. he absence or hypoplasia of all or part of one or more extremities is a limb-reduction dect. he birth prevalence is 4 to 8 in 10,000 (Kucik, 2012; Stoll, 2010; Vasluian, 2013). Approximately half of these are isolated defects, up to on� third occur as part of a recognized syndrome, and individuals in the remaining cases have other coexisting anomalies (Stoll, 2010; Vasluian, 2013). Upper extremities are afected more frequently than lower ones. Of categories, a terminal transverse limb dect lacks part or all of a distal limb to create a stump (Fig. 10-48). his is more common than a longitudinal dect, which is complete or partial absence of the long bone(s) on only one side of a given extremity.

Absence of an entire extremity is termed amelia. Phocomelia, associated with thalidomide exposure, is an absence of one or more long bones with the hands or feet attached to the trunk (Chap. 12, p. 246). Limb-reduction defects are associated with numerous genetic syndromes, such as Roberts syndrome, an autosomal recessive condition characterized by tetraphocomelia. A clubhand dormiy, usually from an absent radius, is associated with trisomy 18 and is also a component of the thrombocytopenia-absent radius syndrome (Fig. 13-5B, p. 258). Limb-reduction defects may occur in the setting of a disruption such as amnionic-band sequence (Chap. 6, p. 116). hey have also been associated with chorionic villus sampling when performed before 10 weeks' gestation (Fig. 14-6, p. 294).

During the past two decades, three-dimensional (3-D) sonography has gone from a novelty to a standard feature of most modern ultrasound equipment (Fig. 10-49). 3-D sonography is not routiney used during a standard examination nor considered a required modality. However, it may be a component of specialized evaluations.

Most 3-D scanning uses a special transducer developed for this purpose. After a region of interest is identiied, a 3-D volume is acquired that can be rendered to display axial, sagittal, coronal, or oblique images. Sequential "slices" may be generated, similar to computed tomographic (CT) or MR images. Unlike two-dimensional (2-D) scanning, which appears to be in "real time," 3-D imaging is static and obtained by processing a volume of stored images. With our-dimensional (4-DJ sonography, also known as real-time 3-D sonography, rapid reconstruction of the rendered images conveys the impression that the scanning is in real time.

FIGURE 10-48 Transverse limb-reduction defect. A. At 18 weeks' gestation, only a rudimentary hand was visible. B. By 24 weeks, the radius and ulna were normal in size and appearance, and small rudimentary digits were evident.

For 4-D imaging, one application known as spatiotemporal image co rrelatio n-S TIC improves visualization of cardiac anatomy. During an automated sweep over the heart, the STIC application acquires a volume that includes thousands of 2D images captured at a rate as high as 150 frames per second (Devore, 2003). These individual images are obtained at diferent locations in the heart but at the same point in time. These views are subsequently arranged according to their spatial and temporal domains. his permits display of an ordered sequence of volume sets in a continuous cine loop (or video clip) of the cardiac cycle (Yeo, 2016). For example, after obtaining a volume sweep over the cardiac apex, an application such as Fetal Intelligent Navigation Echocardiography (FINE) can be applied to

FIGURE 10-49 Fetal face. Surface rendered three-dimensional image of a normal fetal face and hand at 32 weeks.

display videos of each of the diferent cardiac views shown in

Fig. 10-28 (Garcia, 2016). It is hoped that such technology may eventually improve detection of fetal cardiac anomalies.

For selected anomalies, such as those of the face and skel eton, for tumors, and for some cases of neural-tube defects, 3-D sonography can add useful information (American College of

Obstetricians and Gynecologists, 2016; Goncalves, 2005). That said, comparisons of 3-D and conventional 2-D sonography for the diagnosis of most congenital anomalies have not demon strated better overall detection rates (Goncalves, 2006; Reddy, 2008). The American College of Obstetricians and Gynecolo gists (2016) concludes that proof of a clinical advantage of 3-D S sonography for prenatal diagnosis is generally lacking. D hen sound waves strike a moving target, the frequency of the waves reflected back is shifted in proportion to the velocity and direction of that moving target-a phenomenon known as the Doppler sht. Because the magnitude and direction of the frequency shift depend on the relative motion of the moving target, Doppler can help evaluate low within blood vessels. The Doppler equation is shown in Figure 10-50.

n important component of the equation is the angle of insonation, abbreviated as theta (8). This is the angle between the sound waves from the transducer and low within the vessel. Measurement error becomes large when 8 is not close to zero, in other words, when blood flow is not coming directy toward or away from the transducer. For this reason, ratios are often used to compare diferent waveform components, allowing cosine 8 to cancel out of the equation. Figure 10-51 is a schematic of the Doppler waveform and describes the three ratios commonly used. he simplest is the systolic-diastolic ratio (SID ratio), which compares the maximal (or peak) systolic low with end-diastolic flow to evaluate downstream impedance to flow. Currently, two types of Doppler modalities are available for clinical use.

Continuous-wave Doppler equipment has two separate types of crystals-one transmits high-frequency sound waves, and ,,,I ,

FIGURE 10-50 Doppler equation. Ultrasound emanating from the transducer with initial frequency fo strikes blood moving at velocity v. Reflected frequency fd is dependent on angle e between beam of sound and vessel.

FIGURE 10-51 Doppler systolic-diastolic waveform indices of blood flow velocity. S represents the peak systolic flow or velocity, and D indicates the end-diastolic flow or velocity. The mean, which is the time-average mean velocity, is calculated from computerdigitized waveforms.

another continuously captures signals. In M-mode imaging, continuous-wave Doppler is used to evaluate motion through time, however, it cannot image individual vessels.

Pulsed-wave Doppler uses only one crystal, which transmits the signal and then waits until the returning signal is received before transmitting another one. It allows precise targeting and visualization of the vessel of interest. Pulsed-wave Doppler can be conigured to allow color-low mapping-such that blood flowing toward the transducer is displayed in red and that flowing away from the transducer appears in blue. Various combinations of pulsed-wave Doppler, color-flow Doppler, and real-time sonography are commercially available.

Umbilical artery Doppler has been subjected to more rigorous assessment than any previous test of fetal health. he umbilical artery difers from other vessels in that it normally has forward low throughout the cardiac cycle. Moreover, the amount of low during diastole increases as gestation advances, and this reflects decreasing placental impedance. As a result, the SID ratio normaly declines rom approximatey 4.0 at 20 weeks' gestation, to generaly less than 3.0 ter 30 weeks' and inaly to 2.0 at term. Because of downstream impedance to low, more end-diastolic low is observed at the placental cord insertion than at the fetal ventral wall. hus, abnormalities such as absent or reversed enddiastolic low will appear first at the fetal cord insertion site. The International Society of Ultrasound in Obstetrics and Gynecology recommends that umbilical artery Doppler measurements be made in a free loop of cord (Bhide, 2013). However, assessment close to the ventral wall insertion may optimize measurement reproducibility when low is diminished (Berkley, 2012).

The waveform is considered abnormal if the SID ratio is >95th percentile for gestational age. In extreme cases of growth restriction, end-diastolic flow can become absent or even reversed (Fig. 44-8, p. 854). Such reversal of end-diastolic flow has been associated with greater than 70-percent obliteration of the small muscular arteries in placental tertiary stem villi (Kingdom, 1997; Morrow, 1989).

As described in Chapter 44 (p. 854), umbilical artery Doppler aids management of fetal-growth restriction and has been associated with improved outcome in these cases (American College of Obstetricians and Gynecologists, 2015). It is not recommended for complications other than growth restriction. Similarly, its use for growth-restriction screening is not advised (Berkley, 2012). Abnormal umbilical artery Doppler findings should prompt a complete fetal evaluation, if not already done, because abnormal measurements are associated with major fetal anomalies and aneuploidy (Wenstrom, 1991).

Doppler evaluation of the ductus arteriosus has been used primarily to monitor fetuses exposed to indomethacin and other nonsteroidal antiinlammatory agents (NSAIDs). Indomethacin, which is used by some for tocolysis, may cause ductal constriction or closure, particularly when used in the third trimester (Huhta, 1987). The resulting increased pulmonary flow can cause reactive hypertrophy of the pulmonary arterioles and eventual development of pulmonary hypertension. In a review of 12 randomized controlled trials involving more than 200 exposed pregnancies, Koren and coworkers (2006) reported that NSAIDs raised the odds of ductal constriction 15-fold. When these agents are indicated, their duration is typically limited to less than 72 hours. And, women taking NSAIDs are closely monitored so that these can be discontinued if ductal constriction is identified. Fortunately, ductal constriction is often reversible after NSAID discontinuation.

Uterine blood low is estimated to rise from 50 mLlmin early in gestation to 500 to 750 mLlmin by term. he uterine artery Doppler waveform is characterized by high diastolic low velocities and markedly turbulent flow. Greater resistance to flow and development of a diastolic notch are associated with later development of gestational hypertension, preeclampsia, and fetal-growth restriction. Zeeman and coworkers (2003) also found that women with chronic hypertension who had elevated uterine artery impedance at 16 to 20 weeks' gestation were at greater risk to develop superimposed preeclampsia. However, the technique, best testing interval, and defining criteria for this indication have not been standardized. As the predictive value of uterine artery Doppler testing is considered to be low, its use for screening or for clinical decision-making is not recommended in either high-risk or low-risk pregnancies (Sciscione, 2009).

Doppler interrogation of the middle cerebral artery (MCA) has been investigated and applied clinically for fetal anemia detection and fetal-growth restriction evaluation. Anatomically, the path of the MCA is such that flow often approaches the transducer "head-on," allowing for accurate determination of low velocity (Fig. 10-52). he MCA is imaged in an axial view of the head at the base of the skull, ideally within 2 mm of the internal carotid artery origin. Velocity measurement is optimal when the insonating angle is close to zero, and no more than 30 degrees of angle correction should be used. In general, velocity assessment is not performed in other fetal vessels, because a larger insonating angle is needed and confers significant measurement error.

When fetal anemia is present, the peak systolic velociy is enhanced due to greater cardiac output and decreased blood viscosity (Segata, 2004). This has permitted the reliable, noninvasive detection of fetal anemia in cases of blood-group alloimmunization. Mari and colleagues (2000) demonstrated that an MCA peak systolic velocity threshold of 1.50 MoM could reliably identiy fetuses with moderate or severe anemia. As discussed in Chapter 15 (p. 303), MCA peak systolic velocity has replaced

FIGURE 10-52 Middle cerebral artery (MCA) Doppler. A. Color Doppler of the circle of Willis, demonstrating the correct location to sample the MCA. B. The waveform demonstrates a peak systolic velocity exceeding 70 cm/sec in a 32-week fetus with severe fetal anemia secondary to Rh alloimmunization.

invasive testing with amniocentesis as the preferred test for fetal anemia detection (Society for Maternal-Fetal Medicine, 2015).

MCA Doppler has also been studied as an adjunct in evaluation of fetal-growth restriction. Fetal hypoxemia is believed to result in increased blood flow to the brain, heart, and adrenal glands, leading to greater end-diastolic low in the MCA. his phenomenon, "brain-sparing," is actually a misnomer, as it is not protective for the fetus but rather is associated with perinatal morbidity and mortality (Bahado-Singh, 1999; CruzMartinez, 2011). The utility ofMCA Doppler to aid the timing of delivery is uncertain. It has not been evaluated in randomized trials or adopted as standard practice in the management of growth restriction (American College of Obstetricians and Gynecologists, 2015; Berkley, 2012).

he ductus venosus is imaged as it branches from the umbilical vein at approximately the level of the diaphragm. Fetal position poses more of a challenge in imaging the ductus venosus than it does with either the umbilical artery or the middle cerebral artery. he waveform is biphasic and normally has forward flow throughout the cardiac cycle. The irst peak reflects ventricular systole, and the second is ventricular diastolic illing. These are followed by a nadir during atrial contraction-termed the a-wave.

It is believed that Doppler indings in preterm fetuses with growth restriction show a progression in which umbilical artery Doppler abnormlities are followed by ones in the middle cerebral artery and then in the ductus venosus. However, manifestations of these abnormalities vary widely (Berkley, 2012). With severe fetal-growth restriction, cardiac dysfunction may lead to low in the a-wave that is decreased, absent, and eventually reversed, along with pulsatile low in the umbilical vein (Fig. 10-53).

Ductus venosus abnormalities have potential to identiy preterm growth-restricted fetuses that are at greatest risk for adverse outcomes (Baschat, 2003, 2004; Bilardo, 2004; Figueras, 2009). As noted by the Society for Maternal-Fetal Medicine, however, they have not been suiciently evaluated in randomized trials (Berkley, 2012). In sum, Doppler assessment of vessels other than the umbilical artery has not been shown to improve perinatal outcome, and thus their role in clinical practice remains uncertain (American College of Obstetricians and Gynecologists, 2015).

Image resolution with MR is oten superior to that with sonography because it is not as hindered by bony interfaces, maternal obesity, oligohydramnios, or an engaged fetal head. Thus, it can serve as an adjunct to sonography in evaluating suspected fetal abnormalities. Examples include complex abnormalities of the fetal CNS, thorax, gastrointestinal system, genitourinary system, and musculoskeletal system. MR has also been used in the evaluation of maternal pelvic masses and placental invasion. MR imaging, however, is not portable, it is time-consuming, and its use is generally limited to referral centers with expertise in fetal imaging.

To guide clinical use, the American College of Radiology and Society for Pediatric Radiology (2015) have developed

FIGURE 10-53 Venous Doppler abnormalities. A. Reversal of a-wave flow in the ductus venosus. Arrows depict a-waves below the baseline. This finding may be identified with cardiac dysfunction in the setting of severe fetal-growth restriction. B. Pulsatile flow in the umbilical vein. The undulating umbilical venous waveform below the baseline indicates tricuspid regurgitation. Above the baseline is the umbilical artery waveform, in which there is no visible end-diastolic flow. Because the venous waveform is below the baseline in this image, it is not possible to determine whether the umbilical artery end-diastolic flow is reversed.

a practice guideline for fetal MR imaging. This document acknowledges primacy of sonography as the preferred screening modality. Moreover, it recommends that fetal MR imaging be used for problem solving to ideally contribute to prenatal diagnosis, counseling, treatment, and delivery planning. Specific indications for fetal MR imaging are listed in Table 10-11 and are discussed subsequently.

MR imaging uses no ionizing radiation, but theoretical concerns include the efects of luctuating electromagnetic ields and high sound-intensity levels. The strength of the magnetic

TABLE 10-11. Fetal Conditions for Which Magnetic Resonance Imaging May Be Indicateda

Agenesis of the corpus callosurn

Solid or cyJtic masses Vascular malformations Hydranencephaly Infarction. Hemorrhage

Skull, face, and neck

Other abnormalities with potential airway obstruction

Evaluation of pulmonary hypoplasia secondary to diaphragmatic hernia, oligohydramnios, chest mass, or ske!etal dysplasia

Abdomen, pelvis, and retroperitoneum

Abdominopelvic cystic mass evaluation Tumor evaluation (sacrococcygeal teratoma, neuroblastoma, hemangioma, suprarenal or renal masses) Complex genitourinary anomalies (bladder outlet obstruction syndromes, bladder exstrophy, cloacal exstrophy)

Assess rena! anomalies with oligohydramnios

Diagnose bowel anomalies (anorectal malformations,

Complications of monochorionic twins

Determine vascular anatomy prior to laser treatment Assess morbidity ater death of a monochorionic co-twin

Fetal brain anatomy before and after surgical intervention Anomalies for which fetal surgery is planned aln some cases, magnetic resonance (MR) imaging is indicated only if the anomaly is ed but cannot be adequately characterized sonographically, vvhich is assessed on a case-by case basis.

Data from American College of Radiology, 2015.

field is measured in tesLa (), and most imaging studies during pregnancy are performed using 1.5 T. A few preliminary studies advocate the use of 3 T for fetal imaging to potentially improve signal-to-noise ratios and thus image clarity (Victoria, 2016). For safety, all clinical examinations must adhere to the speciic absorption rate, which is regulated by the Food and Drug Administration, and the ALARA principle should be followed. Thus, for routine clinical examinations, the lower ield strength of 1.5 T is recommended (Prayer, 2017).

Human and tissue studies support the safety of fetal MR imaging. Repetitive exposure of human lung fibroblasts to a static 1.5-T magnetic ield does not afect cellular proliferation (Wiskirchen, 1999). Fetal heart rate patterns have been evaluated before and during MR imaging, and no signiicant diferences were observed (Vadeyar, 2000). Children exposed to MR as fetuses do not show a greater incidence of disease or disability when tested at age 9 months or 3 years (Baker, 1994; Clements, 2000).

Glover and associates (1995) attempted to mimic the sound level experienced by the fetal ear by having an adult volunteer swallow a microphone while the stomach was illed with a liter of luid to represent the amnionic sac. Sound intensity was attenuated at least 30-dB from the body surface to the fluidfilled stomach and reduced the sound pressure from 120 dB to below 90 dB. This level is considerably less than the 135 dB experienced from vibroacoustic stimulation used in antepartum well-being assessments (Chap. 17, p. 337). Cochlear function testing in infants exposed to 1.5-T MR imaging as fetuses showed no hearing impairment (Reeves, 2010).

he American College of Radiology (2013) concludes that based on available evidence, MR imaging has no documented deleterious efects on the developing fetus. Therefore, MR imaging can be performed in pregnancy if data are needed to care for the fetus or mother. Health-care providers who are pregnant may work in and around an MR unit, but it is recommended that they not remain in the MR scanner magnet room-known as Zone IV-while an examination is in progress.

Gadolinium-based MR contrast agents are gadolinium (Gd3+) chelates. These contrast agents readily enter the fetal circulation and are excreted via fetal urination into amnionic luid, where they may remain for an indeterminate period before being ingested and reabsorbed. he longer the gadolinium-chelate molecule remains in a protected space such as the amnionic sac, the greater the potential for dissociation of the toxic Gd3+ ion. Accordingly, gadolinium contrast should be avoided during pregnancy because of this potential for dissociation. Routine use of gadolinium is not recommended unless there are overwhelming potential benefits (American College of Radiology, 2013). In adults with renal disease, this contrast agent has been associated with development of nephrogenic systemic fibrosis, a potentially severe complication.

Before MR examination, all women complete a written safety questionnaire that includes information about metallic implants, pacemakers, or other metal-or iron-containing devices that may alter the study (American College of Radiology, 2013).

Iron supplementation may cause artifact in the colon but does not usually afect the resolution of fetal images. In more than nancy during the past 15 years, maternal anxiety secondary to claustrophobia and/or fear of MR equipment has developed in less than 1 percent of our patients. To reduce maternal anxiety in this small group, a single oral dose of diazepam, 5 to 10 mg, or lorazepam, 1 to 2 mg, may be given.

To begin an MR examination, women are placed in a supine or left lateral decubitus position. A torso coil is used in most circumstances to send and receive the radiofrequency pulses, but a body coil can be used alone to accommodate large mater nal habitus. A series of three-plane localizers, or scout views, are obtained relative to the maternal coronal, sagittal, and axial planes. he gravid uterus is imaged in the maternal axial plane (7-mm slices, 0 gap) with a T2-weighted fast acquisition.

Typically, these may be a single-shot fast spin echo sequence (SSFSE), half-Fourier acquisition single-shot turbo spin echo (HASTE), or rapid acquisition with relaxation enhancement (AE), depending on the brand of machine. Next, a fast

T1-weighted acquisition such as spoiled gradient echo (SPGR) is performed (7-mm thickness, 0 gap). hese large-field-of-view acquisitions through the maternal abdomen and pelvis are par ticularly good for identiying fetal and maternal anatomy.

Orthogonal images of targeted fetal or maternal structures are then obtained. In these cases, 3-to 5-mm slice thickness, o gap T2-weighted acquisitions are performed in the coronal, sagittal, and axial planes. Depending on the anatomy and underlying suspected abnormality, T1-weighted images can be performed to evaluate for subacute hemorrhage, fat, or location of normal structures that appear bright on these sequences, such as liver and meconium in the colon (Brugger, 2006; Zaretsky, 2003b).

Short Tl inversion recovey (STIR) and frequency-selective fat-saturated T2-weighted images may provide diferentiation in cases in which the water content of the abnormality is similar to that of the normal structure. An example is a thoracic mass compared with normal lung. Difusion-weighted imaging may be employed to evaluate for restricted difusion, which can be seen in ischemia, cellular tumors, or clotted blood (Brugger, 2006; Zaretsky, 2003b). Our series also includes an axial brain 3-to 5-mm T2-weighted sequence to obtain head biometry for gestational age estimation using the biparietal diameter and head circumference (Reichel, 2003).

Whenever a fetal abnormality is identiied, indings from the afected organ and other organ systems should be thoroughly characterized. Accordingly, a fetal anatomical survey is generally completed during each MR examination. In a recent prospective study, nearly 95 percent of the anatomical components recommended by the Inter- national Society of Ultrasound in Obstetrics and Gynecology were visible at 30 weeks' gestation (Millischer, 2013). he aorta and pulmonary artery were the most diicult to evaluate. Zaretsky and coworkers (2003a) similarly found that with the exclusion of cardiac structures, fetal anatomical evaluation was possible in 99 percent of cases.

For intracranial anomalies, very fast T2-weighted images produce excellent tissue contrast, and eSF-containing structures are hyperintense or bright. This allows exquisite detail of the posterior fossa, midline structures, and cerebral cortex. T1-weighted images are used to identiy hemorrhage.

eNS biometry obtained with MR imaging is comparable with that obtained using sonography (Twickler, 2002). Nomograms have been published for multiple intracranial structures, including corpus callosum and cerebellar vermis lengths (Garel, 2004; Tilea, 2009).

MR imaging provides valuable added information for cerebral abnormalities suspected sonographically (Benacerraf, 2007; Li, 2012). In early studies, MR imaging changed the diagnosis in 40 to 50 percent of cases and afected management in 15 to 50 percent (Levine, 1999b; Simon, 2000; Twickler, 2003). Additional information is more likely to be gained when the examination is performed beyond 24 weeks' gestation. More recently, Griiths and associates (2017) reported that MR evaluation of suspected fetal brain anomalies identified additional indings in nearly 50 percent and changed prognosis in 20 percent.

Fetuses with a cerebral abnormality may have a signiicant lag in cortical development. Levine and colleagues (l999a) demonstrated that MR imaging accurately portrays cerebral gyration and sulcation patterns (Fig. 10-54). Sonography permits limited evaluation of subtle migrational abnormalities, and MR imaging provides greater accuracy, particularly later in gestation.

For ventriculomegaly, fetal MR imaging is selected to help identiy associated underlying eNS dysmorphology (p. 193). In cases of septo-optic dysplasia, MR imaging may confirm absence of the septum pellucidum and display hypoplastic

FIGURE 10-54 Axial images of the fetal brain at 23 weeks' gestation (A) and at 33 weeks (8) demonstrate the normal gyration and sulcation progression during fetal development. These images were obtained using a Half Fourier Acquisition Single Shot Turbo Spin Echo (HASTE) sequence because it is relatively motion insensitive.

optic tracts (Fig. 10-55). In other fetuses, MR imaging can also assist with identiying agenesis or dysgenesis of the corpus callosum and characterizing migrational abnormalities (Benacerraf, 2007; Li, 2012; Twickler, 2003).

Another fetal MR imaging indication is evaluation of suspected intraventricular hemorrhage (IVH). Fetal IVH risk factors include atypical-appearing ventriculomegaly, neonatal alloimmune thrombocytopenia, and a monochorionic multifetal gestation complicated by demise of one fetus or by severe twin-twin transu

FIGURE 10-55 Septo-optic dysplasia. Axial (A) and coronal (B) images at 30 weeks' ges sion syndrome (Hu, 2006). If hemorrhage tation confirm absence of the cavum septum pellucidum (arrowheads) in both. There is is seen, MR imaging characteristics may also associated mild ventriculomegaly (arrow).

FIGURE 10-56 Terminal myelocystocele, 36 weeks' gestation. A. In this sagittal T2-weighted image, the spinal cord is tethered, expanding into the terminal cyst (arrow).

B. Seen in this Tl-weighted image, the meningocele and terminal cyst are covered by subcutaneous fat (arrows) and skin.

indicate which structures are involved and approximately when bleeding occurred. In the setting of congenital fetal infections, ,1R imaging can delineate the variable degrees of neural parenchymal abnormality and subsequent maldevelopment (Soares de Oliveira-Szejnfeld, 2016).

Aside from cerebral structure, suspected spinal dysraphisms, including neural-tube defects, can also be further characterized for surgical planning. Figure 10-56 demonstrates a complex skin-covered dysraphism with associated tethering of the spinal cord. his terminal myelocystocele will benefit from early intervention following delivery.

Many thoracic abnormalities are readily seen with targeted sonography. MR imaging, however, may help delineate the location and size of space-occupying thoracic lesions and quantiy remaining lung tissue volumes. MR imaging can aid in characterizing the type of congenital cystic adenomatoid malformation and in visualizing the blood supply of pulmonary sequestration (p. 200). With congenital diaphragmatic hernia, MR imaging can help veriy and quantiy the abdominal organs within the thorax. his includes the volume of herniated liver and compressed lung tissue volumes (Fig. 10-57) (Debus, 2013; Lee, 2011; Mehollin-Ray, 2012). Also in fetuses with diaphragmatic hernia, MR imaging can assist in identiying other organ-system abnormalities, which may greatly afect fetal prognosis (Kul, 2012). MR imaging similarly is used for chest evaluation in skeletal dysplasia and to measure lung volumes in pregnancies with prolonged oligohydramnios secondary to renal disease or ruptured membranes (Messerschmidt, 2011; Zaretsky, 2005).

When sonographic viewing of fetal abdominal abnormalities is limited by oligohydramnios or maternal obesity, MR imaging may add value (Caire, 2003). Hawkins and coworkers (2008) found that lack of signal in a contracted fetal bladder on T2-weighted sequences was associated with lethal renal abnormalities (Fig. 10-58). Diferences in signal characteristics between meconium in the fetal colon and urine in the bladder may permit deinition of cystic abdominal abnormalities (Farhataziz, 2005). Given the predictable pattern of meconium accumulation within the gastrointestinal tract and high signal intensity on T1-weighted sequences, MR imaging is a complementary tool in diagnosing gastrointestinal abnormalities and complex cloacal malformations (Furey, 2016). Peritoneal calciications related to meconium peritonitis are more readily apparent

FIGURE 10-57 A. Coronal image of normal lungs on a balanced sequence at 29 weeks' gestation. The liver (L) and stomach (5) lie below the diaphragm. B. Left-sided congenital diaphragmatic hernia (CDH) (dotted ellipse) seen on balanced sequence at 33 weeks. C. The T1o-weighted sequence confirms the subdiaphragmatic position of the liver and better delineates the small bowel (arrow) and meconium-containing colon (arrowhead) that have herniated into the chest. D. Another image of a left-sided CDH at 22 weeks demonstrates no normal lung, the heart (H) displaced into the right chest, and an elevated liver (dotted ellipse).

sonographically, whereas pseudocysts and resultant abnormalities of meconium migration are better delineated with MR imaging .

• Adjunct to Fetal Therapy

As indications for fetal therapy have grown, MR imaging is used preoperatively to outline abnormalities. At some centers, before laser ablation of placental anastomoses for twin-twin transfusion syndrome, MR imaging is performed to assess the fetal brain for IVH or periventricular leukomalacia (Chap. 45, p. 878) (Hu, 2006; Kline-Fath, 2007). Because of its precision in visualizing brain and spine indings in cases of myelomeningocele, it is often used preoperatively. For sacrococcygeal teratomas, if fetal surgery is considered, MR imaging may identiY tumor extension into the fetal pelvis (Avni, 2002; Neubert, 2004; Perrone, 2017). With a fetal neck mass for which an EIT is considered, MR imaging may help delineate the lesion extent and its efect on the oral cavity, hypopharynx, and trachea (Hirose, 2003; Lazar, 2012; Ogamo, 2005; Shiraishi, 2000). Finally, vfR imaging can also calculate a jaw index when an EIT procedure may be needed for severe micrognathia (MacArthur, 2012; Morris, 2009). Fetal therapy is discussed in Chapter 16 (p. 327).

FIGURE 10-58 A. Sagittal short T1 inversion recovery (STIR) image through a fetus with posterior urethral valve at 23 weeks' gestation. Notice the characteristic dilation of the posterior urethra (arrowhead). B. At 31 weeks, a coronal image shows progression of severe hydronephrosis, cystic changes in the parenchyma, hydroureter, and anhydramnios. The lungs (L) show a decreased signal and are small. C. An axial balanced sequence shows a distended bladder (B) with thickened wall (arrows).

The clinical importance of identiying women with placenta accreta is discussed in Chapter 41 (p. 777). Sonography is gen erally used to identiy placental invasion into the myometrium, however, MR evaluation is an adjunct for indeterminate cases.

bands on T2-weighted images, focal bulging, and placental heterogeneity (Leyendecker, 2012). When used in a comple mentary role, MR imaging sensitivity is high for detection of placental invasion, although the depth of invasion is diicult to predict. Clinical risk factors and sonographic indings should be taken into account when interpreting MR placental images.

Of these, MR difusion tensor imaging and tractography may allow urther understanding of neural development and more precise definition of abnormality and pathology (Kasprian, 2008; Mitter, 2015). Automatic and semiautomated extraction of quantitative data from MR imaging volumetric acquisitions of fetal brain and placenta may enable subanalyses of massive datasets not previously possible with laborious manual segmentation (Tourbier, 2017; Wang, 2016). Using multiparametric MR of the placenta in vivo will expand our understanding of function and pathology without risk to mother or fetus. Last, although echocardiography will always be paramount in fetal heart assessment, MR imaging may contribute to volumetric cardiac analysis and will urther evaluation of the aorta, which is oten diicult to completely examine sonographically (Lloyd, 2017).

Adzick NS, Harrison MR, Glick PL, et al: Fetal cystic adenomatoid malformation: prenatal diagnosis and natural history. J Pediatr Surg 20:483, 1985

Al-Kaf A, MacDonald Sc, Kent N, et al: Delivery planning for pregnancies with gastroschisis: findings from a prospective national registry. Am J Obstet Gynecole213(4):557.e1,e2015

Altman P, Randolph JG, Lilly JR: Sacrococcygeal teratoma: American Academy of Pediatrics Surgical Section survey-1973. J Pediatr Surg 9:389, 1974 American College of Obstetricians and Gynecologists: Fetal growth restriction.

Practice Bulletin No. 134, May 2013, Reairmed 2015 American College of Obstetricians and Gynecologists: Ultrasound in pregnancy. Practice Bulletin No. 175, December 2016

American College of Obstetricians and Gynecologists: Management of suboptimally dated pregnancies. Committee Opinion No. 688, March 2017a American College of Obstetricians and Gynecologists: Methods for estimating the due date. Committee Opinion No. 700, May 20e17b American College of Radiology: Expert Panel on MR Saety: ACR guidance document on MR safe practices. J Magn Reson Imaging 37:501,e2013

American College of Radiology and Society for Pediatric Radiology: ACR-SPR practice guideline for the safe and optimal performance of fetal magnetic resonance imaging. Resolution No. 11, 2015. Available at: https://www.acr.org/ -/ medilCB384A65345F402083639E6756CE513F .pdf Accessed July 10, 2017 American Institute of Ultrasound in Medicine (AlUM): Oicial statements. Prudent use in pregnancy. 2012. Available at: http://www.aium.org/oicalStatements/33. Accessed July H), 2017 American Institute of Ultrasound in Medicine (AlUM): Oicial statements. Statement on the safe use of Doppler ultrasound during 11-14 weeks scans (or earlier in pregnancy). 2016. Available at: http://ww.aium.org/ oicialStatements/42. Accessed September 16, 20e17 American Institute of Ultrasound in Medicine (AlUM): Practice guideline for rhe performance offetal echo cardiography. J Ultrasound Med 32(6): 1067, 2013a American Institute of Ultrasound in Medicine (AlUM): Practice guideline for the performance of obstetric ultrasound examinations. J Ultrasound Med 32(6):1083,e2013b

Avni FE, Guibaus L, Robert Y, et al: MR imaging of fetal sacrococcygeal teratoma: diagnosis and assessment. AJR Am J Roentgenol 178(1): 179, 2002

Axt-Fliedner R, Schwarze A, Smrcek J, et al: Isolated ventricular septal defects dated by color Doppler imaging: evolution during fetal and first year of postnatal life. Ultrasound Obstet Gynecol 27:266, 2006

Azizkhan RG, Crombleholme TM: Congenital cystic lung disease: contemporary antenatal and postnatal management. Pediatric Surg Int 24:643, 2008 Bahado-Singh RO, Kovanci E, Jefres A, et al: he Doppler cerebroplacental ratio and perinatal outcome in intrauterine growth restriction. Am J Obstet GynecoIe180(3):750, 1999 Baker PN, Johnson IR, Harvey PR, et al: A three-year follow-up of children imaged in utero with echo-planar magnetic resonance. Am J Obstet Gynecol 170:32, 1994

Baschat A: Doppler application in the delivery timing of the preterm growthrestricted fetus: another step in the right direction. Ultrasound Obstet GynecoIe23:1e11,e2004

Baschat A: Relationship between placental blood low resistance and precordial venous Doppler indices. Ultrasound Obstet Gynecol 22:561, 2003

Benacerraf BR, Shipp TO, Bromley B, et al: What does magnetic resonance imaging add to the prenatal sonographic diagnosis of ventriculomegaly? J Ultrasound Med 26:1513,e2007

Berkley E, Chauhan SP, Abuhamad A: Society for Maternal-Fetal Medicine Clinical Guideline: Doppler assessment of the fetus with intrauterine growth restriction. Am J Obstet Gynecol 206(4):300, 2012

Best E, Tennant PWG, Addor M, et al: Epidemiology of small intestinal atresia in Europe: a register-based study. Arch Dis Child Fetal Neonatal Ed 97(5):F353,e2012

Bhide A, Acharya G, Bilardo CM, et al: ISUOG Practice Guidelines: use of Doppier ultrasonography in obstetrics. Ultrasound Obstet Gynecol41 (2):233, 2013

Bilardo CM, Wolf H, Stigter RH, et al: Relationship between monitoring parameters and perinatal outcome in severe, early intrauterine growth restriction. Ultrasound Obstet Gynecol 23: 119, 2004

Bonafe L, Cormier-Daire V, Hall C, et al: Nosology and classification of genetic skeletal disorders: 2015 revision. Am J Med Genet 167A(12):2869, 2015

Bromley B, Shipp TO, Lyons J, et al: Detection of fetal structural anomalies in a basic first-trimester screening program for aneuploidy. J Ultrasound Med 33(10):1737,e2014

Bronshtein M, Ornoy A: Acrania: anencephaly resulting from secondary degeneration of a closed neural tube: two cases in the same family. J Clin Ultrasound 19(4):230, 1991

Brugger PC, Stuhr F, Lindner C, et al: Methods of fetal MR: beyond T2-weighted imaging. Euro J Radiol 57(2): 172, 2006

Burge 0, Wheeler R: Increasing incidence of detection of congenital lung lesions. Pediatr Pulmono1e45(1):103, 2010

Caire JT, Ramus RM, Magee KP, et al: MRI of fetal genitourinary anomalies.

AJR Am J RoentgenoIe181:1381, 2003

Canield A, Honein A, Yuskiv N, et al: National estimates and race/ethnicspecific variation of selected birth defects in the United States, 1999-2001. Birth Defects Res A Clin Mol Teratol 76(11):747, 2006

Carey M, Bower C, Mylvaganam A, et al: Talipes equinovarus in Western Australia. Paediatr Perinat Epidemiol 17: 187, 2003

Cavoretto P, Molina F, Poggi S, et al: Prenatal diagnosis and outcome of echogenic fetal lung lesions. Ultrasound Obstet Gynecol 32:769, 2008

Centers for Disease Control and Prevention: Workplace solutions. Preventing work-related musculoskeletal disorders in sonography. DHHS (NIOSH) Publication No. 2006-148, 2006

Chitty LS, Altman DG: Charts of fetal size: kidney and renal pelvis measurements. Prenat Diagn 23:891, 2003

Christensen N, Andersen H, Garne E, et al: Atrioventricular septal defects among infants in Europe: a population-based study of prevalence, associated anomalies, and survival. Cardiol Young 23(4):560,e2013

Clements H, Duncan KR, Fielding K, et al: Infants exposed to MRI in utero have a normal paediatric assessment at 9 months of age. B J Radiol 73(866):190,e2000

Colvin J, Bower C, Dickinson JE, et al: Outcomes of congenital diaphragmatic hernia: a population-based study in Western Australia. Pediatr 116:e356, 2005

Copel JA, Liang R, Demasio K, et al: he clinical significance of the irregular fetal heart rhythm. Am J Obstet Gynecol 182:813,e2000

Cragan JD, Gilboa SM: Including prenatal diagnoses in birth defects monitoring: experience of the Metropolitan Atlanta Congenital Defects Program. Birth Defects Res A Clin Mol Teratol 85:20, 2009

Cruz-Martinez R, Figueras F, Hernandez-Andrade E, et al: Fetal brain Doppler to predict cesarean delivery for nonreassuring fetal status in term small-forgestational-age fetuses. Obstet Gynecol 117:618, 2011

Curran PF, Jelin EB, Rand L, et al: Prenatal steroids for microcystic congenital adenomatoid malformations. J Pediatr Surg 45:145,e2010

Dashe JS, Mcintire DO, Twickler OM: Efect of maternal obesity on the ultrasound detection of anomalous fetuses. Obstet Gynecol 113(5):1001,o2009

De Biasio P, Ginocchio G, Aicardi G, et al: Ossification timing of sacral vertebrae by ultrasound in the mid-second trimester of pregnancy. Prenat Diagn 23:1056,o2003

Debus A, Hagelstein C, Kilian A, et al: Fetal lung volume in congenital diaphragmatic hernia: association of prenatal MR imaging indings with postnatal chronic lung disease. Radiology 266(3):887,o2013

Derikx JP, De Backer A, Van De Schoot L, et al: Factors associated with recurrence and metastasis in sacrococcygeal teratoma. Br J Surg 93: 1543, 2006

Devaseelan P, Cardwell C, Bell B, et al: Prognosis of isolated mild to moderate fetal cerebral ventriculomegly: a systematic review. J Perinat Med 38:401, 20o10

De Veciana M, Major CA, Porto M: Prediction of an abnormal karyotype in fetuses with omphalocele. Prenat Diagn 14:487, 1994

DeVore GR, Falkensammer P, Sklansky MS, et al: Spatio-temporal image correlation (STIC): new technology for evaluation of the fetal heart. Ultrasound Obstet Gynecol 22:380, 2003

Dolk H, Loane M, Garne E: The prevalence of congenital anomalies in Europe.

Adv Exp Med Bioi 686:349, 2010

Duncombe GJ, DickinsonoJE, Kikiros CS: Prenatal diagnosis and management of congenital cystic adenomatoid malformation of the lung. Am J Obstet Gynecol 187(4): 950, 2002

Ecker JL, Shipp TO, Bromley B, et al: The sonographic diagnosis of DandyWalker and Dandy-Walker variant: associated indings and outcomes. Prenat Diagn 20:328, 2000

EUROCAT: Prenatal Detection Rates. Available at: http://ww.eurocatnetwo rk. eu/ p rena talscreen inganddiagnosis/ p rena taldetectio n (pd) ra tes. Accessed July 10, 2017

Farhataziz N, Engels JE, Ramus RM, et al: Fetal MRI of urine and meconium by gestational age for the diagnosis of genitourinary and gastrointestinal abnormalities. AJR Am J Roentgenol 184: 1891, 2005

Feinstein JA, Benson OW, Dubin M, et al: Hypoplastic let heart syndrome: current considerations and expectations. J Am ColI Cardiol 59(1 Suppl):SI, 2012

Figueras F, Benavides A, Del Rio M, et al: Monitoring of fetuses with intrauterine growth restriction: longitudinal changes in ductus venosus and aortic isthmus flow. Ultrasound Obstet Gynecol 33(1):39, 2009

Food and Drug Administration: Avoid fetal "keepsake" images, heartbeat monitors. 2014. Available at: https://www.fda.gov/ForConsumers/ ConsumerUpdates/ucm095508.htm. Accessed July 10, 2017

Franklin 0, Burch M, Manning N, et al: Prenatal diagnosis of coarctation of the aorta improves survival and reduces morbidity. Heart 87:67, 2002 Furey A, Bailey A, Twickler OM: Fetal MR imaging of gastrointestinal abnormalities. Radiographies 36(3):904, 2016

Gaglioti P, Oberto M, Todros T: he signiicance of fetal ventriculomegaly: etiology, short-and long-term outcomes. Prenat Diagn 29(4):381, 2009

Gallot 0, Boda e, Ughetto S, et al: Prenatal detection and outcome of congenital diaphragmatic hernia: a French registry-based study. Ultrasound Obstet Gynecol 29:276, 2007

Garcia M, Yeo L, Romero R, et al: Prospective evaluation of the fetal heart using Fetal Intelligent Navigation Echocardiography (FINE)o. Ultrasound Obstet GynecoIo47(4):450, 2016

Garel C (ed): Development of the fetal brain. In MRI of the Fetal Brain: Normal Development and Cerebral Pathologies. New York, Springer, 2004

Game E, Loane M, Dolk H, et al: Spectrum of congenital anomalies in pregnancies with pregestational diabetes. Birth Defects Res A Clin Mol Teratol 94(3):134,o2012

Glass HC, Shaw GM, Ma e, et al: Agenesis of the corpus callosum in California 1983-2003: a population-based study. Am J Med Genet A 146A:2495, 2008

Glover P, Hykin J, Gowland P, et al: An assessment of the intrauterine sound intensity level during obstetric echo-planar magnetic resonance imaging. Br J Radiol 68: 1 090, 1995

Goldstein I, Reece EA, Pilu G, et al: Cerebellar measurements with ultrasonography in the evaluation of fetal growth and development. Am J Obstet GynecoIo156:1065,o1987

Goncalves LF, Lee W, Espinoza J, et al: Three-and 4-dimensional ultrasound in obstetric practice: does it help? J Ultrasound Med 24: 1599, 2005

Goncalves LF, Nien JK, Espinoza J, et al: What does 2-dimensional imaging add to 3-and 4-dimensional obstetric ultrasonography? J Ultrasound Med 25:691,o2006

Griiths PO, Bradburn M, Campbell MJ, et al: Use ofMRI in the diagnosis of fetal brain abnormlities in utero (MERIDIAN): a multicenter, prospective cohort study. Lancet 389(10068):538, 2017

Gucciardo L, Uyttebroek A, de Wever I, et al: Prenatal assessment and management of sacrococcygeal teratoma. Prenat Diagn 31 :678, 2011

Hains OS, Bates CM, Ingraham S, et al: Management and etiology of the unilateral multicystic dysplastic kidney: a review. Pediatr NephroIo24:233, 2009

Hartman Rj, Rasmussen SJ, Botto LD, et al: he contribution of chromosomal abnormalities to congenital heart defects: a population-based study. Pediatr CardioIo32:1o147,o201o1

Hawkins JS, Dashe JS, Twickler OM: Magnetic resonance imaging diagnosis of severe fetal renal anomalies. Am J Obstet Gynecol 198:328.e 1, 2008

Hayden SA, Russ PO, Pretorius DH, et al: Posterior urethral obstruction. Prenatal sonographic indings and clinical outcome in fourteen cases. J Ultrasound Med 7:371, 1988

Hirose S, Sydorak M, Tsao K, et al: Spectrum of intrapartum management strategies for giant fetal cervical teratoma. J Pediatr Surg 38(3):446, 2003

Hobbins Je, Robero R, Grannum P, et al: Antenatal diagnosis of renal anomalies with ultrasound: 1. Obstructive uropathy. m J Obstet Gynecol 148:868, 1984

Hofman CK, Filly A, Callen PW: he "lying down" adrenal sign: a sono graphic indicator of renal agenesis or ectopia in fetuses and neonates. J Ultrasound Med 11:533, 1992

Howe DT, Rankin J, Draper ES: Schizencephaly prevalence, prenatal diagnosis and clues to etiology: a register-based study. Ultrasound Obstet Gynecol 39(1):75,o2012

Hu LS, Caire J, Twickler OM: MR indings of complicated multifetal gestations. Obstet Gynecol 36(1): 76, 2006

Huhta Je, Moise KJ, Fisher OJ, et al: Detection and quantitation of construction of the fetal ductus arteriosus by Doppler echocardiography. Circulation 75:406, 1987 lams JD, Grobman WA, Lozitska A, et al: Adherence to criteria for transvaginal ultrasound imaging and measurement of cervical length. Am J Obstet GynecoIo209(4):365.e1,o2013

International Society of Ultrasound in Obstetrics and Gynecology: Sonographic examination of the fetal central nervous system: guidelines for performing the "basic examination" and the "fetal neurosonogram." Ultrasound Obstet GynecoIo29:109,o2007

International Society of Ultrasound in Obstetrics and Gynecology: ISUOG statement on ultrasound exposure in the irst trimester and autism spectrum disorders. 20o16. Available at: http://ww.isuog.org/NRI rdonlyres/57 A3E1 B7-5022-4D7F-BEOE-93E 1 D239F29D/0/ISUOG_ statemencon_ultrasound_exposure_in_the_irsctrimester_and_autism_ spectrum_disorders. pdf. Accessed July 28, 2017

Ismaili K, Hall M, Donner C, et al: Results of systematic screening for minor degrees of fetal renal pelvis dilatation in an unselected population. Am J Obstet Gynecol 188:242, 2003

James CA, Watson R, Twining P, et al: Antenatally detected urinary tract abnormalities: changing incidence and management. Eur J Pediatr 157:508, 1998

Janga 0, Akinfenwa 0: Work-related repetitive strain injuries amongst practitioners of obstetric and gynecologic ultrasound worldwide. Arch Gynecol Obstet 286(2):353, 2012

Jani JC, Peralta CFA, Nicolaides KH: Lung-to-head ratio: a need to uniy the technique. Ultrasound Obstet Gynecol 39:2, 2012

Johnson MP, Johnson A, Holzgreve W, et al: First-trimester simple hygroma: cause and outcome. Am J Obstet Gynecol 168: 156, 1993

J ones M, IsenburgJ, Salemi JL, et al: Increasing prevalence of gastroschisis-14 states, 1995-2012. MMWR 65(2):23,o2016

J06 JG, T6th Z, Beke A, et al: Etiology, prenatal diagnoses and outcome of ventriculomegaly in 230 cases. Fetal Diagn her 24(3):254, 2008

Karim IN, Roberts NW, Salomon LJ, et al: Systematic review of irst trimester ultrasound screening in detecting fetal structural anomalies and factors afecting screening performance. Ultrasound Obstet Gynecol 50(4):429, 20o17

Kasprian G, Brugger pe, Weber M, et al: In utero tractography of fetal white matter development. Neuroimage 43:213,o2008

Kharrat R, Yamamoto M, Roume J, et al: Karyotype and outcome of fetuses diagnosed with cystic hygroma in the irst trimester in relation to nuchal translucency thickness. Prenat Diagn 26:369, 2006

Kingdom JC, Burrell SJ, Kaufmann P: Pathology and clinical implications of abnormal umbilical artery Doppler waveforms. Ultrasound Obstet Gynecol 9:271, 1997

Kitchanan S, Patole SK, Muller R, et al: Neonatal outcome of gastroschisis and exomphalos: a 10-year review. J Paediatric Child Health 36:428, 2000

Kline-Fath BM, Calvo-Garcia A, O'Hara SM, et al: Twin-twin transfusion syndrome: cerebral ischemia is not the only fetal MR imaging inding. Pediatr RadioIo37(1):47, 2007

Knott-Craig CJ, Elkins RC, Lane MM, et al: A 26-year experience with surgical management of tetralogy of Fallot: risk analysis for mortality or late reintervention. Ann horac Surg 66:506, 1998

Koren G, Florescu A, Costei AM, et al: Nonsteroidal antiinlammatory drugs during third trimester and the risk of premature closure of the ductus arteriosus: a meta-analysis. Ann Pharmacother 40(5):824, 2006

Kucik]E, Alverson C], Gliboa SM, et al: Racial/ethnic variations in the prevalence of selected major birth defects, Metropolitan Atlanta, 1994-2005. Public Health Reports 127(1):52,o2012

Kul S, Korkmaz HA, Cansu A, et al: Contribution of MRI to ultrasound in the diagnosis of fetal anomalies.o] Magn Reson Imaging 35:882,o2012

Lauson S, Alvarez C, Patel MS, et al: Outcome of prenatally diagnosed isolated clubfoot. Ultrasound Obstet Gynecol 35:708, 2010

Lazar DA, Cassady CI, Olutoye 00, et al: Tracheoesophageal displacement index on predictors of airway obstruction for fetuses with neck masses. ] Pediatr Surg 47:46,o20o12

Lazebnik N, Bellinger MF, Ferguson ]E, et al: Insights into the pathogenesis and natural history of fetuses with multicystic dysplastic kidney disease. Prenat Diagn 19:418, 1999

Lee RS, Cendron M, Kinnamon DD, et al: Antenatal hydronephrosis as a predictor of postnatal outcome: a meta-analysis. Pediatrics 11o8:586, 2006

Lee TC, Lim FY, Keswani SG, et al: Late gestation fetal magnetic resonance imaging-derived total lung volume predicts postnatal survival and need for extracorporeal membrane oxygenation support in isolated congenital diaphragmatic hernia.] Pediatr Surg 46(6):1165,o2011

Levine D, Barnes PD: Cortical maturation in normal and abnormal fetuses as assessed with prenatal vIR imaging. Radiology 210:751, 1999a

Levine D, Barnes PD, Madsen ]R, et al: Central nervous system abnormalities assessed with prenatal magnetic resonance imaging. Obstet Gynecol 94:1011, 1999b

Leyendecker ]R, DuBose M, Hosseinzadeh K, et al: MRI of pregnancy-related issues: abnormal placentation. A]R Am] Roentgenol 198(2):311, 2012

Li Y, Estrof ]A, Khwaja 0, et al: Callosal dysgenesis in fetuses with ventriculomegaly: levels of agreement between imaging modalities and postnatal outcome. Ultra Obstet Gynecol 40(5): 522,o2012

Lloyd DF, Rutherford MA, Simpson ]M, et al: The neurodevelopmental implications of hypoplastic let heart syndrome in the fetus. Cardiol Young 27(2):217,o2017 Lodeiro ]G, Feinstein S], Lodeiro SB: Fetal premature atrial contractions associated with hydralazine. Am] Obstet Gynecol 160: 105, 1989

Long A, Moran P, Robson S: Outcome of fetal cerebral posterior fossa anomalies. Prenat Diagn 26:707, 2006

Maarse W, Berge Sj, Pistorius L, et al: Diagnostic accuracy of transabdominal ultrasound in detecting prenatal cleft lip and palate: a systematic review. Ultrasound Obstet Gynecol 35:495, 2010

Maarse W, Pistorius LR, Van Eeten WK, et al: Prenatal ultrasound screening for orofacial clets. Ultrasound Obstet Gynecol 38:434, 2011

MacArthur C]: Prenatal diagnosis of fetal cervicofacial anomalies. Curr Opin Otolaryngol Head Neck Surg 20(6):482,o2012 Mahle T, Clancy RR, McGaurn SP, et al: Impact of prenatal diagnosis on survival and early neurologic morbidiry in neonates with the hypoplastic let heart syndrome. Pediatrics 107: 1277, 2001 Malone FD, Ball RH, Nyberg DA, et al: First-trimester septated cystic hygroma: prevalence, natural history, and pediatric outcome. Obstet Gynecol 106:288, 2005

Mammen L, Benson CB: Outcome of fetuses with clubfeet diagnosed by prenatal sonography. ] Ultrasound Med 23:497, 2004 Mann S, Johnson MP, Wilson RD: Fetal thoracic and bladder shunts. Semin Fetal Neonatal Med 15:28,o2010 Mari G, Deter L, Carpenter L, et al: Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative group for Doppler assessment of the blood velociry in anemic fetuses. N Englo] Med 342:9, 2000 Mehollin-Ray AR, Cassady CI, Cass DL, et al: Fetal MR imaging of congenital diaphragmatic hernia. Radiographics 32(4):1067,o2012 Messerschmidt A, Pataraia A, Helber H, et al: Fetal MRI for prediction of neonatal mortaliry following preterm premature rupture of the fetal membranes. Pediatr Radiol 41: 1416, 201o1 Millischer E, Sonigo P, Ville Y, et al: Standardized anatomical examination of the fetus at MRI. A feasibiliry study. Ultrasound Obstet Gynecol 42(5):553, 20o13 Mitter C, Jakab A, Brugger PC, et al: Validation of in utero tractography of human fetal commissural and internal capsule ibers with histological structure tensor analysis. Front Neuroanat 24:164, 2015 Morris LM, Lim F-Y, Elluru RG, et al: Severe micrognathia: indications for EXIT-to-Airway. Fetal Diagn Ther 26(30):162,o2009 Morrow R], Abramson SL, Bull SB, et al: Efect of placental embolization of the umbilical artery velociry waveform in fetal sheep. Amo] Obstet Gynecol 151:1055, 1989

Mullassery D, Ba'ath ME, ]esudason EC, et al: Value of liver herniation in prediction of outcome in fetal congenital diaphragmatic hernia: a systematic review and meta-analysis. Ultrasound Obstet GynecoIo35:609, 2010

Nelson DB, Dashe ]S, McIntire DD, et al: Fetal skeletal dysplasias: sonographic indices associated with adverse outcomes. ] Ultrasound Med 33(6):1085, 2014

Nelson DB, Martin R, Twickler DM, et al: Sonographic detection and clinical importance of growth restriction in pregnancies with gastroschisis. ] Ultrasound Med 34(12):2217, 2015

Nelson ]S, Stebbins RC, Strassle PD, et al: Geographic distribution of live births with tetralogy ofFailot in North Carolina 2003 to 2012. Birth Defect Res A Clin Mol Teratol 106(1o1):881,o2016

Nembhard N, Waller DK, Sever LE, et al: Patterns of first-year survival among infants with selected congenital anomalies in Texas, 1995-1997. Teratology 64:267,o2001

Neubert S, Trautmann K, Tanner B, et al: Sonographic prognostic factors in prenatal diagnosis ofSCT. Fetal Diagn Ther 19(4): 319, 2004

Nguyen HT, Herndon CDA, Cooper C, et al: he Sociery for Fetal Urology consensus statement on the evaluation and management of antenatal hydronephrosis.o] Pediatr Urol 6:212,o2010

Nicolaides KH, Campbell S, Gabbe SG, et al: Ultrasound screening for spina biida: cranial and cerebellar signs. Lancet 2:72, 1986

Oei SG, Vosters RP, van der Hagen NL: Fetal arrhythmia caused by excessive intake of cafeine by pregnant women. BM] 298:568, 1989

Oferdal K, ]ebens N, Swertsen T, et al: Prenatal ultrasound detection of facial cleft: a prospective study of 49,314 deliveries in a non-selected population in Norway. Ultrasound Obstet Gynecol 31:639, 2008

Ogamo M, Sugiyama T, Maeda T, et al: The ex utero intrapartum treatment (EIT) procedure in giant fetal neck masses. Fetal Diagn her 20(3):214, 2005

Oluyomi-Obi T, Kuret V, Puligandla P, et al: Antenatal predictors of outcome in prenatally diagnosed congenital diaphragmatic hernia (CDH). ] Pediatr Surg 52(5):881,o2017

Orioli 1M, Catilla EE: Epidemiology of holoprosencephaly: prevalence and risk factors. Am ] Med Genet Part C Semin Med Genet 154C: 13, 20o10 Overcash RT, DeUgarte DA, Stephenson ML, et al: Factors associated with gastroschisis outcomes. Obstet GynecoIo124(3):551, 2014

Paladini D, Alirevic Z, Carvalho ]S, et al: ISUOG consensus statement on current understanding of the association of neurodevelopmental delay and congenital heart disease: impact on prenatal counseling. Ultrasound Obstet Gynecol 49(2):287, 2017

Paladini D, Russo M, Teodoro A, et al: Prenatal diagnosis of congenital heart disease in the Naples area during the years 1994-1999-the experience of a joint fetal-pediatric cardiology unit. Prenatal Diagn 22(7):545, 2002

Pavone V, Bianca S, Grosso G, et al: Congenital talipes equinovarus: an epidemiological study in Sicily. Acta Orthop 83(3):294, 2012

Pedersen RN, Calzolari E, Husby S, et al: Oesophageal atresia: prevalence, prenatal diagnosis and associated anomalies in 23 European regions. Arch Dis Child 97:227, 2012

Peranteau WH, Boelig MM, Khalek N, et al: Efect of single and multiple courses of maternal betamethasone on prenatal congenital lung lesion growth and fetal survival.] Pediatr Surg 51(1):28,o2016 Perrone EE, Jarboe MD, Maher CO, et al: Early delivery of sacrococcygeal teratoma with intraspinal extension. Fetal Diagn Ther May 3, 2017 [Epub ahead of print]

Phelan ]P, Ahn MO, Smith CV, et al: Amnionic luid index measurements during pregnancy. ] Reprod Med 32:601, 1987

Pilu G: Prenatal diagnosis of cerebrospinal anomalies. In: Fleischer AC, Toy EC, Lee W, et al (eds): Sonography in Obstetrics and Gynecology: Principles and Practice, 7th ed. New York, McGraw-Hill, 201o1 Prayer D, Malinger G, Brugger PC, et al: ISUOG Practice Guidelines: performance of fetal magnetic resonance imaging. Ultrasound Obstet Gynecol 49(5):671,o2017 Rabinowitz R, Peters MT, Vyas S, et al: Measurement of fetal urine production in normal pregnancy by real-time ultrasonography. Am ] Obstet Gynecol 161:1264, 1989 Rahemtullah A, McGillivray B, Wilson RD: Suspected skeletal dysplasias: femur length to abdominal circumference ratio can be used in ultrasonographic prediction of fetal outcome. Am ] Obstet Gynecol 177:864, 1997 Ramos GA, Romine LE, Gindes L, et al: Evaluation of the fetal secondary palate by 3-dimensional sonography. ] Ultrasound Med 29:357, 2010 Ramus RM, Martin LB, Twickler DM: Ultrasonographic prediction of fetal outcome in suspected skeletal dysplasias with use of the femur lengthto-abdominal circumference ratio. Am ] Obstet Gynecol 179(5): 1348, 1998

Reddy UM, Abuhamad AZ, Levine 0, et al: Fetal imaging: executive summary of a joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Institute of Ultrasound in Medicine, American College of Obstetricians and Gynecologists, American College of Radiology, Society for Pediatric Radiology, and Society of Radiologists in Ultrasound Fetal Imaging workshop. Obstet Gynecol 123(5): 1070, 2014

Reddy UM, Filly A, Copel JA: Prenatal imaging: ultrasonography and magnetic resonance imaging. Obstet GynecoIoI12:145, 2008

Reeves MJ, Brandreth M, Whitby EH, et a1: Neonatal cochlear function: measurement after exposure to acoustic noise during in utero MR imaging. Radiology 257(3):802, 2010

Reichel TF, Ramus RM, Caire JT, et al: Fetal central nervous system biometry on MR imaging. Am J RoentgenoIo180(4): 1155,o2003

Roll SC, Evans KD, Hutmire CD, et al: An analysis of occupational factors related to shoulder discomfort in diagnostic medical sonographers and vascular technologists. Work 42(3):355, 2012

Romosan G, Henriksson E, Rylander A, et al: Diagnostic performance of routine ultrasound screening for fetal malformations in an unselected Swedish population 2000-2005. Ultrasound Obstet Gynecol 34:526, 2009

Rydberg C, Tunon K: Detection of fetal abnormalities by second-trimester ultrasound screening in a non-selected population. Acta Obstet Gynecol Scand 96(2):176, 2017

Salomon LJ, Alirevic Z, Berghella V, et al: Practice guidelines for performance of the routine mid-trimester fetal ultrasound scan. Ultrasound Obstet Gynecol 37(1):116, 2011

Sanford A, Saadai P, Lee H, et al: Congenital high airway obstruction sequence (CHAOS)o: a new case and a review of phenotypic features. m J Med Genet 158A(12):3126,o2012

Santiago-Munoz Pc, McIntire DO, Barber RG, et al: Outcomes of pregnancies with fetal gastroschisis. Obstet Gynecol 110:663, 2007

Schreuder MF, Westland R, van Wijk JA: Unilateral multicystic dysplastic kidney: a meta-analysis of observational studies on the incidence, associated urinary tract malformations and the contralateral kidney. Nephrol Dial Transplant 24:1810,o2009

Sciscione AC, Hayes EJ, Society for Maternal-Fetal Medicine: Uterine artery Doppler Row studies in obstetric practice. Am J Obstet Gynecol 201 (2): 121, 2009

Segata M, Mari G: Fetal anemia: new technologies. Curr Opin Obstet Gynecol 16: 153, 2004

Sharma R, Stone S, Alzouebi A, et al: Perinatal outcome of prenatally diagnosed congenital talipes equinovarus. Prenat Diagn 31:142, 2011

Sheih CP, Liu MB, Hung CS, et al: Renal abnormalities in schoolchildren.

Pediatrics 84: 1086, 1989

Shipp TO, Bromley B, Hornberger LK, et al: Levorotation of the fetal cardiac axis: a clue for the presence of congenital heart disease. Obstet Gynecol 85:97, 1995

Shiraishi H, Nakamura M, lchihashi K, et al: Prenatal MRl in a fetus with a gian t neck hemangioma: a case report. Prenat Diagn 20(12): 1004, 2000

Shulman LP, Emerson DS, Felker RE, et a1: High frequency of cytogenetic abnormalities in fetuses with cystic hygroma diagnosed in the irst trimester. Obstet Gynecol 80:80, 1992

Simon EM, Goldstein RB, Coakley FV, et al: Fast MR imaging of fetal CNS anomalies in utero. Am J NeuroradioIo21:1688, 2000

Soares de Oliveira-Szejnfeld P, Levine D, Melo AS, et al: Congenital brain abnormalities and Zika virus: what the radiologist can expect to see prenatally and postnatally. Radiology 281 :203, 2016

Society for Maternal-Fetal Medicine, Mari G, Norton ME, et al: SMFM Clinical Guideline No.o8: The fetus at risk for anemia-diagnosis and management. Am J Obstet Gynecol 212(6):697, 2015

Society for Maternal-Fetal Medicine: SMFM resolution on ultrasound practice accreditation. 2013. Available at: https://www.smfm.org/publications/150smfm-resolution-on-ultrasound-practice-accreditation. Accessed July 28, 20o17

Solomon BD, Rosenbaum KN, Meek JM, et al: Holoprosencephaly due to numeric chromosome abnormalities. Am J Med Genet Part C Semin Med Genet 154C: 146, 2010

Sotiriadis A, Makrydimas G: Neurodevelopment after prenatal diagnosis of isolated agenesis of the corpus callosum: an integrative review. Am J Obstet Gynecol 206(4):337.el, 2012

South AP, Stutey M, Meinzen-Derr J, et al: Metaanalysis of the prevalence of intrauterine fetal death in gastroschisis. Am J Obstet Gynecol 209(2):1o14.e.l,o2013

Stege G, Fenton A, Jafray B: Nihilism in the 1990s: the true mortality of congenital diaphragmatic hernia. Pediatr 11o2:532, 2003

Stevenson DA, Carey JC, Byrne JL, et al: Analysis of skeletal dysplasias in the Utah population. Am J Med Genet 158A: 1046, 2012

Stocker JT: Congenital pulmonary airway malformation: a new name and expanded classiication of congenital cystic adenomatoid malformation of the lung. Histopathology 41 (Suppl):424, 2002

Stocker JT, Madewell JE, Drake RM: Congenital cystic adenomatoid malformation of the lung: classiication and morphologic spectrum. Hum Pathol 8:155, 1977

Stoll C, Alembik Y, Dott B, et al: Associated malformations in patients with limb reduction deiciencies. Eur J Med Genet 53(5):286, 2010

Swamy R, Embleton N, Hale J, et al: Sacrococcygeal teratoma over rwo decades: birth prevalence, prenatal diagnosis and clinical outcomes. Prenat Diagn 28: 1048, 2008

Syngelaki A, Chelemen T, Dagklis T, et al: Challenges in the diagnosis of fetal non-chromosomal abnormalities at 11-13 weeks. Prenat Diagn 31:90, 2011

Szabo N, Gergev G, Kobor J, et al: Corpus callosum abnormalities: birth prevalence and clinical spectrum in Hungary. Pediatr Neurol 44:420, 2011

Tilea B, Alberti C, Adamsbaum C, et al: Cerebral biometry in fetal magnetic resonance imaging: new reference data. Ultrasound Obstet Gynecol 33(2): 173, 2009

T ourbier S, Velasco-Annis C, T aimouri V, et al: Automated template-based brain localization and extraction for fetal brain MRl reconstruction. Neuroimage 155:460, 2017

Tredwell SJ, Wilson 0, Wilmink MA, et al: Review of the efect of early amniocentesis on foot deformity in the neonate. J Pediatr Orthol 21 :636, 2001 Trivedi N, Levy D, Tarsa M, et al: Congenital cardiac anomalies: prenatal read ings versus neonatal outcomes. J Ultrasound Med 31:389, 2012

Turkbey B, Ocak I, Daryanani K, et al: Autosomal recessive polycystic kidney disease and congenital hepatic ibrosis. Pediatr Radiol 39: 1 00, 2009

Twickler DM, Magee KP, Caire J, et al: Second-opinion magnetic resonance imaging for suspected fetal central nervous system abnormalities. Am J Obstet Gynecol 188:492, 2003

Twickler OM, Reichel T, McIntire DD, et al: Fetal central nervous system ventricle and cisterna magna measurements by magnetic resonance imaging. Am J Obstet Gynecol 187:927,o2002

Tworetzky W, McElhinney DB, Reddy VM, et al: Improved surgical outcome ater fetal diagnosis of hypoplastic let heart syndrome. Circulation 103:1269,o2001

Vadeyar SH, Moore RJ, Strachan BK, et al: Efect of fetal magnetic resonance imaging on fetal heart rate patterns. Am J Obstet Gynecol 182:666, 2000

Vasluian E, van der Sluis CK, van Essen AJ, et al: Birth prevalence for congenital limb defects in the northern Netherlands: a 30-year population-based study. BMC Musculoskel Disord 14:323,o2013

Vergani P, Ceruti P, Locatelli A, et al: Accuracy of prenatal ultrasonographic diagnosis of duplex renal system. J Ultrasound Med 18:463, 1998

Victoria T, Johnson M, Edgar JC, et al: Comparison berween 1.5-T and 3-T MRl for fetal imaging: is there an advantage to imaging with a higher ield strength? AJRAmJ RoentgenoI206:195, 2016

Walker SJ, Ball RH, Babcook C], et al: Prevalence of aneuploidy and additional anatomic abnormalities in fetuses and neonates with cleft lip with or without cleft palate. A population-based study in Utah. J Ultrasound Med 20(1o1):1o175,o2001

Wang G, Zuluaga MA, Pratt R, et al: Slic-Seg: a minimally interactive segmentation of the placenta from sparse and motion-corrupted fetal MRl in multiple views. Med Image Anal 24:137, 2016

Wax JR, Benacerraf BR, Co pel J, et al: Consensus report on the 76811 scan: modiication. J Ultrasound Med 34(10): 1915

Wax J, Minkof H, Johnson A, et al: Consensus report on the detailed fetal anatomic ultrasound examination: indications, components, and qualiications. J Ultrasound Med 33(2):189,o2014

Wenstrom KD, Weiner CP, Williamson A: Diverse maternal and fetal pathology associated with absent diastolic Row in the umbilical artery of high-risk fetuses. Obstet Gynecol 77:374, 1991

Whitten SM, Wilcox DT: Duplex systems. Prenat Diagn 21:952, 2001

Wiesel A, Queisser-Luft A, Clementi M, et al: Prenatal detection of congenital renal malformations by fetal ultrasonographic examination: an analysis of 709,030 births in 12 European countries. Euro J Med Genet 48:131, 2005

Wilhelm L, Borgers H: The "equals sign": a novel marker in the diagnosis of fetal isolated sot palate. Ultrasound Obstet Gynecol 36:439, 2010 Williams B, Tareen B, Resnick M: Pathophysiology and treatment of ureteropelvic junction obstruction. Curr Urol Rep 8: Ill, 2007

Wiskirchen J, Groenewaeller EF, Kehlbach R, et al: Long-term efects of repetitive exposure to a static magnetic ield 1.o5 T on proliferation of human fetal lung ibroblasts. Magn Reson Med 41 :464, 1999

Woodward M, Frank 0: Postnatal management of antenatal hydronephrosis.

BJU Int 89:o149, 2002

Worley KC, Dashe JS, Barber RG, et al: Fetal magnetic resonance imaging in isolated diaphragmatic hernia: volume of herniated liver and neonatal outcome. Am J Obstet GynecoI200(3):318.e1, 2009

Yamada 5, Uwabe C, Fujii 5, et al: Phenotypic variability in human embryonic holoprosencephaly in the Kyoto collection. Birth Defects Res Part A Clin Mol TeratoIo70:495,o2004

Yeo L, Romero R: How to acquire cardiac volumes for sonographic examination of the fetal heart, part I. J Ultrasound Med 35 (5): 1 021, 2016 Yildirim G, Gungorduk K, Asian H, et al: Prenatal diagnosis of extralobar pulmonary sequestration. Arch Gynecol Obstet 278: 181, 2008

Zaretsky M, Ramus R, McIntire 0, et al: MRI calculation of lung volumes to predict outcome in fetuses with genitourinary abnormalities. AJR Am J RoentgenoIo185:1328,o2005

Zaretsky MV, McIntire DO, Twickler DM: Feasibility of the fetal anatomic and maternal pelvic survey by magnetic resonance imaging at term. Am J Obstet Gynecol 189:997, 2003a

Zaretsky MY, Twickler OM: Magnetic imaging in obstetrics. Clin Obstet Gynecol 46:868, 2003b

Zeeman GG, McIntire DO, Twickler DM: Maternal and fetal artery Doppler findings in women with chronic hypertension who subsequently develop superimposed pre-eclampsia. J Matern Fetal Neonatal Med 14:318,o2003

Zerres K, Mucher G, Becker J, et al: Prenatal diagnosis of autosomal recessive polycystic kidney disease: molecular genetics, clinical experience, and fetal morphology. Am J Med Genet 6:l37, 1998

NORMAL AMNIONIC FLUID VOLUME .......... .....225

PHYSIOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .... 225

SONOGRAPHIC ASSESSMENT . .......... . .i..226

HYDRAMNIOS ......... ...i...i..i......... .....227

OLIGOHYDRAMNIOS ..i........ .... ....... .....230

BORDERLINE OLIGOHYDRAMNIOS ........... ...i.. 232

It is generaly agreed that amniotic luid represents in great part a transudation from the matenal vesses, but many authorities consider that a portion of it is derived rom urinay secretion of the oetus.

-J. Whitridge Williams (1903)

At the time Williams wrote this, the fetal kidney was thought by many to be nonfunctional. Since that time, however, much has been learned of this complex multifunctional liquor amnii. mnionic fluid serves several roles during pregnancy. Fetal breathing of amnionic fluid is essential for normal lung growth, and fetal swallowing permits gastrointestinal (GI) tract development. Amnionic fluid also creates a physical space for fetal movement, which is necessary for neuromusculoskeletal maturation. It further guards against umbilical cord compression and protects the fetus from trauma. Amnionic luid even has bacteriostatic properties. Abnormalities of volume may result from fetal or placental pathology-indicating a problem with luid production or its circulation. These volume extremes may be associated with increased risks for adverse pregnancy outcome.

Amnionic luid volume increases from approximately 30 mL at 10 weeks to 200 mL by 16 weeks and reaches 800 mL by the mid-third trimester (Brace, 1989; Magann, 1997). The luid is approximately 98-percent water. A full-term fetus contains roughly 2800 mL of water and the placenta another 400 mL, such that the term uterus holds nearly 4 liters of water (Modena, 2004). Abnormally decreased luid volume is termed oligohydramnios, whereas abnormally increased luid volume is termed hydramnios or poyhydramnios.

Early in pregnancy, the amnionic cavity is filled with luid that is similar in composition to extracellular luid. During the first half of pregnancy, transfer of water and other small molecules takes place across the amnion-transmembranous low; across the fetal vessels on placental surface-intramembranous low; and transcutaneous low-across fetal skin. Fetal urine production begins between 8 and 11 weeks' gestation, but it does not become a major component of amnionic luid until the second trimester, which explains why fetuses with lethal renal abnormalities may not manifest severe oligohydramnios until after 18 weeks. Water transport across the fetal skin continues until keratinization occurs at 22 to 25 weeks. This explains why extremely preterm neonates can experience signiicant luid loss across their skin.

With advancing gestation, four pathways playia major role in amnionic luid volume regulation (Table

First, fetal urination is the primary source of amnionic luid in the second half of pregnancy. By term, fetal urine production may exceed 1 liter per day, and the entire amnionic luid volume is recirculated on a daily basis. Fetal urine osmolality is similar to that of amnionic luid and significantly hypotonic to that of maternal and fetal plasma. Speciically, the osmolality of maternal

TABLE 11-1. Amnionic Fluid Volume Regulation in Late Pregnancy

Data from Magann, 201l1; Modena, 2004; Moore, 201l0.

and fetal plasma approximates 280 mOsm/mL, whereas that of amnionic fluid is about 260 mOsm/L. The hypotonicity of amnionic luid accounts for significant intramembranous fluid transfer across and into fetal vessels on the placental surface. This transfer reaches 400 mL per day and is a second regulator of fluid volume (Mann, 1996). In the setting of maternal dehydration, the resultant increase in maternal osmolality favors fluid transfer from the fetus to the mother, and then from the amnionic luid compartment into the fetus (Moore, 2010).

n important third source of amnionic fluid regulation is the respiratory tract. Approximately 350 mL of lung fluid is produced daily late in gestation, and half of this is immediately swallowed. Last, fetal swallowing is the primary mechanism for amnionic luid resorption and averages 500 to 1000 mL per day (Mann, 1996). Impaired swallowing, secondary to either a central nervous system abnormality or GI tract obstruction, can result in an impressive degree of hydramnios. The remaining pathways are transmembranous and transcutaneous low, which together account for a far smaller proportion of fluid transport in the second half of pregnancy.

From a practical standpoint, the actual volume of amnionic luid is rarely measured outside of the research setting. That said, direct measurement and dye-dilution methods of luid quantification have contributed to our understanding of normal physiology. These measurements have further been used to validate sonographic fluid assessment techniques. Dye dilution involves injecting a small quantity of a dye such as aminohippurate into the amnionic cavity under sonographic guidance and then sampling the amnionic fluid to determine the dye concentration and hence to calculate the volume.

Brace and Wolf (1989) reviewed 12 studies done through the 1960s in which amnionic fluid volume was assessed using these measurement techniques. Although fluid volume increased across gestation, they found that the mean value did not change significantly between 22 and 39 weeks-it was approximately 750 mL. There was considerable variation at each week of gestation, especially in the mid-third trimester, when the 5th percentile was 300 mL and the 95th percentile nearly 2000 mL. In contrast, Magann and colleagues (1997), using dye-dilution measurements, found that amnionic fluid volume rose with advancing gestation. Specifically, the average fluid volume was approximately 400 mL between 22 and 30 weeks, doubling thereafter to a mean of 800 mL. he volume remained at this level until 40 weeks and then declined by approximately 8 percent per week. The two reports difered in the regression methodology employed, and despite diferent conclusions, both identiied a wide normal range, particularly in the third trimester. This normal variation is similarly observed sonographically.

Amnionic fluid volume evaluation is a component of every standard sonogram performed in the second or third trimester (Chap. 10, p. 188). It may be measured using either of two semi-quantitative techniques, the single deepest pocket of fluid or the amnionic fluid index (API), which was described by Phelan and associates (1987). Both measurements are reproducible and, in the setting of a fluid abnormality, can be followed serially over time to assess trends and to aid communication among providers. For these reasons, semiquantitative assessment of amnionic luid is preferred to qualitative or subjective estimation (American College of Obstetricians and Gynecologists, 2016). Using either technique, a fluid pocket must be at least 1 em in width to be considered adequate. Fetal parts or loops of umbilical cord may be visible in the pocket, but they are not included in the measurement. Color Doppler is generally used to veriY that umbilical cord is not within the measurement.

his is also called the largest or maximal vertical pocket of amnionic fluid. he ultrasound transducer is held perpendicular to the floor and parallel to the long axis of the woman. Then, while scanning in the sagittal plane, the largest vertical pocket of luid is identified and measured. The single deepest pocket measurement is considered normal f above 2 cm and less than 8 cm, with values below and above this range indicating oligohydramnios and hydramnios, respectivey. hese thresholds are based on data from Chamberlain and associates (1984) and correspond to the 3rd and 97th percentiles. When evaluating twin pregnancies and other multi fetal gestations, a single deepest pocket of amnionic fluid is assessed in each gestational sac, again using a normal range of more than 2 em to less than 8 em (Hernandez, 2012; Society for Maternal-Fetal Medicine, 2013). The fetal biophysical profile similarly uses a single deepest vertical pocket threshold of more than 2 em to indicate normal amnionic luid volume. This is discussed further in Chapter 17 (p. 337).

28 Mild hydramnios 26 24E 22>;'20 ) 180.� 16Q:J=14= > 12·c0 10·cE 8« 6 4 2 0

FIGURE 11-1 Amnionic fluid index (AFI) according to gestational-age-specific and threshold values. The blue curves represent the 25th, 50th, and 975th AFI percentile values, based on the nomogram by Moore (1o990). Red and tan curves represent 50th percentile values for AFI from Machado (2007) and from Hinh and Ladinsky (2005), respectively. The light blue and yellow shaded bars indicate threshold values used to define hydramnios and oligohydramnios, respectively.

or a gestational age-specific percentile reference range. he AFI is generally considered normal if greater than 5 cm and below 24 or 25 cm. Values outside these ranges indicate oligohydramnios and hydramnios, respectively. The upper threshold of 24 cm is used in consensus documents (American College of Obstetricians and Gynecologists, 2016; Reddy, 2014). The 25-cm threshold is oten applied in research studies (Khan, 2017; Luo, 2017; Pri-Paz, 2012). Moore and Cayle (1990) have provided normal curves for AFI values based on a cross-sectionl evaluation of nearly 800 uncomplicated pregnancies. he mean AFI was found to be between 12 and 15 cm from 16 weeks until 40 weeks' gestation. Other investigators have published nomograms with similar mean values (Hinh, 2005; Machado, 2007). Figure 11-1 depicts these AFI nomogram reference values in relation to commonly used thresholds for hydramnios and oligohydramnios.

This is an abnormally increased amnionic luid volume, and it complicates 1 to 2 percent of singleton pregnancies (Dashe, 2002; Khan, 2017; Pri-Paz, 2012). It is more frequently noted in multifetal gestations (Hernandez, 2012). Hydramnios may be suspected if the uterine size exceeds that expected for gestational age. The uterus may feel tense, and palpating fetal small parts or auscultating fetal heart tones may be diicult. An extreme example is shown in Figure 11-2.

Hydramnios may be urther categorized according to degree. Such categorization is primarily used in research studies to stratiy risks. Several groups have termed hydramnios as mid if the AFI is 25 to 29.9 cm; moderate, if 30 to 34.9 cm; and severe, if 35 cm or more (Lazebnik, 1999; Luo, 2016; Odibo, 2016; Pri-Paz, 2012). Mild hydramnios is the most common, comprising

As with the single deepest luid pocket measurement, the ultrasound transducer is held perpendicular to the loor and parallel to the long axis of the woman. The uterus is divided into four equal quadrants-the right and left upper and lower quadrants, respectively. The AFI is the sum of the single deepest pocket from each quadrant. The intraobserver variability of the AFI approximates 1 cm, and the interobserver variability is about 2 cm. Variations are larger when luid volumes are above the normal range (Moore, 1990; Rutherford, 1987). A useful guideline is that the AFI approximates three times the single deepest pocket of fluid (Hill, 2003).

Determination of whether the AFI is normal may be based on either a static numerical threshold

FIGURE 11-2 Severe hydramnios-5500 mL of amnionic fluid was measured at delivery.

97.5th percentile 2.5th percentile

FIGURE "-3 Sonogram of severe hydramnios at 35 weeks in a pregnancy complicated by fetal aqueductal stenosis. This pocket of amnionic fluid measureso> 15 cm, and the amnionic fluid index measured nearly 50 cm.

approximately two thirds of cases; moderate hydramnios accounts for about 20 percent; and severe hydramnios for approximately 15 percent. Using the single deepest pocket of amnionic fluid, mild hydramnios is defined as 8 to 9.9 cm, moderate as 10 to 11.9 cm, and severe hydramnios as 12 cm or more 11-3). In general, severe hydramnios is far more likely to have an underlying etiology and to have consequences for the pregnancy than mild hydramnios, which is frequently idiopathic and benign.

Underlying causes ofhydramnios include fetal anomalies-either structural abnormalities or genetic syndromes-in approximately 15 percent, and diabetes in 15 to 20 percent (Table 11-2). Congenital infection, red blood cell alloimmunization, and placental chorioangioma are less frequent etiologies. Infections that may present with hydramnios include cytomegalovirus, toxoplasmosis, syphilis, and parvovirus. Hydramnios is oten a component of hydrops etalis, and several of the above causes-selected anomalies, infections, and alloimmunization-may result in a hydropic fetus and placenta. he underlying pathophysiology in such cases is complex but is frequently related to a high cardiacoutput state. Severe fetal anemia is a classic example. Because the etiologies of hydramnios are so varied, hydramnios treatment also difers and is tailored in most cases to the underlying cause.

Selected anomalies and the likely mechanism by which they cause hydramnios are shown in Table 11-3. Many of these abnormalities are depicted and discussed in Chapter 10. Because of this association, targeted sonography is indicated whenever hydramnios is identiied. If a fetal abnormality is encountered concurrent with hydramnios, amniocentesis with chromosomal microarray analysis should be ofered, because the aneuploidy risk is signiicantly elevated (Dashe, 2002; Pri-Paz, 2012).

Importantly, the degree of hydramnios correlates with the likelihood of an anomalous infant (Lazebnik, 1999; Pri-Paz, 2012). At Parkland Hospital, the prevalence of an anomalous neonate was approximately 8 percent with mild hydramnios, 12 percent with moderate hydramnios, and more than 30 percent with severe hydramnios (Dashe, 2002). Even if no abnormality was detected with targeted sonography, the likelihood of a major anomaly identified at birth was 1 to 2 percent if hydramnios was mild or moderate and 10 percent if hydramnios was severe. he overall reported risk that an underlying anomaly will be discovered ater delivery has ranged from 9 percent in the neonatal period to 28 percent among infants followed to 1 year of age (Abele, 2012; Dorleijn, 2009). he anomaly risk is particularly high with hydramnios coexistent with fetal-growth restriction (Lazebnik, 1999).

Although amnionic luid volume abnormalities are associated with fetal malformations, the converse is not usually the case. In the Spanish Collaborative Study of Congenital Malformations that included more than 27,000 anomalous infants, only 4 percent of pregnancies were complicated by hydramnios, and another 3 percent with oligohydramnios (Martinez-Frias, 1999).

he amnionic luid glucose concentration is higher in diabetic women than in those without diabetes, and the AFI may

TABLE "e-2. Hydramnios: Prevalence and Associated Etiologies-Values in Percent aA signiicant correlation was identified between severity of hydramnios and likelihood of an anomalous infant.

TABLE 11-3. Selected Anomalies and Mechanism for Hydramnios

Cystic adenomatoid malformation?

Tetralogy of Fallet with absent Thyroto/icosis�

Functional cardiac etiology Cardiom 'apathy, myocarditisa Cardiac arrhythmia tnali flutter, atrial fibrillation, supraventricular tachycardia Bradyarrhythmiaa.

Neurological or muscular etiology Arthrogryposis, akinesia sequence Myotonic dystrophy Neoplastic etiology Sacrococcygeal teratomaa Mesoblastic nephromaa aPoses risk for hydrops.

CHAOS = congenital high-airway obstruction sequence; GI = gastrointestinal.

correlate with the amnionic fluid glucose concentration (Dashe, Idiopathic Hydramnios 2000; Spellacy, 1973; Weiss, 1985). Such findings support the his accounts for up to 70 percent of cases of hydramnios and is hypothesis that maternal hyperglycemia causes fetal hyperglythus identified in as many as 1 percent of pregnanciescemia, with resulting fetal osmotic diuresis into the amnionic (Panting-Kemp, 1999; Pri-Paz, 2012; Wiegand, 2016). Idiopathic luid compartment. hat said, rescreening for gestational diahydramnios is rarely identiied during midtrimester sonography betes in pregnancies with hydramnios does not appear to be and is oten an incidental inding later in gestation. he gestabeneicial, provided that the second-trimester glucose tolerance tional age at sonographic detection usually lies between 32 and 35 test result was normal (F rank Wolf, 2017).

weeks (Abele, 2012; Odibo, 2016; Wiegand, 2016). Although it is a diagnosis of exclusion, an underlying fetal abnormality may subsequently become apparent with advancing gestation, particu

Hydramnios is generally deined in multifetal gestations as larly if the degree of hydramnios becomes severe. In the absence a single deepest amnionic luid pocket measuring 8 cm or of an etiology, idiopathic hydramnios is mild in approximately 80 more. It may be further characterized as moderate if the single percent of cases, and resolution is reported in more than a third deepest pocket is at least 10 cm and severe if this pocket is of afected pregnancies (Odibo, 2016; Wiegand, 2016). Mild, at least 12 cm. In a review of nearly 2000 twin gestations, idiopathic hydramnios is most commonly a benign finding, and

Hernandez and colleagues (20i12) identified hydramnios in associated pregnancy outcomes are usually good.

18 percent of both monochorionic and dichorionic pregnancies. As in singletons, severe hydramnios was more strongly associated with fetal abnormalities. In monochorionic gestations, hydramnios of one sac and oligohydramnios of the Unless hydramnios is severe or develops rapidly, maternal other are diagnostic criteria for twin-twin transfusion synsymptoms are infrequent. With chronic hydramnios, luid drome (TTTS), discussed in Chapter 45 (p. 878). Isolated accumulates gradually, and a woman may tolerate excessive hydramnios of one sac also may precede the development abdominal distention with relatively little discomfort. Acute of this syndrome (Chon, 2014). In the absence of TTTS, hydramnios, however, tends to develop earlier in pregnancy. hydramnios does not generally raise pregnancy risks in nonIt may result in preterm labor before 28 weeks or in symptoms anomalous twins (Hernandez, 2012). that become so debilitating as to necessitate intervention.

Symptoms may arise from pressure exerted within the overdistended uterus and upon adjacent organs. When distention is excessive, such as that shown in Figure 11-2, the mother may sufer dyspnea and orthopnea to such a degree that she may be able to breathe comfortably only when upright. Edema may develop as a consequence of major venous system compression by the enlarged uterus, and it tends to be most pronounced in the lower extremities, vulva, and abdominal wall. Rarely, oliguria may result from ureteral obstruction by the enlarged uterus (Chap. 53, p. 1037). Maternal complications such as these are typically associated with severe hydramnios from an underlying etiology.

Maternal complications associated with hydramnios include placental abruption, uterine dysfunction during labor, and postpartum hemorrhage. Placental abruption is fortunately infrequent. It may result from the rapid decompression of an overdistended uterus that follows fetal-membrane rupture or therapeutic amnioreduction. With prematurely ruptured membranes, a placental abruption occasionally occurs days or weeks after amniorrhexis. Uterine dysfunction consequent to overdistention may lead to postpartum atony and, in turn, postpartum hemorrhage.

Some outcomes more common with hydramnios include birthweight >4000 g, cesarean delivery, and importantly, perinatal mortality. Pregnancies with idiopathic hydramnios are associated with birthweights exceeding 4000 g in nearly 25 percent of cases, and the likelihood appears to be greater if the hydramnios is moderate or severe (Luo, 2016; Odibo, 2016; Wiegand, 2016). A rationale for this association is that larger fetuses have higher urine output, by virtue of their increased volume of distribution, and fetal urine is the largest contributor to amnionic luid volume. Cesarean delivery rates are also higher in pregnancies with idiopathic hydramnios, with reported rates of 35 to 55 percent (Dorleijn, 2009; Khan, 2017; Odibo, 2016).

An unresolved question is whether hydramnios alone raises the risk for perinatal mortality. Some studies have found no increase in stillbirth or neonatal death rates with idiopathic hydramnios, whereas others show a greater risk (Khan, 2017; Pilliod, 2015; Wiegand, 2016). Using birth certificate data from the state of California, Pilliod and coworkers (2015) identified hydramnios in 0.4 percent of singleton, nonanomalous pregnancies, and afected pregnancies had significantly greater stillbirth rates. At 37 weeks, the stillbirth risk was sevenfold higher in pregnancies with hydramnios. By 40 weeks, this risk was more than tenfold higher-66 per 10,000 births compared with 6 per 10,000 without hydramnios.

isks appear to be compounded when a growth-restricted fetus is identiied with hydramnios (Erez, 2005). The combination also has a recognized association with trisomy 18. When an underlying cause is identified, degree of hydramnios has been associated with likelihood of preterm delivery, smallfor-gestational age newborn, and perinatal mortality (Pri-Paz, 2012). However, idiopathic hydramnios is generally not associated with preterm birth (Magann, 2010; Many, 1995; PantingKemp, 1999).

s previously noted, treatment is directed to the underlying cause. Occasionally, severe hydramnios may result in early preterm labor or the development of maternal respiratory compromise. In such cases, large-volume amniocentesis-termed amnioreduction-may be needed. he technique is similar to that for genetic amniocentesis, described in Chapter 14 (p. 292). One diference is that it is generally done with a larger needle, 18-or 20-gauge, and uses either an evacuated container bottle or a larger syringe. Approximately 1000 to 2000 mL of luid is slowly withdrawn over 20 to 30 minutes, depending on the severity of hydramnios and gestational age. he goal is to restore amnionic fluid volume to the upper normal range. Hydramnios severe enough to necessitate amnioreduction almost invariably has an underlying cause, and subsequent amnioreduction procedures may be required as oten as weekly or even semiweekly.

In a review of 138 singleton pregnancies requiring amnioreduction for hydramnios, a fetal GI malformation was identified in 20 percent, a chromosomal abnormality or genetic condition in almost 30 percent, and a neurological abnormality in 8 percent (Dickinson, 2014). In only 20 percent of cases was the hydramnios idiopathic. he initial amnioreduction procedure in this series was performed at 31 weeks' gestation, and the median gestational age at delivery was 36 weeks. Complications within 48 hours of amnioreduction included deliveY in 4 percent and ruptured membranes in 1 percent. here was no instance of chorioamnionitis, placental abruption, or bradycardia requiring delivery (Dickinson, 2014).

his is an abnormally decreased amount of amnionic luid. Oligohydramnios complicates approximately 1 to 2 percent of pregnancies (Casey, 2000; Petrozella, 2011). When no measurable pocket of amnionic fluid is identiied, the term anhydramnios may be used. Unlike hydramnios, which is often mild and often confers a benign prognosis in the absence of an underlying etiolo)i, oligohydramnios is always a cause for concern, as discussed on page 231.

The sonographic diagnosis of oligohydramnios is usualy based on an API less than 5 cm or a single deepest pocket of amnionic luid below 2 cm (American College of Obstetricians and Gynecologists, 2016). Using the Moore nomogram, an API threshold of 5 em is below the 2.5th percentile throughout the second and third trimesters (see Fig. 11-1). Either criterion is considered acceptable. However, use of API rather than single deepest pocket will identiy more pregnancies as having oligohydramnios, without evidence of improvement in pregnancy outcomes (Kehl, 2016; Nabhan, 2010). When evaluating multifetal pregnancies for TTTS, a single deepest pocket below 2 em is used to define oligohydramnios (Society for Maternal-Fetal Medicine, 2013).

Pregnancies complicated by oligohydramnios include those in which the amnionic luid volume has been severely diminished since the early second trimester and those in which the fluid volume was normal until near-term or even full-term. The prognosis depends heavily on the underlying cause and thus varies. Whenever oligohydramnios is diagnosed, it becomes an important consideration in clinical management.

When amnionic fluid volume is abnormally decreased from the early second trimester, it may reflect a fetal abnormality that precludes normal urination, or it may represent a placental abnormality suiciently severe to impair perfusion. In either circumstance, the prognosis is poor. Ruptured membranes should be excluded, and targeted sonography is performed to assess for fetal and placental abnormalities.

When amnionic luid volume becomes abnormally decreased in the late second or in the third trimester, it is very often associated with fetal-growth restriction, with a placental abnormality, or with a maternal complication such as preeclampsia or vascular disease (Table 11-4). The underlying cause in such cases is frequently uteroplacental insuiciency, which can impair fetal growth and reduce fetal urine output. Exposure to selected medications has also been linked with oligohydramnios as discussed subsequently. Investigation of third-trimester oligohydramnios generally includes evaluation for ruptured membranes and sonography to assess fetal growth. Umbilical artery Doppler studies are recommended if growth restriction is identiied (Chap. 10, p. 213). Oligohydramnios is commonly encountered in lateterm and postterm pregnancies (Chap. 43, p. 837). Magann and coworkers (1997) found that amnionic luid volume decreased by approximately 8 percent per week beyond 40 weeks.

By approximately 18 weeks, the fetal kidneys are the main contributor to amnionic luid volume. Selected renal abnormalities that lead to absent fetal urine production include bilateral renal agenesis, bilateral multicystic dysplastic kidney, unilateral renal agenesis with contralateral multicystic dysplastic kidney, and the infantile form of autosomal recessive poycystic kidney dis ease. Urinary abnormalities may also result in oligohydramnios because of fetal bladder outlet obstruction. Examples of this are posterior urethral valves, urethral atresia or stenosis, or the megacystis microcolon intestinal hypoperistalsis syndrome. Complex fetal genitourinary abnormalities such as persistent cloaca and sirenomelia similarly may result in a lack of amnionic luid. Many of these renal and urinary abnormalities are discussed and depicted in Chapter 10 (p. 208). If no amnionic luid is visible beyond the mid-second trimester due to a genitourinary etiology, the prognosis is extremely poor unless fetal therapy is an option. Fetuses with bladder-outlet obstruction may be candidates for vesicoamnionic shunt placement (Chap. 16, p. 325).

Oligohydramnios has been associated with exposure to drugs that block the renin-angiotensin system. These include angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers, and nonsteroidal antiinlammatory drugs (NSAIDs). When taken in the second or third trimester, ACE inhibitors and angiotensin-receptor blockers may create fetal hypotension, renal hypoperfusion, and renal ischemia, with subsequent anuric renal failure (Bullo, 2012; Guron, 2000). Fetal skull bone hypoplasia and limb contractures have also been described (Schaefer, 2003). NSAIDs can be associated with fetal ductus arteriosus constriction and with lower fetal urine production. In neonates, their use may result in acute and chronic renal insuiciency (Fanos, 2011). These agents are discussed in Chapter 12 (p. 241).

Oligohydramnios is associated with adverse pregnancy outcomes. Casey and colleagues (2000) found that an AFI �5 em

TABLE 11-4. Pregnancy Outcomes in Women Diagnosed with Oligohydramnios between 24 and 34 Weeks' Gestation

AFI �5 em AFI 8 to 24 em Factor (n = 166) (n = 28,1s85) P Value

Major malformation 42 (25) 634 (2) <.00l1 1) <.001

Gestational age at deliverya 35.1 ± 3.3 39.2 ± 2.0 <.001 Preterm birth, spontaneousa 49 (42) 1698 (6) <.001

Preterm birth, indicateda 20) 405 (2) <.001

Cesarean delivery for nonreassuring 10l(9) 1083 (4) <.001

Birthweight < 10th percentilea 61 (53) 3388 (12) <.001 <3rd percentilea 43 (37) 1130 (4) <.001 1) <.OOllb

Data expressed as No. (%) and mean ± standard deviation. aAnomalous infants excluded.

bThis difference was no longer significant after adjustment for gestational age at delivery. Data from 2011.

complicated 2 percent of pregnancies undergoing sonography at Parkland Hospital ater 34 weeks' gestation. Fetal malformation rates were elevated in those with oligohydramnios. Even in their absence, rates of stillbirth, growth restriction, nonreassUfing heart rate pattern, and meconium aspiration syndrome were higher than in nonafected pregnancies. Petrozella and associates (2011) similarly reported that an AFI :;5 em identiied between 24 and 34 weeks was associated with increased risks for stillbirth, spontaneous or medically indicated preterm birth, heart rate pattern abnormalities, and growth restriction (see Table 11-4). In one metaanalysis comprising more than 10,000 pregnancies, women with oligohydramnios had a twofold greater risk for cesarean delivery for fetal distress and a ivefold higher risk for an Apgar score <7 at 5 minutes compared with pregnancies with a normal AFI (Chauhan, 1999).

As discussed, evidence suggests that if oligohydramnios is defined as an AFI :;5 em rather than a single deepest pocket :;2 em, more pregnancies will be classiied as such. One review of trials encompassing more than 3200 high-risk and low-risk pregnancies compared outcomes according to which deinition was used (Nabhan, 2008). Rates of cesarean delivery, neonatal intensive care unit admission, umbilical artery pH <7.1, or Apgar score <7 at 5 minutes did not difer between groups. Using AFI criteria, however, twice as many pregnancies were diagnosed with oligohydramnios. In this group, there was a doubling of the labor induction rate and a 50-percent increase in the cesarean delivery rate for fetal distress. Kehl and colleagues (2016) performed a prospective trial with more than 1000 term pregnancies in which women with oligohydramnios, deined either by an AFI < 5 em or a single deepest pocket <2 em, were randomized to labor induction or expectant care. Signiicantly more pregnancies were diagnosed with oligohydramnios using the AFI criterion-10 percent compared with just 2 percent-when single deepest pocket was used. This led to a higher rate of labor induction in the AFI group, but no diference in neonatal outcomes.

When diminished amnionic luid is first identiied before the mid-second trimester, particularly before 20 to 22 weeks, pulmonary hypoplasia is a signiicant concern. he underlying etiology is a major factor in the prognosis for such pregnancies. Severe oligohydramnios secondary to a renal abnormality generally has a lethal prognosis. If a placental hematoma or chronic abruption is severe enough to result in oligohydramnios-the chronic abruption-oligohydramnios sequence (CAOS)-it commonly also causes growth restriction (Chap. 41, p. 768). he prognosis for this constellation is similarly poor. Oligohydramnios that results from membrane rupture in the second trimester is reviewed in Chapter 42 (p. 821).

Initially, an evaluation for fetal anomalies and growth is essential. In a pregnancy complicated by oligohydramnios and fetal-growth restriction, close fetal surveillance is important because of associated morbidity and mortality (Chap. 44, p. 855). Oligohydramnios detected before 36 weeks' gestation in the presence of normal fetal anatomy and growth is generally managed expectantly in conjunction with enhanced fetal surveillance. However, evidence of fetal or maternal compromise will override potential complications from preterm delivery. Antepartum management of oligohydramnios may include maternal hydration. In a recent review of 16 trials of pregnancies with apparent isolated oligohydramnios, oral or intravenous hydration was associated with significant improvement in the AFI. However, it was not clear whether this translated into better pregnancy outcomes (Gizzo, 2015).

Amnioinfusion, discussed in Chapter 24 (p. 475), may be used intrapartum to help resolve variable fetal heart rate decelerations. It is not considered treatment for oligohydramnios per se, although the decelerations are presumed secondary to umbilical cord compression resulting from lack of amnionic luid. Amnioinfusion is not the standard of care for other etiologies of oligohydramnios and is not generally recommended.

he term borderline AFI or borderline oligohydramnios is somewhat controversial. It usually refers to an AFI between 5 and 8 em (Magann, 2011; Petrozella, 2011). Through the mid-third trimester, an AFI value of 8 em is below the 5th percentile on the Moore nomogram (see Fig. 11-1). Petrozella and colleagues (2011) found that pregnancies between 24 and 34 weeks with an AFI between 5 and 8 em were not more likely than those with an AFI above 8 em to be complicated by maternal hypertension, stillbirth, or neonatal death. That said, higher rates of preterm delivery, cesarean delivery for a nonreassuring fetal heart rate pattern, and fetal-growth restriction were found. Wood and colleagues (2014) similarly reported a higher rate of fetal-growth restriction in pregnancies with borderline AFI. Thus, results evaluating pregnancy outcomes with borderline AFI have been mixed. Magann and associates (2011) concluded that evidence is insuicient to support fetal testing or delivery in this setting.

Abele H, Starz S, Hoopmann M, et al: Idiopathic polyhydramnios and postnatal abnormalities. Fetal Diagn Ther 32(4) :251, 2012

American College of Obstetricians and Gynecologists: Ultrasound in pregnancy. Practice Bulletin No. 175, December 2016

Biggio JR Jr, Wenstrom D, Dubard MB, et al: Hydramnios prediction of adverse perinatal outcome. Obstet Gynecol 94:773, 1999

Brace A, Wolf EJ: Normal amniotic luid volume changes throughout pregnancy. Am J Obstet Gynecol 161 (2):382, 1989

Bulla M, Tschumi S, Bucher BS: Pregnancy outcome following exposure to angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists: a systematic review. Hypertension 60:444, 2012

Casey BM, Mcintire DO, Bloom SL, et al: Pregnancy outcomes after antepartum diagnosis of oligohydramnios at or beyond 34 weeks' gestation. Am J Obstet GynecoIo182:909, 2000

Chamberlain PF, Manning FA, Morrison I, et al: Ultrasound evaluation of amniotic fluid. he relationship of marginal and decreased amniotic fluid volumes to perinatal outcome. Am J Obstet GynecoIo150:245, 1984

Chauhan Sp, Sanderson M, Hendrix NW, et al: Perinatal outcome and amniotic fluid index in the antepartum and intrapartum periods: a meta-analysis. Am J Obstet Gynecol 181: 1473, 1999

Chon AH, Korst LM, Llanes A, et al: Midtrimester isolated polyhydramnios in monochorionic diamniotic multiple gestations. Am J Obstet Gynecol 211(3):303.e1,o2014

Dashe ]S, McIntire DO, Ramus M, et al: Hydramnios: anomaly prevalence and sonographic detection. Obstet Gynecolo100(l):134, 2002

Dashe ]S, Nathan L, McIntire DO, et al: Correlation between amniotic fluid glucose concentration and amniotic fluid volume in pregnancy complicated by diabetes. Amo] Obstet Gynecol 182(4):901,o2000

Dickinson ]E, Tjioe ¥, Jude E, et al: Amnioreduction in the management of polyhydramnios complicating singleton pregnancies. Amo] Obstet Gynecol 211:434.e.1,o2014

Dorleijn OM, Cohen-Overbeek TE, Groenendaal F, et al: Idiopathic polyhydramnios and postnatal indings.] Matern Fetal Neonatal Med 22(4):315, 2009

Erez 0, Shoham-Vardi I, Sheiner E, et al: Hydramnios and small for gestational age are independent risk factors for neonatal mortality and maternal morbidity. Arch Gynecol Obstet 271 (4):296,o2005

Fanos V, Marcialis MA, Bassareo PP, et al: Renal safety of Non Steroidal Anti Inflammatory Drugs (NSAIDs) in the pharmacologic treatment of patent ductus arteriosus.] Matern Fetal Neonatal Med 24(S1):50, 201o1

Frank Wolf M, Peleg 0, Stahl-Rosenzweig T, et al: Isolated polyhydramnios in the third trimester: is a gestational diabetes evaluation of value? Gynecol EndocrinoIo33(1l):849,o2017

Gizzo S, Noventa M, Vitagliano A, et al: An update on maternal hydration strategies for amniotic luid improvement in isolated oligohydramnios and normohydramnios: evidence from a systematic review of literature and meta-analysis. PLoS One 10(12):e0144334, 2015

Golan A, Wolman I, Saller Y, et al: Hydramnios in singleton pregnancy: sonographic prevalence and etiology. Gynecol Obstet Invest 35:91, 1993 Guron G, Friberg P: An intact renin-angiotensin system is a prerequisite for normal renal development.] Hypertens 18(2):123,o2000

Hernandez ]S, Twickler OM, McIntire OM, et al: Hydramnios in twin gestations. Obstet GynecoIo120(4):759, 2012

Hill LM, Sohaey R, Nyberg DA: Abnormalities of amniotic fluid. In Nyberg DA, McGahan ]P, Pretorius DH, et al (eds): Diagnostic Imaging of Fetal Anomalies. Philadelphia, Lippincott Williams & Wilkins, 2003

Hinh NO, Ladinsky ]L: Amniotic fluid index measurements in normal pregnancy after 28 gestational weeks. Int] Gynaecol Obstet 91:132, 2005

Kehl S, Schelkle A, Thomas A, et al: Single deepest vertical pocket or amniotic luid index as evaluation test for predicting adverse pregnancy outcome (SAFE trial): a multicenter open-label, randomized controlled trial. Ultrasound Obstet Gynecol 47:674,o2016

Khan S, Donnellyo]: Outcome of pregnancy in women diagnosed with idiopathic polyhydramnios. Aust N Z] Obstet Gynaecol 57(1):57,o2017

Lazebnik N, Many A: The severity of polyhydramnios, estimated fetal weight and preterm delivery are independent risk factors for the presence of congenital anomalies. Gynecol Obstet Invest 48:28, 1999

Luo QQ, Zou L, Gao H, et al: Idiopathic polyhydramnios at term and pregnancy outcomes: a multicenter observational study.o] Matern Fetal Neonatal Med 30(14):1755, 2017

Machado MR, Cecatti ]G, Krupa F, et al: Curve of amniotic fluid index measurements in low risk pregnancy. Acta Obstet Gynecol Scand 86:37, 2007 Magann EF, Bass ]0, Chauhan SP, et al: Amniotic luid volume in normal singleton pregnancies. Obstet Gynecol 90(4):524, 1997

Magann EF, Chauhan CP, Hitt WC, et al: Borderline or marginal amniotic fluid index and peripartum outcomes: a review of the literature. ] Ultrasound Med 30(4):523, 2011

Magann EF, Doherty 0, LutegendorfMA, et al: Peripartum outcomes of highrisk pregnancies complicated by oligo-and polyhydramnios: a prospective longitudinal study. ] Obstet Gynaecol Res 36(2):268, 2010

Mann SE, Nijland M], Ross MG: Mathematic modeling of human amniotic fluid dynamics. Amo] Obstet Gynecol 175(4):937, 1996

Many A, Hill LM, Lazebnik N, et al: he association between polyhydramnios and preterm delivery. Obstet Gynecol 86(3):389, 1995

Martinez-Frias ML, Bermejo E, Rodriguez-Pinilla E, et al: Maternal and fetal factors related to abnormal amniotic luid. ] Perinatol 19:514, 1999 Modena AB, Fieni S: Amniotic luid dynamics. Acta Bio Medica Ateneo Parmanese 75(Suppl 1):11,o2004 Moore TR: Amniotic fluid dynamics relect fetal and maternal health and disease. Obstet Gynecol 116(3):759,o2010

Moore TR, Cayle ]E: The amniotic luid index in normal human pregnancy.

Amo] Obstet GynecoIo162(5):1168, 1990

Nabhan AF, Abdelmoula YA: Amniotic luid index versus single deepest vertical pocket as a screening test for preventing adverse pregnancy outcome. Cochrane Database Syst Rev 3:CD006953, 2008

Odibo IN, Newville TM, Ounpraseuth ST, et al: Idiopathic polyhydramnios: persistence across gestation and impact on pregnancy outcomes. Euro] Obstet Gynecol Reprod Bioi 199: 175, 2016

Panting-Kemp A, Nguyen T, Chang E, et al: Idiopathic polyhydramnios and perinatal outcome. Am ] Obstet Gynecol 181 (5): 1 079, 1999

Petrozella LN, DasheJS, McIntire DO, et al: Clinical signiicance of borderline amniotic luid index and oligohydramnios in preterm pregnancy. Obstet Gynecol 117(2 pt 1):338, 2011

Phelan ]P, Smith CV, Broussard P, et al: Amniotic luid volume assessment with the four-quadrant technique at 36-42 weeks' gestation. ] Reprod Med 32:540, 1987

Pilliod A, Page ]M, Butwick RM, et al: he risk of fetal death in nonanomalous pregnancies afected by polyhydramnios. Am ] Obstet Gynecol 213:410.e.1,o2015

Pri-Paz S, Khalek N, Fuchs vf, et al: Maximal amniotic luid index as a prognostic factor in pregnancies complicated by polyhydramnios. Ultrasound Obstet Gynecol 39(6):648, 2012

Reddy UM, Abuhamad AZ, Levin 0, et al: Fetal imaging: executive summary of a joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Institute of Ultrasound in Medicine, ArIerican College of Obstetricians and Gynecologists, American College of Radiology, Society for Pediatric Radiology, and Society of Radiologists in Ultrasound Fetal Imaging Workshop. Obstet GynecoIo123(5):1070, 2014

Rutherford SE, Smith CV, Phelan ]P, et al: Four-quadrant assessment of amniotic fluid volume. Interobserver and intraobserver variation. ] Reprod Med 32(8):587, 1987

Schaefer C: Angiotensin II-receptor-antagonists: further evidence of fetotoxicity but not teratogenicity. Birth Defects Res A Clin Mol Teratol 67(8):591, 2003

Society for Maternal-Fetal Medicine, Simpson LL: Twin-twin transfusion syndrome. Amo] Obstet GynecoIo208(1):3, 2013

Spellacy N, Buhi WC, Bradley B, et al: Maternal, fetal, amniotic fluid levels of glucose, insulin, and growth hormone. Obstet GynecoIo41:323, 1973 Weiss PA, Hofmann H, Winter R, et al: Amniotic luid glucose values in nor mal and abnormal pregnancies. Obstet Gynecol 65:333, 1985

Wiegand SL, Beamon q, Chescheir NC, et al: Idiopathic polyhydramnios: severity and perinatal morbidity. Amo] Perinatol 33(7):658, 2016

Wood SL, Newton ]M, Wang L, et al: Borderline amniotic luid index and its relation to fetal intolerance of labor: a 2-center retrospective cohort study. ] Ultrasound Med 33(4):705, 2014

CHAPTER 12 Teratology, Teratogens, and Fetotoxic Agents

TERATOLOGY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235

CRITERIA FOR DETERMINING TERATOGENICITY .e... 235

COUNSELING FOR MEDICATION EXPOSURE . ..e...e. 238

KNOWN AND SUSPECTED TERATOGENS .e.. .e. 239

Al inectious diseases have a tendency to bring about death of the chid and its subsequent expulsion from the uterus. The atal result is usualy due to the transmission of toxins, and occasionaly the speciic micro-organisms from the mother to the chil. Poisoning with phosphorus, lead, iluminating gas, and other substances may lead to similar results.

-J. Whitridge Williams (1903)

Other than referring to fetal deformities that might impede vaginal delivery, little is written in the first edition of this book regarding teratogens and fetal malformations. his is despite the fact that birth defects are common, and 2 to 3 percent of all newborns have a major congenital abnormality detectable at birth (Cragan, 2009; Dolk, 2010). There are undoubtedly medications that pose significant risk to the developing embryo or fetus (Table 12-1). However, 80 percent of birth defects do not have an obvious etiology, and of those with an identified cause, nearly 95 percent' of cases have chromosomal or genetic origins (Feldkamp, 2017). The Food and Drug Administration (FDA) (2005) estimates that less than 1 percent of all birth defects are caused by medications. Their remarkably small contribution to congenital abnormalities is shown in Figure

That said, signiicant concern surrounds medication use in pregnancy. This is because so many pregnant women are prescribed medications and because safety data are often lacking. Investigators from the National Birth Defects Prevention Study found that women take an average of two to three medications per pregnancy and that 70 percent use medication in the first trimester (Mitchell, 2011). And, in one review of medications approved by the FDA between 2000 and 2010, the Teratogen Information System (TERIS) advisory board deemed the

TABLE 12-1. Selected Teratogens and Fetotoxic Agents

Teratology, Teratogens, and Fetotoxic Agents 235 teratogen may be deined as any agent that acts during embryonic or fetal development to produce a permanent alteration of form or function. Thus, a teratogen may be a medication or other chemical substance, a physical or environmental factor such as heat or radiation, a maternal metabolite as in diabetes or phenylketonuria, or an infection such as cytomegalovirus. Even obesity is considered a teratogen (Stothard, 2009; Waller, 2007).

Strictly defined, a teratogen causes only structural abnormalities. A hadegen-after the god Hades-is an agent that interferes with organ maturation and function, and from a population-based review of 270,878 births.

pregnancy risk "undetermined" for more than 95 percent of these agents (Adam, 2011).

he study of birth defects and their etiology is termed teratology, derived from the Greek teratos, meaning monster. A

TABLE 12-2. Criteria for Determining Teratogenicity

Essential Criteria: 1.

Careful delineation of clinical cases, particularly if there is a speciic defect or syndrome 2.

Proof that exposure occurred at critical time during development (see Fig. 12-2) 3.

Consistent indings by at least two epidemiological studies with: a.

exclusion of bias, b.

adjustment for confounding variables, c.

adequate sample size (power), d.

prospective ascertainment if possible, and e.

relative risk (RR) of 3.0 or greater, some recommend RR of 6.0 or greater

For a rare environmental exposure associated with a rare defect, at least three reported cases. This is easiest if defect is severe

Ancillary Criteria: 4.

The association is biologically plausible 5.

Teratogenicity in experimental animals is important but not essential 6.

The agent acts in an unaltered form in an experimental model

Data from from Shepard 1994, 2002a.

term teratogen is used to refer to all three types of agents.

The guidelines shown in Table 12-2 were proposed by Shepard (1994) as a framework for discussion and have proven useful for more than 25 years. Although each individual criterion is not required to establish teratogenicity, the following tenets must be considered (Shepard, 2002a): • The defect has been completely characterized. This is preferably done by a geneticist or dysmorphologist because various genetic and environmental factors may produce similar anomalies. It is easiest to prove causation when a rare exposure produces a rare defect, when at least three cases with the same exposure have been identified, and when the defect is severe.

• he agent must cross the placenta. Although almost all drugs cross the placenta, transport must be of suicient quantity to directly inluence embryonic or fetal development or to alter maternal or placental metabolism to exert an indirect efect. Placental transfer depends on maternal metabolism; on speciic characteristics of the drug, such as protein binding and storage, molecular size, electrical charge, and lipid solubility; and on placental metabolism, such as by the cytochrome P 450 enzyme system. In early pregnancy, the placenta also has a relatively thick membrane that slows difusion.

• Exposure must occur during a critical developmental period.

o Thepreimplantation period is the 2 weeks between fertilization and implantation and is known as the "all or none" period. As the zygote undergoes cleavage, an insult damaging a large number of cells typically causes embryonic death. However, if only a few cells are injured, compensation may be possible and allow normal development (Clayton-Smith, 1996). From animal data, insults that appreciably diminish the cell number in the inner cell mass may produce a dose-dependent diminution in body length or size (Iahnaccone, 1987).

Fertilization to bilaminar disc formation

FIGURE 12-2 Timing of organogenesis during the embryonic period. (Reproduced with permission from Salder W: Langman's Medical

Embryology, 6th ed. Baltimore, Williams & Wilkins; 1990.)

The embyonic period extends from the second through the eighth week postconception. It encompasses organogenesis and is thus the most crucial period with regard to structural malformations. Critical developmental periods for each organ system are illustrated in Figure 12-2.

heetal period, which is beyond 8 weeks postconception, is characterized by continued maturation and unctional development. During this time, certain organs remain vulnerable.

• A biologically plausible association is supportive. Because birth defects and medication exposures are both common, they may be temporally but not causally related.

• Epidemiological indings must be consistent. Because initial evaluation of teratogen exposure is often retrospective, it may be hampered by recall bias, inadequate reporting, and incomplete assessment of the exposed population. Potential confounding factors include varying dosages, concomitant drug therapy, and comorbid maternal disease(s). Familial and environmental variables can also inluence development of birth defects. hus, an important criterion for teratogenicity is that two or more high-quality epidemiological studies report similar findings. Finally, a relative risk of 3.0 or reater is generally considered necessary to support the hypothesis, whereas a lesser risk is interpreted with caution (Khoury, 1992).

• he suspected teratogen causes a defect in animal studies. his criterion is not obligatory. In fact, the Teratology Society (2005) states that establishment of causation in teratology-related litigation requires human data.

Failure to employ these tenets and criteria has contributed to erroneous conclusions regarding the safety of some widely used drugs. he poster child for this is the medicolegal iasco surrounding Bendectin. This antiemetic was a combination of doxylamine and pyridoxine, with or without dicyclomine, and was safe and efective for nausea and vomiting in early pregnancy. More than 30 million women used this drug worldwide, and the 3-percent congenital anomaly rate among exposed fetuses was not diferent from the background rate (McKeigue, 1994). Despite considerable evidence that this combination of an antihistamine and a B-vitamin is not teratogenic, Bendectin was the target of numerous lawsuits, and the inancial burden of defending these forced its withdrawal from the marketplace. As a consequence, hospitalizations for hyperemesis doubled (Koren, 1998). Ironically, the combination of doxylamine and pyridoxine was subsequently remarketed under the brand name Diclegis and was approved by the FDA in 2013.

he study of medication safetyor teratogenicity-in pregnant women is fraught with complications. First, animal studies are considered necessary but insuicient. For example, thalidomide is harmless in sveral animal species but resulted in phocomelia in thousands of children born across Europe in the late 1950s and early 1960s. Second, medications are rarely approved by the FDA for a pregnancy-related indication. Instead, pregnant women are considered a special population and summarily excluded from medication trials. Last, drug concentration and thus embyo-fetl exposure are afected by pregnancy physiology. hese include changes in volume of distribution, cardiac output, gastrointestinal absorption, hepatic metabolism, and renal clearance. In the absence of research trials, counseling is based on case reports or series, casecontrol studies, cohort studies, and pregnancy registry data.

Many, if not most, major teratogens were irst described by clinicians who observed a rare defect occurring after a rare exposure. his has been termed the "astute clinician model" (Carey, 2009). Congenital rubella syndrome was identiied in this way by Gregg (1941), an Australian ophthalmologist whose observations challenged the view that the uterine environment was impervious to noxious agents. Other teratogens identiied through case series include thalidomide and alcohol a ones, 1973; Lenz, 1962). Shepard (2002a) recommended that establishment of teratogenicity in this way requires proven exposure at a critical time in development and probably at least three such cases, each carefully delineated. Unfortunately, teratogens are less likely to be identiied if the exposure is uncommon, if the defects are relatively nonspeciic, or if abnormalities develop in only a small proportion of exposed fetuses. A major limitation of case series is their lack of a control group.

hese studies begin with groups of afected infants (cases) and unafected controls and are structured to allow retrospective assessment of prenatal exposure to particular substances. Casecontrol studies are an eicient way to study rare outcomes (Alwan, 2015). These permit investigators to evaluate associations and generate useful hypotheses. However, case-control studies have inherent potential for recal bias. Namely, parents of an afected infant are often more likely to recall exposure than those whose child is not ill. Confounding by indication is another concern, that is, the indication for the medication may be the cause of the birth defect. And importantly, birth defect registries have statistical power to detect small diferences that may not be clinically meaningful. Grimes and Schulz (2012) have cautioned that unless odds ratios in case-control studies are above three-to fourfold, the observed associations may not be correct.

The National Birth Defects Prevention Study n excellent example of a population-based case-control study is the National Birth Defects Prevention Study (NBDPS). Funded by Congress and coordinated by the National Center on Birth Defects and Developmental Disabilities, the NBDPS . took place between 1997 and 2013 across ten states with active birth defects surveillance programs. Clinical geneticists reviewed each potential case, and standardized telephone interviews were conducted with mothers whose pregnancies were afected or unafected to obtain information regarding medication exposure and risk factors (Mitchell, 2011i; Reehuis, 2015). Live births, stillbirths, and terminated pregnancies were included and totaled approximately 32,000 cases and nearly 12,000 controls.

he NBDPS has yielded more than 200 scientiic manuscripts. It identified novel-although often small-associations between individual birth defects and the following classes of medications: antibiotics, antidepressants, antiemetics, antihypertensives, asthma medications, nonsteroidal antiinlammatory drugs (NSAIDs), and opioids (Ailes, 2016; Broussard, 2011; Fisher, 2017; Hernandez, 2012; Lin,

Teratology, Teratogens, and Fetotoxic Agents 237 2012; Munsie, 201i1). he NBDPS also found associations between birth defects and exposures such as secondhand smoke, pesticides, and nitrogen oxide, which is a marker of traic-related air pollution (Hoyt, 2016; Rocheleau, 2015;

Stingone,i2017).

The NBDPS did have limitations related to study design.

First, interviews were conducted 6 weeks to 2 years following delivery, which raised the likelihood of recall bias. For example, 25 percent of women could not remember which antibiotic they had taken (Ailes, 2016). Another weakness was that only two thirds of women agreed to participate, and there were diferences in ethnicity and socioeconomic status between cases and controls. These factors potentially led to selection bias (Reefhuis, 2015). In addition, medical records were not reviewed to veriy dosage, and this precluded assessment of dose-response relationships. And a major limitation was that because the NBDPS included only a small number of cases of each birth defect and analyzed them for multiple maternal exposures, it was not possible to adjust for multiple comparisons. As a result, some of the associations observed were likely due to chance (Alwan, 2015). For example, the study of antibiotics and birth defects included 43 comparisons and identiied four signiicant associations, but chance alone predicted that two associations would be identiied (Ailes, 2016). Last, the low absolute risk of an abnormality complicates counseling and prenatal management. In many instances, the risk identiied by the NBDPS was as low as 1 case per 1000 exposed pregnancies.

These studies begin with cohorts of pregnant women who are exposed or unexposed to a particular medication. The percentage of infants or children afected with birth defects is examined in each cohort. Because individual birth defects are rare, cohort studies require a vey large sample size. Medicaid datasets and private insurance claims databases are commonly used for cohort studies of teratogenicity in the United States (Ehrenstein, 2010). Inability to adjust for confounding variables-such as the indication for which the medication was needed-may be an important limitation of this study design.

Potentially harmful agents may be monitored by clinicians who prospectively enroll exposed pregnancies in a registry. he FDA (20 17b) maintains an active list on their webpage titled Pregnancy Registries. As of 2017, this included registries for 100 individual medications and for medication groups used to treat asthma, autoimmune disease, cancer, epilepsy, human immunodeiciency virus (HIV) infection, and transplant rejection. Similar to case series, exposure registries are hampered by lack of a control group. The prevalence of an abnormality identiied through a registry requires knowledge of the baseline prevalence of that anomaly in the population. Investigators typically use a birth defect registry to assess population prevalence. One example is the Metropolitan Atlanta Congenital Defects Program, which is an active surveillance program established in 1967 for fetuses and infants with birth defects.

medications in pregnancy. Five categories-A, B, C, D, and

X-were intended to summarize available evidence from

Questions regarding medication and illicit drug use should human or animal studies of embryonic-fetal risk. These letbe part of routine preconceptional and prenatal care. Misinters also conveyed beneits of the given medication balanced formation is common. Individuals tend to underestimate the against its potential risks. The system, shown in Table 12-3, background risk for birth defects in the general population and was intended to simpliY risk-beneit data. exaggerate potential risks associated with medication exposure. Unfortunately, information regarding medication risk was In a recent population-based study of more than 270,000 births very oten incomplete and led to an overreliance on the deinifrom Utah that included 5500 fetuses and infants with major tion of the letter category alone. However, a higher letter grade birth defects, only 4 cases were attributed to medication expodid not necessarily mean greater risk, and drugs in the same catesure (see Fig. 12-1) (Feldkamp, 2017). And yet, Koren and gory oten had very diferent risks. Very few medications-fewer colleagues (1989) reported that a fourth of women exposed to than 1 percent-had demonstrated safety in human pregnancy nonteratogenic drugs thought they had a 25-percent risk for (category A), and most had no safety data in human or animal fetal anomalies. Misinformation may be amplified by inaccurate studies (category C). Another diiculty was that the classiication reports in the lay press. Knowledgeable counseling may allay system did not address inadvertent exposure, a common reason anxiety considerably and may even avert pregnancy termination. for counseling. Ultimately, it is the responsibility of the clinician

Several sources are available to assist providers with accurate to interpret letter category information in the context of mediand updated risk information. PubMed is a free tool from the cation dosage and route, timing of exposure during pregnancy, National Center for Biomedical Information that aids rapid other medications used, and underlying medical condition(s). search of published research. Online databases, such as Reprotox, To address these deiciencies, new labeling requirements were TERIS, and Shepard's Online Catalog of Teratogenic Agents, created and went into efect in 2015. Updates to older mediofer reviews of medication risks. hey summarize human and cations will be phased in over time (Food and Drug Adminanimal studies of teratogenicity and fetotoxicity, address the istration, 2014). With the new requirements, the FDA letter quality of the available evidence, and provide magnitude of risk. categories have been (or will be) removed from all prescription Lactmed, a database from the National Library of Medicine, drug and biological product labeling. he format for providing speciically deals with medication use by breastfeeding women. information includes a summary of risks, clinical considerations, Its entries on speciic medications describe levels in breast milk and available data. The pregnancy subsection has registry inforand potential efects on the infant. Finally, with recent changes mation, if available, as well as labor and delivery information. to the FDA labeling requirements, discussed next, the manufacFor each medication, a lactation subsection-formerly called turer's prescribing information has become increasingly helpful. "nursing mothers"-is included. There is also a section to address potential risks in females and males with reproductive potential .

• The Food and Drug Administration:

In 1979, the FDA developed a letter classiication system In addition to potential embryonic and fetal risks from drug in an efort to provide therapeutic guidance for prescribing exposure, counseling should discuss the risks and/or genetic

TABLE 12-3. Food and Drug Administration Letter Categories for Drugs and Medications (1•979-2015)a

Category A: Studies in pregnant women have not shown an increased risk for fetal abnormalities if administered during the first (second, third, or all) trimester(s) of pregnancy, and the possibility of fetal harm appears remote.

Category B: Animal reproduction studies have been performed and have revealed no evidence of impaired fertility or harm to the fetus.

Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus during the first trimester of pregnancy, and there is no evidence of a risk in later trimesters.

Category C: Animal reproduction studies have shown that this medication is teratogenic (or embryocidal or has other adverse effect), and there are no adequate and well-controlled studies in pregnant women.

There are no animal reproduction studies and no adequate and well-contolled studies in humans.

Category 0: This medication can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy or if a woman becomes pregnant while taking this medication, she should be apprised of the potential hazard to the fetus.

Category X: This medication is contraindicated in women who are or may become pregnant. It may cause fetal harm.

aMedications approved after June 2015 are not assigned a letter category, whereas older medications will have letter categories phased out after this date.

implications of the underlying condition for which the drug is given. Risks associated with not treating the condition are also described. Even the manner in which information is presented afects perception. For example, women given negative information-such as a 2-percent chance of a malformed newborn-are more likely to perceive an exaggerated risk than women given positive information-such as a 98-percent chance of an unafected infant Gasper, 2001). Instead of citing a higher odds ratio, it may be helpful to provide the absolute risk for a particular defect or the attributable risk, which is the diference between prevalence in exposed and unexposed individuals (Conover, 2011). The association between oral corticosteroid medications and cleft lip sounds far more concerning when presented as a tripling or 200-percent increase in risk than when described as an increase from 1 per 1000 to 3 per 1000 or as a 99.7 -percent likelihood of no cleft development following exposure.

With a few notable exceptions, most commonly prescribed drugs and medications can be used with relative safety during pregnancy. Many drugs discussed in this chapter are lowrisk teratogens, which are medications that produce defects in fewer than 10 per 1000 maternal exposures (Shepard, 2002a). Because risks conferred by low-risk teratogens are so close to the population background rate of fetal anomalies, they may not be a major factor in deciding whether to discontinue treatment for an important condition (Shepard, 2002b). Remember that al women have an approximate 3-percent chance of having a newborn with a birth dect. Although exposure to a confirmed teratogen may elevate this risk, the magnitude of the increase is usually only 1 or 2 percent or at most, doubled or tripled. The concept of risk versus benefit is often central to counseling. Some untreated diseases pose a more serious threat to both mother and fetus than medication exposure risks.

Considering the thousands of compounds available, relatively few medications and other substances are considered to be major human teratogens. The most common examples are listed in Table 12-1. With few exceptions, in every clinical situation potentially requiring therapy with a known teratogen, alternative drugs can be given with relative safety. Realizing limitations in available evidence, pregnant women should be advised to take any medication only when it is clearly needed. In general, targeted sonography is indicated if there has been exposure to any major teratogen during the embryonic period.

Ethanol is a potent and prevalent teratogen. It is considered the leading cause of preventable developmental disabilities worldwide (Hoyme, 2016). In the United States, 8 percent of pregnant women report drinking alcohol and between 1 and 2 percent admit to binge drinking (Centers for Disease Control and Prevention, 2012).

The fetal efects of alcohol abuse have been recognized since the 1800s. Lemoine (1968) and Jones (1973) and their coworkers are credited with describing the spectrum of alcohol-related

Teratology, Teratogens, and Fetotoxic Agents 239 fetal defects known asetal acohol syndrome (Table 12-4). For every child with the syndrome, many more are born with neurobehavioral deicits from alcohol exposure (American College of Obstetricians and Gynecologists, 2013). Fetal acohol spectrum disorder is an umbrella term that includes ive conditions attributed to prenatal alcohol damage: (1) fetal alcohol syndrome, partial fetal alcohol syndrome, (3) alcohol-related birth defects, (4) alcohol-related neurodevelopmental disorder, and neurobehavioral disorder associated with prenatal alcohol exposure (Williams, 2015). The birth prevalence of fetal alcohol syndrome is estimated to be as high as 1 percent in the United States (Centers for Disease Control, 2012; Guerri, 2009).

TABLE 12-4. Criteria for Prenatal Alcohol Exposure, Fetal Alcohol Syndrome, and Alcohol-Related Birth Defects 1.

::6 drinks per week for ::2 weeks 2.

::3 drinks per occasion for ::2 occasions 3.

Risk identiied with a validated screening questionnaire 4.

5.

Documentation of an alcohol-related legal or social 1. Dysmorphic facial features (::2 required) a.

b.

Thin vermilion border of the upper lip c.

2.

Prenatal and/or postnatal growth impairment, � 10th percentile 3.

Abnormal brain growth, morphogenesis, or physiology (::1 required) a.

b.

c.

4. Neurobehavioral impairment (deined as > 1.5 SO below mean) a.

Child <3 years: developmental delay b.

Child ::3 years: global cognitive impairment, r cognitive deicit in at least 1 neurobehavioral domain, or behavioral deicit in at least 1 domain

Cardiac: atrial or ventricular septal defect, aberrant great vessels, conotruncal heart defects

Skeletal: radioulnar synostosis, vertebral segmentation defects, joint contractures, scoliosis

Renal: aplastic or hypoplastic kidneys, dysplastic kidneys, horseshoe kidney, ureteral duplication

Eyes: strabismus, ptosis, retinal vascular abnormalities, optic nerve hypoplasia

Ears: conductive or neurosensory hearing loss

Data from Hoyme, 2016.

FIGURE 12-3 Fetal alcohol syndrome. A.At 2Y2 years. B. At 12 years. Note persistence of short palpebral fissures, epicanthal folds, flat midface, hypoplastic philtrum, and thin upper vermilion border. (Reproduced with permission from Streissguth AP, Clarren,

SK, Jones KL. Natural history of fetal alcohol syndrome: a la-year follow-up of eleven patients, Lancet. 1985 Jul 13;2(8446):85-91.)

But, studies of school children have identiied fetal alcohol spectrum disorder in 2 to 5 percent (May, 2009, 2014).

Fetal alcohol syndrome has speciic criteria (see Table 12-4). hese include central nervous system (CNS) abnormalities, preor postnatal growth impairment, and a characteristic pattern of minor facial abnormalities (Fig. 12-3). Similar criteria have been established for the other conditions that make up fetal alcohol spectrum disorder (Hoyme, 2016). Prenatal alcohol exposure criteria are also available to assist with assessment.

Alcohol-related birth defects include cardiac and renal anomalies, orthopedic problems, and abnormalities of the eyes and ears (see Table 12-4). An association has further been reported between periconceptional alcohol use and omphalocele and gastroschisis (Richardson, 2011). here are no established sonographic criteria for prenatal diagnosis of fetal alcohol syndrome. hat said, in some cases, major abnormalities or growth restriction may be suggestive (Paintner, 2012).

Fetal vulnerability to alcohol is modiied by genetic components, nutritional status, environmental factors, coexisting maternal disease, and maternal age (Abel, 1995). The Centers for Disease Control and Prevention (CDC) and the American Academy of Pediatrics have stressed that no amount of alcohol can be considered safe in pregnancy (Williams, 2015). Binge drinking, however, is believed to pose particularly high risk for alcohol-related birth defects and has also been linked to a higher risk for stillbirth (Centers for Disease Control, 2012; Maier, 2001; Strandberg-Larsen, 2008).

Traditionally, women with epilepsy requiring treatment with medication were informed that their risk for fetal malformations was increased. More recent data suggest that the risk may not be as great as once thought, particularly for newer agents. The most frequently reported anomalies are orofacial clets, cardiac malformations, and neural-tube defects.

Of agents in current use, valproic acid confers the greatest risk (Vajda, 2014). he North American Antiepileptic Drug (NAAED) Pregnancy Registry reported that major malformations developed in 9 percent of fetuses with irst-trimester valproate exposure. his included a 4-percent risk for neural-tube defects (Hernandez-Diaz, 2012). School-aged children with in utero exposure to valproic acid have poorer cognitive development-including signiicantly lower intelligence quotient (I) scores-than children exposed to other antiepileptic drugs (Bromley, 2014; Meador, 2009).

Regarding other speciic anticonvulsants, one recent metaanalysis identiied higher malformation rates among exposed children compared with rates among children born to women with untreated epilepsy. Rates were twofold higher among children exposed to carbamazepine or phenytoin, threefold higher among those exposed to phenobarbital, and fourfold higher among those exposed to topiramate as mono therapy (Weston, 2016). The risk for fetal malformations is approximately doubled if multiple agents are required (Vajda, 2016). Several older anticonvulsants also produce a constellation of malformations similar to the fetal hydantoin syndrome, which is described in

Figure 1i2-4.

FIGURE 12-4 Fetal hydantoin syndrome. A. Facial features including upturned nose, mild midfacial hypoplasia, and long upper lip with thin vermilion border. B. Distal digital hypoplasia. (Reproduced with permission from Buehler BA 1, Delimont D, van Waes M, et al: Prenatal prediction of risk of the fetal hydantoin syndrome, N Engl J Med. 1990 May 31;322(22):1567-1572.)

These risks do not appear to hold for the newer agents leve tiracetam and lamotrigine, although the number of reported pregnancies to date is smaller (M0Igaard-Nielsen, 2011;

Weston, 2016). The Motherisk Program reviewed eight stud ies of levetiracetam and concluded that mono therapy was associated with a 2-percent major malformation rate, which is no diferent from that for the general population (Chaudhry, 2014).

Providers are encouraged to enroll pregnant women treated with antiepileptic medication in the NAAED Pregnancy Reg istry. Management of epilepsy in pregnancy is discussed in

Chapter 60 (p. 1159).

These medications may result in ACE-inhibitor etopathy. Normal renal development depends on the fetal renin-angiotensin system. ACE-inhibitor medication may cause fetal hypotension and renal hypoperfusion, with subsequent ischemia and anuria (Guron, 2000; Pryde, 1993). Reduced perfusion can result in fetal-growth restriction and calvarium maldevelopment, and oligohydramnios may lead to pulmonary hypoplasia and limb contractures (Barr, 1991). Because angiotensin-receptor blockers have a similar mechanism of action, concerns regarding fetotoxicity have been generalized to include this entire medication class.

Concerns were also raised about ACE-inhibitor embryotoxiciy, although these have largely been disproven. In 2006, a review of 29,000 infants from the Tennessee Medicaid database identified a two-to threefold greater risk for neonatal cardiac and CNS abnormalities among the 209 that had prenatal ACE-inhibitor exposure (Cooper, 2006). Subsequent larger studies have not corroborated these observations. First, in a retrospective cohort study of more than 460,000 pregnancies, risks for birth defects were not greater with ACE inhibitors than with other antihypertensive medications (Li, 201i1). Similarly, Bateman and coworkers (2017) reviewed 1.3 million pregnancies from the Medicaid Analytic eXtract and found no higher risk for any malformation with ACE-inhibitor exposure after adjusting for confounding factors such as diabetes. hus, women with inadvertent irst-trimester exposure to these medications can be reassured. However, given the many therapeutic options for treating hypertension during pregnancy, discussed in Chapter 50 (p. 980), it is recommended that ACE inhibitors and angiotensin receptor-blocking drugs be avoided in pregnancy.

From this class of drugs, fluconazole has been associated with a pattern of congenital malformations resembling the autosomal recessiveAntly-Bixler syndrome. Abnormalities include oral clets, abnormal facies, and cardiac, skull, long-bone, and joint abnormalities. Such indings have been reported only with chronic, irsttrimester, high-dose treatment at doses of 400 to 800 mg daily.

Regarding low-dose treatment of vulvovaginal candidiasis, the Motherisk Program recently conducted a systematic review of pregnancies with first-trimester fluconazole exposure of 150

Teratology, Teratogens, and Fetotoxic Agents 241 or 300 mg in total (Alsaad, 2015). The overall risk for birth defects was not greater, although a small increase in rates of cardiac malformations could not be excluded. A populationbased cohort study from Denmark identified a threefold greater risk for tetralogy of FaIlor following exposure to low-dose fluconazole (M0Igaard-Nielsen, 2013). The birth prevalence of tetralogy of Fallot rose from 3 to 10 cases per 10,000. This is a risk so low that we would not endorse specialized sonography for this indication. Notably, investigators did not identiy increased risks for 14 other birth defects previously associated with exposure to high-dose azole antifungal agents (M0IgaardNielsen,i20l3).

such as ibuprofen and indomethacin. They exert their efects by inhibiting prostaglandin synthesis. In a report from the

NBDPS, at least 20 percent of pregnant women recall first trimester NSAID use, particularly ibuprofen and aspirin, and such exposure is not a major risk factor for birth defects (Her nandez, 2012).

However, when taken in late pregnancy, indomethacin may cause constriction of the fetal ductus arteriosus and subsequent pulmonary hypertension. Fetal ductal constriction is more likely when the drug is taken in the third trimester for longer than 72 hours. he risk is IS-fold higher among indomethacin-exposed pregnancies (Koren, 2006). he drug also may decrease fetal urine production and amnionic luid volume (Rasanen, 1995; van der Heijden, 1994; Walker, 1994). In one systematic review, indomethacin tocolysis was associated with neonatal morbidity (Hammers, 2015a,b). Specifically, the risk for bronchopulmonary dysplasia, severe intraventricular hemorrhage, and necrotizing enterocolitis was increased approximately 50 percent (odds ratio 1.5).

With aspirin, a low dosage of 100 mg daily or less does not confer a greater risk for constriction of the ductus arteriosus or for adverse infant outcomes (Di Sessa, 1994; Grab, 2000). As with other NSAIDs, however, high-dose aspirin use should be avoided, particularly in the third trimester.

his is a pyrimidine-synthesis inhibitor used to treat rheuma toid arthritis but is contraindicated in pregnancy. In several animal species, it results in fetal hydrocephalus, eye anoma lies, skeletal abnormalities, and embryo death when given at or below human-equivalent doses (Sanoi-Aventis, 2016). The active metabolite, terilunomide, is detectable in plasma for up to 2 years following discontinuation of the medication. Women who become pregnant while taking leflunomide, and even those of childbearing potential who have discontinued it, are recommended to undergo an accelerated drug elimination procedure with either cholestyramine or activated charcoal (Sanoi-Aventis, 2016). Reassuringly, in a cohort of 60 women with irst-trimester lelunomide exposure who completed cholestyramine washout, the rate of birth defects was not increased (Chambers, 2010).

Medications used to treat infections are among those most frequently administered during pregnancy. Over the years, experience has accrued regarding their general safety. With a few exceptions cited below, most of the commonly used antimicrobial agents are considered safe for the embryo-fetus.

Some preterm neonates treated with gentamicin or streptomycin have developed nephrotoxicity and otoroxicity. Despite theoretical concern for potential fetal toxicity, no adverse efects have been demonstrated, and no congenital defects resulting from prenatal exposure have been identified.

his antimicrobial is not considered teratogenic and is no lon ger routinely used in the United States. More than 50 years ago, a constellation of findings termed the gray baby syndrome was described in neonates who received the medication. Pre..i term newborns were unable to conjugate and excrete the drug and manifested abdominal distention, respiratory abnormali ties, an ashen-gray color, and vascular collapse (Weiss, 1960).

due to theoretical concerns.

From NBDPS results, first-trimester nitrofurantoin exposure is linked to a twofold risk for cleft lip (Ailes, 2016; Crider, 2009). Considering that the birth prevalence of clefts approximates 1 case per 1000, the likelihood that a nitrofurantoin-exposed fetus would not have a cleft would thus be 998 per 1000. For other birth defects, initial associations with this antibiotic did not persist in the inal NBDPS cohort (Ailes, 2016).

In one systematic review of nitrofurantoin exposure in pregnancy, results of cohort and case-control studies difered (Goldberg, 2015). Five cohort studies included 9275 exposed pregnancies and nearly 1.5 million unexposed pregnancies, and the review found no higher risk for any malformation. However, among three case-control studies that had nearly 40,000 cases matched with 130,000 controls, the rate of hypoplastic left heart syndrome was threefold greater (Goldberg, 2015). For context, this increase in risk would result in a birth prevalence of fewer than 1 case per 1000 exposed infants. The American College of Obstetricians and Gynecologists (2017 e) has concluded that irst-trimester nitrofurantoin use is appropriate if no suitable alternatives are available.

These drugs are often combined with trimethoprim and used to treat infections during pregnancy. One indication is treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection. The NBDPS, which included 107 pregnancies with periconceptional trimethoprim-sulfamethoxazole exposure and birth defects, identiied a fivefold greater risk to have ofspring with esophageal atresia or diaphragmatic hernia (Ailes, 2016). Similar to findings with nitrofurantoin exposure, this degree of increase would confer a risk of approximately 1 case per 1000 exposed infants for these selected birth defects. However, these findings have not been corroborated by other reports. One review from the Medication Exposure in Pregnancy Risk Evaluation Program included more than 7500 infants with irst-trimester exposure to trimethoprim-sulfamethoxazole (Hansen, 2016). Compared with either unexposed infants or those exposed to penicillins or cephalosporins, no greater risk for any congenital abnormality was identified. The American College of Obstetricians and Gynecologists (2017 e) considers sulfonamides appropriate for irst-trimester use if suitable alternatives are lacking.

Sulfonamides displace bilirubin from protein-binding sites.

Thus, if given near the time of preterm delivery, these agents theoretically might worsen neonatal hyperbilirubinemia. However, a population-based review of more than 800,000 births from Denmark found no association between exposure to sulfamethoxazole in late pregnancy and neonatal jaundice (Klarskov, 2013).

These drugs are no longer commonly used in pregnant women. They are associated with yellowish-brown discoloration of deciduous teeth when used after 25 weeks' gestation. The risk for subsequent dental caries does not appear greater (Billings, 2004; Kutscher, 1966). In contrast, a recent systematic review of doxycycline in pregnancy identified no higher rates of either birth defects or staining of deciduous teeth (Cross, 2016).

Cancer management in pregnancy includes many chemotherapeutic agents generally considered to be at least potentially toxic to the embryo, fetus, or both. For the many novel polyclonal antibody therapies designated as antineoplastics, there are few data concerning their safety. Some risks with these and with other antineoplastic agents are discussed in Chapter 63 (p. 1191). A few of the more common agents for which experience in pregnancy has accrued are considered next.

This alkylating agent inflicts a chemical insult on developing fetal tissues and leads to cell death and heritable DNA alterations in surviving cells. Pregnancy loss rates are increased, and reported malformations include skeletal abnormalities, limb defects, cleft palate, and eye abnormalities (Enns, 1999; Kirshon, 1988). Surviving infants may have growth abnormalities and developmental delays. Environmental exposure among health-care workers is associated with a higher risk for spontaneous abortion (Chap. 18, p. 348).

This folic-acid antagonist is a potent terarogen. It is used for cancer chemotherapy, immunosuppression of autoimmune diseases and psoriasis, nonsurgical treatment of ecropic pregnancy, and medical abortion. It is similar in action to aminopterin, which is no longer used clinically, and can cause defects known collectively as the fetal methotrexate-aminopterin syndrome. This includes craniosynosrosis with a "clover-leaf' skull, wide nasal bridge, low-set ears, micrognathia, and limb abnormalities (Del Campo, 1999).

Teratology, Teratogens, and Fetotoxic Agents 243 he embryo is thought to be most vulnerable at 8 to 10 weeks postconception and at dosages of at least 10 mg/week. However, this is not universally accepted (Feldkamp, 1993).

he standard 50 mg/m2 dose given to treat ectopic pregnancy or to induce elective abortion exceeds this threshold dose. Some reports have suggested an association with cardiac anomalies, particularly conotruncal defects, in intrauterine pregnancies inadvertently treated with methotrexate for suspected ectopic pregnancy (Dawson, 2014; Hyoun, 2012). Thus, ongoing pregnancies after treatment with methotrexate-especially if used in conjunction with misoprostol-raise serious concerns for fetal malformations (N urmohamed, 2011).

This nonsteroidal selective estrogen-receptor modulator (SERM) is used as an adjuvant to treat breast cancer. No pattern of birth defects has been described in limited case reports and series (Braems, 2011). However, tamoxifen has been associated with malformations similar to those caused by diethylstilbestrol (DES) exposure in rodents, including vaginal adenosis. Consequently, women who become pregnant on therapy or within 2 months of its discontinuation should be apprised of the potentialilong-term risks of a DES-like syndrome.

his is a recombinant monoclonal antibody directed to the human epidermal growth factor receptor 2 (HER2) protein. Used to treat breast cancers that express HER2 protein, this drug has not been associated with fetal malformations. However, cases of oligohydramnios sequence resulting in pulmonary hypoplasia, renal failure, skeletal abnormalities, and neonatal deaths have been reported (Genentech, 2017). Surveillance for these complications is recommended for exposed pregnancies and for those treated at any time in the 7 months prior to conception. A trastuzumab pregnancy exposure registry and a pregnancy pharmacovigilance program have been established to monitor pregnancy outcomes. hese warnings also apply to those treated with ado-trastuzumab emtansine.

The number of drugs used to treat viral infections has increased rapidly during the past 20 years. For most, experience in pregnant women is limited.

This nucleoside analogue is a component of therapy for hepatitis C infection, discussed in Chapter 55 (p. 1065). Ribavirin causes birth defects in multiple animal species at doses signiicantly lower than those recommended for human use. Reported malformations include skull, palate, eye, skeleton, and gastrointestinal abnormalities. he drug has a half-life of 12 days and persists in extravascular compartments following therapy discontinuation. Treated women must use two forms of contraception and have monthly pregnancy tests while on therapy and for 6 months following drug discontinuation (Genentech, 2015). Ribavirin use is also contraindicated in men whose partners are pregnant.

This is a nonnucleoside reverse transcriptase inhibitor used to treat HIV infection (Chap. 65, p. 1249). CNS and ocular abnormalities have been reported in cynomolgus monkeys treated with doses comparable to those used in humans. Several case reports also describe neural-tube defects following human exposure to efavirenz. Reassuringly, the Antiretroviral Pregnancy Registry has identiied no increased birth defect rates in more than 800 pregnancies with irst-trimester exposure (Bristol-Meyers Squibb, 2017b).

Bosentan, ambrisentan, and macitentan are three endothelinreceptor antagonists used to treat pulmonary arterial hypertension (Chap. 49, p. 962). he endothelin-receptor signaling pathway is important for neural-crest development. Mice deicient in endothelin receptors develop neural-crest cell defects that include craniofacial and cardiac outflow tract abnormalities (de Raaf, 2015). Each of these three agents has been found to cause similar birth defects in multiple animal species (Actelion, 2017). No human data are available. Endothelin-receptor antagonists may be obtained only through restricted access programs, each of which has stringent requirements that include contraception and monthly pregnancy testing (Actelion, 2016, 2017; Gilead, 2015).

Some of the functions and efects of male and female hormones on the developing fetus are discussed in Chapter 3 (p. 38). It is intuitive that exposure of female fetuses to excessive male sex hormones-and vice versa-might be detrimental.

Androgen exposure in reproductive-aged women typically stems from anabolic steroid use to accrue lean body mass and muscular strength. Exposure of a female fetus may cause varying degrees of virilization and may result in ambiguous genitalia similar to that encountered in congenital adrenal hyperplasia . Findings can include labioscrotal fusion with irst-trimester exposure and phallic enlargement from later fetal exposure (Grumbach, 1960; Schardein, 1980).

This ethinyl testosterone derivative has weak androgenic activity. It is used to treat endometriosis, immune thrombocytopenic purpura, migraine headaches, premenstrual syndrome, and fibrocystic breast disease. In a review of inadvertent exposure during early pregnancy, Brunskill (1992) reported that 40 percent of exposed female fetuses were virilized. There was a doserelated pattern of clitoromegaly, fused labia, and urogenital sinus malformation.

This medication is included for historical context. From 1940 until 1971, between 2 and 10 million pregnant women were given this synthetic estrogen for ill-advised indications. It was removed from the market after Herbst and associates (1971) reported a series of eight women exposed to DES in utero who developed an otherwise rare neoplasm, vaginal clear-cell adenocarcinoma. With no relationship to drug dosage, the absolute cancer risk approximates 1 case per 1000 DES-exposed fetuses. Twofold greater rates of vaginal and cervical intraepithelial neoplasia were also described (Vessey, 1989).

DES exposure has further been associated with genital tract abnormalities in exposed fetuses of both genders. Women may have a hypoplastic, T-shaped uterine cavity; cervical collars, hoods, septa, and coxcombs; and "withered" fallopian tubes (Goldberg, 1999; Salle, 1996). Some are described and illustrated in Chapter 3 (p. 45). Later in life, women exposed in utero have slightly higher rates of earlier menopause and breast cancer (Hoover, 2011). Men may develop epididymal cysts, microphallus, hypospadias, cryptorchidism, and testicular hypoplasia (Klip, 2002; Stillman, 1982).

Some of the immune functions necessary for pregnancy maintenance are discussed in Chapter 5 (p. 95). Given these important interactions, immunosuppressant drugs logically might afect pregnancy.

hese medications include glucocorticoids and mineralocorticoids, which have antiinflammatory and immunosuppressive actions. They are frequently used to treat serious disorders such as asthma and autoimmune disease. Corticosteroids have been associated with clefts in animal studies. In one metaanalysis of case-control studies by the Motherisk Program, systemic corticosteroid exposure was associated with a threefold increase in the rate of clefts. his is an absolute risk of 3 cases per 1000 exposed fetuses (Park-Wyllie, 2000). A 10-year prospective cohort study by the same group, however, did not identiy higher risks for major malformations. Based on these findings, corticosteroids are not considered to represent a major teratogenic risk.

Unlike other corticosteroids, the active metabolite of prednisone, which is prednisolone, is inactivated by the placental enzyme 11�-hydroxysteroid dehydrogenase 2. Thus, it may not efectively reach the fetus.

This inosine monophosphate dehydrogenase inhibitor, and a related agent, mycophenolic acid, are immunosuppressants. They are used to prevent rejection in organ-transplant recipients and to treat autoimmune disease (Chap. 59, p. 1142). Mycophenolate is a potent teratogen. From the National Transplantation Pregnancy Registry, of pregnancies in which mycophenolate was not discontinued until after the first trimester, birth defects complicated 30 percent, and another 30 percent spontaneously aborted (ing, 2017). One prospective review by the European Network of Teratology Information Services similarly identified a spontaneous loss rate of nearly 30 percent in exposed pregnancies. More than 20 percent of liveborn infants had major anomalies (Hoeltzenbein, 2012).

Many afected infants have a pattern of defects termed mycophenolate embyopathy. his includes microtia, auditory canal atresia, clefts, coloboma and other eye anomalies, short ingers with hypoplastic nails, and cardiac defects (Anderka, 2009; Merlob, 2009). A Risk Evaluation and Mitigation Strategy (REMS) has been developed for mycophenolate prescribers who treat women with reproductive potential. REMS are safety strategies mandated by the FDA to help manage known risks associated with a medicine yet still allow patients to have access to the benefits of a given drug.

Radioactive iodine-131 is used for treatment of thyroid cancer and thyrotoxicosis and for diagnostic thyroid scanning. It is also a component of iodine-131 tositumomab therapy, which is employed to treat a type of non-Hodgkin lymphoma. Radioiodine is contraindicated during pregnancy because it readily crosses the placenta and is then concentrated in the fetal thyroid gland by 12 weeks' gestation. It may cause severe or irreversible fetal and neonatal hypothyroidism, which can lead to decreased mental capacity and delayed skeletal maturation Qubilant DraxImage, 2016). Pregnancy testing should be performed before administration of radioiodine-131.

Prenatal lead exposure is associated with fetal-growth abnormalities and with childhood developmental delay and behavioral abnormalities. According to the CDC (2010), no level of lead exposure is considered safe in pregnancy. Care and testing for at-risk pregnancies is discussed in Chapter 9 (p. 170).

Environmental spills of methyl mercury in Minamata Bay, Japan, and rural Iraq demonstrated that the developing nervous system is particularly susceptible to this heavy metal. Prenatal exposure causes disturbances in neuronal cell division and migration. This leads to a range of defects from developmental delay to microcephaly and severe brain damage (Choi, 1978).

he principal concern for prenatal mercury exposure is the consumption of certain species of large fish (Chap. 9, p. 170). The FDA (2017a) advises that pregnant women and breastfeeding mothers avoid consumption of king mackerel, marlin, orange roughy, shark, swordfish, tilefish, and bigeye tuna.

Treatment of psychiatric illness in pregnancy, including a discussion of the risks and benefits of various psychiatric medications, is described in Chapter 61 (p. 1173). Selected birth defects and adverse efects associated with specific medications are presented here.

This medication has been associated with Ebstein anomaly, a rare cardiac abnormality that otherwise complicates only 1 per 20,000 births. Ebstein anomaly is characterized by apical

Teratology, Teratogens, and Fetotoxic Agents 245 displacement of the tricuspid valve, often resulting in severe tri confer signiicant morbidity. A report from the Lithium Baby

Registry initially suggested that the risk for Ebstein anomaly was as high as 3 percent. However, subsequent series have iden right-sided cardiac anomalies of only 1 to 4 per 1000 exposed pregnancies (Patorno, 2017; Yacobi, 2008). In a review of fout case-control studies that included more than 200 infants with

Ebstein anomaly, no cases were attributed to lithium exposure (Cohen, 1994).

ery. he manufacturer recommends that if possible, the dosage should be decreased or drug discontinued 2 to 3 days prior to delivery to reduce this risk (West-Ward, 2016). Findings typically persist for 1 to 2 weeks and may include neonatal hypothyroidism, diabetes insipidus, cardiomegaly, bradycar dia, electrocardiogram abnormalities, cyanosis, and hypotonia (American College of Obstetricians and Gynecologists, 2016).

As a class, these medications are not considered major teratogens (American College of Obstetricians and Gynecologists, 2016). The one exception is paroxetine, which has been associated with a higher risk for cardiac anomalies, particularly atrial and ventricular septal defects. Three large databases-a Swedish national registry, a United States insurance claims database, and the Motherisk Program-each identified a 1.5-to twofold greater risk for cardiac malformations following first-trimester paroxetine exposure (Bar-Oz, 2007; Sebela, 2017). For these reasons, the American College of Obstetricians and Gynecologists (2016) recommends that paroxetine be avoided in women planning pregnancy. Fetal echocardiography should be considered for those with first-trimester paroxetine exposure.

Neonatal efects have been associated with prenatal exposure to selective serotonin-reuptake inhibitors (SSRIs) and selective norepinephrine-reuptake inhibitors (SNRIs). Approximately 25 percent of neonates exposed to SSRIs in late pregnancy manifest one or more nonspecific findings considered to represent poor neonatal adaptation (Chambers, 2006; Costei, 2002; Jordan, 2008). Collectively termed the neonatal behavioral syndrome, findings can include jitteriness, irritability, hyper-or hypotonia, feeding abnormalities, vomiting, hypoglycemia, thermoregulatory instability, and respiratory abnormalities. Fortunately, these neonatal behaviors are typically mild and self-limited and last approximately 2 days. Jordan and coworkers (2008) reported that afected newborns were not more likely to require a higher level of care, to experience respiratory abnormalities, or to have prolonged hospitalization. Rarely, neonates exposed to SSRIs in late pregnancy demonstrated more severe adaptation abnormalities (Ornoy, 2017).

Another concern with late-pregnancy exposure is the possible association of SSRI medications with persistent pulmonary hypertension of the newborn (PPH). he baseline incidence approximates 2 cases per 1000 term newborns. PPHN is characterized by elevated pulmonary vascular resistance with right-to-Ieft shunting and resultant hypoxemia. Two recent population-based cohort studies-together involving more than 5 million pregnancies-identiied an attributable risk of only 1 to 2 cases per 1000 births (Huybrechts, 2015; Kieler, 2012). Not only is the risk for this condition quite low, but cases associated with SSRI medication have not been severe (Ornoy,i2017).

No antipsychotic medications are considered teratogenic. Exposed neonates can manifest abnormal extrapyramidal muscle movements and withdrawal symptoms that include agitation, abnormally enhanced or diminished muscle tone, tremor, sleepiness, feeding diiculty, and respiratory abnormalities. These indings are nonspeciic and transient, similar to the neonatal behavioral syndrome that can follow SSRI exposure. An FDA (2011) alert cites all medications in this class. These include older drugs such as haloperidol and chlorpromazine, as well as newer medications such as aripiprazole, olanzapine, quetiapine, and risperidone.

hese vitamin A derivatives are among the most potent human teratogens. hree retinoids available in the United States are highly teratogenic when orally administered-isotretinoin, acitretin, and bexarotene. By inhibiting neural-crest cell migration during embryogenesis, they create a pattern of cranial neural-crest defects-termed retinoic acid embryopath-that involve the CNS, face, heart, and thymus (Fig. 12-5). Specific anomalies may include ventriculomegaly, maldevelopment of the facial bones or cranium, microtia or anotia, micrognathia, cleft palate, conotruncal heart defects, and thymic aplasia or hypoplasia.

13-cis-Retinoic acid is a vitamin A isomer that stimulates epithelial cell diferentiation and is used for dermatological disorders, especially cystic nodular acne. First-trimester exposure is associated with a high rate of pregnancy loss, and up to a third of fetuses have malformations (Lammer, 1985). he iPLEDGE program is an FDA-mandated REMS for isotretinoin and is found at: ww.ipledgeprogram.com.ihis webbased, restricted-distribution program requires participation for all patients, physicians, and pharmacies to help eliminate embryonic-fetal exposure. Although other countries have instituted similar programs, inadvertent exposure remains a global concern (Crijns, 201l).

This retinoid is used to treat severe psoriasis and was introduced to replace etretinate. he latter is a lipophilic retinoid with such a long hal-life (120 days) that birth defects resulted more than 2 years after therapy was discontinued. Although acitretin has a short half-life, it is metabolized to etretinate, and thus remains in the body for prolonged periods (Stiefel Laboratories, 2015). To obviate exposure, the manufacturer of acitretin has developed a pregnancy risk management program. Called "Do Your P.A.R.T"-Eregnancy prevention Actively Required during

FIGURE 12-5 Isotretinoin embryopathy. A. Bilateral microtia or anotia with stenosis of external (Kaplan, 2015). These results may be reassuring to pregnant women with inadvertent exposure.

Notably, the manufacturer of tazarotene cautions that application over a suicient body surface area could be comparable to oral treatment. Accordingly, its use in pregnancy is not recommended (Allergan, 2017).

There are wo natural forms of vitamin A. Beta-carotene, which is a precursor of provitamin A, is found in fruits and vegetables and has never been shown to cause birth defects (Oakley, 1995). Retinol is preformed vitamin A, ear canal. B. Flat, depressed nasal bridge and ocular hypertelorism. (Used with permission from

Dr. Edward Lammer.) and after Ireatment, this program promotes a delay of conception for at least 3 years following therapy discontinuation.

This retinoid is used to treat cutaneous T-cell lymphoma. When given to rats in doses comparable to those for human therapy, fetuses developed eye and ear abnormalities, cleft palate, and incomplete ossification. For a woman to receive this medication, the manufacturer requires two forms of contraception that are initiated 1 month before therapy and are continued for 1 month after bexarotene discontinuation. This is coupled with monthly pregnancy testing during treatment (Valeant Pharmaceuticals, 2015). Males who have partners who could become pregnant are advised to use condoms during sexual intercourse while taking bexarotene and for 1 month after discontinuing therapy.

These compounds, initially used to treat acne, have become so popular for the treatment of sun damage that they are called cosmeceuticals (Panchaud, 2012). The most commonly used topical agents are tretinoin, isotretinoin, and adapalene. Systemic absorption is low, and this argues against plausible teratogenicity.

Isolated case reports have described malformations following topical tretinoin, and it is unknown whether this is due to variability in absorption or perhaps potential individual susceptibility (Kaplan, 2015). A prospective study by the European Network of Teratology Information Services found no higher rates of birth defects or spontaneous losses, and no case of retinoid embryopathy (Panchaud, 2012). One systematic review by the Motherisk Program included 635 pregnancies with exposure to topical retinoids. Investigators similarly identified no higher risk for congenital malformations, spontaneous abortion, stillbirth, low birthweight, or preterm delivery cranial neural-crest defects when more than 10,000 IU per day is consumed in the first trimester (Rothman, 1995). It seems reasonable to avoid doses of preformed preparations that exceed the recommended 3000 IU daily allowance (American Academy of Pediatrics, 2017).

Possibly the most notorious human teratogen, thalidomide causes malformations in 20 percent of fetuses exposed between 34 and 50 days menstrual age. The characteristic malformation is phocomelia-an absence of one or more long bones. As a result, hands or feet are attached to the trunk, occasionally by a small rudimentary bone. Cardiac malformations, gastrointestinal abnormalities, external ear malformations, eye anomalies, and other limb-reduction defects are also common following thalidomide exposure. The manufacturer reports that up to 40 percent of afected newborns do not survive the neonatal period (Celgene, 2017 a).

Thalidomide was marketed outside the United States from 1956 to 1960, before its teratogenicity was appreciated. The ensuing disaster, with thousands of afected children, was instructive of several important teratological principles. First, the placenta is not an efective barrier to the transfer of toxic substances from mother to embryo (Dally, 1998). Second, diferent species show extreme variability in their susceptibility to drugs and chemicals. Namely, thalidomide produced no defects in multiple rodent species and was assumed to be safe for humans. Last, exposure timing and defect type are often closely related (Vargesson, 2015). For example, upper-limb amelia may develop with thalidomide exposure during days 24 to 30 postconception, upper-limb phocomelia with exposure during days 24 to 33, and lower-limb phocomelia with exposure during days 27 to 33.

halidomide was irst approved in the United States in 1999 and currently is used to treat erythema leprosum nodosum and multiple myeloma (Celgene, 2017a). The FDA has mandated a web-based, restricted-distribu tion program for thalidomide, called THALOMID REMS, which is required before patients, physicians, and pharmacies can access the medication.

Lenalidomide is an analogue of thalidomide that is used to treat some types of myelodys myeloma. It crosses the placenta in multiple animal species, and gene, 2017b). Because of obvi ous teratogenicity concerns, a similar to that used for thalido mide has been developed.

his anticoagulant is a vitamin K antagonist with a long halflife. Because of its low molecular weight, it readily crosses the placenta and may cause embryotoxic and fetotoxic efects. Warfarin analogues, such as Coumadin, are considered contraindicated in pregnancy. An exception, as discussed in Chapter 49 (p. 954), is treatment of women with mechanical heart valves who are at high risk for thromboembolism (Bristol-Myers Squibb,i2017a).

Waarin embryopathy is characterized by stippled epiphyses and nasal hypoplasia (Fig. 12-6). In one review of 63 cases attributed to warfarin exposure, 80 percent displayed characteristic indings, which include depressed nasal bridge with nasal hypoplasia and choanal atresia, along with stippled epiphyses of the femur, humerus, calcanei, and distal phalanges (Van Driel, 2002). It may result from exposure between the 6th and 9th weeks' gestation (Hall, 1980). he prevalence of the warfarin embryopathy following exposure during this critical period is estimated to be 6 percent (van Driel, 2002). One metaanalysis of cases in which the warfarin dosage was ; 5 mg/ d identiied embryopathy in 1 percent of exposed fetuses. his suggests that risk may be dose dependent (Hassouna, 2014).

If used beyond the first trimester, warfarin may lead to hemorrhage into fetal structures, which can cause abnormal growth and deformation from scarring (Warkany, 1976). Nearly 50 percent of reported embryopathy cases also have CNS anomalies (van Driel, 2002). Abnormalities can include agenesis of the corpus callosum; cerebellar vermian agenesis, which is the Dandy-Walker malformation; microphthalmia; and optic atrophy (Hall, 1980). Afected infants are also at risk for blindness, deafness, and developmental delays.

With various herbal remedies, associated risks are more challenging to estimate because studies are few and because these compounds are not FDA-regulated. he European Committee of Herbal Medicinal Products provides assessment reports and

Teratology, Teratogens, and Fetotoxic Agents 247

FIGURE 12-6 Warfarin embryopathy or fetal warfarin syndrome: nasal hypoplasia and depressed nasal bridge seen in a fetal sonographic image (A) and in the same newborn (8).

monographs on selected herbal substances and preparations, but safety data are generally limited (Wiesner, 2017). Animal studies have not been conducted, and thus knowledge of complications often derives from reports of acute toxicity (Hepner, 2002; Sheehan, 1998). Further, the identity, quantity, and purity of each ingredient are usually unknown. Given these uncertainties, it seems prudent to counsel pregnant women to avoid these substances. A list of selected herbal compounds and their potential efects is shown in Table 12-5.

Not uncommonly, fetuses are exposed to one or more illicit drugs. Assessment of outcomes attributable to these drugs may be confounded by factors such as poor maternal health, malnutrition, infectious disease, and polysubstance abuse. Moreover, illegal substances may contain toxic contaminants such as lead, cyanide, herbicides, and pesticides. Impurities added as diluents may independently have serious adverse perinatal efects. As noted on page 239, alcohol is a significant teratogen. Because it is legally obtained and ubiquitous, its use also confounds the study of illicit drug teratogenicity.

hese sympathomimetic amines are not considered to be major teratogens. Methamphetamine enhances dopamine release and blocks its reuptake. It is prescribed to treat attention-deicit/ hyperactivity disorder and narcolepsy. Methamphetamine abuse has been rising in the United States since the late 1980s (American College of Obstetricians and Gynecologists, 2017b). In utero exposure has been consistently associated with higher rates of small-for-gestational age newborns (Gorman, 2014; Smith, 2006). Hypertensive complications, placental abruption, preterm birth, and stillbirth are other associated complications (Gorman, 2014). Behavioral abnormalities have been described in both infants and school-aged children (Eze, 2016).

TABLE 12-5. Pharmacological Actions and Adverse Effects of Some Herbal Medicines

Echinacea: purple coneflower root

Ephedra: ma huang

Garlic: ajo

Kava: awa, intoxicating pepper, kawa Valerian: all heal, garden heliotrope, vandal root Yohimbe

Contains linoleic acids, a prostaglandin precursor

Cyclooxygenase inhibitor, thromboxane synthetase inhibitor

Lowers blood glucose; inhibition of platelet aggregation Sedation, anxiolysis

Data from Ang-Lee, 2001; Briggs, 2015; Hall, 2012; Wiesner, 2017.

With this CNS stimulant, most adverse outcomes result from its vasoconstrictive and hypertensive efects. Serious potential maternal complications are cerebrovascular hemorrhage, myocardial damage, and placental abruption. Studies of congenital abnormalities and cocaine exposure have yielded conflicting results, but associations with cleft palate, cardiovascular abnormalities, and urinary tract anomalies have been reported (Chasnof, 1988; Lipshultz, 1991; van Gelder, 2009). Cocaine use is also associated with fetal-growth restriction and preterm delivery. Children exposed as fetuses have risks for behavioral abnormalities and cognitive impairments (Bada, 2011; Gouin, 2011).

The dramatic rise in narcotic use among non-pregnant and pregnant individuals has been aptly termed an epidemic. Opioids are not considered to be major teratogens. he NBDPS did identiY a slightly greater risk for spina biida, gastroschisis, and cardiac abnormalities with periconceptional opioid exposure (Broussard, 2011). The American College of Obstetricians

Allergic reactions; decreases immunosuppressant efectiveness; possible immunosuppression with long-term use arrhythmias, myocardial ischemia, stroke; depletes endogenous catecholamines; lifethreatening interaction with monoamine oxidase inhibitors Possible complications if used for labor induction

Risk of bleeding, especially when combined with other platelet aggregation inhibitors

Increased risk of bleeding

Risk of bleeding; interferes with monoamine oxidase inhibitors Hypoglycemia; hypertension; risk of bleeding

Sedation; hepatotoxicity, benzodiazepine-like acute withdrawal Hypertension, arrhythmias and Gynecologists (2017 c) stresses that this potential, small increase in birth defects with maintenance therapy should be weighed against the risks associated with uncontrolled opioid abuse. Heroin addiction is associated with adverse pregnancy outcomes from the efects of repeated narcotic withdrawal on the fetus and placenta (American College of Obstetricians and Gynecologists, 2017 c). These include preterm birth, placental abruption, fetal-growth restriction, and fetal death.

Neonatal narcotic withdrawal, called the neonatal abstinence syndrome, may manifest in 40 to 90 percent of exposed newborns (Blinick, 1973; Creanga, 2012; Dashe, 2002; Zelson, 1973). As discussed in Chapter 33 (p. 625), CNS irritability may progress to seizures if untreated and may be accompanied by tachypnea, apneic episodes, poor feeding, and failure to thrive. At-risk neonates are closely monitored using a scoring system, and those severely afected are treated with opioids (Finnegan, 1975). he proportion of exposed newborns developing neonatal abstinence syndrome has risen significantly in recent years (Creanga, 2012; Lind, 2015).

he American College of Obstetricians and Gynecologists (2017 c) recommends that pregnant women with opioid-use disorder be maintained on opioid-agonist therapy to reduce the risks associated with illicit opioid abuse and associated behaviors. Treatment includes either methadone, usually through a licensed outpatient opioid treatment program, or buprenorphine, which may be given in an oice-based setting by a licensed buprenorphine prescriber. A multidisciplinary treatment program is recommended to reduce the likelihood of additional opioid abuse while on maintenance therapy. he College (2017 c) discourages withdrawal from methadone during pregnancy because of high relapse rates. At Parkland Hospital, pregnant opioid users who decline maintenance therapy are ofered inpatient hospitalization for controlled methadone taper, with the goal of reducing the likelihood of neonatal abstinence syndrome (Dashe, 2002; Stewart, 2013).

This is the illicit drug most commonly used in pregnancy (American College of Obstetricians and Gynecologists, 2017a). Based on data from the National Survey on Drug Use and Health, the prevalence of marijuana use in pregnancy was nearly 4 percent in 2014 (Brown, 2017). Cannabinoids are not considered to be major teratogens, but there is concern because endogenous cannabinoids play key roles in human brain development. In one metaanalysis of nearly 8000 exposed pregnancies, adverse outcomes such as preterm birth and low birthweight were increased only in the presence of concomitant tobacco use (Conner, 2016).

Phencyclidine (PCP) or angel dust is not associated with congenital anomalies. More than half of exposed newborns, however, experience withdrawal symptoms characterized by tremors, jitteriness, and irritability. Toluene is a common solvent used in paints and glue. Occupational exposure is reported to have signiicant fetal risks (Wilkins-Haug, 1997). When abused by women in early pregnancy, it is associated with toluene embyopathy, which is phenotypically similar to fetal alcohol syndrome. Abnormalities include pre-and postnatal growth deficiency, microcephaly, midface hypoplasia, short palpebral fissures, and wide nasal bridge (Pearson, 1994) . Up to 40 percent of exposed children have developmental delays (Arnold, 1994).

Cigarette smoke contains a complex mixture of nicotine, cotinine, cyanide, thiocyanate, carbon monoxide, cadmium, lead, and various hydrocarbons (Stillerman, 2008). In addition to being fetotoxic, many of these substances have vasoactive efects or reduce oxygen levels. Tobacco is not considered a major teratogen, although selected birth defects have been reported to occur with greater frequency among newborns of women who smoke. It is plausible that the vasoactive properties of tobacco smoke could produce congenital defects related to vascular disturbances. For example, the prevalence of Poland sequence, which is caused by an interruption in the vascular supply to one side of the fetal chest and ipsilateral arm, is twofold greater in smokers (Martinez-Frias, 1999). A small increased risk for cardiac anomalies has also been reported and may be dose related (Alverson, 2011; Malik, 2008; Sullivan,

Teratology, Teratogens, and Fetotoxic Agents 249 2015). One study analyzing more than 6 million births found an association between maternal smoking and hydrocephaly, microcephaly, omphalocele, gastroschisis, cleft lip and palate, and hand abnormalities (Honein, 2001). Electronic nicotine delivery systems are not considered safe, as nicotine may have adverse efects on fetal brain and lung development (American College of 0bstetricians and Gynecologists, 2017 d).

he best-documented adverse reproductive outcome from smoking is a dose-response reduction in fetal growth. Newborns of mothers who smoke weigh on average 200 g less than newborns of nonsmokers (D'Souza, 1981). Smoking doubles the risk of low birthweight and raises the risk of fetal-growth restriction two-to threefold (Werler, 1997). Even secondhand smoke increases the risk for low birthweight (Hegaard, 2006). Women who stop smoking early in pregnancy may have neonates with normal birthweights (Cliver, 1995). Other adverse outcomes associated with cigarette smoking include preterm birth, placenta previa, placenta abruption, spontaneous abortion, and sudden infant death syndrome (American College of Obstetricians and Gynecologists, 2017d). Risks of childhood asthma and obesity are also increased.

Abel EL, Hannigan ]H: Maternal risk factors in fetal alcohol syndrome: provocative and permissive inluences. Neurotoxicol Teratolo17(4):445, 1995

Actelion Pharmaceuticals: Opsumit (Macitentan) prescribing information, 2017. Available at: http://www.opsumit.com/opsumit-prescribing-information. pd. Accessed September 24, 2017

Actelion Pharmaceuticals: T racleer (Bosentan) prescribing information, 2016.

Available at: www.tracleer.com/assets/PD Rs/T racleer_Full_Prescribin� Information. pdf. Accessed September 24, 2017

Adam MP, Polifka ]E, Friedman ]M: Evolving knowledge of the teratogenicity of medications in human pregnancy. Am] Med Genet C Semin Med Genet 157(3):175,o2011

Ailes EC, Gilboa SM, Gill SK, et al: Association between antibiotic use among pregnant women and urinary tract infections in the irst trimester and birth defects, National Birth Defects Prevention Study 1997 to 2011. Birth Defects Res A Clin Mol Teratol 106(1o1):940, 2016

Allergan: Tazorac (Tazarotene) prescribing information, 2017. Available at: https:/ /www.allergan.com/assets/pdfltazorac_cream_pi.pd. Accessed September 24, 201o7

Alsaad AM, Kaplan YC, Koren G: Exposure to luconazole and risk of congenital malformations in the ofspring: a systematic review and meta-analysis. Reprod Toxicol 52:78, 2015

Alverson q, Strickland M], Gilboa SM, et al: Maternal smoking and congenital heart defects in the Baltimore-Washington Infant Study. Pediatrics 12 (3):e647,o2011

Alwan S, Chambers CD: Findings from the National Birth Defects Prevention Study: interpretation and translation for the clinician. Birth Defects Res A Clin Mol Teratolo103(8):721, 2015

American Academy of Pediatrics and American College of Obstetricians and Gynecologists: Guidelines for Perinatal Care, 8th ed. Elk Grove Village, AAP,o2017

American College of Obstetricians and Gynecologists: At-risk drinking and alcohol dependence: obstetric and gynecologic implications. Committee Opinion No. 496, August 2013

American College of Obstetricians and Gynecologists: Use of psychiatric medications during pregnancy and lactation. Practice Bulletin No. 92, April 2008, Reairmed 2016

American College of Obstetricians and Gynecologists: Marijuana use during pregnancy and lactation. Committee Opinion No. 722, October 20 17a

American College of Obstetricians and Gynecologists: Methamphetamine abuse in women of reproductive age. Committee Opinion No. 479, March 2011, Reairmed 2017b

American College of Obstetricians and Gynecologists: Opioid use and opioid use disorder in pregnancy. Committee Opinion No. 71o1, August 2017c

American College of Obstetricians and Gynecologists: Smoking cessation during pregnancy. Committee Opinion No. 721, October 20o17 d

American College of Obstetricians and Gynecologists: Sulfonamides, nitrofurantoin, and risk of birth defects. Committee Opinion No. 717, September 2017e Anderka MT, Lin AE, Abuelo ON, et al: Reviewing the evidence for mycophenolate mofetil as a new teratogen: case report and review of the literature. Am J Med Genet A 149A( 6): 1241, 2009

Ang-Lee MK, Moss J, Yuan CS: Herbal medicines and perioperative care.

JAMA 286(2):208,o2001

Arnold GL, Kirby RS, Langendoerfer S, et al: Toluene embryopathy: clinical delineation and developmental follow-up. Pediatrics 93(2):216, 1994 Bada HS, Bann CM, Bauer CR, et al: Preadolescent behavior problems after prenatal cocaine exposure: relationship between teacher and caretaker ratings (Maternal Lifestyle Study). Neurotoxicol Teratol 33(1): 8,o201o1 Bar-Oz B, Einarson T, Einarson A, et al: Paroxetine and congenital malformations: meta-analysis and consideration of potential confounding factors. Clin her 29(5):918,o2007 Barr M, Cohen MM: ACE inhibitor fetopathy and hypo calvaria: the kidneyskull connection. Teratology 44(5):485, 1991 Bateman BT, Patorno E, Desai RJ, et al: Angiotensin-converting enzyme inhibitors and the risk of congenital malformations. Obstet GynecoIo129(1): 174,o2017 Billings RJ, Berkowitz RJ, Watson G: Teeth. Pediatrics 113(4Suppl):1120, 2004 Blinick G, Jerez E, Wallach RC: Methadone maintenance, pregnancy, and progeny. JAMA 225(5):477, 1973 Braems G, Denys H, De Wever 0, et al: Use of tamoxifen before and during pregnancy. Oncologist 16(11):1547,2011 Briggs GG, Freeman RK: Drugs in Pregnancy and Lactation, 10th ed. Philadelphia, Lippincott Williams & Wilkins, 20o15 Bristol-Meyers Squibb Pharmaceuticals: Coumadin (Warfarin) prescribing information, 2017a. Available at: https://packageinserts.bms.com/pi/pi_ coumadin. pdf. Accessed September 24, 2017 Bristol-Meyers Squibb Pharmaceuticals: Sustiva (Efavirenz) prescribing information, 2017b. Available at: https://packageinserts.bms.com/pi/pi_sustiva. pdf. Accessed September 24, 20o17 Bromley R, Weston J, Adab N, et al: Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child. Cochrane Database Syst Rev 1 O:CDO 1 0236, 2014 Broussard CS, Rasmussen SA, Reefhuis J, et al: Maternal treatment with opioid analgesics and risk for birth defects. Am J Obstet Gynecol 204(4):314.e1, 2011 Brown QL, Sarvet AL, Shmulewitz 0, et al: Trends in marijuana use among pregnant and nonpregnant reproductive-aged women, 2002-2014. JAMA 317(2):207,o2017 Brunskill PJ: he efects offetal exposure to danazol. BJOG 99(3):212, 1992 Buehler BA, Delimont 0, van Waes M, et al: Prenatal prediction of risk of the fetal hydantoin syndrome. N Engl J Med 322: 1567, 1990 Carey JC, Martinez L, Balken E, et al: Determination of human teratogenicity by the astute clinician method: review of illustrative agents and a proposal of guidelines. Birth Defects Res A Clin Mol Teratol 85(1):63, 2009 Celgene Corporation: Thalomid (Thalidomide) prescribing information, 2017 a. Available at: http://www.celgene.com/content/uploadslthalomid-pi. pd. Accessed September 24, 2017 Celgene Corporation: Revlimid (Lenalinomide) prescribing information, 2017b. Available at: http://www.celgene.com/content/uploadslrevlimid-pi. pdf. Accessed September 24, 2017 Centers for Disease Control and Prevention: Alcohol use and binge drinking among women of childbearing age-United States, 2006-2010. MMWR 61o(28):534,o2012 Centers for Disease Control and Prevention: Guidelines for the Identification and Management of Lead Exposure in Pregnant and Lactating Women. 2010. Available at: http://ww.cdc.gov/nceh/lead/publications/leadandpregnancy20 1 o.pdf. Accessed September 24, 2017 Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al: Selective serotoninreuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 354(6):579, 2006 Chambers CD, Johnson DL, Robinson LK, et al: Birth outcomes in women who have taken leflunomide during pregnancy. Arthritis Rheum 62(5): 1494, 2010 Chasnof IJ, Chisum GM, Kaplan WE: Maternal cocaine use and genitourinary tract malformations. Teratology 37(3):201, 1988 Chaudhry SA, Jong G, Koren G: The fetal safety of levetiracetam: a systematic review. Reprod ToxicoIo46(l):40, 2014 Choi BH, Lapham L W, Amin-Zaki L, et al: Abnormal neuronal migration, deranged cerebellar cortical organization, and difuse white matter astrocytosis of human fetal brain. A major efect of methyl mercury poisoning in utero. J Neuropathol NeuroIo37(6):719, 1978

Clayton-Smith J, Donnai 0: Human malformations. In Rimoin DL, Connor JM, Pyeritz E (eds): Emery and Rimoin's Principles and Practice of Medical Genetics, 3rd ed. New York, Churchill Livingstone, 1996

Cliver SP, Goldenberg L, Cutter GR, et al: The efect of cigarette smoking on neonatal anthropometric measurements. Obstet Gynecol 85(4):625, 1995 Cohen LS, Friedman JM, Jeferson JW, et al: A reevaluation of risk of in utero exposure to lithium. JAMA 1(2):146, 1994

Conner SN, Bedell V, Lipsey K, et al: Maternal marijuana use and adverse neonatal outcomes. Obstet GynecoIo128(4):713, 2016

Conover EA, Polifka JE: he art and science of teratogen risk communication.

Am J Med Genet C Semin Med Genet 157(3):227,2011

Cooper WO, Hernandez-Diaz S, Arbogast PG, et al: Major congenital malformation after irst-trimester exposure to ACE inhibitors. N Engl J Med 354(23):2443, 2006

Costei AM, Kozer E, Ho T, et al: Perinatal outcome following third trimester exposure to paroxetine. Arch Pediatr Adolesc Med 156(11): 1129, 2002

Cragan JD, Giboa SM: Including prenatal diagnoses in birth defects monitoring: experience of the Metropolitan Atlanta Congenital Birth Defects Program. Birth Defects Res A Clin Mol Teratol 85(1)20, 2009

Creanga A, Sabel JC, Ko JY, et al: Maternal drug use and its efect on neonates: a population-based study in Washington state. Obstet Gynecol 119(5):924,o2012

Crider KS, Cleves MA, Reefhuis J, et al: Antibacterial medication use during pregnancy and risk of birth defects, National Birth Defects Prevention Study. Arch Pediatr Adolesc Med 163:978,o2009

Crijns HJ, Straus SM, Gispen-de Wied C, et al: Compliance with pregnancy prevention programmes of isotretinoin in Europe: a systematic review. Br J DermatoIo164(2):238,o2011

Cross R, Ling C, Day NP, et al: Revisiting doxycycline in pregnancy and early childhood-time to rebuild its reputation? Expert Opinion Drug Saf 15(3):367,o2016 Dally A: halidomide: was the tragedy preventable? Lancet 351: 1197, 1998 Dashe JS, Sheield JS, Olscher DA, et al: Relationship between maternal methadone dosage and neonatal withdrawal. Obstet Gynecolo100(6):1244, 2002 Dawson AL, Riehle-Colarusso T, Reefhuis J, et al: Maternal exposure to methotrexate and birth defects: a population-based study. Am J Med Genet 164A(9):2212,o2014

De Raaf MA, Beekhuijzen M, Guignabert C, et al: Endothelin-1 receptor antagonists in fetal development and pulmonary arterial hypertension. Reprod Toxicol 56:45, 2015 Del Campo M, Kosaki K, Bennett FC, et al: Developmental delay in fetal aminopterin/ methotrexate syndrome. Teratology 60( 1): 10, 1999 Di Sessa TG, Moretti ML, Khoury A, et al: Cardiac function in fetuses and newborns exposed to low-dose aspirin during pregnancy. Am J Obstet GynecoIo171(4):892,o1994 Dolk H, Loane M, Garne E: The prevalence of congenital anomalies in Europe. Adv Exp Med BioI 686:349, 2010 D'Souza SW, Black P, Richards B: Smoking in pregnancy: associations with skinfold thickness, maternal weight gain, and fetal size at birth. BMJ 282(6227):1661, 1981 Ehrenstein V, Sorensen HT, Bakketeig LS, et al: Medical databases in studies of drug teratogenicity: methodological issues. Clin EpidemioIo2(1):37, 2010 Enns GM, Roeder E, Chan RT, et al: Apparent cyclophosphamide (Cytoxan) embryopathy: a distinct phenotype? Am J Med Genet 86(3):237, 1999

Eze N, Smith LM, LaGasse LL, et al: School-aged outcomes following prenatal methamphetamine exposure: 7.5-year follow-up from the infant development, environment, and lifestyle study. J Pediatr 170:34.e1, 2016 Feldkamp M, Carey JC: Clinical teratology counseling and consultation case report: low dose methotrexate exposure in the early weeks of pregnancy. Teratology 47(6):533, 1993 Feldkamp ML, Carey Jc, Byrne JL, et al: Etiology and clinical presentation of birth defects: population based study. BMJ 357:j2249, 2017 Finnegan LP, Connaughton JF, Kron E et al: Neonatal abstinence syndrome: assessment and management. Addict Dis 2(1-2):141, 1975 Fisher SC, Van Zutphen AR, Werler MM, et al: Maternal antihypertensive medication use and congenital heart defects: updated results from the National Birth Defects Prevention Study. Hypertension 69(5):798,o2017 Food and Drug Administration: Advice about eating fish, from the Environmental Protection Agency and Food and Drug Administration; revised fish advice; availability. Federal Register 82(12):6571, 2017a Food and Drug Administration: Antipsychotic drug labels updated on use during pregnancy and risk of abnormal muscle movements and withdrawal symptoms in newborns. 2011. Available at: http://www.fda.gov/Drugs/ DrugSafety/ucm243903.htm. Accessed September 24, 2017 Food and Drug Administration: Content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling. Final rule. Fed Regist 79(233):72036,o2014

Food and Drug Administration: Pregnancy registry information for health professionals.

b. Available at: https:!lwww.fda.gov/ScienceResearch/ SpecialT opics/WomensHealthResearchl ucm256789 .hnn. Accessed September 24,s2017

Food and Drug Administration: Reviewer guidance: evaluating the risks of drug exposure in human pregnancies. 2005. Available at: https:llwww.fda. gov/downloads/Drugsl ..

1645.pdf. Accessed September 24,s2017

Genentech: Copegus (Ribavirin) prescribing information, 2015. Available at: https:! Iwww.gene.com/download/pdf/ copegus_prescribing. pdf. Accessed September 24,s201

Genentech: Herceptin (Trastuzumab) prescribing information, 2017. Available at: https:llwww.gene.com/download/pdf/herceptin_prescribing.pdf. Accessed September 24,s2017

Gilead Sciences: Letairis (Ambrisentan) prescribing information, 2015. Available at: www.gilead.com/-I media/iles/pdfsl medicines/cardiovascular/letairisl letairis_pi.pd. Accessed September 24, 2017

Goldberg ]M, Falcone T: Efect of diethylstilbestrol on reproductive functions.

Fertil Steril 72(1): 1, 1999

Goldberg 0, Moretti M, Levy A, et al: Exposure to nitrofurantoin during early pregnancy and congenital malformations: a systematic review and metaanalysis. ] Obstet Gynaecol Can (2): 150, 2015

Gorman MC, Orme KS, Nguyen NT, et al: Outcomes in pregnancies complicated by methamphetamine use. Am] Obstet Gynecols211 (4):429.el, 2014

Gouin K, Murphy K, Shah PS, et al: Efects of cocaine use during pregnancy on low birth weight and preterm birth: systematic review and meta-analyses. Am] Obstet GynecoI204(4):340.el, 2011

Grab D, Paulus WE, Erdmann M, et al: Efects of low-dose aspirin on uterine and fetal blood low duting pregnancy: results of a randomized, placebocontrolled, double-blind trial. Ultrasound Obstet Gynecol 15(1):19,s2000

Gregg NM: Congenital cataract following German measles in the mother.

Trans Ophthalmol Soc 3:35, 1941

Grimes DA, Schulz KF: False alarms and pseudo-epidemics: the limitations of observational epidemiology. Obstet Gynecol 120(4):920,s2012

Grumbach MM, Ducharme ]R: The efects of androgens on fetal sexual development. Androgen-induced female pseudohermaphrodism. Fertil Steril 11:157, 1960

Guerri C, Bazinet A, Riley EP: Foetal alcohol spectrum disorders and alterations in brain and behaviour. Alcohol 44(2):108, 2009

Guron G, Friberg P: An intact renin-angiotensin system is a prerequisite for normal renal development.] Hypertension 18(2):123,s2000

Hall ]G, Pauli RM, Wilson K: Matenal and fetal sequelae of anticoagulation during pregnancy. Am] Med 68(1): 122, 1980

Hall HG, McKenna LG, Griiths DL: Complementary and alternative medicine for induction oflabor. Women Birth 25(3): 142,s2012

Hammers AL, Sanchez-Ramos L, Kaunitz AM: Antenatal exposure to indomethacin increases the risk of severe intraventricular hemorrhage, necrotizing enterocolitis, and periventricular leukomalacia: a systematic review with metaanalysis. Am] Obstet Gynecol 212(4):505.el, 2015a

Hammers L, Sanchez-Ramos L, KaunitzAM: Indomethacin as a tocolytic harmful to preterm infant. Author reply. Ams] Obstet Gynecol 213(6):879, 2015b

Hansen C, Andrade SE, Freiman H, et al: Trimethoprim-sulfonamide use during the irst trimester of pregnancy and the risk of congenital anomalies. Pharmacoepidemiol Drug Saf25(2):170, 2016

Hassouna A, Allam H: Limited dose warfarin throughout pregnancy in patients with mechanical heart valve prosthesis: a meta-analysis. Interact Cardiovasc horac Surg 97,2014

Hegaard HK, Kjaergaard H, loller LF, et al: The efect of environmental tobacco smoke during pregnancy on birth weight. Acta Obstet Gynecol Scand 85(6):675, 2006

Hepner DL, Harnett M, Segal S, et al: Herbal medicine use in parturients.

Anesth Analg 94(3):690, 2002

Herbst AL, Ulfelder H, Poskanzer DC: Adenocarcinoma of the vagina. Asso ciation of matenal stilbestrol therapy. N Engl ] Med 8, 1971

Henandez RK, WerleI' MM, Romitti P, et al: Nonsteroidal antiinlammatory drug use among women and the risk of birth defects. Ams] Obstet Gynecol 206(3):228.el,s2012

Henandez-Diaz S, Smith CR, Shen A, et al: Comparative safety of antiepileptic drugs during pregnancy. Neurology 78(21):1692,s2012

Hoeltzenbein M, Elefant E, Vial T, et al: Teratogenicity of mycophenolate conirmed in a prospective study of the European Network of Teratology Information Services. Am] Med Genet A 158A(3):588, 2012

Honein MA, Paulozzi L], Watkins ML: Maternal smoking and birth defects: validity of birth certiicate data for efect estimation. Public Health Rep 116(4):327,s2001

Hoover RN, Hyer v!, Pfeifer M, et al: Adverse health outcomes in women exposed in utero to diethylstilbestrol. N Engl] Med 365(14):1304, 2011

Teratology, Teratogens, and Fetotoxic Agents 251

Hoyme HE, Kalberg WO, Elliott A], et al: Updated clinical guidelines for diagnosing fetal alcohol spectrum disorders. Pediatrics 138(2) e20154256, 2016

Hoyt AT, Canield MA, Romitti PA, et al: Associations between maternal periconceptional exposure to secondhand tobacco smoke and major birth defects. Am] Obstet GynecoIs215(5):613, 2016

Huybrechts KF, Bateman BT, Palmsten K, et al: Antidepressant use late in pregnancy and risk of persistent pulmonary hypertension of the newborn. ]AMA 313(21):2142,s2015

Hyoun Sc, Obican SG, Scialli AR: Teratogen update: methotrexate. Birth Defects Res A Clin Mol TeratoIs94(4):187, 2012

Iahnaccone PM, Bossert NL, Connelly CS: Disruption of embryonic and fetal development due to preimplantation chemical insults: a critical review. Am ] Obstet Gynecol 157(2):476, 1987

Jasper ]D, Goel R, Einarson A, et al: Efects of framing on teratogenic risk perception in pregnant women. Lancet 358(9289): 1237, 2001

Jones KL, Smith DW, Ulleland CN, et al: Pattern of malformation in ofspring of chronic alcoholic mothers. Lancet 1 (7815): 1267, 1973

Jordan AE, Jackson GL, Deardorf D, et al: Serotonin reuptake inhibitor use in pregnancy and the neonatal behavioral syndrome. ] Matern Fetal Neonatal Med 21(10):745,s2008

Jubilant DraxImage: HICON (Sodium Iodine 131) prescribing information, 2016. Available at: http://www.draximage.com/wp-content/ uploads/2016/111HICON-prod-ins-US.pdf. Accessed September 24,s2017

Kaplan YC, Ozsarfati], Etwel F, et al: Pregnancy outcomes following irst-trimester exposure to topical retinoids: a systematic review and meta-analysis. Br] Dernutol 173(5): 1117, 2015

Khoury M], James LM, Flanders WD, et al: Interpretation of recurring weak association obtained from epidemiologic studies of suspected human teratogens. Teratology 46(1):69, 1992

Kieler H, Artama M, Engeland A, et al: Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population based cohort study from the ive Nordic countries. BM] 344:d8012, 2012

King RW, Baca M], Armenti VT, et al: Pregnancy outcomes related to mycophenolate exposure in female kidney transplant recipients. Ams] Transplant 17(1):151,s2017

Kirshon B, Wasserstrum N, Willis R, et al: Teratogenic efects of irst trimester cyclophosphamide therapy. Obstet Gynecol 72(3Pt2):462, 1988

Klarskov P, Andersen ]T, Jimenez-Solem E, et al: Short-acting sulfonamides near term and neonatal jaundice. Obstet Gynecolsl22(1):105, 2013

Klip H, Verloop], van Gool ]D, et al: Hypospadias in sons of women exposed to diethylstilbestrol in utero: a cohort study. Lancet 359(9312): 11 02, 2002

Koren G, Bologa M, Long D, et al: Perception of teratogenic risk by pregnant women exposed to drugs and chemicals during the irst trimester. Am ] Obstet GynecoIs160(5Ptl):1190, 1989

Koren G, Florescu A, Costei AM, et al: Nonsteroidal anti-inflammatory drugs during third trimester and the risk of premature closure of the ductus arteriosus: a meta-analysis. Ann Pharmacother 40(5):824, 2006

Koren G, PastuszakA, Ito S: Drugs in pregnancy. N Engl] Med 338(16):1128, 1998

Kutscher AH, Zegarelli EV, Tovell HM, et al: Discoloration of deciduous teeth induced by administration of tetracycline antepartum. Am] Obstet Gynecol 96(2):291, 1966

Lammer E], Chen DT, Hoar M, et al: Retinoic acid embryopathy. N Engls] Med 313(14):83 , 1985

Lemoine P, Harouusseau H, Borteyru]P, et al: Les enfants de parents alcooliques: anomalies observees, a propos de 127 cas. Ouest Med 21 :476, 1968

Lenz W, Knapp K: Thalidomide embryopathy. Arch Environ Health 5: 1 00, 1962

Li DK, Yang C, Andrade S, et al: Matenal exposure to angiotensin converting enzyme inhibitors in the irst trimester and risk of malformations in ofspring: a retrospective cohort study. BM] 343:d5931, 2011

Lin S, Munsie ]P, Herdt-Losavio ML, et al: Maternal asthma medication use and the risk of selected birth defects. Pediatrics 129(2):317, 2012

Lind ]N, Petersen EE, Lederer PA, et al: Infant and maternal characteristics in neonatal abstinence syndrome-selected hospitals in Florida, 2010-2011. MMWR 64(8):213,s2015

Lipshultz SE, Frassica JJ, Orav E]: Cardiovascular abnormalities in infants prenatally exposed to cocaine.] Pediatr 118(1):44,s1991

Maier SE, West ]R: Drinking pattens and alcohol-related birth defects. Alcohol Res Health 25(3):168, 2001

Malik S, Cleves MA, Honein A, et al: Maternal smoking and congenital heart defects. Pediatrics 121(4):e810, 2008

Martinez-Frias ML, Czeizel AE, Rodriguez-Pinilla E, et al: Smoking during pregnancy and Poland sequence: results of a population-based registry and a case-control registry. Teratology 59(1):35, 1999

May PA, Baete A, Russo J, et al: Prevalence and characteristics of fetal alcohol spectrum disorders. Pediatrics 134(5):855,o2014

May PA, Gossage JP, Kalberg WO, et al: Prevalence and epidemiologic characteristics ofFASD from various research methods with an emphasis on recent in-school studies. Dev Disabil Res Rev 15(3): 176, 2009

McKeigue PM, Lamm SH, Linn S, et al: Bendectin and birth defects: 1. A meta-analysis of the epidemiologic studies. Teratology 50(1):27, 1994

Meador KJ, Baker GA, Browning N, et al: Cognitive function at 3 years of age ater fetal exposure to antiepileptic drugs. N EnglJ Med 360(16):1597,o2009 Merlob P, Stahl B, Klinger G: Tetrada of the possible mycophenolate mofetil embryopathy: a review. Reprod ToxicoIo28(1):105, 2009

Mitchell A, Gilboa SM, Werler MM, et al: Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008. Am J Obstet GynecoIo205(1):51,e1,2011

M0lgaard-Nielsen D, Hviid A: Newer-generation antiepileptic drugs and the risk of major birth defects. JAMA 305(19):1996,o2011

M01gaard-Nielsen D, Pasternak B, Hviid A: Use of oral fluconazole during pregnancy and the risk of birth defects. N Engl J Med 369(9):830, 2013 Munsie JW, Lin S, Browne ML, et al: Maternal bronchodilator use and the risk of oral clefts. Hum Reprod 26(11):3147,o2011

Nurmohamed L, Moretti ME, Schechter T, et al: Outcome following highdose methotrexate in pregnancies misdiagnosed as ectopic. Am J Obstet GynecoIo205(6):533.e1,o2011

Oakley GP, Erickson JD: Vitamin A and birth defects. N Engl J Med 333(21):1414, 1995

Ornoy A, Koren G: Selective serotonin reuptake inhibitors during pregnancy: do we have now more definite answers related to prenatal exposure? Birth Defects Res 109(12):898:2017

Paintner A, Williams AD, Burd L: Fetal alcohol spectrum disorders-implications for child neurology, Part 2: diagnosis and management. J Child NeuroIo27(3):355,o2012

Panchaud A, Csajka C, Merlob P, et al: Pregnancy outcome following exposure to topical retinoids: a multicenter prospective study. J Clin Pharmacol 52(12):1844,o2012

Park-Wyllie L, Mazzota P, Pastuszak A, et al: Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology 62(6):385, 2000

Patorno E, Huybrechts KF, Bateman BT, et al: Lithium use in pregnancy and the risk of cardiac malformations. N Engl J Med 376(23):2245, 2017

Pearson MA, Hoyme HE, Seaver LH, et al: Toluene embryopathy: delineation of the phenotype and comparison with fetal alcohol syndrome. Pediatrics 93(2):211, 1994

Pryde PG, Sedman AB, Nugent CE, et al: Angiotensin converting enzyme inhibitor fetopathy. J Am Soc NephroIo3(9):1575, 1993

Rasanen J, Jouppila P: Fetal cardiac function and ductus arteriosus during indomethacin and sulindac therapy for threatened preterm labor: a randomized study. Am J Obstet Gynecol 173(1):20, 1995

Reefhuis J, Gilboa SM, Anderka M, et al: The National Birth Defects Prevention Study: a review of the methods. Birth Defects Res A Clin Mol Teratol 103(8):656,o2015

Richardson S, Browne ML, Rasmussen SA, et al: Associations between periconceptional alcohol consumption and craniosynostosis, omphalocele, and gastroschisis. Birth Defects Res A Clin Mol Teratol 91 (7):623,2011

Rocheleau CM, Bertke SJ, Lawson CC, et al: Maternal occupational pesticide exposure and risk of congenital heart defects in the National Birth Defects Prevention Study. Birth Defects Res A Clin Mol Teratolo103(1 0):823,2015 Rothman KJ, Moore LL, Singer MR, et al: Teratogenicity of high vitamin A intake. N Engl J Med 333(21):1369, 1995 Sadler W (ed): Langman's Medical Embryology, 6th ed. Baltimore, Williams & Wilkins, 1990, p 130

Salle B, Sergeant P, Awada A, et al: Transvaginal ultrasound studies of vascular and morphological changes in uteri exposed to diethylstilbestrol in utero. Hum Reprod 11(11):2531, 1996

Sanofi-Aventis: Arava (Lelunomide) prescribing information, 20o16. Available at: http://products.sanoi.us/arava/arava.htmll. Accessed September 24, 2017 Schardein JL: Congenital abnormalities and hormones during pregnancy: a clinical review. Teratology 22(3):251,o1980

Sebela Pharmaceuticals: Pexeva (Paroxetine) prescribing information, 2017. Available at: ww.pexeva.com/pdf/Pexeva_20140728_ver .pd. Accessed September 24, 2017

Sheehan DM: Herbal medicines, phytoestrogens and toxicity: risk:beneit considerations. Proc Soc Exp BioI Med 21 (3):379, 1998

Shepard TH: Annual commentary on human teratogens. Teratology 66(6):275, 2002a Shepard TH: Letters: "proof' of human teratogenicity. Teratology 50(2):97, 1994

Shepard TH, Brent L, Friedman JM, et al: Update on new developments in the study of human teratogens. Teratology 65(4): 153, 2002b

Smith LM, LaGasse LL, Derauf C, et al: he infant development, environment, and lifestyle study: efects of prenatal methamphetamine exposure, polydrug exposure, and poverty on intrauterine growth. Pediatrics 118(3): 1149,2006

Stewart D, Nelson DB, Adhikari EH, et al: he obstetrical and neonatal impact of maternal opioid detoxification in pregnancy. Am J Obstet Gynecol 209(3):267, 2013

Stiefel Laboratories Soriatane (acitretin) prescribing information. 2015.

Available at: https:/ Iwww.gsksource.com/pharma/ con tentl dam I G laxoSmi thKline/USI en/P rescribin�Informationl Soriatanel pdfl SO RIA T ANEPI-MG. PDF. Accessed September 24,o2017

Stillerman KP, Mattison DR, Giudice LC, et al: Environmental exposures and adverse pregnancy outcomes: a review of the science. Reprod Sci 15(7):631, 2008

Stillman RJ: In utero exposure to diethylstilbestrol: adverse efects on the reproductive tract and reproductive performance in male and female ofspring. Am J Obstet Gynecol 142(7):905, 1982 Stingone JA, Luben TJ, Carmichael SL, et al: Maternal exposure to nitrogen dioxide, intake of methyl nutrients and congenital heart defects in ofspring. AmoJ EpidemioIo186(6):719, 2017 Stothard KJ, Tennant PWG, Bell R, et al: Maternal overweight and obesity and the risk of congenital anomalies: a systematic review and meta-analysis. JAMA 301(6):636,o2009

Strandberg-Larsen K, Nielsen NR, Gf0nbaek M, et al: Binge drinking in pregnancy and risk of fetal death. Obstet Gynecol III(3):602, 2008 Streissguth AP, Clarren SK, Jones L: Natural history of fetal alcohol syndrome: a 10-year follow-up of eleven patients. Lancet 2:85, 1985

Sullivan PM, Dervan A, Reiger S, et al: Risk of congenital heart defects in the ofspring of smoking mothers: a population-based study. J Pediatr 166(4):978,o2015

Teratology Society Public Afairs Committee: Causation in teratology-related litigation. Birth Def Res A Clin Mol Teratol 3(6):421,o2005

Vajda FJ, O'Brien TJ, Lander CM, et al: Antiepileptic drug combinations not involving valproate and the risk of fetal malformations. Epilepsia 57(7):1048,o2016

Valeant Pharmaceuticals: Tagretin (Bexarotene) prescribing information, 2015. Available at: http://ww.valeant.com/Portals/25/PDF/TargretinCapsulesP1.pd?ver=2016-05-1o1-044521-020. Accessed September 24,o2017 van der Heijden BJ, Carlus C, Narcy F, et al: Persistent anuria, neonatal death, and renal microcystic lesions after prenatal exposure to indomethacin. Am J Obstet GynecoIo171(3):617, 1994

Van Driel D, Wesseling J, Sauer PJ, et al: Teratogen update: fetal efects after in utero exposure to coumarins overview of cases, follow-up findings, and pathogenesis. Teratology 66(3):127,o2002

Van Gelder MM, Reehuis J, Caton R, et al: Maternal periconceptional illicit drug use and the risk of congenital malformations. Epidemiology 20:60, 2009 Vargesson N: halidomide-induced teratogenesis: history and mechanisms.

Birth Defects Res C Embryo Today 105(2):140, 2015

Vessey MP: Epidemiological studies of the efects of diethylstilbestrol. IARC Sci Pub1o335, 1989

Walker MP, Moore TR, Brace A: Indomethacin and arginine vasopressin interaction in the fetal kidney. A mechanism of oliguria. Am J Obstet Gynecol 171(5):1234, 1994

Waller DK, Shaw GM, Rasmussen SA, et al: Prepregnancy obesity as risk factor for structural birth defects. Arch Pediatr Adolesc Med 161(8):745,2007 Warkany J: Warfarin embryopathy. Teratology 14(2):205, 1976

Weiss CF, Glazko AJ, Weston JK: Chloramphenicol in the newborn infant: a physiologic explanation of its toxicity when given in excessive doses. N Engl J Med 262:787, 1960

Werler MM: Teratogen update: smoking and reproductive outcomes. Teratology 55(6):382, 1997

Weston J, Bromley R, Jackson CF, et al: Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database Syst Rev 11 :CDO 1 0224, 2016

West-Ward Pharmaceuticals: Lithium prescribing information, 20o16. Available at: https:/ Idailymed.nlm.nih.gov/dailymed/fda/fdaDruXsl.cfm?setid =a226a88d-eb5 7 -4c96-afda-93980 1 bcaOa9&type=display. Accessed September 24, 2017

Wiesner J, Knoss W: Herbal medicinal products in pregnancy-which data are available? Reprod Toxicol 72:142, 201

Wilkins-Haug L: Teratogen update: toluene. Teratology 55(2):145, 1997 Williams JF, Smith VC, American Academy of Pediatrics Committee on Substance Abuse: Fetal alcohol spectrum disorders. Pediatrics 136(5):e1395, 2015

Yacobi S, Ornoy A: Is lithium a real teratogen? What can we conclude from the prospective versus retrospective studies? A review. Isr J Psychiatry Relat Sci 45(2):95, 2008

Zelson C, Lee SJ, Casalino M: Neonatal narcotic addiction: comparative efects of maternal intake of heroin and methadone. N Engl J Med 289(23):1216, 1973

GENOMICS IN OBSTETRICSe. . . . . . . . . . . . . . . . . . . . . . . 253

ABNORMALITIES OF CHROMOSOME NUMBER .e.e. .e. 254

ABNORMALITIES OF CHROMOSOME STRUCTURE .... 260

CHROMOSOMAL MOSAICISM .. .e. .e.... .e.. ... . . 263

MODES OF INHERITANCE .. .e... ..e...e. ..e.e. .e. ..e. 264

CYTOGENETIC ANALYSIS . . . . . . . . . . . . . . . . . . . . . . . . 270

CHROMOSOMAL MICROARRAY ANALYSIS . .e.. .e. .e... 271

WHOLE GENOME AND WHOLE EXOME SEQUENCINGe.. 272

FETAL DNA IN THE MATERNAL CIRCULATION ...e. .e. 273

Foetal death may be due to abnormalities in the ovum itsef or due to some disease on the part of the mother, and now and again of the ather. The death of the oetus is frequenty due to abnormalities in the development of the embyo which are inconsistent with oetal le.

-J. Whitridge Williams (1903)

In Williams' irst edition of Obstetrics, he rarely referenced inherited conditions that Gregor Mendel had described 50 years earlier. Fast-forward to 2017, when the science of genetics is a major obstetrical discipline.

Genetics is the study of genes, heredity, and the variation of inherited characteristics. Medical genetics deals with the etiology and pathogenesis of human diseases that are at least partially genetic in origin, along with their prediction and prevention. Thus, it is closely linked to genomics, which is the study of gene function and interaction. In addition to chromosomal, mendelian, and nonmendelian genetic conditions reviewed in this chapter, medical genetics includes prenatal and preimplantation genetic diagnosis, as well as newborn genetic screening, which are discussed in Chapters 14 and 32, respectively.

Genetic disease is common. Between 2 and 3 percent of newborns have a recognized structural defect. In another 3 percent of individuals, a defect is diagnosed by age 5, and another 8 to 10 percent of persons are discovered by age 18 to have one or more functional or developmental abnormalities. Advances in genomics are used increasingly to provide information regarding susceptibility to genetic diseases, and every indication suggests that this ield will reshape prenatal diagnosis.

Completed in 2003, the Human Genome Project identiied more than 25,000 human genes and led to rapid expansion of genomic research to better understand disease biology (McKusick, 2003). More than 99 percent of our DNA is identical. However, genetic code varies every 200 to 500 base pairs, usually as a single-nucleotide polymorphism. The human genome contains more than 80 million such genetic variants, and understanding their potential role in disease requires not only sophisticated interpretation but also integration of resources (Rehm, 2015).

The National Center for Biotechnology Information (NCB!) maintains genetic and genomic databases that are freely accessible to clinicians and researchers. Several of these databases are particularly useful in obstetrics and maternal-fetal medicine practice. he GeneReviews database provides in-depth clinical information for nearly 700 genetic conditions, including diagnostic criteria, management, and genetic counseling considerations (National Center for Biotechnology Information, 2017a). The Genetic Testing Registry (GTR) database contains information regarding the beneits and limitations of available tests for a given disorder. It lists more than 48,000 genetic tests and instructions for specimen collection and transport to individual laboratories throughout the world (National Center for Biotechnology Information, 2017b). Another database, Online Mendelian Inheritance in Man (OMIM), is a comprehensive catalog of human genes and phenotypes that allows clinicians to search for syndromes based on particular traits or abnormalities. As of early 2017, OMIM included more than 15,000 genes and nearly 5000 mendelian and mitochondrial conditions with a known molecular basis Oohns Hopkins University, 2017). The National Library of Medicine (2017) has also established a database of genetic information intended for patients-one that trainees may find especially helpful-the Genetics Home Reerence (GHR). his database contains data on more than 2400 genetic conditions and genes, including resources for families.

Chromosomal abnormalities igure prominently in genetic disease. Aneuploidy accounts for more than 50 percent of irst-trimester miscarriages, approximately 20 percent of second-trimester losses, and 6 to 8 percent of stillbirths and early-childhood deaths (Reddy, 2012; Stevenson, 2004; Wou, 2016). In the European Surveillance of Congenital Anomalies (EUROCAT) network of population-based registries, chromosomal abnormalities were identiied in 0.4 percent of births (Wellesley, 2012). Of recognized pregnancies with aneuploidy, trisomy 21 composes just more than half of all cases. Trisomy 18 accounts for almost 15 percent, and trisomy 13 for 5 percent (Fig.

Karyotypes are described using the International System for Human Cytogenomic Nomenclature (McGowan-Jordan,

Trisomy 21 (23:10,000) 0 45,X (3:10,000)

Trisomy 18 (6: 1 0,000) o 47,XXX; 47,XXY; 47,XYY (2:1e0,000) o Trisomy 13 (2:10,000) o Other (23: 10,000)

FIGURE 13-1 Prevalence and relative proportion of selected chromosomal abnormalities from EUROCAT (European Surveillance of Congenital Anomalies) population-based registries that included > 10,000 aneuploid live births, fetal deaths, and pregnancy terminations, 2000-2006. (Data from Wellesley, 2012.) 2016). Abnormalities fall into two broad categories-those of chromosome number, such as trisom)i, and those of chromosome structure, such as a deletion or translocation. Each chromosome has a short arm, termed the "p" or petit arm, and a long arm, known as the "q" arm, selected because it is the next letter in the alphabet. The two arms are separated by the centromere.

When reporting a karyotype, the total number of chromosomes is listed irst, corresponding to the number of centro meres. This is followed by the sex chromosomes, X or Y, and then by a description of any structural variation. Speciic abnormalities are indicated by standard abbreviations, such as del (deletion) and inv (inversion). he afected region or bands of the p or q arms are then designated, so that the reader will know the exact abnormality location and type. Examples are shown in Table

Terminology is similar for fluorescence in situ hybridization. Described on page 270, this technique is used to rapidly identiy of a specific chromosome abnormality and veriy suspected microdeletion or microduplication syndromes. The report begins with the designation ish for in situ hybridization performed on metaphase cells and nuc ish for hybridization performed on interphase nuclei. If no abnormality is identified, this is followed by the probe's specific chromosomal region, such as 22q 11i.2, and then the name of the probe and the number of signals visualized-for example, HIRAx2. If a deletion is identified, del is included before the chromosomal region, and the name of the probe is followed by a minus sign (HIRA-), as shown in Table 13-1. The 22q 11.2 microdeletion syndrome is discussed on page 260.

A recent addition to the standard nomenclature is terminology to represent copy number variants identiied by chromosomal microarray anaysis, which is discussed on page 271. Copy number variant is another term for a microdeletion or microduplication of DNA too small to be visualized with a standard karyotype. The array designation begins with the abbreviation arr and the version of the genome build to which the nucleotide designations are aligned, such as GRCh38 for Genome Reference Consortium human build 38. his is followed by the number of the chromosome on which the abnormality is identified, by the p or q arm, and by the speciic bands in question. Array reports next include the afected base pair coordinates, thus conveying the exact size and location within the genome for every abnormality identiied-including copy number variants of uncertain signiicance .

• Abnormalities of Chromosome Number

The most easily recognized chromosomal abnormalities are numerical. Aneuploidy is inheritance of either an extra chromosome-resulting in trisomy, or loss of a chromosomemonosomy. These difer from poyploidy, which is an abnormal number of haploid chromosome sets, such as triploidy. The estimated incidence of various numerical chromosomal abnormalities is shown in Figure 13-1.

These account for approximately half of all chromosomal abnormalities. In most cases, trisomy results from nondisjunction,

TABLE 13-1. Examples of Karyotype Designations Using the 2016 International System for Human Cytogenetic Nomenclature 46,XX Normal female chromosome constitution 47,XY,+21 Male with trisomy 21 47,XX,+21/46,XX Female who is a mosaic of trisomy 21 cells and cells with normal constitution 46,XY,del(4)(p 14) Male with terminal deletion (del) of the short arm of chromosome 4 at band p 14 46,XX,dup(5)(p 14p 15.3) Female with duplication (dup) of the short arm of chromosome 5 from band p14 to band p15.3 45,XY,derCi 3;14)(q 1 O;q 10) Male with balanced robertsonian translocation (der) of the long arms of chromosomes 13 and 14-the karyotype now has one normal 13, one normal 14, and the translocation chromosome. reducing the normal 46 chromosome complement to 45 46,XX,t(11 ;22)(q23;q 11l.2) Female with a balanced reciprocal translocation (t) between chromosomes 11 and 22, with breakpoints at 11 q23 and 22q 11l.2 46,XY,inv(3)(p21 q 13) Male with inversion (inv) of chromosome 3 that extends from p21 to q 13-a pericentric inversion because it includes the centromere 46,X,r(X)(p22.1 q27) Female with one normal X and one ring (r) X chromosome, with the regions distal to p22.1 and q27 deleted from the ring 46,X,i(X)(q 10) Female with one normal X chromosome and an isochromosome (i) of the long arm of the ish 22q11l.2(HIRAx2) FISH of metaphase cells using a probe for the HIRA locus of the 22q 11l.2 region, with 2 signals identified (no evidence of microdeletion) ish del(22)(q 11.2q 11l.2) (HIRA-) FISH of metaphase cells using a probe for the HIRA locus of the 22q11l.2 region, with only one signal identified, consistent with the microdeletion arr[GRCh38] 18p 11.32q23 Microarray analysis (arr), genome build GRCh38, showing a single copy gain on (102328_79093443)x3 chromosome 18 from band p11.32 to band q23 (essentially the entire chromosome), consistent with trisomy 18 arr[GRCh38] 4q32.2q35.1 Microarray analysis (arr), genome build GRCh38, showing a copy loss on the long arm of (163146681_183022312)x1 chromosome 4 at bands q32.2 through q35.1 (19.9 Mb) arr[GRCh38] 15q 11l.2q26 SNP microarray analysis (arr), genome build GRCh 38, showing homozygosity for the entire (23123715_101888908)x2 long arm of chromosome 15 cycle regulator; SNP = single nucleotide pleomorphism.

Used with permission from Dr. Kathleen S. Wilson.

which is failure of normal chromosomal pairing and separation during meiosis. Nondisjunction may occur if the chromosomes: (1) fail to pair up, (2) pair up properly but separate prematurely, or (3) fail to separate.

he risk of any autosomal trisomy rises steeply with maternal age, particularly after age 35 (Fig. 13-2). Oocytes are suspended in midprophase of meiosis I from birth until ovulation, in some cases for 50 years. Following completion of meiosis at ovulation, nondisjunction results in one gamete having two copies of the afected chromosome, leading to trisomy if fertilized. he other gamete, receiving no copy of the afected chromosome, will be monosomic if fertilized. It is estimated that 10 to 20 percent of oocytes are aneuploid secondary to meiotic errors, compared with 3 to 4 percent of sperm. lthough each chromosome pair is equally likely to have a segregation error, programs in the United States, 2006-2010, which included live it is rare for trisomies other than 21, 18, or 13 to result in a births, stillbirths, and pregnancy terminations. (Data from Mai, 2013. term pregnancy, and most fetuses with trisomies 18 and 13 die Redrawn with permission from Dashe JS: Aneuploidy screening. before term. Obstet GynecoIo128(1):181, 2016.) 6 10 11'.13 14 16 19

FIGURE 13-3 Abnormal male karyotype with trisomy 21, consistent with Down syndrome (47,XY,+21). (Used with permission from

Dr. Frederick Elder.)

Mter a pregnancy with an autosomal trisomy, the risk for any autosomal trisomy in a future pregnancy approximates 1 percent until the woman's age-related risk exceeds this. Accordingly, prenatal diagnosis with chorionic villus sampling or amniocentesis is ofered in these subsequent pregnancies (Chap. 14, p. 292). Parental chromosomal studies are not indicated unless the afected pregnancy was caused by an unbalanced translocation or other structural rearrangement.

Trisomy 21-Down Syndrome. In 1866, ]. L. H. Down described a group of intellectually disabled children with distinctive physical features. Nearly 100 years later, Lejeune (1959) demonstrated that Down syndrome is caused by an autosomal trisomy (Fig. 13-3). Trisomy 21 causes 95 percent of Down syndrome cases, whereas 3 to 4 percent of cases are due to a robertsonian translocation, described later (p. 262). he remaining 1 to 2 percent results from an isochromosome or from mosaicism. he nondisjunction that yields trisomy 21 occurs during meiosis I in approximately 75 percent of cases, and the remaining events are during meiosis II.

Down syndrome is the most common nonlethal trisomy.

Its approximate prevalence is 1 in 500 recognized pregnancies. However, fetal losses and pregnancy terminations yield an estimated prevalence of 13.5 in 10,000 births in the United States-1 per 740 (Mai, 2013; Parker, 2010). he fetal death rate beyond 20 weeks' gestation approximates 5 percent (Loane, 2013). Coinciding with the older maternal age distribution during the past four decades, the prevalence of Down syndrome has risen approximately 33 percent (Loane, 2013; Parker, 2010; Shin, 2009).

Notably, adult women with Down syndrome are fertile, and a third of their ofspring will have Down syndrome (Scharrer, 1975). Males with Down syndrome are almost always sterile because of markedly reduced spermatogenesis.

Approximately 30 percent of second-trimester fetuses with Down syndrome have a major malformation that can be identified sonographically (Hussamy, 2017; Vintzileos, 1995). As discussed in Chapter 14 (p. 286), when both major anomalies and minor aneuploidy markers are considered, an estimated 50 to 60 percent of Down syndrome pregnancies can be detected sonographically (American College of Obstetricians and Gynecologists, 2016d). Approximately half of liveborn neonates with Down syndrome are found to have cardiac defects, particularly ventricular septal defects and endocardial cushion defects (Figs. 10-29 and 10-30, p. 202) (Bergstrom, 2016; Freeman, 2008). Gastrointestinal abnormalities are identiied in 12 percent and include esophageal atresia, Hirschsprung disease, and duodenal atresia (Fig. 10-38, p. 207) (Bull, 2011).

Characteristic features of Down syndrome are shown in

Figure 13-4. Typical indings include brachycephaly; epicanthaI folds and up-slanting palpebral issures; Brushield spots, which are grayish spots on the periphery of the iris; a lat nasal bridge; and hypotonia. Infants often have loose skin at the nape of the neck, short ingers, a single palmar crease, hypoplasia of the middle phalanx of the fifth finger, and a prominent space or "sandal-toe gap" between the irst and second toes. Some of these indings are prenatal sonographic markers for Down syndrome, reviewed in Chapter 14 (p. 286).

Health problems common in children with Down syndrome include hearing loss in 75 percent, severe optical refractive

FIGURE 13-4 Trisomy 21-Down syndrome. A. Characteristic facial appearance. B. Redundant nuchal tissue. C. Single transverse palmar crease. (Used with permission from Dr. Charles P. Read and Dr. Lewis Waber.) errors in 50 percent, cataracts in 15 percent, obstructive sleep apnea in 60 percent, thyroid disease in 15 percent, and a higher incidence of leukemia (Bull, 2011). The degree of mental impairment is usually mild to moderate, with an average intelligence quotient (IQ) score of 35 to 70. Social skills in afected children are often higher than predicted by their IQ scores.

Data suggest that approximately 95 percent of liveborn infants with Down syndrome survive the irst year. The 10-year survival rate is at least 90 percent overall and is 99 percent if major malformations are absent (Rankin, 2012; Vendola, 2010). Several organizations ofer education and support for prospective parents faced with prenatal diagnosis of Down syndrome. These include the March of Dimes, National Down Syndrome Congress (ww.ndsccenter.org), and National Down Syndrome Society (ww.ndss.org).

Trisomy l8-Edwards Syndrome. he association between this constellation of abnormalities and an autosomal trisomy was irst described by Edwards (1960). In population-based series, prevalence of trisomy 18 approximates 1 in 2000 recognized pregnancies-including abortuses, stillbirths, and live births, and approximately 1 in 6600 liveborn neonates (Loane, 2013; Parker, 2010). he diference in prevalence is explained by the high in-utero lethality of the condition and the termination of many afected pregnancies. Perhaps not surprisingly, survival of liveborn neonates is likewise bleak. .10re than half die within the irst week, and the I-year survival rate approximates only 2 percent (Tennant, 2010; Vendola, 2010). The syndrome is three-to fourfold more common in females (Lin, 2006; Rosa, 2011) . Unlike Down and Patau syndromes, which involve acrocentric chromosomes and thus may stem from a robertsonian translocation, Edwards syndrome uncommonly results from a chromosomal rearrangement.

Virtually every organ system can be afected by trisomy 18. Common major anomalies include heart defects in more than 90 percent-particularly ventricular septal defects, as well as cerebellar vermian agenesis, myelomeningocele, diaphragmatic hernia, omphalocele, imperforate anus, and renal anomalies such as horseshoe kidney (Lin, 2006; Rosa, 2011; Yeo, 2003).

Sonographic images of several of these are shown in Chapter 10.

Cranial and extremity abnormalities are also frequent and include a prominent occiput, posteriorly rotated and malformed ears, micrognathia, clenched hands with overlapping digits, radial aplasia with hyperflexion of the wrists, and rockerbottom or clubbed feet (Fig. 13-5). A "strawberry-shaped" cranium is noted in approximately 40 percent of cases, abnormally wide cavum septum pellucidum in more than 90 percent, and choroid plexus cysts in up to 50 percent (Abele, 2013; Yeo, 2003). Importantly, isolated choroid plexus cysts are not associated with trisomy 18. These cysts only raise the risk for trisomy 18 if fetal structural abnormalities or an abnormal aneuploidy screening test result is also present (Reddy, 2014).

Pregnancies with trisomy 18 that reach the third trimester often develop fetal-growth restriction, and the mean birthweight is <2500 g (Lin, 2006; Rosa, 201l). Because abnormal fetal heart rate tracings are common during labor, mode of delivery and management of heart rate abnormalities should be discussed in advance. In older reports, more than half of undiagnosed fetuses underwent cesarean delivery for "fetal distress" (Schneider, 1981).

Trisomy l3-Patau Syndrome. This constellation of fetal abnormalities and their association with an autosomal trisomy was irst described by Patau and colleagues (1960). The prevalence of trisomy 13 approximates 1 in 12,000 live births and 1 in 5000 recognized pregnancies, which includes abortuses and stillbirths (Loane, 2013; Parker, 2010). As with trisomy 18, trisomy 13 is highly lethal, and most afected fetuses are lost or terminated.

Approximately 80 percent of pregnancies with Patau syndrome result from trisomy 13. The remainder is caused by a robertsonian translocation involving chromosome 13. The most frequent structural chromosomal rearrangement is a translocation between chromosomes 13 and 14, der(l3; 14) (q 1 O;q 10). This translocation is carried by approximately 1 in 1300 individuals, although the risk of an afected liveborn neonate is less than 2 percent (Nussbaum, 2007).

FIGURE 13-5 Trisomy 18-Edwards Syndrome. A. This transventricular sonographic view shows fetal choroid plexus cysts and an angulated "strawberry-shaped" skull. B. Radial clubhand is manifested as a single forearm bone (radius), with the hands in a fixed, hyperflexed position at right angles to the forearms. C. This three-dimensional (3-�) sonographic image shows the characteristic hand position of clenched fists with overlapping digits. D. 3-D sonographic image displays a rockerbottom foot.

Trisomy 13 is associated with abnormalities of virtually every organ system. One characteristic finding is holoprosencephaly (Fig. 10-15, p. 195). his is present in approximately two thirds of cases and may be accompanied by microcephaly, hypotelorism, and nasal abnormalities that range from a single nostril to a proboscis. Cardiac defects are found in up to 90 percent of fetuses with trisomy 13 (Shipp, 2002). Other abnormalities that suggest trisomy 13 include neural-tube defectsparticularly cephalocele, microphthalmia, cleft lip-palate, omphalocele, cystic renal dysplasia, polydactyly, rockerbottom feet, and areas of skin aplasia (Lin, 2007). For the fetus or newborn with a cephalocele, cystic kidneys, and polydactyly, the diferential diagnosis includes trisomy 13 and the autosomalrecessive Meckel-Gruber syndrome. Sonographic images of several of these are shown in Chapter 10 (p. 192).

Few fetuses with trisomy 13 survive until birth. Of those that do, the I-week survival rate approximates 40 percent, and I-year survival rate is only about 3 percent (Tennant, 2010; Vendola, 2010). Counseling regarding prenatal diagnosis and management options is similar to that described for trisomy 18.

Unlike other aneuploidies, fetal trisomy 13 confers risk to the pregnant woman. Hyperplacentosis and preeclampsia develop in up to half of pregnancies with trisomy 13 carried beyond the second trimester (Tuohy, 1992). Chromosome 13 contains the gene for soluble fms-like tyrosine kinase-1 (sFlt-l), which is an anti angiogenic protein associated with preeclampsia (Chap. 40, p. 716). Investigators have documented overexpression of the slt-1 protein by trisomic 13 placentas and in serum of women with preeclampsia (Bdolah, 2006; Silasi, 2011).

Other Trisomies. In the absence of mosaicism, discussed later (p. 263), other autosomal trisomies rarely yield a liveborn neonate. Case of live births with trisomy 9 and with trisomy 22 have been noted (Kannan, 2009; Tinkle, 2003). Trisomy 16 is the most common trisomy found with first-trimester losses and accounts for 16 percent of these losses. However, it is not identiied later in gestation. Trisomy 1 has never been reported.

Nondisjunction creates an equal number of nullisomic and disomic gametes. As a rule, missing chromosomal material is more devastating than extra chromosomal material, and almost all monosomic conceptuses are lost before implantation. he one exception is monosomy for the X chromosome (45,X), Turner syndrome, which is discussed subsequently. Despite the strong association between maternal age and trisomy, maternal age and monosomy are not linked.

This is an abnormal number of complete haploid chromosomal sets. Polyploidy accounts for approximately 20 percent of spon taneous abortions but is rare in later gestations.

Triploid pregnancies have three haploid sets-69 chromosomes. One parent must contribute two sets, and the phenotypic presentation difers according to the parent of origin. With diandric triploidy, also known as type I triploidy, the extra chromosomal set is paternal, resulting from fertilization of one egg by two sperm or by a single diploid-and thus abnormal-sperm. Diandric triploidy produces a partial molar pregnancy, discussed in Chapter 20 (p. 389). Diandric triploidy accounts for most triploid conceptions, but their first-trimester loss rate is extremely high. As a result, two thirds of triploid pregnancies identified beyond the first trimester are caused instead by diynic triploidy Q auniaux, 1999). With a digynic triploid pregnancy, also known as type II triploidy, the extra chromosomal set is maternal, and the egg fails to undergo the irst or second meiotic division before fertilization. Digynic triploid placentas do not develop molar changes. However, the fetus usually displays asymmetrical growth restriction.

he prevalence of recognized triploid pregnancies approximates 1 in 5000 pregnancies (Zalel, 2016). Triploidy is a lethal aneuploidy, and more than 90 percent of fetuses with either the diandric or digynic form have multiple structural anomalies. hese include central nervous system defects-particularly involving the posterior fossa, as well as cardiac, renal, and extremity anomalies Qauniaux, 1999; Zalel, 2016). Counseling, prenatal diagnosis, and delivery options are similar to those for trisomies 18 and 13. he recurrence risk for a woman whose triploid fetus survived past the first trimester is 1 to 1.5 percent, and thus prenatal diagnosis is ofered in future pregnancies (Gardner, 1996).

Tetraploid pregnancies have four haploid sets of chromosomes, resulting in either 92,XXor 92,YY. This suggests a postzygotic failure to complete an early cleavage division. The conceptus invariably succumbs, and the recurrence risk is minimal.

45, X-Turner Syndrome. First described by Turner (1938), this syndrome later was found to be caused by monosomy X (Ford, 1959). he prevalence of Turner syndrome is approximately 1 in 2500 liveborn girls (Cragan, 2009; Dolk, 2010). The missing X chromosome is paternally derived in 80 percent of cases (Cockwell, 1991; Hassold, 1990). Screening for Turner syndrome with cell-free DNA is discussed in Chapter 14 (p. 284).

Turner syndrome is the only monosomy compatible with life, but it is also the most common aneuploidy in first-trimester losses, accounting for 20 percent. his is explained by the wide range in phenotype. Approximately 98 percent of afected conceptuses are so abnormal that they abort early in the first trimester. Of the remainder, many manifest large, septated cystic hygromas in the late irst or early second trimester (Fig. 10-22, p. 198). When cystic hygromas are accompanied by hydrops fetalis, fetuses nearly always die in utero (Chap 15, p. 309).

Less than 1 percent of pregnancies with Turner syndrome yield a liveborn neonate. And, only half of these actually have monosomy X. Approximately a fourth have mosaicism, such as 45,X/46,XX or 45,Xl46,XY, and another 15 percent have isochromosome X, that is, 46,X,i(Xq) (Milunsky, 2004; Nuss baum, 2007).

Abnormalities associated with Turner syndrome include left sided cardiac defects-such as coarctation of the aorta, hypo plastic left heart syndrome, or bicuspid aortic valve-in 30 to 50 percent; renal anomalies, particularly horseshoe kidney; and hypothyroidism. Other features are short stature, broad chest with widely spaced nipples, congenital lymphedema-pui ness over the dorsum of hands and feet, and a "webbed" pos terior neck resulting from cystic hygromas. Intelligence scores are generally in the normal range, but afected individuals are at risk for diiculties with visual-spatial organization, nonver bal problem solving, and interpretation of social cues Q ones, 2006). Growth hormone is typically administered in childhood to ameliorate short stature (Kappelgaard, 201i1). More than 90 starting just before adolescence. An exception is mosaicism involving the Y chromosome, as this confers risk for germ cell neoplasm-regardless of whether the child is phenotypically male or female. Accordingly, eventual prophylactic bilateral gonadectomy is indicated (Cools, 2011; Schorge, 2016).

47,XXX. Approximately 1 in 1000 female newborns has an additional X chromosome-47,XXX. The extra X is maternally derived in more than 90 percent of cases (Milunsky, 2004). Afected infants do not have a characteristic appearance, and in the past most children did not come to attention until school age. However, the incidence of 47,XXiis weakly associated with maternal age, and cell-free DNA screening has resulted in increased diagnoses (Table 14-5, p. 281). Frequent features include tall stature, hypertelorism, epicanthal folds, kyphoscoliosis, clinodactyly, and hypotonia (Tartaglia, 2010; Wigby, 2016). More than a third are diagnosed with a learning disability, half have attention deicit disorder, and overall cognitive scores are in the low-average range. No speciic pattern of malformations has been described, but genitourinary problems and seizure disorders are more common (Wigby, 2016). Pubertal development is unafected. Primary ovarian insuiciency has been reported (Holland, 2001). Because of variable presentation and subtle abnormal indings, it is estimated that this diagnosis is ascertained clinically in only 10 percent of afected children.

Females with two or more extra X chromosomes-48,XXior 49,XXXX-are likely to have physical abnormalities apparent at birth. These abnormal X complements are associated with intellectual disability. For both males and females, the IQ score is lower with each additional X chromosome.

47,XXY-Klinefelter Syndrome. his is the most common sex chromosome abnormality and found in approximately 1 in 600 male infants. he additional X chromosome is maternally or paternally derived with equal propensity Qacobs, 1995; Lowe, 2001). The association with either advanced maternal or paternal age is weak (Milunsky, 2004).

Like 47,XX, newborns with 47,Y usually appear phenotypically normal and do not have a higher incidence of anomalies. As children, boys are typically taller than average and have normal prepubertal development. However, they have gonadal dysgenesis, do not undergo normal virilization, and require testosterone supplementation beginning in adolescence. They may develop gynecomastia. IQ scores usually lie in the average to low-average range, and many have delays in language development and reading (Boada, 2009; Girardin, 2011).

47,XY. This aneuploidy occurs in approximately 1 in 1000 male newborns. As with 47,XXand Y individuals, afected boys tend to be tall. A third have macrocephaly, nearly two thirds demonstrate hypotonia, and tremors are also common (Bardsley, 2013). Rates of major anomalies are not elevated, although hypertelorism and clinodactyly may be identified in more than hal. Pubertal development is normal, and fertility is unimpaired. ffected children carry risks for oral and written language impairments, attention deicit disorder is diagnosed in more than half, and the rate of autism spectrum disorder is also increased (Bardsley, 2013; Ross, 2009). Intelligence scores generally lie in the normal range.

Males with more than two Y chromosomes-48Yor with both additional X and Y chromosomes-48,YYor 49,XYY-are more likely to have congenital abnormalities, medical problems, and intellectual disability (Tartaglia, 2011).

• Abnormalities of Chromosome Structure

Structural chromosomal abnormalities include deletions, duplications, translocations, isochromosomes, inversions, ring chromosomes, and mosaicism (see Table 13-1). heir overall birth prevalence approximates 0.3 percent (Nussbaum, 2007). Identiication of a structural chromosomal abnormality raises two primary questions. First, what phenotypic abnormalities or later developmental abnormalities are associated with this finding? Second, is evaluation of parental karyotype indicated-speciically, are the parents at increased risk of carrying this abnormality? If so, what is their risk of having future afected ofspring?

A chromosomal deletion indicates that a portion of a chromosome is missing, whereas a duplication means that a portion has been included twice. Most deletions and duplications occur during meiosis and result from malalignment or mismatching during the pairing of homologous chromosomes. he misaligned segment may then be deleted, or if the mismatch remains when the two chromosomes recombine, it may result in a deletion in one chromosome and duplication in the other (Fig. 13-6). When a deletion or duplication is identified in a fetus or infant, parental karyotyping should be ofered, because if either parent carries a balanced translocation, the recurrence risk in subsequent pregnancies is signiicantly increased. Deletions involving DNA segments large enough to be seen with standard cytogenetic karyotyping are identiied in approximately 1 in 7000 births (Nussbaum, 2007). Common

FIGURE 13-6 A mismatch during pairing of homologous chromosomes may lead to a deletion in one chromosome and a duplication in the other. Del = deletion; Dupl duplication.

deletions may be referred to by eponyms-for example, del 5p is called cri du chat syndrome.

Microdeletions and Microduplications. These chromosomal deletions or duplications-smaller than 3 to 5 million base pairs-are too small to be detected with standard karyotyping. However, prenatal chromosomal micro array analysis (CMA) , described later (p. 271), permits identification of syndromes associated with these microdeletion or duplications. When CMA is used, the region of DNA that is missing or duplicated is termed a genomic copy number variant. Despite the relatively small size, a microdeletion or duplication may involve a stretch of DNA that contains multiple genes-causing a contiguous gene syndrome, which can encompass serious but unrelated phenotypic abnormalities (Schmickel, 1986). In some cases, a micro duplication may involve the exact DNA region that causes a recognized microdeletion syndrome (Table 13-2). When a speciic microdeletion syndrome is suspected clinically, it is confirmed using either CMA or luorescence in situ hybridization.

22qlel.2 Microdeletion Syndrome. his syndrome is also known as DiGeorge syndrome, Shprintzen syndrome, and velocardiofacial syndrome. It is the most common microdeletion, with a prevalence of 1 in 3000 to 6000 births. Although inherited in an autosomal dominant fashion, more than 90 percent of cases arise from de novo mutations. The full deletion includes 3 million base pairs, encompasses 40 genes, may include 180 diferent features, and thus poses some counseling challenges (Shprintzen, 2008). Features can vary widely, even among afected family members. Previously, diferent constellations of features were thought to characterize the DiGeorge and Shprintzen phenotypes, but it is now accepted that they represent the same microdeletion (McDonald-McGinn, 2015).

In approximately 75 percent of afected individuals, associated abnormalities include conotruncal cardiac anomalies,

Prevalence reflects live births.

Data from National Library of Medicine, 2017; Johns Hopkins University, 2017.

such as tetralogy of Fallot, truncus arteriosus, interrupted aortic arch, and ventricular septal defects (McDonald-McGinn, 2015). Immune deiciency, such as T-cell lymphopenia, also develops in approximately 75 percent. More than 70 percent have velopharyngeal insuiciency or cleft palate. Learning disabilities, autism spectrum disorder, and intellectual disability are also common. Other manifestations include hypocalcemia, renal anomalies, esophageal dysmotility, hearing loss, behavioral disorders, and psychiatric illness-particularly schizophrenia. Short palpebral issures, bulbous nasal tip, micrognathia, short philtrum, and small or posteriorly rotated ears are characteristic facial features.

hese are DNA rearrangements in which a segment of DNA breas away from one chromosome and attaches to another. he rearranged chromosomes are called derivative (der) chromosomes. here are two types-reciprocal and robertsonian translocations.

Reciprocal Translocations. A double-segment or reciprocal translocation begins when breaks occur in two diferent chromosomes. The broken fragments are then exchanged, so that each afected chromosome contains a fragment of the other. If no chromosomal material is gained or lost in this process, the translocation is considered balanced. he prevalence of reciprocal translocations approximates 1 in 600 births (Nussbaum, 2007). Although the balanced translocation carrier is usually normal phenotypically, repositioning of specific genes within chromosomal segments can cause abnormalities. he risk of a major sttuctural or developmental abnormality in an apparent balanced translocation carrier is approximately 6 percent. Interestingly, using CMA technology, up to 20 percent of individuals who appear to have a balanced translocation are found instead to have missing or redundant DNA segments (Manning,i2010).

Balanced translocation carriers are at risk to produce unbalanced gametes, resulting in abnormal ofspring. As shown in

FIGURE 13-7 A carrier of a balanced translocation may produce offspring who are also carriers ofthe balanced rearrangement (8), ofspring with unbalanced translocations (C, D), or ofspring with normal chromosomal complements (A).

n.N

Figure 13-7, if an oocyte or sperm contains a translocated chromosome, fertilization results in an unbalanced translocation-monosomy for part of one afected chromosome and trisomy for part of the other. he observed risk of a specific translocation can often be estimated by a genetic counselor. In general, translocation carriers identified after the birth of an abnormal child have a 5-to 30-percent risk of producing liveborn ofspring with an unbalanced translocation. Carriers identiied for other reasons, for example, during an infertility evaluation, have only a 5-percent risk. his is likely because the gametes are so abnormal that conceptions are nonviable.

Robertsonian Translocations. These involve only acrocentric chromosomes, which are chromosomes 13, 14, 15,i21, and 22. he acrocentric chromosomes have extremely short p arms. In a robertsonian translocation, the q arms of two acrocentric chromosomes fuse at one centromere to form a derivative chromosome. he other centromere and both sets of p arms are lost. Because the number of centromeres determines the chromosome count, a robertsonian translocation carrier has only 45 chromosomes. Fortunately, the p arms of the acrocentric chromosomes-the satellite regions-contain redundant copies of genes that code for ribosomal RNA. As these are present in multiple copies on other acrocentric chromosomes, their loss does not afect the translocation carrier, who is usually phenotypically normal. However, when the derivative chromosome is paired during fertilization with a haploid chromosome from the partner, resulting ofspring will be trisomic for that chromosome.

Robertsonian translocations are found in 1 in 1000 individuals. The incidence of abnormal ofspring approximates 15 percent if a robertsonian translocation is carried by the mother and 2 percent if carried by the father. Robertsonian translocations are not a major cause of miscarriage and are found in fewer than 5 percent of couples with recurrent pregnancy loss. When a fetus or child is found to have a translocation trisomy, both parents should be ofered karyotype analysis. If neither parent is a carrier, the recurrence risk is extremely low.

Balanced robertsonian carriers have reproductive diiculties for a number of reasons. Ifthe fused chromosomes are homologous, that is, from the same chromosome pair, the carrier can produce only unbalanced gametes. Each egg or sperm contains either both copies of the translocated chromosome, which would result in trisomy if fertilized, or no copy, which would result in monosomy. If the fused chromosomes are nonhomologous, four of the six possible gametes would be abnormal. he most common robertsonian translocation is der(13; 14) (ql0;ql0), which accounts for up to 20 percent of cases of Patau s) ndrome (p. 257).

These abnormal chromosomes are composed of either two q arms or two p arms of one chromosome fused together.

Isochromosomes are thought to arise when the centromere breaks transversely instead of longitudinally during meiosis II or mitosis. They can also result from a meiotic error in a chromosome with a robertsonian translocation. An isochromosome containing the q arms of an acrocentric chromosome behaves like a homologous robertsonian translocation, and such a carrier can produce only abnormal unbalanced gametes. When an isochromosome involves non acrocentric chromosomes, with p arms containing important genetic material, the fusion and abnormal centromere break results in two isochromosomes. One is composed of both p arms, and one is composed of both q arms. It is likely that one of these isochromosomes would be lost during cell division, resulting in the deletion of all the genes located on the lost arm. Thus, a carrier is usually phenotypically abnormal and produces abnormal gametes. The most common isochromosome involves the long arm of the X chromosome, i(Xq), which is the etiology of 15 percent of cases of T umer syndrome.

When there are two breaks in the same chromosome, and the intervening genetic material is inverted before the breaks are repaired, the result is a chromosomal inversion. Although no genetic material is lost or duplicated, the rearrangement may alter gene function. There are two types-pericentric and paracentric inversions.

PericentricInversion. This results from breaks in both the p and q arms of a chromosome, such that the inverted material includes the centromere (Fig. 13-8). A pericentric inversion causes problems in chromosomal alignment during meiosis and confers signiicant risk for the carrier to produce abnormal gametes and abnormal ofspring. In general, the observed risk of abnormal ofspring in a peri centric inversion carrier is 5 to 10 percent if ascertainment was made after the birth of an abnormal child. But the risk is only 1 to 3 percent if prompted by another indication. An important exception is a pericentric inversion on chromosome 9. his is inv(9)(pllq12), which is a normal variant present in approximately 1 percent of the population.

Paracentric Inversion.If there are two breaks within one arm of a chromosome-either p or q-the inverted material does not include the centromere, and the inversion is paracentric (see Fig. 13-8). he carrier makes either normal balanced gametes or gametes that are so abnormal as to preclude fertilization. Thus, although infertility may be a problem, the risk of having an abnormal ofspring is extremely low.

If there are deletions at each end of the same chromosome, the ends may come together to form a ring chromosome. he telomere regions, which are the ends of a chromosome, contain specialized nucleoprotein complexes that stabilize the chromosome. If just the telomeres are lost, all necessary genetic material is retained, and the carrier is essentially balanced. If a deletion extends more proximally than the telomere, the carrier is likely to be phenotypically abnormal. An example of this is a ring X chromosome, which may result in T umer syndrome.

centric inversion (one involving the centromere) or paracentric inversion (not involving the centromere). Individuals with pericen tric inversions are at increased risk for producing offspring with a duplication/deletion. Those with paracentric inversions are at increased risk for early pregnancy loss.

A mosaic individual has two or more cytogenetically distinct cell lines that are derived from a single zygote. Phenotypic expression of mosaicism depends on several factors, including whether the cytogenetically abnormal cells involve the fetus, part of the fetus, just the placenta, or some combination. Of amnionic luid cultures, mosaicism is found in approximately 0.3 percent but may not reflect the fetal chromosomal complement (Carey, 2014). When the abnormal cells are present in only a single lask of amnionic luid, the inding is likely pseudomosaicism, caused by cell-culture artifact (Bui, 1984; Hsu, 1984). When abnormal cells involve multiple cultures, however, true mosaicism is more likely, and further testing may be warranted. A second cell line is veriied in 60 to 70 percent of these fetuses (Hsu, 1984; Worton, 1984).

With chorionic villus sampling, studies demonstrate that up to 2 percent of placentas are mosaic, with the mosaicism conined to the in most of these cases (Bafero, 2012; Henderson, 1996). Amniocentesis should be ofered. In a series of more than 1000 pregnancies with mosaicism found from chorionic villus sampling, subsequent amniocentesis identiied true fetal mosaicism in 13 percent. Uniparental disomy, discussed later (p. 268), was found in 2 percent, and the remainder resulted from confined placental mosaicism (Malvestiti, 2015).

If mosaicism is detected for a chromosome known to contain imprinted genes-such as chromosomes 6, 7, 11, 14, or 15testing for uniparental disomy should be considered, as there may be fetal consequences (Grati, 2014a).

lthough outcomes with conined placental mosaicism are generally good, fetal-growth restriction is more common, and the stillbirth risk is also higher (Reddy, 2009). Fetal-growth restriction may stem from impaired functioning of the aneuploid placental cells (Bafero, 2012). Placental mosaicism for trisomy 16 confers a particularly poor prognosis.

Mosaicism confined to the gonads likely arises from a mitotic error in cells destined to become the gonad, resulting in a population of abnormal germ cells. Because spermatogonia and oogonia divide throughout fetal life, and spermatogonia continue to divide throughout adulthood, gonadal mosaicism may also follow a meiotic error in previously normal germ cells. Gonadal mosaicism can account for de novo diseases in the ofspring of normal parents. Autosomal dominant examples are achondroplasia and osteogenesis imperfecta, and X-linked ones include Duchenne muscular dystrophy. Gonadal mosaicism also explains the 6-percent recurrence risk after the birth of a child with a disease caused by a "new" mutation.

A monogenic or mendelian disorder is caused by a mutation or alteration in a single locus or gene in one or both members of a gene pair. Types of mendelian inheritance include autosomal dominant, autosomal recessive, X-linked, and Y-linked. Other monogenic inheritance patterns, described subsequently, include mitochondrial inheritance, uniparental disomy, imprinting, and trinucleotide repeat expansion-also termed anticipation. By age 25, approximately 0.4 percent of the population exhibits an abnormality attributed to a monogenic disorder, and 2 percent will have at least one such disorder during their lifetime (Table 13-3).

When considering inheritance, it is the phenotype that is dominant or recessive, not the genotype. With a dominant disease, the normal gene may direct the production of normal protein, but the phenotype is abnormal because it is determined by protein produced by the abnormal gene. With a recessive disease, a heterozygous carrier may produce detectable levels of an abnormal gene product but have no features of the condition because the phenotype is directed by the product of the normal co-gene. For example, erythrocytes from carriers of sickle-cell anemia contain approximately 30 percent hemoglobin S, but because the other 70 percent is hemoglobin A, these cells do not usually sickle in vitro.

Genetic heterogeneiy explains how diferent genetic mechanisms can result in the same phenotype. Locus heterogeneiy indicates

TABLE 13-3. Selected Monogenic (Mendelian) Disorders that a speciic disease phenotype can be caused by mutations in diferent genetic loci. It also explains why some diseases appear to follow more than one type of inheritance. An example is retinitis pigmentosa, which may develop following mutations in at least 35 diferent genes or loci and may result in autosomal dominant, autosomal recessive, or X-linked forms.

Alelic heterogeneiy describes how diferent mutations of the same gene may afect presentation of a particular disease. For example, although only one gene has been associated with cystic ibrosis-the cystic ibrosis conductance transmembrane regulator gene-more than 2000 mutations in this gene have been described and result in variable disease severity (Chaps. 14 and 51, pp. 289 and 997).

can arise from diferent mutations in the same gene. As an example, mutations in the ibroblast growth actor receptor 3 (FGF3) gene may result in several diferent skeletal disorders, including achondroplasia and thanatophoric dysplasia, both of which are discussed in Chapter 10 (p. 210).

If only one copy of a gene pair determines the phenotype, that gene is considered to be dominant. Carriers have a 50-percent chance of passing on the afected gene with each conception. A gene with a dominant mutation generally speciies the phenotype in preference to the normal gene. That said, not all individuals will necessarily manifest an autosomal dominant condition the same way. Factors that afect the phenotype of an autosomal dominant condition include penetrance, expressivity, and occasionally, presence of codominant genes.

his characteristic describes whether or not a dominant gene is expressed at all. A gene with recognizable phenotypic expression in all individuals is 100-percent penetrant, whereas penetrance is incomplete if some carriers express the gene but some do not. his may be quantitatively expressed-for example, a gene that is expressed in some way in 80 percent of individuals who have that gene is 80-percent penetrant. Importantly, incomplete penetrance explains why some autosomal dominant diseases may appear to "skip" generations.

Individuals with the same autosomal dominant trait may manifest the condition diferently, even within the same family. Genes with variable expressivity can produce disease manifestations that range from mild to severe. Examples include neuroibromatosis, tuberous sclerosis, and adult polycystic kidney disease.

If two diferent alleles in a gene pair are both expressed in the phenotype, they are considered to be codominant. Blood type, for example, is determined by expression of dominant A and B red-cell antigens that can be expressed simultaneously. Another example of codominance is the group of genes responsible for hemoglobin production. An individual with one gene directing production of hemoglobin S and the other directing production of hemoglobin C will produce both Siand C hemoglobin (Chap. 56, p. 1082).

Paternal age older than 40 is associated with increased risk for spontaneous genetic mutations, particularly single base substitutions. This may result in ofspring with new autosomal dominant disorders or X-linked carrier states. In particular, advanced paternal age has been associated with mutations in the ibroblast growth actor receptor 2 (FGF2) gene, which may cause craniosynostosis syndromes such as Apert, Crouzon, and Pfei fer syndromes; mutations in the FGF3 gene, which may result in the ET proto-oncogene, which may cause multiple endo crine neoplasia syndromes Qung, 2003; Toriello, 2008). Using whole genome sequencing, described later (p. 272), Kong and utes to a rise in the rate of single-nucleotide polymorphisms among ofspring. his rate is approximately two mutations for each year of paternal age. Because individual autosomal domi nant disorders are uncommon, the actual risk for any speciic condition is low, and no screening or testing is speciically rec ommended.

Advanced paternal age has also been associated with a structural abnormalities (Grewal, 2012; Toriello, 2008; Yang, 2007). It is not generally considered to pose an elevated risk for other aneuploidies, probably because the aneuploid sperm cannot fertilize an egg.

Recessive diseases develop only when both gene copies are abnormal. Many enzyme deficiency diseases display autosomal recessive inheritance, and enzyme activity in the carrier is usually about half of normal. Unless carriers are screened for a specific disease, such as cystic ibrosis, they usually are recognized only after the birth of an afected child or the diagnosis of an afected family member (Chap. 14, p. 289). If a couple has a child with an autosomal recessive disease, the recurrence risk is 25 percent for each subsequent pregnancy. hus, 1/4 of ofspring will be homozygous normal, 2/4 will be heterozygous carriers, and 114 will be homozygous abnormal. In other words, three of four children will be phenotypically normal, and 2/3 of phenotypically normal siblings are actually carriers.

A heterozygous carrier of a recessive condition is only at risk to have afected children if his or her partner is heterozygous or homozygous for the disease. Genes for rare autosomal recessive conditions have low prevalence in the general population. Thus, the likelihood that a partner will be a gene carrier is small, unless there is consanguinity or the partner is a member of an at-risk group. Heterozygous carriers are usually undetectable clinically but may have biochemical test abnormalities that can be used for carrier screening. Other recessive conditions can be identified only by molecular genetic testing (Chap. 14, p. 288).

Inborn Errors of Metabolism

Most of these autosomal recessive diseases result from absence of a crucial enzyme, leading to incomplete metabolism of proteins, lipids, or carbohydrates. The metabolic intermediates that build up are toxic to various tissues and may result in intellectual disability or other abnormalities.

Phenylketonuria. Also known as phenylalanine hydroxylase (PAH) deficiency, this autosomal recessive disease is caused by mutations in the PAH gene. PAH metabolizes phenylalanine to tyrosine, and homozygotes have diminished or absent enzyme activity. This leads to abnormally high levels of phenylalanine, resulting in progressive intellectual impairment, autism, seizures, motor deficits, and neuropsychological abnormalities (Blau, 2010). Because phenylalanine competitively inhibits tyrosine hydroxylase-which is essential for melanin production, afected individuals also have hair, eye, and skin hypopigmentation. More than 500 PAH gene mutations have been characterized, and the carrier frequency is 1 in 60, such that the disease afects approximately 1 in 15,000 newborns (American College of Obstetricians and Gynecologists, 2017 c). Prompt diagnosis and restriction of dietary phenylalanine beginning early in infancy are essential to prevent neurological damage, and all states mandate newborn screening for phenylketonuria (PKU).

Phenylalanine restriction alone would result in inadequate protein consumption, and phenylalanine-free amino acid-based supplementation is required. lso, in 2007, a synthetic form of the P AH cofactor tetrahydrobiopterin (sapropterin) was approved for PKU treatment. Approximately 25 to 50 percent of afected individuals are sapropterin-responsive and may experience a significant decline in phenylalanine levels and improvement in neuropsychiatric symptoms (Vockley, 2014). Lifelong maintenance of phenylalanine concentrations in the range of 2 to 6 mg/dL (120 to 360 �mol/L) is necessary to prevent worsening neurocognitive and psychiatric problems (American College of Obstetricians and Gynecologists, 2017 c). Fortunately, even those who have previously discontinued therapy may experience improved neuropsychological function with treatment.

During pregnancy, women with PKU whose phenylalanine levels remain above the recommended range are at risk to have otherwise normal (heterozygous) ofspring who sustain in utero damage as a result of being exposed to toxic phenylalanine concentrations. Phenylalanine is actively transported to the fetus. Hyperphenylalaninemia raises the risk for miscarriage and for PKU embryopathy, characterized by intellectual disability, microcephaly, seizures, growth impairment, and cardiac anomalies. Among women on unrestricted diets, the risk to have a child with intellectual disability exceeds 90 percent, microcephaly occurs in more than 70 percent, and as many as 1 in 6 children have cardiac defects (Lenke, 1980). he Maternal Phenylketonuria Collaborative Study, which included 572 pregnancies followed more than 18 years, reported that maintenance of serum phenylalanine levels in the recommended range between 2 and 6 mg/dL signiicantly reduced the fetal abnormality risk and resulted in childhood IQ scores in the normal range (Koch, 2003; Platt, 2000). Preconceptional counseling and consultation with providers from experienced PKU centers is recommended.

Two individuals are considered consanguineous if they have at least one recent ancestor in common. Although uncommon in Western countries, more than 1 billion people are estimated to live in countries in which 20 to 50 percent of marriages are consanguineous (Romeo, 2014). In medical genetics, a union is consanguineous if between second cousins or closer relatives. First-degree relatives share half of their genes, second-degree relatives share a fourth, and third-degree relatives-first cousins-share one eighth. Because of the potential for shared deleterious genes, consanguinity confers an increased risk to have ofspring with otherwise rare autosomal recessive diseases or multifactorial disorders. In population-based series, first cousins are reported to have a twofold risk for congenital anomalies (Sheridan, 2013; Stoltenberg, 1997). Consang�inity also is associated with a greater rate of stillbirth (Kapurubandara, 2016). Because CMA performed using a single-nucleotide polymorphism platform may identiy consanguinity, it is important that preprocedural counseling include this possibility.

Incest is defined as a sexual relationship between first-degree relatives such as parent-child or brother-sister and is universally illegal. Progeny of such unions carry the highest risk of abnormal outcomes, and older studies reported that up to 40 percent of ofspring were abnormal as a result of recessive and multifactorial disorders (Baird, 1982; Freire-Maia, 1984).

Most X-linked diseases are recessive. Common examples include color blindness, hemophilia A and B, and Duchenne and Becker muscular dystrophy. Males with an X-linked recessive gene are usually afected by the disease it causes, because they lack a second X chromosome to express the normal dominant gene. A male with an X-linked disease cannot have afected sons because they cannot receive his X chromosome. When a woman carries a gene causing an X-linked recessive condition, each of her sons has a 50-percent risk of being afected, and each daughter has a 50-percent chance of being a carrier.

Women with an X-linked recessive gene are generally unaffected by the disease it causes. In some cases, however, the random inactivation of one X chromosome in each cell-termed lyonization-is skewed, and female carriers may have features of the condition. For example, approximately 10 percent of female carriers of hemophilia A will have factor VIII levels less than 30 percent of normal, and a similar proportion of female hemophilia B carriers have factor IX levels less than 30 percent. Levels below these thresholds confer a greater risk for abnormal bleeding when afected women give birth (Plug, 2006). Indeed, even with higher levels, carriers are reported to be at increased risk for bleeding complications (Olsson, 2014). Similarly, female carriers of Duchenne or Becker muscular dystrophy carry an elevated risk for cardiomyopathy, and periodic evaluation for cardiac dysfunction and neuromuscular disorders is recommended (American Academy of Pediatrics, 2008).

X-linked dominant disorders mainly afect females, because they tend to be lethal in males. Two examples are vitamin D-resistant rickets and incontinentia pigmenti. One exception is fragile X syndrome, which is discussed subsequently.

he prevalence of Y-linked chromosomal disorders is low.

This chromosome carries genes important for sex determination and various cellular functions related to spermatogenesis and bone development. Deletion of genes on the long arm of Y results in severe spermatogenic defects, whereas genes at the tip of the short arm are critical for chromosomal pairing during meiosis and for fertility.

Human cells contain hundreds of mitochondria, each with its own genome and associated replication system. Oocytes contain approximately 100,000 mitochondria. Sperm hold only about 100, and these are destroyed after fertilization. Each mitochon drion has multiple copies of a 16.5-kb circular DNA molecule that contains 37 genes. Mitochondrial DNA encodes peptides and transfer RNAs.

Mitochondria are inherited exclusively from the mother.

hus, although males and females both can be afected by a mitochondrial disorder, transmission is only through the mother. When a cell replicates, mitochondrial DNA sorts randomly into each of the daughter cells, a process termed replicative segregation. A consequence of replicative segregation is that any mitochondrial mutation will be propagated randomly into the daughter cells. Because each cell holds multiple copies of mitochondrial DNA, the mitochondrion may contain only normal or only abnormal DNA, termed homoplasmy. Alternatively, it may contain both normal and mutated DNA, namely heteroplasmy. If a heteroplasmic oocyte is fertilized, the relative proportion ofmutated DNA may afect whether the individual manifests a given mitochondrial disease. It is not possible to predict the potential degree of heteroplasmy among ofspring, and this poses challenges for genetic counseling.

As of 2016, 33 mitochondrial diseases or conditions with known molecular basis were described in Online Mendelian Inheritance in Man Qohns Hopkins University, 2017). Examples include myoclonic epilepsy with ragged red fibers (MERRF), Leber optic atrophy, Kearns-Sayre syndrome, Leigh syndrome, several forms of mitochondrial myopathy and cardiomyopathy, and susceptibility to chloramphenicol toxicity.

Mendel's irst law is that genes are passed unchanged from parent to progeny, and barring new mutations, this is true for many genes or traits. However, certain genes are unstable, and their size, and thus function, may be altered during parentto-child transmission. This is manifested clinically by anticipation-a phenomenon in which disease symptoms seem to be more severe and to appear at an earlier age in each successive generation. Examples of some DNA triplet (trinucleotide) repeat diseases are shown in Table 13-4.

his is the most common inherited form of intellectual disability and afects approximately 1 in 3600 males and 1 in 4000 to 6000 females (American College of Obstetricians and Gynecologists, 2017a). Fragile X syndrome is caused by expansion

TABLE 13-4. Some Disorders Caused by DNA Triplet Repeat Expansion of a repeated trinucleotide DNA segment-cytosine-guanineguanine (CGG)-at chromosome Xq27.3. When the CGG repeat number reaches a critical size-the full mutation-the ragile X mental retardation 1 (FMR1) gene becomes methyl ated. Methylation inactivates the gene, which halts expression of FMR1 protein. his protein is most abundant in nerve cells and is essential for normal cognitive development.

Although transmission of the syndrome is X-linked, both the sex of the afected individual and the number of CGG repeats determine the degree of clinical normalcy or impair ment. Intellectual disability is generally more severe in males, in whom average IQ scores are 35 to 45 (Nelson, 1995). Afected tion-deicit/hyperactivity disorder. Fragile X syndrome is also the most common known cause of autism or "autistic like" behavior. Associated phenotypic abnormalities become more prominent with age and include a narrow face with large jaw, prominent ears, connective tissue abnormalities, and macroor chidism in postpubertal males. Clinically, four groups have been described (American College of Obstetricians and Gyne •cologists, 2017a):

Premutation-55 to 200 repeats

Intermediate-45 to 54 repeats

Full mutations are expressed (penetrant) in all males and many females. When a full mutation is present, males typically have significant cognitive and behavioral abnormalities and phenotypic features. In females, random X-inactivation, however, results in variable expression, and the disability may be much less severe. With rare exception, the parent of origin of repeat expansion that leads to a full mutation is female (Monaghan, 2013).

For individuals with a premutation, evaluation and counseling are more complex. A female with the fragile X premutation is at risk to have ofspring with the full mutation, depending on the repeat number. The risk ofa full mutation in an ofspring is 5 percent or less if the CGG repeat number is <70 but exceeds 95 percent with 100 to 200 CGG repeats (Nolin, 2003). Expansion is extremely unlikely in a male premutation carrier, but all of his daughters will carry the premutation. Among women with no risk factors, approximately 1 in 250 carries a fragile X premutation, and the risk approximates 1 in 90 in those with a family history of intellectual disability (Cronister, 2008). Premutation carriers may themselves experience significant health consequences. Males with the premutation are at increased risk for the fragile X tremor ataxia syndrome (FXTAS). his syndrome is characterized by memory loss, executive function deficits, anxiety, and dementia (Monaghan, 2013). Females are at risk for FXTAS as well, although less so. hey also have a 20-percent risk for fragile X-associated primary ovarian insuficiency.

he American College of Obstetricians and Gynecologists (2016c, 2017a) recommends carrier screening for women with a family histof) of fragile X syndrome; individuals with unexplained intellectual disability, developmental delay, or autism; and women with primary ovarian insuiciency.

Prenatal diagnosis can be accomplished by amniocentesis or chorionic villus sampling. Specimens obtained by either can define the CGG repeat number, although chorionic villus sampling may not accurately determine FMRl gene methylation status.

his term describes some genes that are inherited but not expressed, depending on whether they are inherited from the mother or father. hus, the resulting phenotype varies according to the parent of origin. Imprinting afects gene expression by epigenetic control, which modiies genetic structure using methods other than altering the underlying nucleotide sequence. For example, methyl group addition may alter gene expression and thereby afect the phenotype without changing the genotype. Importantly, the efect may be reversed in a subsequent generation, because a female who inherits an imprinted gene from her father will pass it in her oocytes with a maternal-rather than paternal-imprint, and vice versa.

Selected diseases that can involve imprinting are shown in

Table 13-5. A useful example includes two very diferent dis eases that afect the same region of DNA. First, Prader-Willi syndrome is characterized by obesity and hyperphagia; short stature; small hands, feet, and external genitalia; and mild mental retardation. In more than 70 percent of cases, PraderWilli syndrome is caused by microdeletion or disruption for the paternal 15q 11.2-q 13. The remaining cases are due to maternal uniparental disomy or due to maternal gene imprinting with the paternal gene inactivated.

In contrast, Angelman syndrome includes severe intellectual disability; normal stature and weight; absent speech; seizure disorder; ataxia and jerky arm movements; and paroxysms of inappropriate laughter. In approximately 70 percent of cases, Angelman syndrome is caused by microdeletion for the maternal 15q 11.2-q 13. In 2 percent, the syndrome is caused by paternal uniparental disomy, and another 2 to 3 percent is due to paternal gene imprinting with the maternal genes inactivated.

here are other examples of imprinting important to obstetrics. Complete hydatidiform mole, with a paternally derived diploid chromosomal complement, is characterized by abundant

TABLE 13-5. Some Disorders That Can Involve Imprinting

Angelman lSq11.2-q13 Maternal

Beckwith-Wiedemann 11 p1S.5 Paternal

Prader-Willi lSq11l.2-q13 Paternal

Pseudohypoparathyroidism 20q13.2 Variable

Russell-Silver syndrome 7p1l1.2 Maternal

Data from Online Mendelian Inheritance in Man (Johns Hopkins University, 201l7.) placental growth with no fetal structures (Chap. 20, p. 389). Conversely, an ovarian teratoma, with a maternally derived diploid chromosomal complement, is characterized by the growth of various fetal but no placental tissues (Porter, 1993).

his occurs when both members of a chromosome pair are inherited from the same parent. Often, uniparental disomy does not have clinical consequences. Although both copies are inherited from one parent, they are not identical. However, if chromosomes 6, 7, 11, 14, or 15 are involved, ofspring are at increased risk for an abnormality because of parent-of-origin diferences in gene expression (Shafer, 2001). Several genetic mechanisms may cause uniparental disomy, the most common of which is trisomic rescue, shown in Figure 13-9. After a nondisjunction event produces a trisomic conceptus, one of the three homologues may be lost. his will result in uniparental disomy for that chromosome in approximately one third of cases.

Isodisomy is the unique situation in which an individual receives two identical copies of one chromosome in a pair from one parent. his mechanism explains some cases of cystic ibrosis, in which only one parent is a carrier but the fetus inherits two copies of the same abnormal chromosome from that parent (Spence, 1988; Spotila, 1992). It also has been implicated in abnormal growth related to placental mosaicism.

Traits or diseases are considered to have multifactorial inheritance if they are determined by the combination of multiple genes and environmental factors (Table 13-6). Polygenic traits are determined by the combined efects of more than one gene. Most congenital and acquired conditions, as well as common traits, display multifactorial inheritance. Examples include malformations such as clefts and neural-tube defects, diseases such as diabetes and heart disease, and features or traits such as head

TABLE 13-6. Characteristics of Multifactorial Diseases

There is a genetic contribution:

No mendelian pattern of inheritance

No evidence of single-gene disorder

Nongenetic factors are also involved in disease causation: Lack of penetrance despite predisposing genotype Monozygotic twins may be discordant

Familial aggregation may be present:

Relatives are more likely to have disease-predisposing alleles

Expression more common among close relatives:

Adapted from Nussbaum, 2007. Genetics 269

FIGURE 13-9 Mechanism of uniparental disomy arising from trisomic "rescue." A. In normal meiosis, one member of each pair of homologous chromosomes is inherited from each parent. B. If nondisjunction results in a trisomic conceptus, one homologue is sometimes lost. In a third of cases, loss of one homologue leads to uniparental disomy.

size or height. Abnormalities that display multifactorial inheritance tend to recur in families, but not according to a mendelian pattern. If a couple has had a child with a multifactorial birth defect, their empirical risk to have another afected child is 3 to 5 percent. This risk declines exponentially with successively more distant relationships.

Multifactorial traits that have a normal distribution in the population are termed continuously variable. A measurement that is more than two standard deviations above or below the population mean is considered abnormal. Continuously variable traits tend to be less extreme in the ofspring of afected individuals, because of the statistical principle of regression to the mean.

Some multifactorial traits do not appear until a threshold is exceeded. Genetic and environmental factors that create propensity or liability for the trait are themselves normally distributed, and only individuals at the extreme of the distribution exceed the threshold and exhibit the trait or defect. Phenotypic abnormality is thus an all-or-none phenomenon. Examples include cleft lip-palate and pyloric stenosis.

Certain threshold traits have a clear male or female predominance. If an individual of the less common gender has the characteristic or defect, the recurrence risk is greater in his or her ofspring (Fig. 13-10). An example is pyloric stenosis, which is approximately four times more common in males (Krogh, 2012). A female with pyloric stenosis has likely inherited more predisposing genetic factors than are necessary to produce the defect in a male, and the recurrence risk for her children or siblings is thus higher than the expected 3 to 5 percent. Her male siblings or male ofspring would have the highest liability because they not only will inherit more than the usual number of predisposing genes but also are the more susceptible gender.

he recurrence risk for threshold traits is also greater if the defect is severe. For example, the recurrence risk after the birth of a child with bilateral cleft lip and palate is approximately 8 percent, but it is only about 4 percent following a child with unilateral cleft lip alone.

Structural cardiac anomalies are the most common birth defects, with a birth prevalence of 8 cases per 1000. More than o.�c 5.

o..=

FIGURE 13-10 Schematic example of a threshold trait, such as pyloric stenosis, which has a predilection for males. Each gender is normally distributed, but at the same threshold, more males than females will develop the condition.

100 genes believed to be involved in cardiovascular morphogenesis have been identiied, including those directing production of various proteins, protein receptors, and transcription factors (Olson, 2006; Weismann, 2007).

he risk of having a child with a cardiac anomaly is approximately 5 to 6 percent if the mother has the defect and 2 to 3 percent if the father has the defect (Burn, 1998). Selected left-sided lesions, including hypoplastic left heart syndrome, coarctation of the aorta, and bicuspid aortic valve, may have recurrence risks four-to sixfold higher (Lin, 1988; Lupton, 2002; Nora, 1988). Observed recurrence risks for specific cardiac malformations are listed in Table 49-4 (p. 953).

These disorders are also classic examples of multifactorial inheritance. Development of neural-tube defects (NTDs) may be influenced by hyperthermia, hyperglycemia, teratogen exposure, ethnicity, family history, fetal gender, and various genes. Selected risks are more strongly associated with the specific defect location. Hyperthermia has been linked with anencephaly risk; pregestational diabetes with cranial and cervicalthoracic defects; and valproic acid exposure with lumbosacral defects (Becerra, 1990; Hunter, 1984; Lindhout, 1992). Sonographic features ofNTDs are described in Chapter 10 (p. 192), their prevention with folic acid is discussed in Chapter 9 (p. 169), and fetal therapy for myelomeningocele is reviewed in Chapter 16 (p. 319).

More than 50 years ago, Hibbard and Smithells (1965) postulated that abnormal folate metabolism was responsible for many NTDs. For a woman with a prior afected child, the recurrence risk of 3 to 5 percent is decreased by at least 70 percent-and potentially by as much as 85 to 90 percent-with periconceptional oral folic acid supplementation at a dosage of 4 mg/d (Grosse, 2007; MRC Vitamin Study Research Group, 1991). However, most NTD cases do not occur in the setting of maternal folic acid deiciency, and it has become clear that the gene-nutrient interactions underlying folate-responsive NTDs are complex. he NTD risk may be afected by genetic variation in folate transport or accumulation, impaired folate utilization via secondary nutrient deficiencies such as vitamin BI2 or choline deficiency, and genetic variation in activity of folate-dependent metabolic enzymes (Beaudin, 2009).

All pregnant women should have the option of prenatal aneuploidy screening and prenatal genetic diagnosis (American College of Obstetricians and Gynecologists, 2016b). Aneuploidy screening may be performed with serum analyte-based screening or with a DNA-based screen, namely, cell-free DNA found in the maternal circulation. Prenatal genetic screening of the parents also aids carrier status determination in at-risk individuals (Chap. 14, p. 288).

For prenatal genetic diagnosis, the most commonly used tests are cytogenetic analysis (karyotyping), luorescence in situ hybridization (FISH), and chromosomal microarray analysis. Testing may be performed on amnionic fluid or chorionic villi. In selected circumstances, whole genome or whole exome sequencing may be considered, but these are not recommended for routine use. To diagnose a specific disease whose genetic basis is known, DNA-based tests are often employed, typically using polymerase chain reaction (PCR) for rapid ampliication of DNA sequences.

Karyotype analysis is commonly performed to test for chromosomal abnormalities. Any tissue containing dividing cells or cells that can be stimulated to divide is suitable for cytogenetic analysis. Karyotyping detects numerical abnormalities, that is, aneuploidy. It also identiies balanced or unbalanced structural rearrangements of at least 5 to 10 megabases in size. Karyotyping has diagnostic accuracy exceeding 99 percent.

The dividing cells are arrested in metaphase, and their chromosomes are stained to reveal light and dark bands. The most commonly used technique is Giemsa staining, which yields the G-bands shown in Figure 13-3. Each chromosome has a unique banding pattern that permits its identiication and detection of deleted, duplicated, or rearranged segments. he accuracy of cytogenetic analysis rises with the number of bands produced. High-resolution metaphase banding routinely yields 450 to 550 visible bands per haploid chromosome set. Banding of prophase chromosomes generally yields 850 bands.

Because only dividing cells can be evaluated, the rapidity with which results are obtained correlates with the rapidity of cell growth in culture. Amnionic fluid, which contains epithelial cells, gastrointestinal mucosal cells, and amniocytes, usually yields results in 7 to 10 days. Fetal blood cells may provide results in 36 to 48 hours but are rarely needed (Chap. 14, p. 294). If fetal skin fibroblasts are evaluated postmortem, stimulation of cell growth can be more diicult, and cytogenetic analysis may take 2 to 3 weeks (Chap. 35, p. 647).

This technique may be used for rapid identiication of a speciic chromosome abnormality and for veriication of suspected microdeletion or duplication syndromes, such as the 22q 11.2 microdeletion described earlier (p. 260). Because of its 1-to 2-day turnaround time, FISH is often selected for cases in which indings may alter pregnancy management. To perform FISH, cells are ixed onto a glass slide, and fluorescent-labeled probes are hybridized to the ixed chromosomes (Figs. 13-11 and 13-12). Each probe is a DNA sequence that is complementary to a region of the chromosome or gene being investigated. If the DNA sequence is present, hybridization is detected as a bright signal visible by microscopy. The number of signals indicates the number of chromosomes or genes of that type in the cell being analyzed. Findings are probe-speciic. Namely, FISH does not provide information on the entire chromosomal complement but merely the chromosomal or gene region of interest.

he most common prenatal application of FISH involves testing interphase chromosomes with DNA sequences speciic to chromosomes 21, 18, 13, X, and Y. Figure 13-12 shows an example of interphase FISH using a-satellite probes for chromosomes 18, X, and Y to conirm trisomy 18. In a review of

FIGURE 13-1 1 Steps in fluorescence in situ hybridization (FISH).

more than 45,000 samples, the concordance between FISH analysis and standard cytogenetic karyotyping was 99.S percent (Tepperberg, 2001). he American College of Obstetricians and Gynecologists (20 16b) recommends that clinical decision-making based on FISH incorporate clinical information consistent with the suspected diagnosis, such as an abnormal aneuploidy screening test result or sonographic inding, or incorporate a conirmatory diagnostic test such as karyotyping or CMA.

his test is 100 times more sensitive than standard karyotyping and detects microduplications and microdeletions as small as

FIGURE 13-12 Interphase fluorescence in situ hybridization (FISH) using a-satellite probes for chromosomes 18, X, and Y. In this case, the three light blue signals, two green signals, and absence of red signals indicate that this is a female fetus with trisomy 18. (Used with permission from Dr. Frederick Elder.)

Fluorescent probe illuminates chromosome region of interest 50 to 100 kilobases. Direct CMA can yield results in 3 to 5 days, whereas if cultured cells are required, results may take 10 to 14 days (American College of Obstetricians and Gynecologists, 2016b). Microarrays use either a comparative genomic hybridization (CGH) platform, a single-nucleotide polymorphism (SNP) platform, or a combination of the two. he CGH microarray platform compares test specimen DNA with a normal control sample. Shown in Figure 13-13, the CGH chip contains reference DNA fragments of known sequenceoligonucleotides. Fetal DNA from the amniocentesis or chorionic villus sampling specimen is labeled with a fluorescent dye and then hybridized to the DNA on the chip. Normal control DNA is labeled with a diferent probe and also hybridized to the chip. hen, the intensity of the luorescent signals from the two samples is compared. With an SNP array, the chip contains known DNA sequence variants-single-nucleotide polymorphisms. When fetal DNA is labeled and hybridized to the chip, the luorescent signal intensity indicates copy number variation.

Both types of platforms detect aneuploidy, unbalanced translocations, and microdeletions and microduplications. Neither type of array platform currently detects balanced chromosomal rearrangements. For this reason, couples with recurrent pregnancy loss should be ofered karyotyping as the first-line test (Society for Maternal-Fetal Medicine, 2016). In addition, SNP arrays are able to identiY triploidy and can detect absence of heterozygosiy. he latter can occur with uniparental disomy when both copies of a chromosome are inherited from one parent. Further, absence of heterozygosity may occur when there is consanguinity, and counseling prior to performance of an SNP array should include this possibility.

Arrays may be genome-wide or may be targeted to known genetic syndromes. Genome-wide arrays are typically used in research settings, for example, to identiY novel microdeletion syndromes in individuals with intellectual disability (Slavotinek, 200S). Targeted arrays are generally preferred prenatally because the likelihood of detecting a copy number variant of uncertain clinical signiicance is lower. In a systematic 1.28 cm

A Actual size of chip

Nonhybridized Thousands of identical nucleotide DNA strands on one cell

B 500,000 cells on each chip

C One cell on chip Labeled fetal DNA is presented to the cells

FIGURE 13-13 Chromosomal microarray analysis. A. Actual microarray chip size. B. Each chip contains thousands of cells (squares). C & D. Each cell contains thousands of identical oligonucleotides on its surface, and each cell is unique in its nucleotide content. E. During genetic analysis, a mixture containing tagged fetal DNA is presented to the chip. Complementary DNA sequences bind. F. If a laser is shined on the chip, DNA sequences that have bound will glow. This identifies a matching sequence. (Modified with permission from Doody J: Treatment of the infertile couple. In Hofman BL, Schorge JO, Schaffer JI, et al (eds): Williams Gynecology, 2nd ed. New York, McGraw-Hili, 2012.) review, Hillman and colleagues (2013) identified copy number variants of uncertain significance in 1 to 2 percent of prenatal specimens. Not unexpectedly, this may be a source of signiicant distress to families, even with comprehensive pretest counseling.

In pregnancies at increased risk for autosomal trisomy based on aneuploidy screening, karyotyping or FISH plus karyotyping should be ofered, and CMA should be made available (American College of Obstetricians and Gynecologists, 2016b). When the karyotype is normal, CMA has identiied clinically relevant copy number variants in approximately 6.5 percent of pregnancies with fetal abnormalities and in 1 to 2 percent with no obvious fetal abnormality (Callaway, 2013). he American College of Obstetricians and Gynecologists (2016b) and the Society for Maternal-Fetal Medicine (2016) recommend that CMA be ofered as a irst-tier test when fetal structural abnormalities are identiied, replacing fetal karyotyping in these cases. If a particular anomaly that strongly suggests a speciic aneuploidy is identiied, such as an endocardial cushion defect (trisomy 21) or alobar holoprosencephaly (trisomy 13), karyotyping or FISH may be ofered as the initial test. It is recommended that genetic counseling include information about the beneits and limitations of both CMA and karyotyping, and that each be made available to women who elect prenatal diagnosis (Society for Maternal-Fetal Medicine, 2016). CMA may identiy instances of autosomal dominant genetic disorders that have not yet manifested in an afected parent, and it may also identiy instances of nonpaternity.

For stillbirth evaluation, CMA is more likely than standard karyotyping to provide a genetic diagnosis, in part because it does not require dividing cells. he Stillbirth Collaborative Research Network found that when karyotyping was uninformative, approximately 6 percent of cases had either aneuploidy or a pathogenic copy number variant identiied with CMA (Reddy, 2012). Overall, CMA yields results nearly 25 percent more often than standard karyotyping alone.

Most fetuses with structural abnormalities have a normal karyotype and a normal CMA result. Whole genome sequencing (WGS) is a technique for analyzing the entire genome. Whole exome sequencing (WES) analyzes just the DNA coding regions, which account for approximately 1 percent of the genome. These next-generation sequencing tools are increasingly used in the postnatal setting to evaluate suspected genetic syndromes and intellectual disability. The American College of Medical Genetics Board of Directors (2012) states that WGS and WES may be considered for evaluation of the fetus with a likely genetic disorder in which CMA has failed to arrive at a diagnosis. The American College of 0bstetricians and Gynecologists (201i6a) suggests that this be in only selected circumstances, for example, with recurrent or lethal anomalies in which other approaches have been noninformative. Importantly, WGS and WES have signiicant limitations in their current form, including turnaround times that may be prohibitively long and a high rate of variants of uncertain signiicance (American College of �1edical Genetics, 2012; Atwal, 2014). As a result, the clinical utility of this promising technology for prenatal cases is currently limited. • Fetal DNA in the Maternal Circulation Fetal cells are present in maternal blood at a very low concentration, only 2 to 6 cells per milliliter (Bianchi, 2006). Sometimes, intact fetal cells may persist in the maternal circulation for decades following delivery. Persistent fetal cells may engraft in the mother and result in microchimerism, which has been implicated in maternal autoimmune diseases such as scleroderma, systemic lupus erythematosus, and Hashimoto thyroiditis. For prenatal diagnosis, the use of intact fetal cells from maternal blood is limited by low cell concentration, cell persistence into successive pregnancies, and diiculties in distinguishing fetal from maternal cells. In these cases, however, cell-free DNA overcomes these limitations. Cell-Free DNA hese DNA fragments are derived from maternal cells and from apoptotic placental trophoblast cells-although DNA from the latter is often termed "fetal." Cell-free DNA can be reliably genotyping Maternal Real-time quantitative PCR Detection of single-gene disorders Genetics 273 detected in maternal blood after 9 to 10 weeks' gestation (American College of 0bstetricians and Gynecologists, 20 17b). he proportion of cell-free DNA that is placental is called the fetal fraction, and it composes approximately 10 percent of the total circulating cell-free DNA in maternal plasma. Unlike intact fetal cells, cell-free DNA is cleared within minutes from maternal blood. In research settings, cell-free DNA has been used to detect numerous single-gene disorders transmitted through paternally inherited alleles. These include myotonic dystrophy, achondroplasia, Huntington disease, congenital adrenal hyperplasia, cystic fibrosis, and a-thalassemia (Wright, 2009). Clinical applications of cell-free DNA are aneuploidy screening, fetal sex determination, and h D genotyping (Fig. 13-14). Aneuploidy Screening. Several diferent types of assays are used to screen for fetal autosomal trisomies and sex chromosomal aneuploidies. hese include whole-genome sequencing, which is also called massively parallel or shotgun sequencing; chromosome selective or targeted sequencing; and analysis of SNPs (American College of Obstetricians and Gynecologists, 2016a,b). By simultaneously sequencing millions of DNA fragments, investigators can identiy whether the proportion or ratio of fragments from one chromosome is higher than expected. Sequences of fetal DNA are specific to individual chromosomes. hus, samples from women with a Down syndrome fetus have a larger proportion of DNA sequences from chromosome 21. The screening performance of cell-free DNA is excellent. In a metaanalysis of 37 studies of largely high-risk pregnancies, the pooled sensitivity to detect Down syndrome was 99 percent, and to identiy trisomies 18 and 13, 96 and 91 percent, respectively. For each, the speciicity was 99.9 percent (Gil, 2015). The false-positive rate is cumulative for each aneuploidy for which screening is performed, but it is usually below 1 percent. As a result, cell-free DNA screening is recommended as !DNA isolation Cell-free fetal DNA determination Massively parallel genomic sequencing Trisomy 21, 18, and 13screening FIGURE 13-14 Cell-free DNA is actually derived from apoptotic trophoblast. The DNA is isolated from maternal plasma, and real-time quantitative polymerase chain reaction (PCR) may be used to target specific regions or sequences. This may be used for Rh D genotyping, detection of paternally inherited single-gene disorders, or fetal sex determination. Screening for autosomal trisomies and sex chromosomal aneuploidies is performed using whole-genome sequencing, chromosome selective or targeted sequencing, and analysis of single nucleotide polymorphisms.

a screening option in those at greater risk for fetal autosomal trisomy (American College of Obstetricians and Gynecologists, 2017b; Society for Maternal-Fetal Medicine, 2015).

Unfortunately, cell-free DNA screens do not yield a result in 4 to 8 percent of cases. This may be due to assay failure, high assay variance, or low fetal fraction (Norton, 2012; Pergame nt, 2014; Quezada, 2015). Such pregnancies carry a greater risk for fetal aneuploidy. In addition, results may not relect the fetal DNA complement but rather may indicate conined placental mosaicism, early demise of an aneuploid cotwin, maternal mosaicism, or rarely occult maternal malignancy (Bianchi, 2015; Curnow, 2015; Grati, 2014b; Wang, 2014). Recommendations for counseling are discussed in Chapter 14 (p. 285).

Fetal Sex Determination. From the standpoint of genetic disease, fetal sex determination may be clinically useful if the fetus is at risk for an X-linked disorder. It may also be beneficial if the fetus is at risk for congenital adrenal hyperplasia because maternal corticosteroid therapy may be avoided if the fetus is male (Chap. 16, p. 317). In a metaanalysis of more than 6000 pregnancies by Devaney and associates (201i1), the sensitivity of cell-free DNA testing for fetal sex determination approximated 95 percent between 7 and 12 weeks' gestation and improved to 99 percent after 20 weeks. The test speciicity was 99 percent at both time periods, suggesting that cellfree fetal DNA is a reasonable alternative to invasive testing in selected cases.

Rh D Genotype In a predominantly white population, nearly 40 percent of fetuses of h D-negative women are themselves h D negative. Fetal h D genotype assessment from maternal blood can eliminate administration of anti-D immune globulin in these pregnancies, thereby reducing cost and potential risk. With h D alloimmunization, early identification of an h D-negative fetus might avoid unnecessary middle cerebral artery Doppler assessment or amniocentesis. Evaluation using cell-free DNA is done using real-time PCR to target several exons of the HD gene. These are typically exons 4,i5, and 7.

h D-genotyping is performed routinely with cell-free DNA in Denmark and the Netherlands (Clausen, 2012; de Haas, 2016). In a population-based study of more than 25,000 h D-negative women screened at 27 weeks, the false-negative rate-in which h D-negative status was missed-was only 0.03 percent. The false-positive rate-in which h immune globulin would be given unnecessarily-was less than 1 percent (de Haas, 2016). Similar results were reported from the United Kingdom, although the false-negative rate was higher in the irst trimester (Chitty, 2014). Investigators concluded that false-negative screening results might increase the alloimmunization risk, but by less than 1 case per million births (Chitty, 2014). h D alloimmunization is discussed in Chapter 15 (p. 301).

Abele H, Babiy-Pachomow 0, Sonek J, et al: The cavum septum pellucidi in euploid and aneuploidy fetuses. Ultrasound Obstet Gynecol 2013; 42(2):156,o2013

American Academy of Pediatrics: Clinical report: cardiovascular health supervision for individuals afected by Duchenne or Becker muscular dystrophy. Pediatrics 116(6):1569,o2005, Reairmed December 2008

American College of Medical Genetics (ACMG) Board of Directors: Points to consider in the clinicl application of genomic sequencing. Genet Med 14(8):759,o2012

American College of Obstetricians and Gynecologists: Microarrays and nextgeneration sequencing technology: the use of advanced genetic diagnostic tools in obstetrics and gynecology. Committee Opinion No. 682, December 20o16a

American College of Obstetricians and Gynecologists: Prenatal diagnostic testing for genetic disorders. Practice Bulletin No. 162, May 2016b

American College of Obstetricians and Gynecologists: Primary ovarian insuficiency. Committee Opinion No. 605, July 2014, Reairmed 2016c

American College of Obstetricians and Gynecologists: Screening for fetal aneuploidy. Practice Bulletin No. 163, May 2016d

American College of Obstetricians and Gynecologists: Carrier screening for genetic conditions. Committee Opinion No. 69o1, March 20 17a American College of Obstetricians and Gynecologists: Cell free DNA screening for fetal aneuploidy. Committee Opinion No. 640, September 2015, Reafirmed 2017b

American College of Obstetricians and Gynecologists: Management of women with phenylketonuria. Committee Opinion No. 636, June 20o15, Reairmed 20ol7c

Arwal PS, Brennan ML, Cox R, et al: Clinical whole-exome sequencing: are we there yet? Genet Med 16(9):717,o2014 Bafero GM, Somigliana E, Crovetto F, et al: Conined placental mosaicism at chorionic villus sampling: risk factors and pregnancy outcome. Prenat Diagn 32(1o1):1o102,o2012 Baird PA, McGillivray B: Children of incest. J Pediatr 101(5): 854,o1982 Bardsley MZ, Kowal K, Levy C, et al: 47,yysyndrome: clinical phenorype and timing of ascertainment. J Pediatr 163(4): 1085, 2013 Bdolah Y, Palomaki GE, Yaron Y, et al: Circulating angiogenic proteins in trisomy 13. Am J Obstet Gynecol 194(1):239,2006 Beaudin E, Stover PJ: Insights into metabolic mechanisms underlying folateresponsive neural tube defects: a minireview. Birth Defects Res A Clin Mol Teratol 85(4):274, 2009 Becerra JE, Khoury MJ, Cordero JF, et al: Diabetes mellitus during pregnancy and the risks for speciic birth defects: a population-based case-con trol study. Pediatrics 85(1):1,o1990

Bergstrom S, Carr H, Petersson G, et al: Trends in congenital heart defects in infants with Down syndrome. Pediatrics 138(1):e210160123, 2016 Bianchi OW, Chudova 0, Sehnert AJ, et al: Noninvasive prenatal testing and incidental detection of occult malignancies. JAMA 314(2):162,o2015 Bianchi OW, Hanson J: Sharpening the tools: a summary of a National Institutes of Health workshop on new technologies for detection of fetal cells in maternal blood for early prenatal diagnosis. J Matern Fetal Neonatal Med 19(4):199,o2006 Blau N, van Spronsen FJ, Levy HL: Phenylketonuria. Lancet 376(9750):1417, 20o10 Boada R, Janusz J, Hutaf-Lee C, et al: he cognitive phenotype in Klinefelter syndrome: a review of the literature including genetic and hormonal factors. Dev Disabil Res Rev 15(4):284,o2009 Bui TH, Iselius L, Lindsten J: European collaborative study on prenatal diagnosis: mosaicism, pseudomosaicism and single abnormal cells in amniotic fluid cultures. Prenat Diagn 4(7):145,o1984 Bull MJ, American Academy of Pediatrics Committee on Genetics: Health supervision for children with Down syndrome. Pediatrics 128(2):393, 2011 Burn J, Brennan P, Little J, et al: Recurrence risks in ofspring of adults with major heart defects: results from first cohort of British collaborative study. Lancet 351 (9099):311, 1998 Callaway JL, Shafer LG, Chitry LS, et al: he clinicaloutiliry of microarray technologies applied to prenatal cytogenetics in the presence of a normal conventional karyotype: a review of the literature. Prenat Diagn 33(12): 1119,o2013 Carey L, Scott F, Murphy K, et al: Prenatal diagnosis of chromosomal mosaicism in over 1600 cases using array comparative genomic hybridization as a first line test. Prenat Diagn 34(5):478, 2014 Chitty LS, Finning K, Wade A: Diagnostic accuracy of routine antenatal determination of fetal RHO status across gestation: population based cohort study. BMJ 349:g5243, 2014 Clausen FB, Christiansen M, Stefensen R, et al: Report of the first nationally implemented clinical routine screening for fetal RHO in 0-pregnant women to ascertain the requirement for antenatal RHO prophylaxis. Transfusion 52(4):752, 2012 Cockwell A, MacKenzie M, Youings S, et al: A cytogenetic and molecular study of a series of 45,X fetuses and their parents. J Med Genet 28(3): 151, 1991

Cools M, Pleskacovao], Stoop H, et al: Gonadal pathology and tumor risk in relation to clinical characteristics in patients with 45,XJ46,XY mosaicism. ] Clin Endocrinol Metab 96( ):Elo171, 2011

Cragan ]0, Gilboa SM: Including prenatal diagnoses in birth defects monitoring: experience of the Metropolitan Atlanta Congenital Defects Program. Birth Defects Res A Clin Mol Teratol 85(1):20, 2009

Cronister A, Teicher ], Rohlfs EM, et al: Prevalence and instability of fragile X alleles: implications for ofering fragile X premutation diagnosis. Obstet Gynecolo111o(3):596,o2008

Curnow K], Wilkins-Haug L, Ryan A, et al: Detection of triploid, molar, and vanishing twin pregnancies by single-nucleotide polymorphism-based noninvasive prenatal test. Am] Obstet Gynecol 212(1):79.e1, 2015

Dashe ]S: Aneuploidy screening in pregnancy. Obstet Gynecol 128(1):181, 20o16 de Haas M, hurik FF, van der Ploeg CP, et al: Sensitivity of fetal RHO screening for safe guidance of targeted anti-D immunoglobulin prophylaxis: a prospective cohort study of a nationwide programme in the Netherlands. BM] 355:i5 89,o2016

Devaney SA, Palomaki GE, Scott ]A, et al: Noninvasive fetal sex determination using cell-free fetal DNA: a systematic review and meta-analysis. ]AMA 306(6):627,o2011

Dolk H, Loane M, Garne E: he prevalence of congenital anomalies in Europe.

Adv Exp Med Bioi 686:349, 2010

Doody K]: Treatment of the infertile couple. In Hofman BL, Schorge ]0, Schafer ]1, et al (eds): Williams Gynecology, 2nd ed. New York, McGrawHill,o2012

Edwards ]H, Harnden DG, Cameron AH, et al: A new trisomic syndrome.

Lancet 1(7128):787,o1960

Ford CE, Jones W, Polani PE, et al: A sex-chromosome anomaly in a case of gonadal dysgenesis (Turner's syndrome). Lancet 1( 075):711, 1959

Freeman SB, Bean LH, Allen EG, et al: Ethnicity, sex, and the incidence of congenital heart defects: a report from the National Down Syndrome Project. Genet Med 10(3):173,o2008

Freire-Maia N: Efects of consanguineous marriages on morbidity and precocious mortality: genetic counseling. Amo] Med Genet 18(3):401, 1984

Gardner R], Sutherland GR: Chromosome Abnormalities and Genetic Counseling, 2nd ed. Oxford Monographs on Medical Genetics No. 29. Oxford, Oxfo rd U ni versi ty Press, 1996

Gil MM, Quezada MS, Revello R, et al: Analysis of cell-free DNA in maternal blood in screening for fetal aneuploidies: updated meta-analysis. Ultrasound Obstet GynecoIo45(3):249, 2015

Girardin CM, Vliet GV: Counselling of a couple faced with a prenatal diagnosis of Klinefelter syndrome. Acta Pediatr 100(6):917,o2011

Grati FR: Chromosomal mosaicism in human feto-placental development: implications for prenatal diagnosis.] Clin Med 3(3):809, 2014a

Grati FR, Malvestiti F, Ferreira ]c, et al: Fetoplacental mosaicism: potential implications for false-positive and false negative non-invasive prenatal screening results. Genet Med 16(8):620, 2014b

Grewal ], Carmichael SL, Yang W, et al: Patenal age and congenital malformations in ofspring in California, 1989-2002. Matern Child Healtho] 16(2):385,o2012

Grosse SO, Collins JS: Folic acid supplementation and neural tube defect recurrence prevention. Birth Defects Res A Clin Mol Teratal 9(11):737, 2007

Hassold T, Arnovitz K, Jacobs PA, et al: he parental origin of the missing or additional chromosome in 45,X and 47,XXofemales. Birth Defects Orig Artic Ser 26(4):297, 1990

Henderson KG, Shaw TE, Barrett 1], et al: Distribution of mosaicism in human placentae. Hum Genet 97(5):650, 1996

Hibbard ED, Smithells RW: Folic acid metabolism and human embryopathy.

Lancet 1:1254, 1965

Hillman Sc, McMullan 0], Hall G, et al: Use of prenatal chromosomal microarray: prospective cohort study and systematic review and meta-analysis. Ultrasound Obstet GynecoIo41(6):610, 2013

Holland CM: 47,XX in an adolescent with premature ovarian failure and autoimmune disease. J Pediatr Adolesc Gynecol 14(2):77, 2001

Hussamy 0], Herrera CL, Twickler OM, et al: How many risk factors do Down syndrome pregnancies have? Am] Obstet Gynecol 216( 1):S 12 ,2017 Hsu LY, Perl is TE: United States survey on chromosome mosaicism and pseudo mosaicism in prenatal diagnosis. Prenat Diagn 4(7):9 , 1984

Hunter AG: Neural tube defects in Eastern Ontario and Western Quebec: demography and family data. Amo] Med Genet 19(1):45, 1984

Jacobs PA, Hassold T]: he origin of numerical chromosomal abnormalities.

Adv Genet 33:101, 1995 ]auniaux E: Partial moles: from posrnatal to prenatal diagnosis. Placenta 20(56):3 9, 1999

Johns Hopkins University: Online Mendelian Inheritance in Man (OMIM). 2017. Available at: http://omim.org/. Accessed February 4,o2017

Jones L: Smith's Recognizable Patterns of Human Malformation, 6th ed.

Philadelphia, Saunders, 2006

Jung A, Schuppe HC, Schill B: Are children of older fathers at risk for genetic disorders? Andrologia 35(4):191, 2003

Kannan TP, Hemlatha S, Ankathil R, et al: Clinical manifestations in trisomy 9. Indian J Pediatr 76(7):745, 2009

Kappelgaard A, Laursen T: The benefits of growth hormone therapy in patients with Turner syndrome, Noonan syndrome, and children born small for gestational age. Growth Horm IGF Res 21(6):305, 2011

Kapurubandara S, Melov S, Shalou E, et al: Consanguinity and associated perinatal outcomes, including stillbirth. Aust N Z] Obstet Gynecol 56(6), 599,o2016

Koch R, Hanley W, Levy H, et al: he Maternal Phenylketonuria International Study: 1984-2002. Pediatrics 112(6 Pt 2):1523,o2003

Kong A, Frigge ML, Masson G, et al: Rate of de novo mutations, father's age, and disease risk. Nature 488(7412):471, 2012

Krogh C, Gortz S, Wohlfahrt], et al: Pre-and perinatal risk factors for pyloric stenosis and their influence on the male predominance. Am ] Epidemiol 176(1):24,o2012

Lejeune], Turpin R, Gautier M: Chromosomic diagnosis of mongolism. Arch Fr Pediatr 16:962, 1959

Lenke RR, Levy HL: Maternal phenylketonuria and hyperphenylalaninemia.

An international survey of the outcome of untreated and treated pregnancies. N Englo] Med 303(21):1202, 1980

Lin AE, Garver L: Genetic counseling for congenital heart defects. ] Pediatr 113(6):1o105,o1988

Lin HY, Chen YJ, Hung HY, et al: Clinical characteristics and survival of trisomy 18 in a medical center in Taipei, 1988-2004. Am J Med Genet 140(9):945,o2006

Lin HY, Lin SP, Chen J, et al: Clinical characteristics and survival of trisomy 13 in a medical center in Taiwan, 1985-2004. Pediatr Int 49(3):380,o2007

Lindhout 0, Omtzigt JG, Cornel MC: Spectrum of neural tube defects in 34 infants prenatally exposed to antiepileptic drugs. Neurology 42(suppl 5):111,o1992

Loane M, Morris ]K, Addor M, et al: Twenty-year trends in the prevalence of Down syndrome and other trisomies in Europe: impact of maternal age and prenatal screening. Eur] Hum Genet 21(1):27, 2013

Lowe X, Eskenazi B, Nelson DO, et al: Frequency of Y sperm increases with age in fathers of boys with Klinefelter syndrome. Am J Hum Genet 69(5):1046,o2001

Lupton M, Oteng-Ntim E, Ayida G, et al: Cardiac disease in pregnancy. Curr Opin Obstet GynecoIo14(2):137, 2002

Mai CT, Kucik ]E, Isenburgo], et al: Selected birth defects data from population-based birth defects surveillance programs in the United States, 2006 to 2010: featuring trisomy conditions. Birth Defects Res A Clin Mol Teratol 97(1o1):709,o2013

Malvestiti F, Agrati C, Grimi B, et al: Interpreting mosaicism in chorionic villi: results of a monocenrric series of 1001 mosaics in chorionic villi with followup amniocentesis. Prenat Diagn 35(11):1117, 2015

Manning M, Hudgins L: Professional Practice and Guidelines Committee: array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med 12(1o1):742,o2010

McDonald-McGinn OM, Sullivan KE, Marino B, et al: 22q 11.2 deletion syndrome. Nat Rev Dis Primers 1:15071,o2015

McGowan-]ordano], Simmons A, Schmid M (eds): ISCN 2016: An International System for Human Cytogenomic Nomenclature. Basel, Karger, 2016 McKusick VA, Ruddle FH: A new discipline, a new name, a new journal. Genomics 1:1,o2003

Milunsky A, Milunsky Jv!: Genetic counseling: preconception, prenatal, and perinatal. In Milunsky A (ed): Genetic Disorders of the Fetus: Diagnosis, Prevention, and Treatment, 5th ed. Baltimore, Johns Hopkins University Press, 2004

Monaghan KG, Lyon E, Spector EB, et al: ACMG Standards and Guidelines for fragile X testing: a revision to the disease-speciic supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics and Genomics. Genet Med 15(7):575, 20o13

MRC Vitamin Study Research Group: Prevention of neural rube defects: results of the Medical Research Council Vitamin Study. Lancet 338(8760): 131, 1991

National Center for Biotechnology Information: GeneReviews. 2017a. Available at: https:llwww.ncbi.nlm.gov/books/NBKIoI161. Accessed February 4, 20o1

National Center for Biotechnology Information: GTR: Genetic Testing Registry. 2017b. Available at: https:llwww.ncbi.nlm.gov/gtrl. Accessed February 4,o201

National Library of Medicine: Genetics Home Reference. 2017. Available at: https:llghr.nlm.nih.gov. Accessed February 4,o2017 Nelson DL: The fragile X syndromes. Semin Cell Bioi 6(1):5, 1995

Nolin SL, Brown T, Glickspan A, et al: Expansion of the fragile X CGG repeat in females with pre mutation or intermediate alleles. Am J Hum Genet 72(2):454, 2003

Nora JJ, Nora AH: Updates on counseling the family with a first-degree relative with a congenital heart defect. m J Med Genet 29(1):137, 1988

Norton ME, Brar H, Weiss J, et al: Non-Invasive Chromosomal Evaluation (NICE) study: results of a multicenter prospective cohort study for detection offetal trisomy 21 and trisomy 18. Am J Obstet GynecoI207(2):137.el, 2012

Nussbaum L, McInnes R, Willard HF (eds): Clinical cytogenetics: disorders of the autosomes and sex chromosomes. In hompson & hompson Genetics in Medicine, 7th ed. Philadelphia, Saunders, 2007

Olsson A, Hellgren M, Berntorp E, et al: Clotting factor level is not a good predictor of bleeding in carriers of haemophilia A and B. Blood Coagul Fibrinolysis 25(5):471, 2014 Olson EN: Gene regulatory networks in the evolution and development of the heart. Science 313(5795): 1922, 2006 Parker SE, Mai CT, Canfield A, et al: Updated national birth prevalence estimates for selected birth defects in the United States, 2004-2006. Birth Defects Res A Clin Mol TeratoIo88(12):1008, 2010 Patau K, Smith DW, herman E, et al: Multiple congenital anomaly caused by an extra autosome. Lancet 1(7128):790, 1960 Pergament E, Cuckle H, Zimmermann B, et al: Single-nucleotide polymorphism-based noninvasive prenatal screening in a high-risk and low-risk cohort. Obstet GynecoIo124(2ptl):210, 2014 Platt LD, Koch R, Hanley B, et al: he international study of pregnancy outcome in women with maternal phenylketonuria: report of a 12-year study. m J Obstet Gynecol 182(2):326,o2000 Plug I, Mauser-Bunschoten EP, Brocker-Vriends AH, et al: Bleeding in carriers of hemophilia. Blood 108(1):52, 2006 Porter S, Gilks CB: Genomic imprinting: a proposed explanation for the different behaviors of testicular and ovarian germ cell tumors. Med Hypotheses 41(1):37, 1993

Quezada MS, Gil MM, Francisco e, et al: Screening for trisomies 21, 18, and 13 by cell-free DNA analysis of maternal blood at 10-1o1 weeks. Ultrasound Obstet GynecoIo45(1):36, 2015 Rankin J, Tennant PWG, Bythell M, et al: Predictors of survival in children born with Down syndrome: a registry-based study. Pediatrics 129(6):e1373, 2012 Reddy UM, Abuhamad Z, Levine D, et al: Fetal Imaging. Executive summary of a joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Sociery for Maternal-Fetal Medicine, American Institute of Ultrasound in Medicine, American College of Obstetricians and Gynecologists, American College of Radiology, Society for Pediatric Radiology, and Society of Radiologists in Ultrasound Fetal Imaging Workshop. Obstet GynecoIo123(5):1070, 2014 Reddy UM, Goldenberg R, Silver R, et al: Stillbirth classification-developing an international consensus for research: executive summary of a National Institute of Child Health and Human Development workshop. Obstet Gynecol 114(4):901,o2009 Reddy UM, Grier PP, Saade GR, et al: Karyotype versus microarray testing for genetic abnormalities ater stillbirth. N Engl J Med 367(23):2185,2012 Rehm HL, BergJS, Brooks LD, et al: ClinGen-he Clinical Genome Resource. N Engl J Med 372(23):2235, 2015 Romeo G, Bittles AH: Consanguinity in the contemporary world. Hum Hered 77(1):6,o2014 Rosa F, Rosa Re, Lorenzen MB, et al: Trisomy 18: experience of a reference hospital from the south of Brazil. Am J Med Genet A 155A(7):1529, 2011 Ross JL, Zeger MP, Kushner H, et al: An extra X or Y chromosome: contrasting the cognitive and motor phenotypes in childhood in boys with 47,yysyndrome or 47,XY Klinefelter syndrome. Dev Disabil Res Rev 15(4):309, 2009 Scharrer S, Stengel-Rutkowski S, Rodewald-Rudescu A, et al: Reproduction in a female patient with Down's syndrome. Case report of a 46,y child showing slight phenotypical anomalies born to a 47,X, +21 mother. Humangenetik 26(3):207, 1975 Schmickel RD: Contiguous gene syndromes: a component of recognizable syndromes. J Pediatr 109(2):231,o1986 Schneider AS, Mennuti MT, Zackai EH: High cesarean section rate in trisomy 18 births: a potential indication for late prenatal diagnosis. m J Obstet GynecoIo140(4):367, 1981 Schorge JO: Ovarian germ cell and sex cord-stromal tumors. In Hofman BL, Schorge JO, Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGraw-Hill Education, 20o16 Shafer LG, Agan N, Goldberg JD, et al: American College of Medical Genetics Statement on diagnostic testing for uniparental disomy. Genet Med 3(3):206,o2001

Sheridan E, Wright J, Small N, et al: Risk factors for congenital anomaly in a multiethnic birth cohort: an analysis of the Born in Branford study. Lancet 382(9901):1350,o2013

Shin M, Besser LM, Kucik JE, et al: Prevalence of Down syndrome in children and adolescents in 10 regions of the United States. Pediatrics 124(6):1o565,o2009 Shipp TD, Benacerraf BR: Second trimester ultrasound screening for chromo somal abnormalities. Prenat Diagn 22(4):296, 2002

Shprintzen RJ: Velo-cardio-facial syndrome: 30 years of study. Dev Disabil Res Rev 14(1):3,o2008

Silasi M, Rana S, Powe e, et al: Placental expression of angiogenic factors in trisomy 13. Am J Obstet Gynecol 204(6):546.e1, 2011

Siavotinek AM: Novel micro deletion syndromes detected by chromosomal microarrays. Hum Genet 124(1):1, 2008

Society for Maternal-Fetal Medicine: Prenatal aneuploidy screening using cellfree DNA. SMFM Consult Series No. 36. June 2015

Society for Maternal-Fetal Medicine: The use of chromosomal micro array for prenatal diagnosis. SMHvl Consult Series No. 41. October 2016

Spence JE, Perciaccante RG, Greig FM, et al: Uniparental disomy as a mechanism for human genetic disease. Am J Hum Genet 42(2):217,o1988

Spotila LD, Sereda L, Prockop DJ: Partial isodisomy for maternal chromosome 7 and short stature in an individual with a mutation at the COLIA2 locus. m J Hum Genet 51(6):1396, 1992

Stevenson DA, Carey JC: Contribution of malformations and genetic disorders to mortality in a children's hospital. Am J Med Genet 126A(4):393, 2004 Stoltenberg C, Magnus P, Lie RT, et al: Birth defects and parental consanguin ity in Norway. m J Epidemiol 145(5):439, 1997

Tartaglia N, Ayari N, Howell S, et al: 48,YY, 48,XY, and 49,UXY syndromes: not just variants of Klinefelter syndrome. Acta Paediatrica 100(6):851,o2011

Tartaglia NR, Howell S, Sutherland A, et al: A review of trisomy X (47,XX).

Orphanet J Rare Dis 5:8, 2010

Tennant PW, Pearce MS, Bythell M, et al: 20-year survival of children born with congenital anomalies: a population-based study. Lancet 375(9715):649, 2010

Tepperberg J, Pettenati MJ, Rao PN, et al: Prenatal diagnosis using interphase fluorescence in situ hybridization (FISH): 2-year multi-center retrospective study and review of the literature. Prenat Diagn 21(4):293,o2001

Tinkle BT, Walker ME, Blough-Pfau I, et al: Unexpected survival in a case of prenatally diagnosed non-mosaic trisomy 22: clinical report and review of the natural history. Am J Med Genet A 118A(1):90, 2003

Toriello HV, Meck JM, Professional Practice and Guidelines Committee:

Statement on guidance for genetic counseling in advanced paternal age. Genet Med 10(6):457, 2008

Tuohy JF, James DK: Pre-eclampsia and trisomy 13. BJOG 99(11):891, 1992 Turner HH: A syndrome of infantilism, congenital webbed neck and cubitus valgus. Endocrinol 23:566, 1938

Vendola e, Canfield M, Daiger SP, et al: Survival of Texas infants born with trisomies 21, 18, and 13. Am J Med Genet A 152A(2):360, 2010 Vintzileos Ni, Egan JF: Adjusting the risk for trisomy 21 on the basis of second-trimester ultrasonography. Am J Obstet GynecoIo172(3):837, 1995

Vockley J, ndersson He, Antshel KM, et al: ACMG Practice Guidelines: phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med 16(2):188,o2014

Wang Y, Chen Y, Tian F, et al: Maternal mosaicism is a significant contributor to discordant sex chromosomal aneuploidies associated with non-invasive prenatal testing. Clin Chen 60(1):251, 2014

Weismann CG, Gelb BD: The genetics of congenital heart disease: a review of recent developments. Curr Opin Cardiol 22(3):200, 2007

Wellesley D, Dolk H, Boyd PA, et al: Rare chromosome abnormalities, prevalence, and prenatal diagnosis rates from population-based congenital anomaly registers in Europe. Eur J Human Genet 20(5):521,o2012

Wigby K, D'Epagnier e, Howell S, et al: Expanding the phenotype of triple X syndrome: a comparison of prenatal versus postnatal diagnosis. Am J Med Genet Part A 170(11):2870, 2016

Worton RG, Stern R: A Canadian collaborative study of mosaicism in amniotic fluid cell cultures. Prenat Diagn 4(7): 131, 1984

Wou K, Hyun Y, Chitayat D, et al: Analysis of tissue from products of conception and perinatal losses using QF-PCR and microarray: a three-year retrospective study resulting in an eicient protocol. Eur J Med Genet 59(8):417, 2016

Wright CF, Burton H: he use of cell-free fetal nucleic acids in maternal blood for non-invasive prenatal diagnosis. Hum Reprod Update 15(1):139,o2009 Yang Q, Wen SW, Leader A, et al: Paternal age and birth defects: how strong is the association? Human Reprod 22(3):696, 2007

Yeo L, Guzman ER, Day-Salvatore D, et al: Prenatal detection of fetal trisomy 18 through abnormal sonographic features. J Ultrasound Med 22(6):581, 2003

Zalel Y, Shapiro I, Weissmann-Brenner A, et al: Prenatal sonographic features of triploidy at 12-16 weeks. Prenat Diagn 36(7)650, 2016

HISTORICAL PERSPECTIVE ..e..e.e.e....e....e277

FIRST-TRIMESTER ANEUPLOIDY SCREENING ...e. 281

SECOND-TRIMESTER ANEUPLOIDY SCREENING .e282

INTEGRATED AND SEQUENTIAL SCREENING ...e.. 284

CELL-FREE DNA SCREENING ..e..e.e.e.e284

SONOGRAPHIC SCREENING ...e..e..e.e..e.e...e286

CARRIER SCREENING FOR GENETIC DISORDERS .e... 288

AMNIOCENTESIS AND CHORIONIC VILLUS SAMPLINGe. .e291

PREIMPLANTATION GENETIC TESTING .e.e.....e.. 295

Carul examination should ordinariy lead to a correct diagnosis of hydrocephalus in the last weeks of pregnancy. In many cases the dormiy can be detected by external papation.

-]. Whitridge Williams (1903)

In the initial edition of Williams Obstetrics, very few fetal disorders could be identiied before delivery. Now, more than 100 years later, prenatal diagnosis has become a separate field of its own. Strictly speaking, prenatal diagnosis is the science of identiying congenital abnormalities, aneuploidies, and other genetic syndromes in the fetus. It encompasses the diagnosis of structural malformations with specialized sonography; routine screening tests for aneuploidy and neural-tube defects; diagnostic tests such as karyotyping and chromosomal microarray analysis performed on chorionic villi and amniocentesis specimens; and additional screening and diagnostic tests ofered to those with pregnancies at risk for speciic genetic disorders. he goal of prenatal diagnosis is to provide accurate information regarding short-and long-term prognosis, recurrence risk, and potential therapy, thereby improving patient counseling and optimizing outcomes.

Management of an afected pregnancy, including whether a woman would elect pregnancy termination, may be incorporated into the discussion of screening and testing options. However, nondirective counseling is central to prenatal diagnosis. his practice provides the patient with unbiased knowledge regarding a diagnosis and preserves her autonomy (Flessel, 2011). Fetal imaging of congenital anomalies is discussed in Chapter 10, and pregnancy termination is discussed in Chapter 18.

More than 40 years ago, Brock (1972, 1973) observed that pregnancies complicated by neural-tube defects had higher levels of alpha-fetoprotein (AFP) in maternal serum and amnionic luid. his formed the basis for the irst maternal serum screening test for a fetal condition. The beginning of widespread serum screening came in 1977, after a collaborative trial from the United Kingdom established the association between elevated maternal serum AFP levels (MSAFP) and fetal open neural-tube defects (Wald, 1977). When screening was performed at 16 to 18 weeks' gestation, detection approached 90 percent for pregnancies with fetal anencephaly and 80 percent for those with myelomeningocele (spina biida). hese sensitivities are comparable to current testing (American College of Obstetricians and Gynecologists, 20 16a).

The terms level I and level II sonography were coined in this context. In the California MSAFP Screening Program of the 1980s and early 1990s, women received serum screening prior to sonography, and those with an elevated MSAFP level would undergo level I sonography to identiy an incorrect gestational age, mulrifetal gestation, or fetal demise (Filly, 1993). A third of pregnancies with an elevated MSAFP level had one of these three etiologies. Although birth defects were occasionally detected during level I sonography, this was not the expectation. If level I sonography did not identiy an etiology for the MSAFP level elevation, amniocentesis would be ofered. Then, only if the amnionic luid AFP concentration were elevated would the woman undergo level II sonography. his more detailed and comprehensive survey of fetal anatomy was performed to detect and characterize the fetal abnormality.

If the amnionic fluid AFP level was elevated, an assay for amnionic luid acetylcholinesterase was concurrently performed. his capitalized on the tendency of acetylcholinesterase to leak directly from exposed neural tissue into the amnionic luid. The presence of both analytes in the amnionic luid was considered diagnostic for neural-tube defects (American College of Obstetricians and Gynecologists, 2016a).

The overall sensitivity of amniocentesis to diagnose open neural-tube defects approximates 98 percent, with a false-positive rate of 0.4 percent (Milunsky, 2004). Importantly, other fetal abnormalities are associated with elevated amnionic fluid AFP levels and positive assay results for acetylcholinesterase. These include ventral wall defects, esophageal atresia, fetal teratoma, cloacal exstrophy, and skin abnormalities such as epidermolysis bullosa. hus, by current standards, these amnionic luid analytes would be considered ancillary screening tests, understanding that a positive result would prompt additional fetal imaging.

With current imaging technology, most neural-tube defects are detected with sonography, and targeted sonography is the diagnostic test of choice (Dashe, 2006). Pregnant women now have the option of neural-tube defect screening with either MSAFP or sonography (American College of Obstetricians and Gynecologists, 20 16c). Although level II is used as a synonym for targeted sonography, the former might best be removed from our lexicon. Namely, today's targeted sonography includes a much more comprehensive evaluation of fetal anatomy (Chap. 10, p. 187).

As MSAFP screening was being adopted, the designation «advanced maternal age" (AMA) became popular. A 1979 National Institutes of Health Consensus Development Conference recommended advising pregnant women who were 35 years and older about the possibility of amniocentesis for fetal karyotyping. he threshold was based on the greater risk for selected fetal chromosomal abnormalities with increasing maternal age and on the assumption that at that time, the loss rate attributable to amniocentesis was equivalent to the fetal Down syndrome risk at maternal age 35. Notaby, this is no longer the case, as discussed later (p. 293).

Serum aneuploidy screening soon became available for women who would be younger than 35 at delivery. In 1984, Merkatz and colleagues reported that MSAFP levels were lower in pregnancies with trisomies 21 and 18 at 15 to 21 weeks' gestation. Maternal age was incorporated into the calculation, such that a speciic risk could be assigned (DiMaio, 1987; New England Regional Geneties Group, 1989). The MSAFP screen detected approximately 25 percent of cases of fetal trisomy 21 when the threshold ratio for a positive result was set at 1 :270. This ratio relects the approximate second-trimester risk for Down syndrome at maternal age 35. This trisomy 21

FIGURE 14-1 Trends in the percentage of births to women aged 35 to 44 years. (Data from the Centers for Disease Control and Prevention, 201o5.) risk threshold and the associated 5-percent false-positive rate became standards that remain in use in some laboratories today.

For more than a decade after its introduction, serum aneuploidy screening was intended for women younger than 35, because it simply did not have suicient sensitivity to be ofered to women who had higher a priori risk. This is also no longer the case. And, because the prevalence of fetal aneuploidy rises sharply with maternal age, the positive-predictive value of all aneuploidy screening tests-whether analyte-based or cellfree DNA tests-is higher in women aged 35 years or older. Women 35 and older now make up more than 15 percent of deliveries in the United States (Fig. 14-1). At Parkland Hospital, this age group accounts for half of births with Down syndrome (Hussamy, 2017).

Aneuploidy is the presence of one or more extra chromosomes, usually resulting in trisomy, or loss of a chromosomemonosomy. Data from population-based registries that include births, fetal deaths, and pregnancy terminations indicate an overall prevalence of 4 such abnormalities per 1000 births (Wellesley, 2012). Aneuploidy accounts for more than 50 percent of first-trimester abortions, about 20 percent of second-trimester losses, and 6 to 8 percent of stillbirths and early-childhood deaths (Reddy, 2012; Stevenson, 2004; Wou, 2016). Of recognized pregnancies with chromosomal abnormalities, trisomy 21 composes approximately half of cases; trisomy 18 accounts for 15 percent; trisomy 13, for 5 percent; and the sex chromosomal abnormalities-45,X, 47,XX, 47,Y, and 47,XY-for approximately 12 percent (Wellesley, 2012).

The risk for fetal trisomy increases with maternal age, particularly after age 35 (Fig. 13-2, p. 255). When counseling, a provider includes specific maternal-age-related aneuploidy risks (Tables 14-1 and 14-2). Other important fetal aneuploidy risk factors include a numerical chromosomal abnormality or structural chromosomal rearrangement in the woman or her partner-such as balanced translocation-or a prior pregnancy with autosomal trisomy or triploidy.

Broadly speaking, there are two types of aneuploidy screening tests, those that are traditional or analyte-based and those that are cell-free DNA-based. All pregnant women should be

TABLE 14-1. Maternal Age-Related Risk for Down Syndrome and Any Aneuploidy at Midtrimester and at Term in Singleton Pregnancies analysis provides information about genetic conditions that screening tests and karyotyping alone currently do not (American College of Obstetricians and Gynecologists, 2016b). This is discussed further on page 291 and in Chapter 13 (p. 271).

3. Is this a multetal gestation? All traditional (analyte-based) aneuploidy screening tests are significantly less efective in multifetal gestations, and cell-free DNA screening is not cur rently recommended with multifetal gestations (p. 285).

37 1/149 1/227 1/83 1/1l30 4. What method will be used or neural-tube deect screening?

1/89 1/137 1/53 1/81 that does not include second-trimester serum analytes, 41 1/53 1/81 1131 1/50 arately, either with MSAFP assessment or with sonography 42 1/41 1/64 1/25 1/39 (American College of Obstetricians and Gynecologists, 43 1/31 1/50 1/19 1/30 2016c).

44 1/25 1/38 1/15 1/24 5. Does the etus have a major anomay? If so, diagnostic testing 1/19 1/30 1/12 1/19 is recommended rather than screening.

Data from Hook EB, Cross PK, Schreinemachers DM: live-born infants, JAMA. 1983 Apr 15;249(15):2034-2038.

ofered aneuploidy screening or diagnostic testing early in pregnancy (American College of Obstetricians and Gynecologists, 2016c). Considerations prior to screening are as follows: 1.

Has the patient elected screening? At least 20 percent of women elect not to receive aneuploidy screening, even when financial barriers are removed. Fewer than 40 percent of women with a positive screening result elect prenatal diagnosis (Dar, 2014; Kuppermann, 2014).

2.

ould the patient preer prenatal diagnosis? Diagnostic testing is safe and efective, and chromosomal microarray

TABLE 14-2. Maternal Age-Related Risk for Down Syndrome and Any Aneuploidy at Midtrimester and at Term in Dizygotic Twin Pregnanciesa

The American College of Obstetricians and Gynecologists (2016c) has airmed that screening for aneuploidy should be an informed patient choice, with an underlying foundation of shared decision making that its her clinical circumstances, values, interests, and goals. Elements of counseling prior to aneuploidy screening are listed in Table 14-3.

Aneuploidy screening can be challenging because the test characteristics of each option may vary with maternal age and with whether the test is analyte-based or cell-free DNA-based. The test sensitivity is the detection rate-that is, the proportion of aneuploid fetuses identiied by the screening test. Its converse, the false-negative rate, is the percentage of cases that the test is expected to miss. A first-trimester screening test with a sensitivity of 80 percent is expected to miss 1 in 5 cases. The sensitivity of screening tests for Down syndrome has increased steadily during the past 30 years, from just 25 percent with serum AFP alone to more than 90 percent with integrated or sequential screening.

Another key characteristic is the false-positive rate, the percentage of unafected pregnancies that will "falsely" screen positive. This approximates 5 percent for first-trimester screening, quadruple-marker screening, or integrated screening options (Baer, 2015; Kazerouni, 2011; Malone, 2005b; Nor 1/160 1/257 1/91 1/126 ton, 2015). The converse of false-posi tive rate is speciici ty percent of unafected pregnancies. lthough test sensitivity 1177 1/118 1/44 1/67 has improved, the false-positive rate has been held constant for many diferent aneuploidy screening tests (Table 14-4).

1/47 1172 1/27 1/44 Both statistics are relevant for counseling. An additional con aRisk applies to one or both fetuses.

Data from Meyers C, Adam R, Dungan J, et al: Aneuploidy in twin gestations: when is maternal age advanced? Obstet

Gynecol. 1997 Feb;89(2):248-251l.

sideration is that with all analyte-based screening tests, women 35 and older have higher rates of positive results (Kazerouni, 2011; Malone, 2005b).

Importantly, neither sensitivity nor false-positive rate conveys individual risk. he statistic that patients and providers usually consider to be the test result is the positive-predictive value, which is the proportion of those with a positive screening result who actually have an aneuploid fetus. It may be expressed

TABLE 14-3. Aneuploidy Screening Counseling Elements 1. All pregnant women have 3 options: screening, diagnostic testing, and no screening or testing.

The purpose of a screening test is to provide information, not to dictate a course of action. Diagnostic testing is safe and effective and provides information that screening does not.

2. The diference between a screening test and a diagnostic test. Screening evaluates whether the pregnancy is at increased risk and estimates degree of risk. Detection rate, false-negative rate, and false-positive rate are provided. Cell-free DNA screening does not always provide a result. Irreversible management decisions should not be based on screening test results. With a positive screening result, a diagnostic test is recommended if the patient wants to know whether the fetus is affected.

3. Basic information is provided about each condition covered by the screening test (prevalence, associated abnormalities, prognosis), and screening test limitations.

A benefit of diagnosis includes earlier identification of associated abnormalities.

In case of trisomy 18 or 13, diagnosis may affect pregnancy management if complications arise such as growth restriction or nonreassuring fetal heart rate.

With sex chromosome aneuploidies, phenotypic expression varies widely. Several are so mild they would otherwise not be diagnosed.

4. The patient's a priori risk for fetal aneuploidy may affect her screening test options or election.

Age-related risk information may be found in reference tables.

If a patient has had a prior fetus with autosomal trisomy, robe sonian translocation, or other chromosomal abnorrnality, additional evaluation and counseling are suggested.

Modified with permission from Dashe JS: Aneuploidy screening in pregnancy, Obstet Gynecol. 2016 Jul;128(1 ):181l-194.

as a l:X ratio or as a percentage. he positive-predictive value value reported in a research trial is the proportion of women is directly afected by disease prevalence, so it is much higher with positive screening results who have afected fetuses for women aged 35 years and older than for younger women (see Table 14-4). Negative-predictive value is the proportion of (Table 14-5). Positive-predictive values can also be reported those with a negative screening test result who have unafected for cohorts of pregnancies. For example, the positive-predictive (euploid) fetuses. Because the prevalence of aneuploidy is so

TABLE 14-4. Characteristics of Screening Tests for Trisomy 21 in Singletons

Screening Test Rate Rate Predictive Valuea Quadruple screen:

AFP, hCG, estriol, inhibin 80-82% 5% 3%

First-trimester screen:

NT, hCG, PAPP-A 80-84% 5% 3-4%

Sequential screening:

Stepwise 92% 5.1l% 5%

Contingent 91% 4.5% 5%

Cell-free DNA screening:

Positive result 99% 0.1% Table 14-5 aThe positive-predictive value represents the overall population studied and cannot be applied to any individual patient.

NT = nuchal translucencyf PA.PP-A = pregnancy-associated plasma protein A.

Data from Baer, 2015f Gil, 2015; Malone, 200Sb; j\lorton, 2015; 2014; Quezada, 2015; Dashe, 201l6.

TABLE 14-5. Positive-Predictive Value of Cell-Free DNA Screening for Autosomal Trisomies and Selected Sex Chromosome Abnormalities, According to Maternal Age

Maternal Age Trisomy 21 Trisomy 18 Trisomy 13 45,X 47,XXY

NA = not available; ��IPT = non-invasive prenatal test.

Positive-predictive values were obtained using the NIPT/Cel1 Free DNA Screening Predictive Value Calculator from the Perinatal Quality Foundation, 2017. Calculations are based on prevalence at 16 weeks' gestation using sensitivities and specificities from Gil, 2015.

low, the negative-predictive value of all aneuploidy screening tests generally exceeds 99 percent (Gil, 2015; Norton, 2015).

are also called conventional or traditional to diferentiate them from cell-free DNA-based screening. There are three categories: irst-trimester screens, second-trimester screens, and combina tions of irst-and second-trimester screens. If the test has a irst trimester component, it almost always includes a measurement of the sonographic nuchal translucency, which is discussed in the next section.

Each maternal serum analyte is measured as a concentration-for example, nanograms per milliliter of AFP. he concentration is converted to a multiple of the median (MoM) by adjusting for maternal age, maternal weight, and gestational age. he nuchal translucency measurement increases with crown-rump length (CRL) , and thus its value is adjusted for CRL and also reported as an MoM. The AFP analyte is further adjusted for maternal race and ethnicity and for presence of diabetes, which all afect the calculation of neural-tube defect risk rather than of aneuploidy risk (Greene, 1988; Huttly, 2004). Reporting these results as an MoM of the unafected population normalizes the distribution of analyte levels and permits comparison of results from diferent laboratories and populations.

he analyte-based aneuploidy screening result is based on a composite likelihood ratio, and the maternal age-related risk is multiplied by this ratio. his principle similarly applies to modiication of fetal Down syndrome risk by selected sonographic markers, which are discussed later on page 286. Each woman is provided with a speciic risk for trisomy 21 and for trisomy 18-or in the irst trimester, for trisomy 18 or 13 in some cases. he result is expressed as a ratio that represents the positive-prediCtive value.

Importantly, each screening test also has a predetermined value at which or above which it is deemed "positive" or abnormal. For second-trimester tests, this threshold has traditionally been set at the risk for fetal Down syndrome in a woman aged 35 years-approximately 1 in 270 in the second trimester (see Table 14-1). he threshold selected for a positive screen relects the laboratory requirement but is somewhat problematic, as it may bear no relationship to patient preference. However, a positive screening result may afect whether the patient is deemed "high risk," receives formal genetic counseling, and is ofered diagnostic testing with chorionic villus sampling or amniocentesis. Thus, it behooves the provider to discuss the patient's preferences prior to screening.

Also called combined irst-trimester screening, this test combines two maternal serum analytes, human chorionic gonadotropin (hCG) and pregnancy-associated plasma protein A (PAPP-A), with the sonographic measurement of the nuchal translucency (NT). It is performed between 11 and 14 weeks' gestation. In cases of fetal Down syndrome, the irst-trimester serum free 3-hCG level is higher and the PAPP-A level is lower. With trisomy 18 and trisomy 13, levels of both analytes are lower (Cuckle, 2000; Malone, 2005b).

Nuchal Translucency. his is the maximum thickness of the subcutaneous translucent area between the skin and soft tissue overlying the fetal spine at the back of the neck (Fig. 14-2). An increased NT thickness is not a fetal abnormality but rather is a marker that confers increased risk. It is measured in the sagittal plane and is valid when the CRL value lies between 38 to 45 mm and 84 mm, with the lower limit varying according to the laboratory. Speciic criteria for NT measurement are listed in Table 10-4 (p. 186). Whenever possible, it is helpful to diferentiate increased NT from cystic hygroma, which is a venolymphatic malformation that appears as a septated hypoechoic space behind the neck, extending along the length of the back (Fig. 10-22, p. 198). Cystic hygroma confers a ivefold increased aneuploidy risk when identiied in the irst trimester (Malone, 2005a).

In addition to aneuploidy, an increased NT thickness is associated with other genetic syndromes and various birth defects, especially fetal cardiac anomalies (Simpson, 2007). And, if the NT measurement reaches 3 mm or more, the aneuploidy risk

FIGURE 14-2 Sagittal image of a normal, 12-week fetus demonstrating correct caliper placement (+) for nuchal translucency measurement. The fetal nasal bone and overlying skin are indicated. The nasal tip and the 3rd and 4th ventricles (asterisk), which are other landmarks that should be visible in the nasal bone image, are also shown. (Used with permission from Dr. Michael Zaretsky.) is unlikely to normalize using serum analyte assessment (Comstock, 2006). Because of this, if the NT measurement is at least 3 mm or exceeds the 99th percentile, the patient should receive counseling and be ofered targeted sonography with fetal echocardiography. In addition, she should be ofered cell-free DNA screening and prenatal diagnosis (American College of Obstetricians and Gynecologists, 2016c).

The NT must be imaged and measured with a high degree of precision for aneuploidy detection to be accurate. This has led to standardized training, certiication, and ongoing quality review programs. In the United States, training, credentialing, and monitoring are available through the Nuchal Translucency Quality Review program of the Perinatal Quality Foundation and through the Fetal Medicine Foundation.

Efficacy of First-Trimester Screening. Before first-trimester screening became widely adopted, four large prospective trials were conducted, together including more than 100,000 pregnancies (Reddy, 2006). When the false-positive rate was set at 5 percent, the overall rate for trisomy 21 detection was 84 percent, comparable to quadruple-marker screening (see Table 14-4). he detection rate is approximately 5 percent higher if performed at 11 weeks' compared with 13 weeks' gestation, and slightly lower-80 to 82 percent-when cases with cystic hygroma are analyzed separately (Malone, 2005a). In a recent multicenter trial, first-trimester screening detected approximately 80 percent of fetuses with trisomy 21, 80 percent with trisomy 18, and 50 percent with trisomy 13 (Norton, 2015).

As an isolated marker, NT detects approximately two thirds of fetuses with Down syndrome, with a false-positive rate of 5 percent (Malone, 2005b). However, NT is generally used as an isolated marker only in screening for multifetal gestations, in which serum screening is less accurate or may not be available. he NT distribution is similar in twins and singletons (Cleary-Goldman, 2005). In twin pregnancies, serum free 3-hCG and PAPP-A levels are approximately double the singleton values (Vink, 2012). Even with speciic curves, a normal dichorionic cotwin will tend to normalize screening results, and thus, the aneuploidy detection rate is at least 15-percent lower (Bush, 2005).

Maternal age afects the performance of first-trimester aneuploidy screening. Prospective trials have demonstrated Down syndrome detection rates of 67 to 75 percent in women younger than 35 years at delivery, which are 10 percent lower than the overall detection rates in these studies (Malone, 2005b; Wapner, 2003). Among women older than 35 at delivery, Down syndrome detection reached 90 to 95 percent, albeit at a higher false-positive rate of 15 to 22 percent.

Unexplained Abnormalities of First-Trimester AnaIytes. There is a signiicant association between serum PAPPA levels below the 5th percentile and preterm birth, growth restriction, preeclampsia, and fetal demise (Cignini, 2016; Dugof, 2004; Jellife-Pawlowski, 2015). Similarly, low levels of free 3-hCG have been associated with fetal demise (Goetzl, 2004). he sensitivity and positive-predictive values of isolated markers are generally too low to make them clinically useful as screening tests.

There has been renewed interest in low-dose aspirin for prevention of early preeclampsia in women identified as at risk based on mean arterial pressure, uterine artery Doppler values, and PAPP-A levels. However, these observations are preliminary (Park, 2015).

Currently, the only second-trimester multiple marker test widely used in the United States is the quadruple marker or "quad" screening test. It is performed from 15 to 21 weeks' gestation, and inclusive gestational age ranges vary according to individual laboratories. Pregnancies with fetal Down syndrome are characterized by lower maternal serum AFP, higher hCG, lower unconjugated estriol, and higher dimeric inhibin levels. When the quad screen was initially described, the Down syndrome detection rate approximated 70 percent. But, by the early 2000s, the reported detection rate in two large prospective trials had improved to 81 to 83 percent, with a 5-percent screen-positive rate (Malone, 2005b; Wald, 1996, 2003). The improved detection rate is attributable, at least in part, to accurate gestational age assessment with sonography. In a review of more than 500,000 pregnancies receiving quadruple-marker screening through the statewide California Prenatal Screening Program, trisomy 21 detection was 78 percent with sonographic gestational age assessment but only 67 percent when the screen was calculated based on last menstrual period alone (Kazerouni, 2011). As with first-trimester screening, aneuploidy detection rates are lower in younger women and higher in women older than 35 years at delivery. If second-trimester serum screening is used in twin pregnancies, aneuploidy detection rates are significantly lower (Vink, 2012). With trisomy 18, the levels of the first three analytes are all decreased, and inhibin is not part of the calculation. Trisomy 18 detection is similar to that for Down syndrome, with a false-positive rate of only 0.5 percent (Benn, 1999).

Although the quadruple-marker screening test is used to screen for Down syndrome and trisomy 18, pregnancies with other chromosomal abnormalities may be identiied as well.

The California Prenatal Screening Program found that the of those with triploidy, in 75 percent with Turner syndrome (45,X), in 44 percent with trisomy 13, and in more than 40 percent of those with other major chromosomal abnormalities (Kazerouni, 2011). Although a speciic risk for these aneuploi dies cannot be provided based on the test result, the informa tion may be relevant for women considering amniocentesis.

Quadruple-marker screening ofers no beneit over irsttrimester screening from the standpoint of trisomy 21 or trisomy 18 detection. As a stand-alone test, it is generally used if women do not begin care until the second trimester or if irst-trimester screening is not available. In 2011, women who initiated prenatal care beyond the irst trimester made up nearly 25 percent of pregnancies in the United States. As subsequently discussed, combining irst-and second-trimester screening yields an even greater aneuploidy detection rate.

Maternal Serum AFP Elevation: Neural-Tube Defect Screening. All pregnant women are ofered screening for fetal open neural-rube defects in the second trimester, either with MSAFP screening or with sonography (American College of Obstetricians and Gynecologists, 20 16c). Measurement of the MSAFP concentration between 15 and 20 weeks' gestation has been ofered as part of routine prenatal care for more than 30 years. Because AFP is the major protein in fetal serum, analogous to albumin in a child or adult, the normal concentration gradient between fetal plasma and maternal serum is on the order of 50,000: 1. Defects in fetal integument, such as neural-tube and ventral-wall defects, permit AFP to leak into the amnionic fluid, resulting in dramatically increased maternal serum levels. he AFP value rises by about 15 percent per week during the screening window (Knight, 1992). he MoM is generally recalculated if the irst-trimester CRL or second-trimester biparietal diameter difers from the stated gestational age by more than 1 week.

Using an MSAFP level of 2.5 MoM as the upper limit of normal, the neural-tube defect detection rate is at least 90 percent for anencephaly and 80 percent for spina biida, with a screen-positive rate of 3 to 5 percent (American College of Obstetricians and Gynecologists, 2016a; Milunsky, 2004). Higher screening threshold values are used in twin pregnancies (Cuckle, 1990).

Virtually all cases of anencephaly and many cases of spina biida may be detected or suspected during a standard second-trimester sonographic examination (Dashe, 2006). Most centers now use targeted sonography as the primary method to evaluate elevated MSAFP levels and as the prenatal diagnostic test of choice for neural-tube defects (Chap. 10, p. 192). If targeted sonography is not available and myelomeningocele cannot be excluded, amniocentesis may be considered for measurement of amnionic luid AFP and acetylcholinesterase levels. That said, we recommend additional imaging prior to establishing the diagnosis, with the understanding that other

TABLE 14-6. Conditions Associated with an Elevated MSAFP Concentration

Renal anomalies-polycystic kidneys, renal agenesis, congenital nephrosis, urinary tract obstruction

Chorioangioma of placenta

MSAFP = maternal serum alpha-fetoprotein.

abnormalities or conditions can result in elevation of these amnionic luid analytes (Table 14-6). Sonographic indings characteristic of fetal neural-tube defects are reviewed in Chapter 10 (p. 192). Fetal surgery for myelomeningocele is discussed in Chapter 16 (p. 319).

Unexplained Abnormalities of Second-Trimester Analytes.

he positive-predictive value of an elevated MSAFP value is only 2 percent. Approximately 98 percent of pregnancies with an MSAFP level exceeding 2.5 MoM have an etiology other than a neural-tube defect. hus, counseling is indicated not only to inform the patient about the beneits and limitations of targeted sonography for the diagnosis of neural-tube defects but also to review the numerous other conditions. Some of these include fetal anomalies, placental abnormalities, and adverse outcomes associated with MSAFP level elevation (see Table 14-6). he likelihood of one of these abnormalities or of an adverse pregnancy outcome in the absence of a recognized abnormality rises in proportion to the AFP level. Adverse outcomes include fetal-growth restriction, preeclampsia, preterm birth, fetal demise, and stillbirth. More than 40 percent of pregnancies may be abnormal if the MSAFP level is greater than 7 MoM (Reichler, 1994).

Second-trimester elevation of either hCG or dimeric inhibin alpha levels also shows signiicant association with adverse pregnancy outcomes. he outcomes reported are similar to those associated with MSAFP level elevation. Moreover, the likelihood of adverse outcome is augmented when levels of several markers are elevated (Dugof, 2005).

Many of these complications are assumed to result from placental damage or dysfunction. However, the sensitivity and positive-predictive values of these markers are considered too low to be useful for screening or management. No speciic program of maternal or fetal surveillance has been found to favorably afect pregnancy outcomes (Dugof, 2010). At Parkland Hospital, prenatal care for these women is not altered unless a specific complication arises. Despite the extensive list of possible adverse outcomes, it is reassuring that most women with unexplained elevation of these analytes have normal outcomes.

Low Maternal Serum Estriol Level. A maternal serum estriol level less than 0.25 MoM has been associated with two uncommon but important conditions. he irst, Smith-Lemli-Opitz syndrome, is an autosomal recessive condition resulting from mutations in the 7 -dehydrocholesterol reductase gene. It is characterized by abnormalities of the central nervous system, heart, idney, and extremities; with ambiguous genitalia; and with fetal-growth restriction. For this reason, the Society for Maternal-Fetal Medicine has recommended that sonographic evaluation be performed if an unconjugated estriol level is <0.25 MoM (Dugof, 2010). If abnormalities are identified, an elevated amnionic luid 7 -dehydrocholesterol level can conirm the diagnosis.

he second condition is steroid suatase diciency, also known as X-linked ichthyosis. It is typically an isolated condition, but it may also occur in the setting of a contiguous gene deletion syndrome (Chap. 13, p. 260). In such cases, it may be associated with Kallmann syndrome, chondrodysplasia punctata, and/or mental retardation (Langlois, 2009). If the estriol level is <0.25 MoM and the fetus appears to be male, chromosomal microarray analysis or fluorescence in situ hybridization to assess the steroid sulfatase locus on the X-chromosome may be considered.

As shown in Table 14-4, if irst-trimester screening is combined with second-trimester screening, aneuploidy detection is signiicantly improved. Combined screening test options require coordination between the provider and laboratory. Specifically, if a second sample is required, it is obtained during the appropriate gestational age window, sent to the same laboratory, and linked to the first-trimester results. The irst-and secondtrimester components cannot be performed independently because if either component yields positive results, then providing accurate risk assessment would be problematic.

Three types of screening strategies are available: 1. Integrated screening combines results of irst-and secondtrimester tests. his includes a combined measurement of fetal NT and serum analyte levels at 11 to 14 weeks' gestation plus quadruple markers at approximately 15 to 21 weeks. n aneuploidy risk is then calculated from these seven parameters. As expected, integrated screening has the highest Down syndrome detection rate-94 to 96 percent, with a false-positive rate of 5 percent (see Table 14-4). If NT measurement is not available, then serum integrated screening includes all six serum markers to calculate risk. his screening, however, is less efective, and Down syndrome detection rates are 85 to 88 percent (Malone, 2005b).

2. Sequential screening involves performing first-trimester screening and informing the patient of the results. his is coupled with the understanding that if the calculated risk value lies above a speciied threshold, she will receive counseling and will be ofered diagnostic testing. here are two testing strategies in this category:

With stepwise sequential screening, women with firsttrimester screen results that confer risk for Down syndrome above a particular threshold are ofered invasive testing, and the remaining women receive secondtrimester screening. Using data from the First-and Second-Trimester Evaluation of Risk (FaSTER) trial, when the first-trimester threshold is set at approximately 1 :30, and the overall threshold is set at 1 :270, stepwise sequential screening resulted in a 92-percent detection rate of Down syndrome pregnancies, with a false-positive rate of 5 percent (see Table 14-4) (Cuckle, 2008).

With contingent sequential screening, women are divided into high-, moderate-, and low-risk groups. Those at highest risk for Down syndrome-for example, riski> 1 :30, are counseled and ofered invasive testing. Women at moderate risk, between 1 :30 and 1: 1500, undergo second-trimester screening, whereas those at lowest risk of < 1: 1500 receive negative screening test results and have no further testing (Cuckle, 2008). Using this strategy, more than 75 percent of those screened are provided with reassuring results almost immediately, while still maintaining a high detection rate of about 91 percent, with a 5-percent false-positive rate (see Table 14-4). his option is lso more cost efective because a second-trimester test is obviated in most patients.

In a population-based review of 450,000 pregnancies from the California Prenatal Screening Program, integrated screening detected 94 percent of trisomy 21 fetuses and 93 percent with trisomy 18 (Baer, 2015). Additionally, the screening result was abnormal in 93 percent of cases of trisomy 13, in 91 percent with triploidy, and in 80 percent with Turner syndrome. Women considering options of integrated screening and cellfree DNA screening may ind this information helpful.

his was introduced in 2011 and has completely changed the prenatal screening paradigm. he test works by identiying DNA fragments that are derived primarily from apoptotic trophoblasts, which are placental cells undergoing programmed cell death. hus, the term cell-free etal DNA is somewhat of a misnomer. Screening is not gestational-age dependent and can be performed at any time ater 9 to 10 weeks' gestation. Results are available in 7 to 10 days (American College of Obstetricians and Gynecologists, 2017 c). hree types of assays are currently available: wholegenome sequencing, which is also called massively parallel or shotgun sequencing; chromosome selective or targeted sequencing; and analysis of single nucleotide polymorphisms.

he screening performance of cell-free DNA is excellent. In a metaanalysis of 37 studies of largely high-risk pregnancies, the pooled sensitivity to detect Down syndrome was 99 percent, and for trisomies 18 and 13, 96 percent and 91 percent, respectively. For each of these autosomal trisomies, the speciicity was 99.9 percent. Thus, most unafected pregnancies received a norml screening result. Cell-free DNA also detects 90 percent with Turner syndrome (45,X) and 93 percent with sex chromosome aneuploidies other than 45,X (Gil, 2015). The false-positive rate is cumulative for each aneuploidy for which screening is performed, but it is usually only 0.5 to 1 percent. s a result, cell-free DNA screening is recommended as a screening option in those at increased risk for fetal autosomal trisomy (American College of Obstetricians and Gynecologists, 2017c; Society for MaternalFetal Medicine, 2015). This includes the following categories: 1.

2.

3.

Sonogram with a minor aneuploidy marker 4.

Prior pregnancy with autosomal trisomy 5.

Known carriage (patient or partner) of a balanced robertsonian translocation involving chromosome 21 or 13.

If cell-free DNA screening is performed as a seconday screen following a positive irst-or second-trimester analyte-based test result, a normal result is not quite as reassuring. The residual risk for chromosomal abnormality is estimated to be 2 percent (Norton, 2014). Compared with amniocentesis, use of cellfree DNA screening after an initial abnormal analyte-based test result is estimated to yield a 20-percent reduction in aneuploidy diagnoses. his takes into consideration false-negative diagnoses and aneuploidies not detectable with cell-free DNA screening (Davis, 2014; Norton, 2014). In addition, definitive diagnosis may be delayed, potentially afecting management. Concurrent or parallel screening is not recommended, and if an aneuploidy screening test of any type yields a negative result, additional screening is not indicated (American College of Obstetricians and Gynecologists, 2016b, 2017c).

he association between increased NT values and fetal structural and genetic abnormalities has raised questions about the role of a NT measurements following cell-free DNA screening. he College (20 16b) has stated that NT measurement is not necessary at the time of cell-free DNA screening but that sonography may help to conirm fetal number and viability and to assign gestational age. he Society for Maternal-Fetal Medicine (20i15) states that after a negative cell-free DNA screening test result, the additional clinical utility of NT measurement to detect other chromosomal or structural abnormalities is unknown but appears to be limited.

Most studies of cell-free DNA have been conducted in highrisk pregnancies. Pragmatically, chromosomal abnormalities are individually so rare that even large studies of low-risk pregnancies contain few afected cases. Available data suggest that the high sensitivity and speciicity for Down syndrome detection are preserved in low-risk pregnancies (Norton, 2015; Pergament, 2014; Zhang, 2015). Importantly, the positive-predictive value of cell-free DNA screening still depends greatly on maternal age and the specific aneuploidy in question (see Table 14-5). For a woman in her early 20s, the positive-predictive value is approximately 50 percent for fetal trisomy 21, 15 percent for trisomy 18, and < 10 percent for trisomy 13. Hence, decisions for irreversible medical intervention should not be based on the results of this or other screening test alone.

Important caveats are considered with selection of cell-free

DNA aneuploidy screening. Because the cell-free DNA that is analyzed is maternal and placental, results may not relect the fetal DNA complement but rather may indicate con ined placental mosaicism, early demise of an aneuploid co twin, maternal mosaicism, or even occult maternal malignancy (Bianchi, 2015; Curnow, 2015; Grati, 2014; Wang, 2014). In addition, if a twin pregnancy is identiied sonographically, cell free DNA screening is not currently recommended because of limited evidence regarding eicacy.

Another limitation is that cell-free DNA testing does not yield a result in approximately 4 to 8 percent of screened pregnancies, due to assay failure, high assay variance, or low fetal fraction (Norton, 2012; Pergament, 2014; Quezada, 2015). Most cell-free DNA is maternal. he fetal fraction is the proportion derived from the placenta and generally is about 10 percent of the total. A low fetal fraction is usually defined as <4 percent of the total and confers signiicantly higher risk for fetal aneuploidy (Ashoor, 2013; Norton, 2015; Pergament, 2014). Women with a low fetal fraction or "no-call" results have fetal aneuploidy rates as high as 4 percent, a percentage comparable to the average predictive value conferred by a positive irst-trimester screening test result (see Table 14-4). The fetal fraction is not related to maternal age or analyte-based screening test results. However, it is lower earlier in pregnancy and appears to be reduced in women of greater weight (Ashoor, 2013).

Because of the increased risk for fetal aneuploidy in cases not generating a cell-free DNA screening result (no-call result), genetic counseling is indicated, and amniocentesis should be ofered. If the patient elects repeat screening, the risk for screen failure may exceed 40 percent (Dar, 2014; Quezada, 2015). Targeted sonography is recommended but is not a substitute for amniocentesis, because it is unclear what the residual risk would be with normal sonogram indings. (American College of Obstetricians and Gynecologists, 2016b, 2017 c). Pretest counseling should include the possibility of a low fetal fraction or no-call result and its clinical signiicance.

Comparison with Analyte-Based Screening

Cell-free DNA screening has obvious advantages, but it is not simply a "better" test-because no screening test is superior for all test characteristics (American College of Obstetricians and Gynecologists, 20 16c). Compared with analyte-based tests, beneits of cell-free DNA screening in women 35 years and older include the lower likelihood of a false-positive result, its higher positive-predictive value, and the fact that isolated minor aneuploidy markers are generally not a concern (p. 286).

But, analyte-based tests are frequently positive with a large range of chromosomal abnormalities, whereas cell-free DNA

TABLE 14-7. Aneuploidy Risk Associated with Selected Major Fetal Anomalies

Cystic hygroma 1/5000 50-70 45,X; 21; 18; 13; triploidy

Nonimmune hydrops 1/1500-4000 10-20 21, 18, 13, 45X, triploidy

Ventricu Iomega Iy 1/1000-2000 5-25 13, 18,21/ triploidy

Holoprosencephaly 1/10,000-15,000 30-40 13, 18, 22, triploidy

Dandy-Walker malformation 1/12,000 40 18/ 13/21, triploidy Clet lip/palate 1/1000 5-15 18,13 Cardiac defects 5-8/1000 10-30 21; 18; 13; 45/X; 22q 11.2 microdeletion

Diaphragmatic hernia 1/3000-4000 5-15 18,l13,l21

Esophageal atresia 1/4000 10 18,l21

Duodenal atresia 1/10,000 30 21 Gastroschisis 112000-4000 No increase

Omphalocele 1/4000 30-50 18, 13, 21, triploidy autosomal trisomies except where indicated. For example, 45,X indicates Turner syndrome. Data from Best, 201l2; Canfield, 2006; Colvin, 2005; Cragan, 2009; Dolk/ 201l0; Ecker, 2000; Gallot/ 2007; Long, 2006; Orioli, 2010; Pedersen/ 2012; Sharma/ 201l1l; Solomon, 2010; Walker/ 2001l.

screens are specific for individual aneuploidies (Baer, 2015; Kazerouni, 2011). Women younger than 35 are at lower risk for the speciic autosomal trisomies for which cell-free DNA screening is typically performed. hus, if the goal is to select a screening test that will identiY the highest proportion of fetuses with any chromosomal abnormality, the yield may be comparable or even slightly higher with integrated or sequentil screening than with current cell-free DNA screening (Baer, 2015; Norton, 2014).

Sonography can augment aneuploidy screening by providing accurate gestational age assessment, by detecting multifetal gestations, and by identiYing major structural abnormalities and minor sonographic markers. s shown in Table 14-7, with rare exceptions, the aneuploidy risk associated with any major abnormality is high enough to warrant ofering prenatal diagnosis. Generally, chromosomal microarray analysis is recommended as the irst-line test. Importantly, a fetus with one abnormality may have others that are less likely to be detected sonographically but that greatly afect the prognosis. Aneuploidy screening-including cell-free DNA-is not recommended if a major abnormality has been identified. The fetal risk cannot be normalized with a normal screening result, not merely because screening results can be falsely negative, but also because major anomalies confer risk for genetic syndromes not identiied through screening tests.

If a major abnormlity is identified, targeted sonography is indicated. Sonography is not an alternative to prenatal diagnosis, but the aneuploidy risk is urther increased if additional findings are identified. An earlier study reported that only 25 to 30 percent of second-trimester fetuses with Down syndrome had a major malformation that could be identiied sonographically (Vintzileos, 1995). When both major anomalies and minor aneuploidy markers are considered, it is estimated that 50 to 60 percent of Down syndrome pregnancies can be detected sonographiclly (American College of Obstetricians and Gynecologists, 2016c). Fortunately, most fetuses with aneuploidy that is likely to be lethal in uterosuch as trisomy 18 and 13 and triploidy-usully have sonographic abnormalities that can be seen by the second trimester.

For three decades, investigators have recognized that the sonographic detection of aneuploidy, particularly Down syndrome, may be improved by minor markers that are collectively referred to as "sot signs." Minor markers are normal variants rather than fetal abnormalities, and in the absence of aneuploidy or an associated abnormality, they do not significantly afect prognosis. They are present in at least 10 percent of unafected pregnancies (Bromley, 2002; Nyberg, 2003). Examples of these sonographic findings are listed in Table 14-8 and depicted in Figure 14-3. Findings are generally useful from 15 to 20 or 22 weeks' gestation. Six of these markers have been the focus of sonographic studies, in which likelihood ratios have been derived that allow a numerical aneuploidy risk to be calculated (Table 14-9). The risk rises steeply with the number of markers identiied. Alternatively, absence of a minor marker has been used to reduce the calculated risk (Agathokleous, 2013). This should be done systematically, following a protocol that specifies the markers included in a model, the definition for what constitutes a inding, and positive-and negative-likelihood ratios (Reddy, 2014).

he nuchal skinod is measured in the trans cerebellar view of the fetal head, from the outer edge of the skull to the outer border of the skin (see Fig. 14-3A). A measurement �6 mm is typically considered abnormal (Benacerraf, 1985). This inding is present in approximately 1 per 200 pregnancies and confers a more than tenfold risk for Down syndrome (Bromley, 2002; Nyberg, 2001; Smith-Bindman, 2001).

An echogenic intracardiac ocus is a focal papillary muscle calcification that is neither a structural nor functional cardiac abnormality. It is usually left-sided (see Fig. 14-3B). Such a focus is present in approximately 4 percent of fetuses, but it

TABLE 14-8. Second-Trimester Sonographic Markers or "Sot Signs" Associated with Fetal Trisomy 21 a

Clinodactyly (hypoplasia of the 5th digit middle phalanx) Echogenic bowel

OUsted alphabetically.

may be found in up to 30 percent of Asian individuals (Shipp, 2000). As an isolated finding, this approximately doubles the risk for fetal Down syndrome (see Table 14-9). Bilateral echogenic foci are associated with trisomy 13 (Nyberg, 2001).

Y1ild renal pelvis dilatation is usually transient or physiological and does not represent an underlying abnormality (Chap. 10, p. 208). The renal pelves are measured in a transverse image of the kidneys, anterior-to-posterior, with calipers placed aHigher in Asian individuals.

Data from Bromley, 2002; Nyberg, 2001; Smith-Bindman, 2001l.

at the inner borders of the fluid collection (see Fig. 14-3C). A measurement �4 mm is found in about 2 percent of fetuses and approximately doubles the risk for Down syndrome. he degree of pelvic dilatation beyond 4 mm correlates with the likelihood of an underlying renal abnormality, and additional evaluation is generally performed at approximately 32 weeks.

Echogenic etal bowel is deined as bowel that appears as bright as fetal bone (see Fig. 14-3D). It is identiied in approximately

FIGURE 14-3 Minor sonographic markers that are associated with increased risk for fetal Down syndrome. A. Nuchal skinfold thickening (bracket). B. Echogenic intracardiac focus (arrow). c. Mild renal pelvis dilatation (pyelectasis) (arrows). D. Echogenic bowel (arrow).

E. Clinodactyly-hypoplasia of the 5th finger middle phalanx creates an inward curvature (arrow). F. "Sandal-gap" (arrow).

0.5 percent of pregnancies and most commonly represents small amounts of swallowed blood, frequently in the setting of maternal serum AFP level elevation. Although typically associated with normal outcomes, it raises the risk for Down syndrome approximately sixfold. Echogenic bowel has also been associated with fetal cytomegalovirus infection and cystic ibrosisrepresenting inspissated meconium in the latter.

The femur and humerus are slightly shorter in Down syndrome fetuses. The femur is considered "short" for Down syndrome screening if it measures below the 2.5th percentile or is shortened to :;90 percent of that expected based on the measured biparietal diameter (American College of Obstetricians and Gynecologists, 2016c; Benacerraf, 1987). As an isolated finding in an otherwise low-risk pregnancy, it is generally not considered to pose great enough risk to warrant counseling modification. Similarly, a humerus shortened to :;89 percent of that expected, based on a given biparietal diameter, has also been associated with an elevated risk for Down syndrome.

If an isolated minor marker is identified in a woman who has not yet received aneuploidy screening, screening should be ofered, and a minor marker is considered an indication to ofer cell-free DNA screening (American College of Obstetricians and Gynecologists, 2016c). If cell-free DNA screening has already been performed, the association between isolated minor markers and aneuploidy risk is no longer considered relevant (Reddy, 2014). And, if the cell-free DNA screening result is negative, the fetal aneuploidy risk is not modified by the marker. Conversely, if a cell-free DNA screening result is positive, the absence of minor markers is not considered reassuring.

Unlike second-trimester soft signs, which may be readily visible during standard sonography, irst-trimester findings associated with aneuploidy require specialized training. The fetal NT measurement has gained widespread use for aneuploidy screening. Other irst-trimester sonographic findings are not routinely used in the United States but may be available in specialized centers. he Perinatal Quality Foundation's Nuchal Translucency Quality Review Program ofers an education program in irsttrimester nasal bone assessment (see Fig. 14-2). he Fetal Medicine Foundation also provides online instruction and certification in first-trimester assessment of nasal bone, ductus venosus low, and tricuspid flow.

Other benefits of irst-trimester sonography in women who elect aneuploidy screening include accurate assessment of gestational age and early detection of multifetal gestation or fetal demise. As discussed in Chapter 10 (p. 186), first-trimester sonography may identiy selected major anomalies associated with aneuploidy, such as cystic hygroma.

Three types of carrier screening may be ofered: ethnicity-based screening, panethnic screening (performed regardless of ethnicity), and expanded carrier screening-which is a type of panethnic screening performed for a larger number of conditions, potentially 100 or more. The goal of screening is to provide individuals with meaningful information to guide pregnancy planning according to their values (American College of Obstetricians and Gynecologists, 2017 a). Each type of screening has beneits, risks, and limitations. For example, so many disorders are included in expanded carrier screening panels that more than 50 percent of those screened may be identified to be carriers for at least 1 condition. his can cause anxiety for families and may pose challenges if genetic counseling resources are limited. Recognizing that each type of screening is an acceptable strategy, it is recommended that obstetrical providers develop a standard approach to ofer one of these three types of carrier screening to pregnant women and couples considering pregnancy (American College of 0bstetricians and Gynecologists, 2017 a). All carrier screening is optional and should be an informed choice.

Couples with a personal or family history of a heritable genetic disorder should be ofered genetic counseling. They are provided an estimated risk of having an afected newborn and given information concerning beneits and limitations of available prenatal testing options. Prenatal diagnosis may be available if the diseasecausing mutation or mutations are known. The publicly unded Genetic Testing Registry website contains detailed information regarding more than 10,000 genetic conditions and 48,000 genetic tests (www.ncbi.nlm.nih.gov/gtrl). hat said, many genetic disorders are characterized by a high degree of penetrance but variable expressivity. Thus, prediction of phenotype may not be possible, even when family members are afected. Common examples include neurofibromatosis, tuberous sclerosis, and Marfan syndrome. There are also conditions for which risk may be refined by detection of associated sonographic abnormalities or by gender determination if X-linked.

Ethniciy-based carrier screening is ofered for certain autosomal recessive disorders that are found in greater frequency in specific racial or ethnic groups (Table 14-10). The ounder eect occurs when an otherwise rare gene is found with greater frequency in a certain population and can be traced back to a single family member or small group of ancestors. his phenomenon may develop when generations of individuals procreate only within their own groups because of religious or ethnic prohibitions or geographical isolation. Because it is becoming increasingly diicult to assign a single ethnicity, a panethnic screening panel is another option.

The American College of Obstetricians and Gynecologists (2017 a) has developed the following criteria for expanded carrier screening panels: 1.

Conditions included in the panel should have a carrier frequency of at least 1: 1 00, which correlates with a population frequency, at minimum, of 1 :40,000.

2.

Conditions should have a well-defined phenotype, detrimental efect on quality of life, cognitive or physical impairment, early onset, or require surgical or medical intervention.

3.

Conditions primarily associated with disease of adult onset are not recommended for inclusion.

4.

If an individual is at increased risk for a speciic condition, such as Tay-Sachs disease or 3-thalassemia, the provider should consider that the test included in the panel may not be the most sensitive one for that condition.

his disorder is caused by a mutation in the cystic ibrosis conductance transmembrane regulator (CFTR) gene, which is located on the long arm of chromosome 7 and encodes a chloride-channel protein. Although the most common CFTR gene mutation associated with classic cystic fibrosis (CF) is the .F508 mutation, more than 2000 mutations have been identiied (Cystic Fibrosis Mutation Database, 2016). CF may develop from either homozygosiy or compound heterozygosiy for mutations in the CFTR gene. In other words, one mutation must be present in each copy of the gene, but they need not be the same mutation. As expected, this results in a tremendous range of clinical disease severity. Median survival is approximately 37 years, but approximately 15 percent have milder disease and can survive for decades longer. Care for the pregnant woman with CF is discussed in Chapter 51 (p. 998).

he American College of Obstetricians and Gynecologists (2017a,b) recommends that all patients who are considering pregnancy or who are already pregnant should be ofered carrier screening for CF, regardless of ethnicity. The current recommended screening panel contains 23 panethnic CF gene mutations, selected because they are present in at least 0.1 percent of patients with classic CF (American College of Obstetricians and Gynecologists, 20 17b). The CF carrier frequency approximates 1 in 25 in non-Hispanic white Americans and those of Ashkenazi Jewish descent, who are from Eastern Europe. Thus, the incidence of CF in a child born to a non-Hispanic white couple approximates 4 X 1/25 X 125, or 1 :2500. As shown in 1i4-11i, both CF incidence and the sensitivity of the screening test are lower for other ethnicities.

lthough a negative screening test result does not preclude the possibility of carrying a less-common mutation, it reduces the risk substantively from the background rate. If both parents are carriers, chorionic villus sampling or amniocentesis can help determine whether the fetus has inherited one or both of the parental mutations. Counseling following identification of two disease-causing mutations is challenging, because phenotype prediction is reasonably accurate only for pancreatic disease, and then only for well-characterized mutations. Prognosis is most heavily afected by the degree of pulmonary disease, which varies considerably even among individuals with the most common genotype associated with classic disease, that is, those homozygous for the .F508 mutation. his likely relects the efect of genetic modiiers on protein function, which may further vary depending on the CFTR mutation and on exposure and susceptibility to environmental factors (Cutting, 2005; Drumm, 2005).

his autosomal recessive disorder results in spinal cord motor neuron degeneration that leads to skeletal muscle atrophy and generalized weakness. here is currently no efective treatment. The prevalence of spinal muscular atrophy (SA) is 1 in 6,000 to 10,000 live births. Types I, II, III, and IV are caused by mutations in the survival motor neuron (SMN1) gene, which is

TABLE 14-1e1. Cystic Fibrosis Detection and Carrier Rates before and ater Testing

Ashkenazi Jewish 94.0 1/24 1 in 384 Caucasian 88.3 '1125 1 in 206 Hispanic American 71.7 1/58 1 in 203 African American 64.5 1/61 1 in 171 Asian American 48.9 1/94 1 in 183

Data from American College of Medical Genetics, 2006.

located on the long arm of chromosome 5 (5q 13.2) and encodes the SMN protein. Types I and II account for 80 percent of cases and are both lethal (American College of Obstetricians and Gynecologists, 2017b). SMA type I, known as WerdnigHofmann, is the most severe. Disease onset is within the first 6 months, and afected children die of respiratory failure by age 2 years. Type II generally has onset before age 2 years, and the age at death can range from 2 years to the third decade of life. Type III also presents before age 2 years, with disease severity that is milder and more variable. Type IV does not present until adulthood.

The American College of Obstetricians and Gynecologists (20 17b) recommends that carrier screening for SMA be ofered to all women who are considering pregnancy or are currently pregnant. The SMA carrier frequency approximates 1:35 in those of non-Hispanic white (caucasian) ethnicity, 1:41 in Ashkenazi Jews, 1:53 in Asians, 1:66 in African Americans, and 1: 117 in those of Hispanic white ethnicity (Hendrickson, 2009). Carrier detection rates range from 90 to 95 percent for each race/ethnicity except African Americans, in whom it just exceeds 70 percent. Approximately 2 percent of individuals with SMNI mutations are not identiied with carrier screening. In addition, although there is usually one copy of the SMNI gene on each chromosome, approximately 3 to 4 percent of individuals have two copies of this gene on one chromosome and no copies on the other. These individuals are carriers for the disease. African mericans are more likely to have this genetic variation, which explains the lower sensitivity of screening in this group. he American College of Obstetricians and Gynecologists (20 17b) recommends that prior to screening for SMA, providers counsel about its potential spectrum of severity, carrier frequency, and its detection rate. Posttest counseling should include the residual risk after a negative screening result, which difers according to the patient's ethnicity and also according to the number of SMNI copies detected. Most unafected individuals have two copies, but a small percentage has three copies and is at even lower risk. If the patient or her partner has a family history of SMA, or if carrier screening is positive, genetic counseling is recommended.

These include sickle-cell anemia, sickle-cell hemoglobin C disease, and sickle-cell 3-thalassemia. Their pathophysiology and inheritance are discussed in detail in Chapter 56 (p. 1081).

African and African-American patients are at increased risk to carry hemoglobin S and other hemoglobinopathies and should be ofered preconceptional or prenatal screening. Of African Americans, 1 in 12 has sickle-cell trait, 1 in 40 carries hemoglobin C, and 1 in 40 carries the trait for 3-thalassemia. Hemoglobin S is also more common among individuals of

Middle Eastern, and Asian Indian descent (Davies, 2000). The American College of Obstetricians and Gynecologists (2015) recommends that patients of African descent be ofered hemoglobin electrophoresis. If a couple is at risk to have a child with a sickle hemoglobinopathy, genetic counseling should be ofered. Prenatal diagnosis can be performed with either chorionic villus sampling or amniocentesis.

These syndromes are the most common single-gene disorders worldwide, and up to 200 million people carry a gene for one of these hemoglobinopathies (Chap. 56, p. 1084). Some individuals with thalassemia have microcytic anemia secondary to decreased synthesis of either a-or 3-hemoglobin chains. In general, deletions of a-globin chains cause a-thalassemia, whereas mutations in 3-globin chains cause 3-thalassemia. Less commonly, an a-globin chain mutation also causes a-thalassemia.

The number of a-globin genes that are deleted may range from one to all four. If two a-globin genes are deleted, both may be deleted from the same chromosome-cis coniguration (aal--), or one may be deleted from each chromosometrans configuration (a-/a-). Alpha-thalassemia trait is common among individuals of African, Mediterranean, Middle Eastern, West Indian, and Southeast Asian descent and results in mild anemia. he cis coniguration is more prevalent among Southeast Asians, whereas those of African descent are more likely to inherit the trans configuration. Clinically, when both parents carry cis deletions, ofspring are at risk for an absence of a-hemoglobin, called Hb Barts disease. This typically leads to hydrops and fetal loss as discussed in Chapter 15 (p. 309).

Detection of a-thalassemia or a-thalassemia trait is based on molecular genetic testing and is not detectable using hemoglobin electrophoresis. Because of this, routine carrier screening is not ofered. If there is microcytic anemia in the absence of iron deiciency and the hemoglobin electrophoresis is normal, then testing for a-thalassemia can be considered, particularly among individuals of Southeast Asian descent (American College of Obstetricians and Gynecologists, 2015).

Mutations in 3-globin genes may cause reduced or absent production of 3-globin chains. If the mutation afects one gene, it results in 3-thalassemia minor. If both copies are afected, the result is either 3-thalassemia major-termed Cooley anemiaor 3-thalassemia intermedia. Because of reduced production of hemoglobin A among carriers, electrophoresis demonstrates elevated levels of hemoglobins that do not contain 3-chains. hese include hemoglobins F and A2.

3-Thalassemia minor is more common among individuals of African, Mediterranean, and Southeast Asian descent. The American College of Obstetricians and Gynecologists (2015) recommends that they be ofered carrier screening with hemoglobin electrophoresis, parti�ularly if found to have microcytic anemia in the absence of iron deiciency. Hemoglobin A2 levels exceeding 3.5 percent conirm the diagnosis. Other ethnicities at increased risk include those of Middle Eastern, West Indian, and Hispanic descent .

This autosomal recessive lysosomal-storage disease is characterized by absence of the hexosaminidase A enzyme. his leads to accumulation of GM2 gangliosides in the central nervous system, progressive neurodegeneration, and death in early childhood. Afected individuals have almost complete absence of the enzyme, whereas carriers are asymptomatic but have less than 55-percent hexosaminidase A activity. The carrier frequency of T ay-Sachs disease in Jewish individuals of Eastern European (Ashkenazi) descent approximates 1 in 30, but it is much lower, only about 1 in 300, in the general population. Other groups at greater risk for Tay-Sachs disease include those of French-Canadian and Cajun descent. An international Tay-Sachs carrier-screening campaign was initiated in the 1970s and met with unprecedented success in the Ashkenazi Jewish population. he incidence of T ay-Sachs disease subsequently declined more than 90 percent (Kaback, 1993). Most cases of Tay-Sachs disease now occur in nonJewish individuals.

he American College of Obstetricians and Gynecologists (20 17b) has the following screening recommendations for T aySachs disease: 1.

Screening should be ofered before pregnancy if both members of a couple are of Ashkenazi Jewish, French-Canadian, or Cajun descent, or if there is a family history ofTay-Sachs disease.

2.

When only one member of the couple is of one of the above ethnicities, the high-risk partner may be screened first, and if found to be a carrier, the other partner also should be ofered screening. If there is a family history ofTay-Sachs disease, an expanded carrier screening panel may not be the best approach unless the familial mutation is included in the panel.

3.

Molecular testing (DNA-based mutation analysis) is highly efective in Ashkenazi Jewish individuals and other high-risk groups, but the detection rate in low-risk groups is more limited.

4.

Biochemical analysis of the hexosaminidase A serum level has a sensitivity of 98 percent and is the test that should be performed in individuals from low-risk ethnicities. Leukocyte testingmust be used if the woman is already pregnant or taking oral contraceptives.

5.

Ifboth partners are found to be carriers ofTay-Sachs disease, genetic counseling and prenatal diagnosis should be ofered. Hexosaminidase activity may be measured from chorionic villus sampling or amniocentesis specimens.

The carrier rate among individuals of Eastern European (Ashkenazi) Jewish descent approximates 1 in 30 for T ay-Sachs disease, 1 in 40 for Canavan disease, and 1 in 32 for familial dysautonomia. Fortunately, the detection rate of screening tests for each is at least 98 percent in this population. Because of their relatively high prevalence and consistently severe and predictable phenotype, the American College of Obstetricians and Gynecologists (2017b) recommends that carrier screening for these three conditions be ofered to Ashkenazi Jewish individuals, either before conception or during early pregnancy. his is in addition to carrier screening for cystic fibrosis and spinal muscular atrophy, which are ofered to all women who are considering pregnancy or who are currently pregnant. Further, there are several other autosomal recessive conditions for which the College recommends that screening be considered (American College of Obstetricians and Gynecologists, 2017b).

As of 20 17, these include Bloom syndrome, familial hyperinsulinism, Fanconi anemia, Gaucher disease, glycogen storage disease type I (von Gierke disease), Joubert syndrome, maple syrup urine disease, mucolipidosis type IV, Niemann-Pick disease, and Usher syndrome. Gaucher disease difers from the other conditions listed in that it is has a wide range in phenotype-from childhood illness to absence of symptoms throughout life. Also, efective treatment is available in the form of enzyme therapy.

Diagnostic procedures used in prenatal diagnosis include amniocentesis, chorionic villus sampling (CVS), and rarely fetal blood sampling. hese enable characterization of an increasingly large number of genetic abnormalities before birth. Karyotype analysis has a diagnostic accuracy of more than 99 percent for aneuploidy and chromosomal abnormalities larger than 5 to 10 megabases. In the setting of a fetal structural abnormality, chromosomal microarray analysis (CMA) is recommended as the first-line genetic test performed, as it may detect clinically significant chromosomal abnormalities in approximately 6 percent of fetuses with normal standard karyotype (Callaway, 2013; de Wit, 2014). An exception would be if the structural abnormality strongly suggests a particular karyotype-such as endocardial cushion defect with trisomy 21 or holoprosencephaly with trisomy 13. In such cases, karyotyping with or without luorescence in-situ hybridization (FISH) may be ofered as the initial test (American College of Obstetricians and Gynecologists, 2016b). Among those without evidence of a fetal structural abnormality and with a normal karyotype, CMA has detected additional chromosomal abnormalities (pathogenic copy number variants) in approximately 1 percent. It is therefore made available whenever a prenatal diagnostic procedure is performed (American College of Obstetricians and Gynecologists, 2016b; Callaway, 2013). Types of CMA platforms and their benefits and limitations are reviewed in Chapter 13 (p. 271).

Ironically, improvements in aneuploidy screening tests, in particular the widespread use of cell-free DNA screening, have resulted in a dramatic drop in the number of prenatal diagnostic procedures. Larion and colleagues (2014) reported a 70-percent decline in CVS procedures and a nearly 50-percent drop in amniocentesis procedures following introduction of cell-free DNA screening in 2012. This urther amplified the decrease in amniocentesis procedures that began following adoption of first-trimester screening (Warso, 2015). In addition, because so many disorders can be diagnosed from amnionic fluid specimens, fetal blood sampling is now rarely, if ever, indicated for genetic diagnoses.

This is the most common prenatal diagnostic procedure. T ransabdominal withdrawal of amnionic luid is generally done between 15 and 20 weeks but may be performed at any point later in gestation. Indications include diagnosis of fetal genetic disorders, congenital infections, and alloimmunization, as well as assessment of fetal lung maturity. The most common types of prenatal diagnostic tests are CMA to assess copy-number gains or losses, karyotype analysis to test for aneuploidy, and FISH to identiY gain or loss of specific chromosomes or chromosome regions (Chap. 13, p. 270). Because amniocytes must be cultured before fetal karyotype can be assessed, the time needed for karyotyping is 7 to 10 days. In contrast, FISH studies are usually completed within 24 to 48 hours. CMA can oten be performed directly on uncultured amniocytes with a turnaround time of only 3 to 5 days, and if amniocyte culture is required, turnaround time is 10 to 14 days (merican College of Obstetricians and Gynecologists, 20 16b).

Amniocentesis is performed using aseptic technique, with a 20or 22-gauge spinal needle and ultrasound guidance (Fig. 14-4). A standard spinal needle is 9 em long, and depending on patient habitus, a longer needle may be required. Measurement of the

TABLE 14-12. Selected Tests Performed on Amnionic Fluid and Typical Volume of Fluid Required

FIGURE 14-4 A. Amniocentesis. B. The amniocentesis needle is seen in the upper right portion of this sonogram. (Reproduced with permission from Mastrobattista JM, Espinoza J: Invasive prenatal diagnostic procedures. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. Ne

York, McGraw-Hili Education, 201o7.) sonographic distance from skin to amnionic luid pocket may aid needle selection. Sonography is used to identiY a pocket of amnionic luid that is close to the midline, being cognizant of uterine size and shape. he needle is inserted perpendicular to the skin and guided into the deepest portion of the luid pocket, avoiding fetal parts and umbilical cord. Eforts are made to puncture the chorioamnion rather than to push or "tent" it away from the uterine wall. he amnion usually uses with the adjacent chorion by 16 weeks' gestation, and the procedure is generally deferred until ater chorioamnion usion has occurred. Discomfort from the procedure is considered minor, and local anesthetic has not been found to be beneicial (Mujezinovic, 2011).

Following the procedure, the color and clarity of the luid are documented. Amnionic fluid should be clear and colorless or pale yellow. Blood-tinged luid is more frequent if there is transplacental passage of the needle. However, it generally clears with continued aspiration. The placenta implants along the anterior uterine wall in approximately half of pregnancies. In these cases, the placenta will be traversed by the needle approximately 60 percent of the time (Bombard, 1995). Needle passage through the placenta is avoided when possible, although fortunately this has not been associated with greater pregnancy loss rates (Marthin, 1997). Dark brown or greenish luid may represent a past episode of intraamnionic bleeding.

he volume of fluid generally needed for commonly performed analyses is shown in Table 14-12. Because the initial 1 to 2 mL of fluid aspirate may be contaminated with maternal cells, it is generally discarded. Approximately 20 to 30 mL of fluid is then collected for either fetal CMA or karyotyping before removing the needle. Sonography is used to observe the uterine puncture site for bleeding, and fetal cardiac motion is documented at the procedure's end. If the patient is h D-negative and unsensitized, anti-D immune globulin is administered following the procedure (Chap. 15, p. 305).

Multifetal Pregnancy. When performing the procedure in a diamnionic twin gestation, careful attention is paid to the aThe volume of fluid needed for each test may vary according to individual laboratory specifications.

bFluorescence in-situ (FISH) is typically performed for chromosomes 21, 18, 13, X, and Y.

PCR = polymerase chain reaction.

location of each sac and the dividing membrane. Until recently, a small quantity of dilute indigo carmine dye was often injected before removing the needle from the irst sac, with return of clear amnionic fluid anticipated following needle placement into the second sac. Because of widespread shortages of indigo carmine dye, most experienced providers ofer amniocentesis in multifetal gestations when indicated, without dye injection. Methylene blue dye is contraindicated because it has been associated with jejunal atresia and neonatal methemoglobinemia (Cowett, 1976; van der Pol, 1992).

he procedure-related loss rate following midtrimester amniocentesis has decreased with improvements in imaging technology. Based on single-center studies and metaanalysis data, the amniocentesis procedure-related loss rate approximates 0.1 to 0.3 percent when performed by an experienced providerabout 1 per 500 procedures (Akolekar, 2015; American College of Obstetricians and Gynecologists, 2016b; Odibo, 2008). he loss rate may be doubled in women with class 3 obesity, which is a body mass index (BMI) >40 kg/m2 (Harper, 2012). In twin pregnancies, Cahill and coworkers (2009) reported a loss rate of 1.8 percent attributable to amniocentesis.

he amniocentesis indication can influence loss rates, which can be greater with some fetal abnormalities, aneuploidies, and conditions such as hydrops. nd, some losses are due to abnor mal placental implantation or abruption, uterine abnormalities, or infection. Wenstrom and colleagues (1990) analyzed 66 fetal deaths following nearly 12,000 procedures and found that 12 per cent were associated with preexisting intrauterine infection.

Other complications of amniocentesis include amnionic fluid leakage or transient vaginal spotting in 1 to 2 percent. Following leakage of amnionic luid, which generally occurs within 48 hours of the procedure, fetal survival exceeds 90 percent (Borgida, 2000). Needle injuries to the fetus are rare. Amnionic fluid culture is successul in more than 99 percent of cases, although cells are less likely to grow if the fetus is abnormal (Persutte, 1995).

This describes amniocentesis performed between 11 and 14 weeks' gestation. he technique is the same as for traditional amniocentesis, but sac puncture may be more challenging due to lack of membrane fusion to the uterine wall. Less luid is typically withdrawn-approximately 1 mL for each gestational week (Shulman, 1994; Sundberg, 1997).

Early amniocentesis is associated with signiicantly higher rates of procedure-related complications than other fetal procedures. hese include development of talipes equinovarus (clubfoot), amnionic luid leakage, and fetal loss (Canadian Early and MidTrimester Amniocentesis Trial, 1998; Philip, 2004). Given these risks, the American College of Obstetricians and Gynecologists (20 16b) recommends that early amniocentesis not be performed.

Biopsy of chorionic villi is typically performed between 10 and 13 weeks' gestation. As with amniocentesis, the specimen is generally sent for karyotyping or CMA. The primary advantage of villus biopsy is that results are available earlier in pregnancy, permitting more time for decision-making and safer pregnancy termination, if desired. Very few analyses speciically require either amnionic luid or placental tissue.

Chorionic villi may be obtained transcervically or transabdominally, using aseptic technique. Both approaches are considered equally safe and efective (American College of Obstetricians and Gynecologists, 2016b). Transcervical CVS is performed using a specifically designed catheter made from lexible polyethylene that contains a blunt-tipped, malleable stylet. Transabdominal sampling is performed using an 18-or 20-gauge spinal needle. With either technique, transabdominal sonography is used to guide the catheter or needle into the early placentachorion rondosum, followed by aspiration of villi into a syringe containing tissue culture media (Fig. 14-5).

FIGURE 14-5 A. Transcervical chorionic villus sampling. B. Catheter entering the placenta is marked and labeled. (Reproduced with permission from Mastrobattista JM, Espinoza J: Invasive prenatal diagnostic procedures. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 201o7.)

Relative contraindications include vaginal bleeding or spotting, active genital tract infection, extreme uterine ante-or retrolexion, or body habitus precluding adequate visualization. If the patient ish D-negative and unsensitized, anti-D immune globulin is administered following the procedure.

he overal loss rate following CVS is higher than that following midtrimester amniocentesis. This is because of background spontaneous losses, that is, losses that would have occurred between the first and second trimester in the absence of a fetal procedure. he procedurerelated fetal loss rate is comparable with that of amniocentesis. Caughey and colleagues (2006) found that the overall loss rate following CVS was approximately 2 percent compared with less than 1 percent following amniocentesis. However, the adjusted procedure-related loss rate approximated 1 per 400 for either procedure. The indication for CVS will also afect the loss rate. For example, fetuses with increased NT thickness have a greater likelihood of demise. Finally, there is a learning curve associated with safe performance of CVS (Silver, 1990; Wijnberger, 2003).

An early problem with CVS was its association with limbreduction dects and oro mandibular limb hypogenesis, shown in Figre 14-6 (Firth, 1991, 1994; Hsieh, 1995). hese were subsequently found to be associated with procedures performed at 7 weeks' gestation (Holmes, 1993). When performed at : 10 weeks' gestation, the incidence of limb defects does not exceed the background population rate of about 1 per 1000 (Evans, 2005; Kuliev, 1996).

Vaginal spotting is not uncommon following transcervical sampling, but it is self-limited and not associated with pregnancy loss. The incidence of infection is less than 0.5 percent (American College of Obstetricians and Gynecologists, 20 16c).

A limitation of CVS is that chromosomal mosaicism is identified in up to 2 percent of specimens (Malvestiti, 2015). In most cases, the mosaicism reflects confined placental mosaicism rather than a true second cell line within the fetus. his is discussed in Chapter 13 (p. 263). Amniocentesis should be ofered, and if the result is normal, the mosaicism is usually presumed to be confined to the placenta. Conined placental mosaicism has been associated with growth-restricted newborns (Bafero, 2012).

his procedure is also called cordocentesis or percutaneous umbilical blood sampling (PUBS). It was initially described for fetal transfusion of red blood cells in the setting of anemia from alloimmunization, and fetal anemia assessment remains the most common indication (Chap. 16, p. 304). Fetal blood sampling is also performed for assessment and treatment of platelet alloimmunization and for fetal karyotype determination, particularly in cases of mosaicism identified following amniocentesis or CVS. Fetal blood karyotyping can be accomplished within 24 to 48 hours. Thus, it is significantly quicker than the 7-to 10-day turnaround time with amniocentesis or CVS. Although fetal blood can be analyzed for virtually any test performed on neonatal blood, improvements in tests available with amniocentesis and CVS have eliminated the need for fetal venipuncture in most cases (Society for Maternal-Fetal Medicine, 2013).

FIGURE 14-6 Oromandibular limb hypogenesis is characterized by transverse limb deficiency and absence or hypoplasia of the tongue or mandible. This is hypothesized to result from vascular disruption with subsequent loss of tissue. A. Sonogram obtained at 25 weeks' gestation demonstrates a fetal limb reduction defect involving the right hand.

B. Photograph of the right extremity of the same newborn. Chorionic villus sampling was not performed in this pregnancy. (Used with permission from Dr. Jamie Morgan.)

Under direct sonographic guidance, using aseptic technique, the operator introduces a 22-or 23-gauge spinal needle into the umbilical vein, and blood is slowly withdrawn into a heparinized syringe (Fig. 14-7). Adequate visualization of the needle is essential. 5 with amniocentesis, a longer needle may be required depending on patient habitus. Fetal blood sampling is often performed near the placental cord insertion site, where it may be easier to enter the cord if the placenta lies anteriorly. Alternatively, a free loop of cord may be punctured. Because fetal blood sampling requires more time than other fetal procedures, a local anesthetic may be administered. Prophylactic antibiotics are used at some centers, although no trils support this policy. Arterial puncture is avoided, because it may result in vasospasm and fetal bradycardia. ter the needle is removed, fetal cardiac motion is documented, and the site is observed for bleeding.

he procedure-related fetal loss rate following fetal blood sampling approximates 1.4 percent (Ghidini, 1993; Tongsong, 2001). The actual loss rate varies according to the procedure indication and the fetal status. Other complications may include cord vessel bleeding in 20 to 30 percent of cases, fetal-maternal bleeding in approximately 40 percent of cases in which the placenta is traversed, and fetal bradycardia in 5 to 10 percent (Boupaijit, 2012; Society for Maternal-Fetal Medicine,

FIGURE 14-7 Fetal blood sampling. A. Access to the umbilical vein varies depending on placental location and cord position. With an anterior placenta, the needle may traverse the placenta. Inset: With posterior placentation, the needle passes through amnionic fiuid before penetrating the umbilical vein. Alternatively, a free loop of cord may be accessed. B. Sonogram shows an anterior placenta with transplacental needle passage into the umbilical vein (U). (Reproduced with permission from Mastrobattista JM, Espinoza J:

Invasive prenatal diagnostic procedures. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 201/.) 2013). Most complications are transitory, with complete recovery, but some result in fetal loss.

In one series of more than 2000 procedures comparing fetal blood sampling near the placental cord insertion site with puncture of a free loop, rates of procedure success, pregnancy loss, visible bleeding from the cord, and fetal bradycardia did not difer. Time to complete the procedure was signiicantly shorter if the cord was sampled at the placental insertion site than in a free 100p-5 versus 7 minutes. However, sampling at the insertion site had a higher rate of maternal blood contamination (T angshewinsirikul, 2011).

For couples undergoing in vitro fertilization (IVF), genetic testing performed on oocytes or embryos before implantation may provide valuable information regarding the chromosomal complement and single-gene disorders. There are two separate categories of testing-preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS)-each with diferent indications. Comprehensive genetic counseling is required before consideration of these procedures. There are three techniques that are used for both categories: 1.

Polar body anaysis is a technique used to infer whether a developing oocyte is afected by a maternally inherited genetic disorder. The irst and second polar bodies are normally extruded from the developing oocyte following meiosis I and II, and their sampling should not afect fetal development. However, two separate micromanipulation procedures are required, and genetic abnormalities of paternal origin are not detected. his technique has been used to diagnose 146 mendelian disorders, and the reported accuracy exceeds 99 percent (Kuliev, 2011).

2.

Blastomere biopsy is done at the 6-to 8-cell (cleavage) stage when an embryo is 3 days old. his allows both maternal and paternal genomes to be evaluated. One cell is typically removed through a hole made in the zona pellucida (Fig. 14-8). A limitation of using this technique for aneuploidy assessment is that because of mitotic nondisjunction, mosaicism of the blastomeres may not reflect the chromosomal complement of the developing embryo (American Society for Reproductive Medicine, 2008). In addition, the implantation rate of normal embryos is slightly lower following this technique.

FIGURE 14-8 Blastomere biopsy. After a blastomere is selected, it is then drawn into the pipette. (Reproduced with permission from Doody J: Treatment of the infertile couple. Hoffman BL, Schorge JO, Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGraw-Hili Education, 2016.) 3. Trophectoderm biopsy involves removal of 5 to 7 cells from a 5-to 6-day blastocyst. An advantage is that because the trophectoderm cells give rise to the trophoblast-the placenta-no cells are removed from the developing embryo. Disadvantageously, because the procedure is performed later in development, if genetic analysis cannot be performed rapidly, then cryopreservation and embryo transfer during a later IVF cycle may be required.

A genetic abnormality-rather than infertility-may be a reason for a couple to elect IVF. With a known carrier(s) of a speciic genetic disease or a balanced chromosomal rearrangement, PGD may be performed to determine if an oocyte or embryo has the defect. Only embryos without the abnormality would be implanted.

This procedure has numerous applications. It is used to diagnose single-gene disorders such as cystic fibrosis, 3-thalassemia, and hemophilia; to determine gender in X-linked diseases; to identiy mutations such as BRA-J that do not cause disease but confer signiicantly greater later cancer risk; and to match human leukocyte antigens for umbilical cord stem cell transplantation for a sibling (de Wert, 2007; Fragouli, 2007; Grewal, 2004; Rund, 2005; Xu, 2004).

Because typically only one or two cells are available for analysis and because rapid completion time is essential, this procedure is technically challenging. Risks include failure to ampliy the genetic region of interest, selection of a cell that does not contain a nucleus, and maternal cell contamination. Infrequently, afected embryos thought to be normal are implanted, and unaffected embryos are misdiagnosed as abnormal and discarded. Because of this, the American Society for Reproductive Medicine (2008) encourages urther prenatal diagnostic testing-either CVS or amniocentesis-to conirm PGD results.

This term is used for aneuploidy screening that is performed on oocytes or embryos before IVF transfer. Such screening is used with couples who are not known to have or carry a genetic abnormality. Although PGS has obvious theoretical advantages, it has faced challenges in practice.

Mosaicism is common in cleavage-stage embryo blastomeres. However, it may not be clinically signiicant because it often does not relect the actual embryonic chromosomal complement. In addition, among women 35 years or older, pregnancy rates following PGS with FISH are significantly lower than rates observed following IVF without PGS (Mastenbroek, 2007,2011). Because the number of chromosome pairs per cell nucleus that can be evaluated with FISH is limited, more recent eforts have focused on the use of chromosomal comprehensive screening with CMA (Dahdouh, 2015).

Agathokleous M, Chaveeva P, Poon LC, et al: Meta-analysis of second-trimester markers for trisomy 2l. Ultrasound Obstet GynecoIo41(3):247, 2013

Akolekar R, Beta J, Picciarelli G, et al: Procedure-related risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review and meta-analysis. Ultrasound Obstet GynecoIo45(1):16, 2015

American College of Medical Genetics: Technical standards and guidelines for CFTR mutation testing, 2006. Available at: https:!lwww.acmg.net/Pagesl ACMG_Activitieslstds-2002/cf.htm. Accessed December 30, 20o16

American College of Obstetricians and Gynecologists: Hemoglobinopathies in pregnancy. Practice Bulletin No. 78, January 2007, Reairmed 2015

American College of Obstetricians and Gynecologists: Neural tube defects. Practice Bulletin No. 44, July 2003, Reairmed 2016a

American College of Obstetricians and Gynecologists: Prenatal diagnostic testing for genetic disorders. Practice Bulletin No. 162, May 2016b

American College of Obstetricians and Gynecologists: Screening for fetal aneuploidy. Practice Bulletin No. 163, May 2016c

American College of Obstetricians and Gynecologists: Carrier screening in the age of genomic medicine. Committee Opinion No. 690, March 2017a

American College of Obstetricians and Gynecologists: Carrier screening for genetic conditions. Committee Opinion No. 691, March

American College of Obstetricians and Gynecologists: Cell-free DNA screening for fetal aneuploidy. Committee Opinion No. 640, September 2015, Reairmed 20o17 c

American Society for Reproductive Medicine: Preimplantation genetic testing: a Practice Committee Opinion. Fertil Steril 90: S 136, 2008

Ashoor G, Syngelaki A, Poon LC, et al: Fetal fraction in maternal plasma cellfree fetal DNA at 11-13 weeks' gestation: relation to maternal and fetal characteristics. Ultrasound Obstet Gynecol 41 (1) :26, 2013 Baer RJ, Fiesselle, Jellife-Pawlowski LL, et al: Detection rates for aneuploidy by irst-trimester and sequential screening. Obstet GynecoIo126(4):753, 2015 Bafero GM, Somigliana E, Crovetto F, et al: Confined placental mosaicism at chorionic villus sampling: risk factors and pregnancy outcome. Prenat Diagn 32(1o1):1o102,o2012 Benacerraf BR, Barss VA, Laboda A: A sonographic sign for the detection in the second trimester of the fetus with Down syndrome. Am J Obstet GynecoIo151(8):1078,o1985 BenacerrafBR, Gelman R, Frigoletto FD: Sonographic identification of secondtrimester fetuses with Down's syndrome. N EnglJ Med 317(22):1371,o1987 Benn PA, Leo MV, Rodis JF, et al: Maternal serum screening for fetal trisomy 18: a comparison of fixed cutof and patient-specific risk protocols. Obstet Gynecolo93 (5 Pt 1):707, 1999

Best E, Tennant PW, Addor Me, et al: Epidemiology of small intestinal atresia in Europe: a register-based study. Arch Dis Child Fetal Neonatal Ed 97(5):F353, 2012

Bianchi DW, Chudova 0, Sehnert AJ, et al: Noninvasive prenatal testing and incidental detection of occult malignancies. JAMA 314(2): 162, 2015

Bombard AT, Powers JF, Carter S, et al: Procedure-related fetal losses in transplacental versus nontransplacental genetic amniocentesis. Am J Obstet Gynecol 172(3):868, 1995

Borgida AF, Mills A, Feldman OM, et al: Outcome of pregnancies complicated by ruptured membranes after genetic amniocentesis. Am J Obstet GynecoIo183(4):937,o2000 Boupaijit K, Wanapirak C, Piyamongkol W, et al: Efect of placental penetration during cordocentesis at mid-pregnancy on fetal outcomes. Prenat Diagn 32(1):83, 2012

Brock OJ, Bolton E,Monaghan JM: Prenatal diagnosis of anencephaly through maternal serum-alpha-fetoprotein measurement. Lancet 2(7835):923, 1973 Brock OJ, Sutclife RG: Alpha-fetoprotein in the antenatal diagnosis of anencephaly and spina bifida. Lancet 2(7770):197, 1972

Bromley B, Lieberman E, Shipp TO, et al: he genetic sonogram, a method for risk assessment for Down syndrome in the mid trimester. J Ultrasound Med 21(10):1087,o2002

Bush MC, Malone FD: Down syndrome screening in twins. Clin Perinatol 32(2):373, 2005

Cahill AG, Macones GA, Stamilio OM, et al: Pregnancy loss rate after mid-trimester amniocentesis in twin pregnancies. Am J Obstet Gynecol 200(3):257.e1,o2009

Callaway JL, Shafer LG, Chitty LS, et al: he clinical utility of micro array technologies applied to prenatal cytogenetics in the presence of a normal conventional karyotype: a review of the literature. Prenat Diagn 33(12): 1119,o2013

Canadian Early and Mid-Trimester Amniocentesis Trial (CEMAT) Group:

Randomised trial to assess safety and fetal outcome of early and mid trimester amniocentesis. Lancet 351(9098):242, 1998

Canfield MA, Honein MA, Yuskiv N, et al: National estimates and racelethnicspecific variation of selected birth defects in the United States, 1999-200l. Birth Defects Res A Clin Mol Teratol 76(1o1):747, 2006

Caughey AB, Hopkins LM, Norton ME: Chorionic villus sampling compared with amniocentesis and the diference in the rate of pregnancy loss. Obstet Gynecolo108(3):612,o2006

Centers for Disease Control and Prevention: Natality trends in the United States, 1909-2013. 2015. Available at: https:llblogs.cdc.gov/nchs-datavisualization/us-natality-trends.l Accessed December 15,o2016

Cignini P, Maggio Savasta L, Gulino FA, et al: Predictive value of pregnancyassociated plasma protein-A (PAPP-A) and free beta-hCG on fetal growth restriction: results of a prospective study. Arch Gynecol Obstet 293(6): 122 , 20o16

Cleary-Goldman J, D'Alton ME, Berkowitz RL: Prenatal diagnosis and multiple pregnancy. Semin Perinatol 29(5):312, 2005

Colvin J, Bower C, Dickinson JE, et l: Outcomes of congenital diaphragmatic hernia: a population-based study in (lestern Australia. Pediatrics 116(3):e356,o2005

Comstock CH, Malone FD, Robert H, et al: Is there a nuchal translucency millimeter measurement above which there is no added beneit from irst trimester screening? Am J Obstet Gynecol 195(3):843, 2006

Cowett MR, Hakanson DO, Kocon RW, et al: Untoward neonatal efect of intraamniotic administration of methylene blue. Obstet Gynecol 48(1 Suppl):74S, 1976

Cragan JD, Gilboa SM: Including prenatal diagnoses in birth defects monitoring: experience of the Metropolitan Atlanta Congenital Defects Program. Birth Defects Res A Clin Mol Teratol 85(1):20, 2009

Cuckle H: Biochemical screening for Down syndrome. Eur J Obstet Gynecol Reprod Bioi 92(1):97, 2000

Cuckle H, Wald N, Stevenson JD, et al: Maternal serum alpha-fetoprotein screening for open neural tube defects in twin pregnancies. Prenat Diagn 10(2):71, 1990

Cuckle HS, Malone FD, Wright 0, et al: Contingent screening for Down syndrome-results from the FaSTER trial. Prenat Diagn 28(2):89, 2008

Curnow KJ, Wilkins-Haug L, Ryan A, et al: Detection of triploid, molar, and vanishing twin pregnancies by single-nucleotide polymorphism-based noninvasive prenatal test. Am J Obstet GynecoIo212(1):79.e1, 2015

Cutting GR: Modiier genetics: cystic ibrosis. Annu Rev Genomics Hum Genet 6:237, 2005

Cystic Fibrosis Mutation Database: CFMDB statistics. Available at: http:// www.genet.sickkids.on.ca/StatisticsPage.html. Accessed November 28, 2016

Dahdouh EM, Balayla J, Audibert F, et al: Technical update: preimplantation genetic diagnosis and screening. J Obstet Gynaecol Can 37(5):451, 2015

Dar P, Curnow KJ, Gross SJ, et al: Clinical experience and follow-up with large scale single nucleotide polymorphism-based noninvasive prenatal aneuploidy testing. Am J Obstet Gynecol 211(5):527.el, 2014

DasheJS: Aneuploidy screening in pregnancy. Obstet GynecoIo128(1):181, 2016

Dashe JS, Twickler OM, Santos-Ramos R, et al: Alpha-fetoprotein detection of neural tube defects and the impact of standard ultrasound. Am J Obstet GynecoIo195(6):1623,o2006

Davies SC, Cronin E, Gill M, et al: Screening for sickle cell disease and thalassemia: a systematic review with supplementary research. Heath Technol Assess 4(3):1,o2000

Davis e, Cuckle H, Yaron Y: Screening for Down syndrome-incidental diagnosis of other aneuploidies. Prenat Diagn 34(1o1): 1044, 2014 de Wert G, Liebaers I, Van De Velde H: The future (r)evolution of preimplantation genetic diagnosis/human leukocyte antigen testing: ethical reflections. Stem Cells 25(9):2167,o2007 de Wit Me, Srebniak MI, Govaerts LC, et al: Additional value of prenatal genomic array testing in fetuses with isolated structural ultrasound abnormalities and a normal karyorype: a systematic review of the literature. Ultrasound Obstet GynecoIo43(2):139, 2014

DiMaio MS, Baumgarten A, Greenstein RM, et al: Screening for fetal Down's syndrome in pregnancy by measuring maternal serum alpha-fetoprotein levels. N Engl J Med 317(6):342,o1987

Dolk H, Loane M, Garne E: The prevalence of congenital anomalies in Europe.

Adv Exp Med Bioi 686:349, 2010

Doody KJ: Treatment of the infertile couple. Hofman BL, Schorge JO, Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGrawHill Education, 20o16

Drumm ML, Konstan MW, Schluchter MD, et al: Genetic modiiers of lung disease in cystic ibrosis. N Engl J Med 353(14):1443, 2005

Dugof L, Hobbins JC, Malone FD, et al: First-trimester maternal serum PAPP-A and free-beta subunit human chorionic gonadotropic concentrations and nuchal translucency are associated with obstetric complications: a population-based screening study (The FaSTER Trial). Am J Obstet Gynecol 191(6):1446, 2004

DugofL, Hobbins JC, Malone FD, et al: Quad screen as a predictor of adverse pregnancy outcome. Obstet Gynecol 106(2):260, 2005

Dugof L, Sociery for Maternal-Fetal Medicine: First-and second-trimester maternal serum markers for aneuploidy and adverse pregnancy outcomes. Obstet GynecoIo115(5):1052, 2010

Ecker JL, Shipp TD, Bromley B, et al: The sonographic diagnosis of DandyWalker and Dandy-Walker variant: associated indings and outcomes. Prenat Diagn 20(3):328, 2000

Evans MI, Wapner RJ: Invasive prenatal diagnostic procedures. Semin PerinatoIo29(4):215,o2005

Filly A, Callen PW, Goldstein RB: Alpha-fetoprotein screening programs: what every obstetric sonologist should know. Radiology 188(1):1, 1993

Firth HV, Boyd PA, Chamberlain PF, et al: Analysis of limb reduction defects in babies exposed to chorionic villus sampling. Lancet 343(8905): 1069, 1994

Firth HV, Boyd PA, Chamberlain P, et al: Severe limb abnormalities after chorion villus sampling at 56-66 days' gestation. Lancet 337(8744):762, 1991

Flessel MC, Lorey FW: The California Prenatal Screening Program: "options and choices" not "coercion and eugenics." Genet Med 13(8): 11,o201o1 Fragouli E: Preimplantation genetic diagnosis: present and future. J Assist

Reprod Genet 24(6):201,o200

Gallot 0, Boda C, Ughetto S, et al: Prenatal detection and outcome of congenital diaphragmatic hernia: a French registry-based study. Ultrasound Obstet Gynecol 29(3):276, 2007

Ghidini A, Sepulveda W, Lockwood CJ, et l: Complications of fetal blood sampling. Am J Obstet GynecoIo168(5):1339, 1993

Gil MM, Quezada MS, Revello R, et al: Analysis of cell-free DNA in maternal blood in screening for fetal aneuploidies: updated meta-analysis. Ultrasound Obstet GynecoIo45(3):249, 2015

Goetzl L, Krantz 0, Simpson JL, et al: Pregnancy-associated plasma protein A, free beta-hCG, nuchal translucency, and risk of pregnancy loss. Obstet Gynecol 104(1):30,o2004

Grati FR, Malvestiti F, Ferreira JC, et al: Fetoplacental mosaicism: potential implications for false-positive and false-negative noninvasive prenatal screening results. Genet Med 16(8):620,o2014

Greene MF, Haddow JE, Palomaki GE, et al: Maternal serum alpha-fetoprotein levels in diabetic pregnancies. Lancet 2(8606):345, 1988

Grewal SS, Kahn JP, MacMillan ML, et al: Successful hematopoietic stem cell transplantation for Fanconi anemia from an unafected HLA-genorypeidentical sibling selected using preimplantation genetic diagnosis. Blood 103(3):o1147,o2004

Harper LM, Cahill AG, Smith K, et al: Efect of maternal obesity on the risk of fetal loss after amniocentesis and chorionic villus sampling. Obstet Gynecol 119(4):745,o2012

Hendrickson Be, Donohoe C, Akmaev VR, et al: Diferences in SMN1 allele frequencies among ethnic groups within North America. J Med Genet 46(9):641,o2009

Holmes LB: Report of National Institute of Child Health and Human Development Workshop on Chorionic Villus Sampling and Limb and Other Defects, October 20,o1992. Teratology 48(4):7,o1993

Hook EB, Cross PK, Schreinemachers OM: Chromosomal abnormality rates at amniocentesis and in live-bon infants. JAMA 249(15):2034, 1983

Hsieh FJ, Shyu MK, Sheu Be, et al: Limb defects after chorionic villus sampling. Obstet Gynecol 85(1):84, 1995

Hussamy DJ, Herrera CL, Twickler DM, et l: How many risk factors do Down syndrome pregnancies have? Am J Obstet Gynecol 216(1):S 127, 2017

Huttly W, Rudnicka A, Wald NJ: Second-trimester prenatal screening markers for Down syndrome in women with insulin-dependent diabetes mellitus. Prenat Diagn 24(10):804, 2004

Jellife-Pawlowski LL, Baer R, Blumenfeld j, et al: laternal characteristics and mid-pregnancy serum biomarkers as risk factors for subtypes of preterm birth. BJOG 122(11):1484,o2015

Kaback M, Lim-Steele J, Dabholkar 0, et al: Tay Sachs disease: carrier screening, prenatal diagnosis, and the molecular era. JAMA 270:2307, 1993

Kazerouni NN, Currier RJ, Flessel M, et al: Detection rate of quadruplemarker screening determined by clinical follow-up and registry data in the statewide California program, July 2007 to February 2009. Prenat Diagn 31(9):901,o2011

Knight GK, Palomaki GE: Maternal serum alpha-fetoprotein and the detection of open neural tube defects. In Elias S, Simpson JL (eds): Maternal Serum Screening. New York, Churchill Livingstone, 1992

Kuliev A, Jackson L, Frosrer U, et al: Chorionic villus sampling safety. Report of World Health Organization/EURO meeting in association with the Seventh International Conference on Early Prenatal Diagnosis of Genetic Diseases, Tel Aviv, Israel, May 21, 1994. Am J Obstet Gynecolo1 4(3):807, 1996

Kuliev A, Rechitsky S: Polar body-based pre implantation genetic diagnosis for Mendelian disorders. Mol Hum Reprod 17(5):275, 2011

Kuppermann M, Pena S, Bishop JT, et al: Efect of enhanced information, values clariication, and removal of inancial barriers on use of prenatal genetic testing: a randomized clinical trial. JAMA 312(12):1210,o2014

Langlois S, Armstrong L, Gall K, et al: Steroid sulfatase deiciency and contiguous gene deletion syndrome amongst pregnant patients with low serum unconjugated estriols. Prenat Diagn 29(10):966, 2009

Larion S, Warsof SL, Romary L, et al: Association of combined first-trimester screen and noninvasive prenatal testing on diagnostic procedures. Obstet GynecoIo123(6):1303,o2014

Long A, Moran P, Robson S: Outcome of fetal cerebral posterior fossa anomalies. Prenat Diagn 26(8):707,o2006

Malone FD, Ball RH, Nyberg DA, et al: First-trimester septated cystic hygroma: prevalence, natural history, and pediatric outcome. Obstet Gynecol 106(2)288, 2005a

Malone FD, Canick JA, Ball RH, et al: First-trimester or second-trimester screening, or both, for Down's syndrome. N Engl J Med 353(19):2005b

Malvestiti F, Agrati C, Grimi B, et al: Interpreting mosaicism in chorionic villi: results of a monocentric series of 1001 mosaics in chorionic villi with followup amniocentesis. Prenat Diagn 35(11): 1117, 2015

Marthin T, Liedgren S, Hammar M: Transplacental needle passage and other risk-factors associated with second trimester amniocentesis. Acta Obstet Gynecol Scand 76(8):728, 1997

Mastenbroek S, Twisk M, van der Veen F, et al: Preimplantation genetic screening: a systematic review and meta-analysis of RCTs. Hum Reprod Update 17(4):454,o2011

Mastenbroek S, Twisk M, van Echten-Arends J, et al: In vitro fertilization with preimplantation genetic screening. N Engl J Med 357(1):9,o2007

Mastrobattista JM, Espinozao]: Invasive prenatal diagnostic procedures. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hill Education, 2017

Merkatz IR, Nitowsky HM, Macri IN, et al: An association between low maternal serum a-fetoprotein and fetal chromosomal abnormalities. Am J Obstet Gynecol 148(7):886, 1984

Meyers C, Adam R, Dungan J, et al: Aneuploidy in twin gestations: when is maternal age advanced? Obstet Gynecol 89(2):248, 1997

Milunsky A, Canick JA: Maternal serum screening for neural tube and other defects. In Milunsky A (ed): Genetic Disorders and the Fetus. Diagnosis, Prevention, and Treatment, 5th ed. Baltimore, Johns Hopkins Universiry Press, 2004 Mujezinovic F, Alfirevic Z: Analgesia for amniocentesis or chorionic villus sampling. Cochrane Database Syst Rev 11:CD008580, 2011 New England Regional Genetics Group Perinatal Collaborative Study of Down Syndrome Screening: Combining maternal serum alpha-fetoprotein measurements and age to screen for Down syndrome in pregnant women under age 35. Am J Obstet Gynecol 160(3):575, 1989 Norton ME, Brar H, Weiss J, et al: Non-Invasive Chromosoml Evaluation (NICE) study: results of a multicenter prospective cohort study for detection offetal trisomy 21 and trisomy 18. Am J Obstet GynecoI207(2): 137.e1, 2012 Norton ME, Jacobsson B, Swamy GK, et al: Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med 372(17): 1589,o2015 Norton ME, Jellife-Pawlowski LL, Currier R]: Chromosomal abnormalities detected by current prenatal screening and noninvasive prenatal testing. Obstet Gynecol 124(5):979,o2014 Nyberg DA, Souter L: Use of genetic sonography for adjusting the risk for fetal Down syndrome. Semin Perinatol 27(2): 130, 2003 Nyberg DA, Souter L, El-Bastawissi A, et al: Isolated sonographic markers for detection of fetal Down syndrome in the second trimester of pregnancy. J Ultrasound Med 20(10):1053, 2001 Odibo AO, Gray DL, Dicke JM, et al: Revisiting the fetal loss rate after secondtrimester genetic amniocentesis: a single center's 16-year experience. Obstet Gynecol 11o1(3):589,o2008 Orioli 1M, Catilla EE: Epidemiology ofholoprosencephaly: prevalence and risk factors. Am J Med Genet Part C Semin Med Genet 154C:13, 2010 Park F, Russo K, Williams P, et al: Prediction and prevention of early-onset pre-eclampsia: impact of aspirin after first-trimester screening. Ultrasound Obstet GynecoIo46(4):419, 2015 Pedersen RN, Calzolari E, Husby S, et al: Oesophageal atresia: prevalence, prenatal diagnosis, and associated anomalies in 23 European regions. Arch Dis Child 97(3):227,o2012 Pergament E, Cuckle H, Zimmermann B, et al: Single-nucleotide polymorphism-based noninvasive prenatal screening in a high-risk and low-risk cohort. Obstet Gynecol 124(2 Pt 1):210, 2014 Perinatal Quality Foundation: NIPT/cell free DNA screening predictive value calculator. 2016. Available at: http://perinatalquality.org/. Accessed December 15, 2016 Persutte H, Lenke RR: Failure of amniotic-fluid-cell growth: is it related to fetal aneuploidy? Lancet 345(8942):96, 1995 Philip J, Silver RK, Wilson D, et al: Late first-trimester invasive prenatal diagnosis: results of an international randomized trial. Obstet Gynecol 103(6):1164,o2004 Quezada MS, Gil MM, Francisco C, et al: Screening for trisomies 21, 18, and 13 by cell-free DNA analysis of maternal blood at 10-11 weeks. Ultrasound Obstet GynecoIo45(1):36, 2015

Reddy UM, Abuhamad Z, Levine D, et al: Fetal imaging: Executive summary of a joint Eunice Kennedy Shriver National Institute for Child Health and Human Development, Society for laternal-FetaloIedicine, American Institute for Ultrasound in Medicine, American College of Obstetricians and Gynecologists, American College of Radiology, Society for Pediatric Radiology, and Society of Radiologists in Ultrasound Fetal Imaging Workshop. Obstet GynecoIo123(5):1070, 2014

Reddy UM, Mennuti MT: Incorporating irst-trimester Down syndrome studies into prenatal screening: executive summary of the National Institute of Child Health and Human Development workshop. Obstet Gynecol 107(1):167,o2006 Reddy UM, Page GP, Saade GR, et al: Karyotype versus microarray testing for genetic abnormalities after stillbirth. N Engl J Med 367(23):2185, 20o12 Reichler A, Hume F Jr, Drugan A, et al: Risk of anomalies as a function of level of elevated maternal serum a-fetoprotein. Am J Obstet Gynecol 1 1(4):1052, 1994 Rund D, Rachmilewitz E: Beta-thalassemia. N Engl J Med 353(11): 1135, 2005

Sharma R, Stone S, Alzouebi A, et al: Perinatal outcome of prenatally diagnosed congenital talipes equinovarus. Prenat Diagn 31(2):142, 2011

Shulman LP, Elias S, Phillips OP, et al: Amniocentesis performed at 14 weeks' gestation or earlier: comparison with irst-trimester transabdominal chorionic villus sampling. Obstet Gynecol 83(4):543, 1994

Silver RK, MacGregor SN, Sholl JS, et al: An evaluation of the chorionic villus sampling learning curve. Am J Obstet Gynecol 163(3):917, 1990 Simpson LL, Malone FD, Bianchi DW, et al: Nuchal translucency and the risk of congenital heart disease. Obstet Gynecol 109(2 Pt 1):376,o2007

Smith-Bindman R, Hosmer W, Feldstein VA, et al: Second-trimester ultrasound to detect fetuses with Down syndrome. A meta-analysis. JAMA 285(8):1044,o2001

Society for Maternal-Fetal Medicine: Prenatal aneuploidy screening using cell-free DNA. SMFM Consult No. 36. Am J Obstet GynecoI212(6):711, 2015

Society for Maternal-Fetal Medicine, Berry SM, Stone J, et al: Fetal blood sampling. Am J Obstet GynecoI209(3):170, 2013

Solomon BD, Rosenbaum KN, Meck JM, et al: Holoprosencephaly due to numeric chromosome abnormalities. Am J Med Genet C Semin Med Genet 154C(1):146,o2010

Stevenson DA, Carey JC: Contribution of malformations and genetic disorders to mortality in a children's hospital. Am J Med Genet (Part A) 126(4):393, 2004

Sundberg K, Bang J, Smidt-Jensen S, et al: Randomised study of risk offetal loss related to early amniocentesis versus chorionic villus sampling. Lancet 350(9079):697, 1997

Tangshewinsirikul C, Wanapirak C, Piyamongkol W, et al: Efect of cord puncture site on cordocentesis at mid-pregnancy on pregnancy outcome. Prenat Diagn 31(9):861, 2011

Tongsong T, Wanapirak C, Kunavikatikul C, et al: Fetal loss rate associated with cordocentesis at midgestation. Am J Obstet Gynecol 184(4):719, 2001 van der Pol JG, Wolf H, Boer K, et al: Jejunal atresia related to the use of methylene blue in genetic amniocentesis in twins. BJOG 99(2): 141, 1992 Vink J, Wapner R, D'Alton ME: Prenatal diagnosis in twin gestations. Semin PerinatoIo36(3):169,o2012

Vintzileos AJ, Egan JF: Adjusting the risk for trisomy 21 on the basis of secondtrimester ultrasonography. Am J Obstet Gynecol 172(3):837, 1995

Wald NJ, Cuckle H, Brock JH, et al: Maternal serum-alpha-fetopro.tein measurement in antenatal screening for anencephaly and spina biida in early pregnancy. Report of UK Collaborative Study on alpha-fetoprotein in relation to neural-tube defects. Lancet 1 (8026): 1323, 1977

Wald NJ, Densem JW, George L, et al: Prenatal screening for Down's syndrome using inhibin-A as a serum marker. Prenat Diagn 16(2): 143, 1996

Wald NJ, Rodeck C, Hackshaw AK, et al: First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). Health Technol Assess 7(11):1, 2003

Walker SJ, Ball RH, Babcook q, et al: Prevalence of aneuploidy and additional anatomic abnormalities in fetuses and neonates with cleft lip with or without cleft palate. A population-based study in Utah. J Ultrasound Med 20(1o1):1o175,o2001

Wang Y, Chen Y, Tian F, et al: Maternal mosaicism is a significant contributor to discordant sex chromosomal aneuploidies associated with non-invasive prenatal testing. Clin Chen 60(1):251, 2014

Wapner R, Thon E, Simpson JL, et al: First-trimester screening for trisomies 21 and 18. N Engl J Med 349(15):1471,o2003

Warsof SL, Larion S, Abuhamad Z: Overview of the impact of noninvasive prenatal testing on diagnostic procedures. Prenat Diagn 35(10):972, 2015

Wellesley D, Dolk H, Boyd PA, et al: Rare chromosome abnormalities, prevaWou K, Hyun Y, Chitayat D, et al: Analysis of tissue from products of conception lence and prenatal diagnosis rates from population-based congenital anomand perinatal losses using F-PCR and microarray: a three-year retrospective aly registers in Europe. Eur J Hum Genet 20(5):521,o2012 study resulting in an eicient protocol. Eur J Med Genet 59(8):417,o2016 Wenstrom KD, Weiner CP, Williamson A, et al: Prenatal diagnosis of fetal Xu K, Rosenwaks Z, Beaverson K, et al: Preimplantation genetic diagnosis for hyperthyroidism using funipuncture. Obstet Gynecol 76(3 Pt 2):513, retinoblastoma: the irst reported liveborn. Am J OphthalmoIo137(1): 18,o2004 1990 Zhang H, Gao Y, Jiang F, et al: Non-invasive prenatal testing for trisomies

Wijnberger LD, van der Schouw T, Christiaens GC: Learning in medicine: 21, 18, and 13: clinical experience from 146,958 pregnancies. Ultrasound chorionic villus sampling. Prenat Diagn 20(3):241, 2003 Obstet Gynecol 45(5):530, 2015

CHAPTER 15 .

FETAL ANEMIA .........e...e..e...e.. .....e....e.... 300

RED CEll AllOIMMUNIZATION ..e.............e.... 301

FETOMATERNAl HEMORRHAGE . . . . . . . . . . . . . . . . . . 306

FETAL THROMBOCYTOPENIA ...e..e..e...e...e.....e. 307

HYDROPS FETAlIS. . . . .. . . . . . . . . . . . . . . . . . . . . . . . . 309

MIRROR SYNDROMEe. . . . . . . . . . . . . . . . . . . . . . . . . . . . 312

General dropsy of the oetus is a rare condition in which the oetus and placenta are markedy oedematous. As the result of iniltration with serum the ormer may attain immense proportions and the latter may be increased to three or our times its normal size. Although a good deal has been written on the subject, no satiactory explanation of the anomay has as yet been arrived at.

-J. Whitridge Williams (1903)

Little was written of fetal disorders in the first edition of this textbook. General dropsy described above is today known as hydrops etalis (p. 309). Hydrops is perhaps the quintessential fetal disorder, as it can be a manifestation of severe illness from a wide variety of etiologies. Fetal disorders may be acquired-such as alloimmunization, they may be genetic-congenital adrenal hyperplasia or aA-thalassemia, or they may be sporadic developmental abnormalities-like many structural malformations. In this chapter, fetal anemia and thrombocytopenia as well as immune and nonimmune fetal hydrops are reviewed. Fetal structural malformations are reviewed in Chapter 10, genetic abnormalities in Chapters 13 and 14, and conditions amenable to medical and surgical fetal therapies in Chapter 16. Because congenital infections arise as a result of maternal infection or colonization, they are considered in Chapters 64 and 65.

Of the many causes of fetal anemia, one of the most frequent is red cell alloimmunization, which results from transplacental passage of maternal antibodies that destroy fetal red cells. Alloimmunization leads to overproduction of immature fetal and neonatal red cells-erythroblastosis etalis-a condition now referred to as hemoytic disease of the etus and newborn (HDFN).

In addition, several congenital infections are also associated with fetal anemia, particularly parvovirus B19, discussed in Chapter 64 (p. 1216). In Southeast Asian populations, x4-thalassemia is a common cause of severe anemia and nonimmune hydrops. Fetomaternal hemorrhage occasionally creates severe fetal anemia and is discussed on page 306. Rare causes of anemia include red cell production disorders-such as Blackfan-Diamond anemia and Fanconi anemia; red cell enzymopathies-glucose-6-phosphate dehydrogenase deficiency and pyruvate kinase deficiency; red cell structural abnormalities-hereditary spherocytosis and elliptocytosis; and myeloproliferative disorders-leukemias. Anemia may be identified through fetal blood sampling, described in Chapter 14 (p. 294), or by Doppler evaluation of the fetal middle cerebral artery (MCA) peak systolic velocity, described on page 303.

Progressive fetal anemia from any cause leads to heart failure, hydrops fetalis, and ultimately death. Fortunately, the prevalence and the course of this otherwise devastating disorder have been dramatically changed by prevention and treatment. Prevention ofD alloimmunization is with anti-D immune globulin. Identiication and treatment of fetal anemia is with MCA Doppler studies and intrauterine transfusions, respectively. Severely anemic fetuses transfused in utero have survival rates exceeding 90 percent, and even in cases of hydrops fetalis, survival rates approach 80 percent (Lindenberg, 2013; Zwiers, 2017).

Currently, 33 diferent blood group systems and 339 red cell antigens are recognized by the International Society of Blood Transfusion (Storry, 2014). Although some of these are immunologically and genetically important, many are so rare as to be of little clinical signiicance. Any individual who lacks a specific red cell antigen may produce an antibody when exposed to that antigen. Such antibodies can prove harmful to that individual if she receives an incompatible blood transfusion. Accordingly, blood banks routinely screen for erythrocyte antigens. hese antibodies may also be harmful to a mother's fetus during pregnancy. As noted, maternal antibodies formed against fetal erythrocyte antigens may cross the placenta to cause fetal red cell lysis and anemia.

Typically, a fetus inherits at least one red cell antigen from the father that is lacking in the mother. hus, the mother may become sensitized if enough fetal erythrocytes reach her circulation to elicit an immune response. Even so, alloimmunization is uncommon for the following reasons: (1) low prevalence of incompatible red cell antigens; (2) insuicient transplacental passage of fetal antigens or maternal antibodies; (3) maternalfetal ABO incompatibility, which leads to rapid clearance of fetal erythrocytes before they elicit an immune response; (4) variable antigenicity; and (5) variable maternal immune response to the antigen.

In population-based screening studies, the prevalence of red cell alloimmunization in pregnancy approximates 1 percent (Bollason, 2017; Koelewijn, 2008). Most cases of severe fetal anemia requiring antenatal transfusion are attributable to anti-D, anti-Kell, anti-c, or anti-E alloimmunization (de Haas, 2015).

At the first prenatal visit, a blood type and antibody screen are routinely assessed, and unbound antibodies in maternal serum are detected by the indirect Coombs test (Chap. 9, p. 160). When the result is positive, the specific antibodies are identified, their immunoglobulin subtype is determined as either immunoglobulin G (IgG) or M (IgM) , and the titer is quantiied. Only IgG antibodies are a concern because IgM antibodies do not cross the placenta. Selected antibodies and their potential to cause fetal hemolytic anemia are listed in Table he critical titer is the level at which significant fetal anemia could potentially develop. This may be diferent for each antibody, is determined individually by each laboratory, and usually ranges between 1:8 and 1 :32. If the critical titer for anti-D antibodies is 1: 16, a titer : 1: 16 indicates the possibility of severe hemolytic disease. An important exception is Kell sensitization, which is discussed on page 302.

he CDE system includes ive red cell proteins or antigens:

C, c, D, E, and e. here is no "d" antigen, and D-negativity is deined as the absence of the D antigen. Although most people are D positive or negative, more than 200 D antigen variants exist (Daniels, 2013). h was formerly termed rhesus because of

TABLE 15-1. Selected Red Cell Antigens and Their Relationship to Fetal Hemolytic Disease

CDE (Rh) 0,E, Bea, Ce, Cw, Cx, ce, c Ow, Evans, e, G, Goal, Hr, Hro, JAL, HOFM,

LOCR, Riv. Rh29, Rh32,

Rh42, Rh46, STEM, Tar k, Kp3, Kpb, K1s1, K22 Ku, Jsa, Jsb, Ula

Jkb, Jk3

MNS M, N, S, s, U, Mtd, Ena, Far, Hil, Hut, Mia, Mit, Mut, Mur, Mv, sO, Vw

Colton Cd, C03 Severe disease risk

Severe disease infrequent, mild disease risk

Severe disease infrequent, mild disease risk

Severe disease infrequent, mild disease risk Not associated with fetal hemolytic disease Severe disease infrequent, mild disease risk Mild disease possible

Severe disease infrequent, mild disease risk

Severe disease infrequent, mild disease risk

Severe disease infrequent, mild disease risk

Dd, Gy3, Hy, Joa Mild disease possible , Ge3, Ge4 , Lsa Mild disease possible

I I, i Not associated with fetal hemolytic disease

Lewis Lea, Leb Not associated with fetal hemolytic disease

From de Haas, 2015; Moise, 2008; Weinstein, 1982.

a misconception that red cells from rhesus monkeys expressed human blood group antigen. In transfusion medicine, "rhesus" is no longer used (Sandler, 2017).

CDE antigens are clinically important. D-negative individuals may become sensitized after a single exposure to as little as 0.1 mL of fetal erythrocytes (Bowman, 1988). The two responsible genes-RHD and RHCE-are located on the short arm of chromosome 1 and are inherited together, independent of other blood group genes. The incidence of antigen positivity varies according to racial and ethnic origin. Nearly 85 percent of non-Hispanic white Americans are D-positive. The incidence approximates 90 percent for Native Americans, 93 percent for frican Americans and Hispanic Americans, and at least 99 percent for Asian individuals (Garratty, 2004).

The prevalence of D alloimmunization complicating pregnancy ranges from 0.5 to 0.9 percent (Koelewijn, 2008; \1artin, 2005). Without anti-D immune globulin prophylaxis, a D-negative woman delivered of a D-positive, ABO-compatible newborn has a 16-percent likelihood of developing alloimmunization. Two percent will become sensitized by the time of delivery, 7 percent by 6 months postpartum, and the remaining 7 percent will be "sensibilized"-producing detectable antibodies only in a subsequent pregnancy (Bowman, 1985). If there is ABO incompatibility, the D alloimmunization risk approximates 2 percent without prophylaxis (Bowman, 2006). The reason for the difering rates relative to ABO blood type results from erythrocyte destruction of ABO-incompatible cells, which thereby limits sensitizing opportunities. D sensitization also may occur following irst-trimester pregnancy complications, prenatal diagnostic procedures, and maternal trauma (Table 15-2).

The C, c, E, and e antigens have lower immunogenicity than the D antigen but can cause hemolytic disease. Sensitization to E, c, and C antigens complicates approximately 0.3 percent of pregnancies in screening studies and accounts for about 30 percent of red cell alloimmunization cases (Howard, 1998; Koelewijn, 2008). Anti-E alloimmunization is the most common, but the need for fetal or neonatal transfusions is greater with anti-c alloimmunization than with anti-E or anti-C (de Haas, 2015; Hackney, 2004; Koelewijn, 2008).

The Grandmother Efect. In virtually all pregnancies, small amounts of maternal blood enter the fetal circulation. Realtime polymerase chain reaction (PCR) has been used to identiy maternal D-positive DNA in peripheral blood from pre term and full-term D-negative newborns (Lazar, 2006). hus, it is possible for a D-negative female fetus exposed to maternal D-positive red cells to develop sensitization. When such an individual reaches adulthood, she may produce anti-D antibodies even before or early in her irst pregnancy. This mechanism is called the grandmother eect or theory because the fetus in the current pregnancy is jeopardized by maternal antibodies that were initially provoked by his or her grandmothers erythrocytes.

Alloimmunization to Minor Antigens

Because routine administration of anti-D immunoglobulin prevents anti-D alloimmunization, proportionately more cases of hemolytic disease are caused by red cell antigens

TABLE 15-2. Causes of Fetomaternal Hemorrhage Associated with Red Cell Antigen Alloimmunizationa

Procedures Chorionic villus sampling Amniocentesis Fetal blood sampling Evacuation of molar pregnancy aFor each of the above, anti-D immune globulin is recom mended.

Expanded from American Academy of Pediatrics and

American College of Obstetricians and Gynecologists, 2017; American College of Obstetricians and

Gynecologists, 2017.

other than D (American College of Obstetricians and Gynecologists, 2016; Koelewijn, 2008). hese are also known as minor antigens. Kell antigens are among the most frequent. Other antigens with potential to cause severe alloimmunization include Duy group A_Fya, MNS, and Kidd-Jka (de Hass, 2015; Moise, 2008). Most cases of sensitization to minor antigens result from incompatible blood transfusions. However, if an IgG red cell antibody is detected and there is any doubt as to its significance, the clinician should err on the side of caution, and the pregnancy should be evaluated for hemolytic disease.

Only a few blood group antigens pose no fetal risk. Lewis antibodies-Lea and Leb, as well as I antibodies, are cold agglutinins. They are predominantly IgVl and are not expressed on fetal red cells (American College of Obstetricians and Gynecologists, 2016). Another antibody that does not cause fetal hemolysis is Duy group B-Fl.

Kell Alloimmunization. Approximately 90 percent of nonHispanic white Americans and up to 98 percent of African Americans are Kell negative. Kell type is not routinely determined. Transfusion history is important, as nearly 90 percent of Kell sensitization cases result from transfusion with Kellpositive blood. .

Kell sensitization may develop more rapidly and may be more severe than with sensitization to D and other blood group antigens. his is because Kell antibodies attach to erythrocyte precursors in the fetal bone marrow, thereby impairing the normal hemopoietic response to anemia. With fewer erythrocytes produced, there is less hemolysis, and severe anemia may not be predicted by the maternal Kell antibody titer. One option is to use a lower critical titer-l:8-for Kell sensitization (Moise, 2012). he American College of Obstetricians and Gynecologists (2016) has recommended that antibody titers not be used to monitor Kell-sensitized pregnancies.

Incompatibility for the major blood group antigens A and B is the most common cause of hemolytic disease in newborns, but it does not cause appreciable hemolysis in the fetus. Approxi mately 20 percent of newborns have ABO blood group incom patibility, yet only 5 percent are afected clinically. And in such cases, the resulting anemia is typically mild.

The condition difers from CDE incompatibility in several respects. First, ABO incompatibility is often seen in firstborn neonates, whereas sensitization to other blood group antigens is not. This is because most group 0 women have developed antiA and anti-B isoagglutinins before pregnancy from exposure to bacteria displaying similar antigens. Second, ABO alloimmunization rarely becomes more severe in successive pregnancies. Last, ABO incompatibility is considered a pediatric diseaserarely of obstetrical concern. his is because most anti-A and anti-B antibodies are IgM and do not cross the placenta. Fetal red cells also have fewer A and B antigenic sites than adult cells and are thus less immunogenic.

Consequently, fetal surveillance and early delivery are not indicated in pregnancies with prior ABO incompatibility. Careful neonatal observation is essential, however, because hyperbilirubinemia may require treatment with phototherapy or occasionally transfusion (Chap. 33, p. 626).

• Management of the Alloimmunized

An estimated 25 to 30 percent of fetuses from D-alloimmunized pregnancies will have mild-to-moderate hemolytic anemia. And without treatment, up to 25 percent will develop hydrops (Tannirandorn, 1990). If alloimmunization is detected and the titer is below the critical value, the titer is generally repeated every 4 weeks for the duration of the pregnancy (American College of Obstetricians and Gynecologists, 2016). Importantly, if a prior pregnancy was complicated by alloimmunization, serial titer assessment is not indicated, and the pregnancy is assumed to be at risk regardless of titer. Management of such pregnancies is discussed subsequently. In any pregnancy in which an antibody titer has reached a critical value, there is no beneit to repeating it. The pregnancy is at risk even if the titer drops, and further evaluation is still required.

Up to 40 percent of D-negative pregnant women carry a D-negative fetus. he presence of anti-D antibodies relects maternal sensitization but does not indicate whether the fetus is D-positive. If a woman became sensitized in a prior pregnancy, her antibody titer might rise to high levels during the current pregnancy even if the current fetus is D-negative, due to an amnestic response. In a non-Hispanic white couple in which the woman is D-negative, there is an 85-percent chance that the man is D-positive. But, in 60 percent of these cases, he will be heterozygous at the D-Iocus. And, if he is heterozygous, then half of his children will be at risk for hemolytic disease.

Transfusion history is relevant. Alloimmunization to a red cell transfusion in the past, and if that antigen is not present on paternal erythrocytes, the pregnancy is not at risk.

Initial evaluation of alloimmunization begins with determining the paternal erythrocyte antigen status. Provided that paternity is certain, if the father is negative for the red cell antigen to which the mother is sensitized, the pregnancy is not at risk. In a D-alloimmunized pregnancy in which the father is D-positive, it is helpful to determine paternal zygosity for the D antigen using DNA-based analysis. If the father is heterozygous-or if paternity is not known-the woman should be ofered assessment of fetal genotype. Traditionally, this was done with amniocentesis and PCR testing of uncultured amniocytes, which has a positive-predictive value of 100 percent and negative-predictive value of approximately 97 percent (American College of Obstetricians and Gynecologists, 2016; Van den Veyver, 1996). Fetal testing for other antigens-such as E/e, C/c, Duy, Kell, Kidd, and �1/N-is also available with this method. Chorionic villus sampling is not recommended because of greater risk for fetomaternal hemorrhage and subsequent worsening of alloimmunization.

Noninvasive fetal D genotyping has been performed using cell-free DNA (cfDNA) from maternal plasma (Chap. 13, p. 273). The reported sensitivity exceeds 99 percent, the speciicity exceeds 95 percent, and positive-or negative-predictive values are similarly very high (de Haas, 2016; Johnson, 2017; Moise, 2016; Vivanti, 2016). Fetal D genotyping with cDNA is routinely used in parts of Europe. There are two potential indications in D-negative pregnant women: (1) in women with D alloimmunization, testing can identiY fetuses that are also D-negative and do not require anemia surveillance, and (2) in women without D alloimmunization, anti-D immune globulin might be withheld if the fetus is D negative. In the case of the latter, the American College of Obstetricians and Gynecologists (2017) does not recommend routine cDNA screening in D-negative pregnancies until it becomes cost-efective.

Management of the alloimmunized pregnancy is individualized and may consist of maternal antibody titer surveillance, sonographic monitoring of the fetal MCA peak systolic velocity, amnionic luid bilirubin studies, or fetal blood sampling. Accurate pregnancy dating is critical. The gestational age at which fetal anemia developed in prior pregnancies is important because anemia tends to occur earlier and be sequentially more severe.

Middle Cerebral Artery Doppler Velocimetry. Serial measurement of the peak systolic velocity of the fetal MCA is the recommended test for detection of fetal anemia (Society for Maternal-Fetal Medicine, 20 15a). he anemic fetus shunts blood preferentially to the brain to maintain adequate oxygenation. he velocity rises because of increased cardiac output and decreased blood viscosity. The technique is discussed

Fetus without anemia or with mild anemiac� nE 120 • Fetus with severe anemia .-u .�::100 u ..o� )� . ) 40n� �u

FIGURE 15-1 Doppler measurements ofthe peak systolic velocity in the middle cerebral artery (MeA) in 165 fetuses at risk for severe anemia. The blue line indicates the median peak systolic velocity in normal pregnancies, and the red line shows 1.5 multiples ofthe median. (Reproduced with permission from Oepkes 0, Seaward PG, Vandenbussche et al: Doppler ultrasonography versus amniocentesis to predict fetal anemia, N Engl J Med. 2006 Jul 13;355(2):156-164.) in Chapter 10 (p. 214) and requires training and experience (American College of Obstetricians and Gynecologists, 2016).

In a landmark study, Mari and coworkers (2000) measured the MCA peak systolic velocity serially in 111 fetuses at risk for anemia and in 265 normal control fetuses. he threshold value of 1.5 multiples ofthe median (MoM) for gestational age correctly identiied all fetuses with moderate or severe anemia. his provided a sensitivity of 100 percent, with a false-positive rate of 12 percent.

he MCA peak systolic velocity is followed serially, and values are plotted on a curve like the one shown in Figure 15-1. If the velocity is between 1.0 and 1.5 MoM and the slope is rising-such that the value is approaching 1.5 Movf-surveillance is generally increased to weekly Doppler interrogation. If the MCA peak systolic velocity exceeds 1.5 \10M and the gestational age is younger than 34 or 35 weeks, fetal blood sampling should be considered and followed by fetal transfusion if needed (Society for Maternal-Fetal Medicine, 2015a). he false-positive rate of MCA peak systolic velocity increases signiicantly beyond 34 weeks, due to the normal augmentation in cardiac output that develops at this gestational age (Moise, 2008; Zimmerman, 2002).

Amnionic Fluid Spectral Analysis. This test is included for historical interest. More than 50 years ago, Liley (1961) demonstrated the utility ofamnionic fluid spectral analysis to measure bilirubin concentration and to thereby estimate hemolysis severity. Amnionic luid bilirubin concentration was measured by a spectrophotometer and was represented as the change in optical density absorbance at 450 nm-10D450. The likelihood of fetal anemia was determined by plotting the 10D45o value on a graph that was divided into zones. hese zones roughly correlated with fetal hemoglobin concentration, and thus with anemia severity. he original Liley graph was valid from 27 to 42 weeks' gestation and was subsequently modiied by Queenan (1993) to include gestational ages as early as 14 weeks. However, the amnionic luid bilirubin level is normally high in midpregnancy, limiting the reliability ofthis technique.

Middle cerebral artery velocimetry is more accurate than 10D45o assessment and does not confer risks for increased alloimmunization associated with amniocentesis. It has replaced 10D45o assessment for this purpose.

If there is evidence of severe fetal anemia, because of either elevated MCA peak systolic velocity or development of fetal hydrops, management is strongly inluenced by gestational age. Fetal blood sampling and intrauterine transfusion are generally performed prior to 34 to 35 weeks (Society for Maternal-Fetal Medicine, 2015a). Intravascular transfusion into the umbilical vein under sonographic guidance is the preferred method of fetal transfusion. Transfusion into the fetal peritoneal cavity may be necessary with severe, early-onset hemolytic disease in the early second trimester, a time when the umbilical vein is too narrow to readily permit needle entry. With hydrops, although peritoneal absorption is impaired, some prefer to transfuse into both the fetal peritoneal cavity and the umbilical vein.

Transfusion is generally recommended only if the fetal hematocrit is <30 percent (Society for Maternal-Fetal Medicine, 2015a). Once hydrops has developed, the hematocrit is generally 15 percent or lower. The red cells transfused are type 0, D-negative, cytomegalovirus-negative, packed to a hematocrit of approximately 80 percent to prevent volume overload, irradiated to prevent fetal graft-versus-host reaction, and leukocyte-poor. he fetal-placental volume allows rapid infusion ofa relatively large quantity ofblood. Before transfusion, a paralytic agent such as vecuronium may be given to the fetus to minimize movement. In a nonhydropic fetus, the target hematocrit is generally 40 to 50 percent. he volume transfused may be estimated by multiplying the estimated fetal weight in grams by 0.02 for each 10-percent rise in hematocrit needed (Giannina, 1998). In the severely anemic fetus at 18 to 24 weeks' gestation, less blood is transfused initially, and another transfusion may be planned for approximately 2 days later. Subsequent transfusions usually take place every 2 to 4 weeks, depending on the hematocrit.

The MCA peak systolic velocity threshold for severe anemia is higher following an initial transfusion-1.70 MoM rather than 1.50 MoYI (Society for Maternal-Fetal Medicine, 2015a). It is hypothesized that the change in threshold compensates for the contribution ofdonor cells in the initial transfusion, because donor cells (from adults) have a smaller mean corpuscular volume. Alternately, the timing ofsubsequent transfusions is based on anemia severity and posttransfusion hematocrit. Following transfusion, the fetal hematocrit generally drops by approximately 1 percent per day. A more rapid initial decline may be encountered in the setting of fetal hydrops.

Outcomes. Procedure-related complications have declined signiicantly at experienced centers in recent years, with overall survival rates exceeding 95 percent (Zwiers, 2017). Complications include fetal death in approximately 2 percent, need for emergent cesarean delivery in 1 percent, and infection and preterm rupture of membranes in 0.3 percent each, respectively. The stillbirth rate exceeds 15 percent if transfusion is required before 20 weeks (Lindenberg, 2013; Zwiers, 2017).

Considering that fetal transfusion is potentially lifesaving in severely compromised fetuses, these risks should not dissuade therapy.

Van Kamp (2001) reported that if hydrops had developed, the survival rate approached 75 to 80 percent. However, of the nearly two thirds with resolution of hydrops following transfu sion, more than 95 percent survived. he survival rate was < 40 percent if hydrops persisted.

Lindenberg (2012) reviewed long-term outcomes following intrauterine transfusion in a cohort of more than 450 alloimmunized pregnancies. Alloimmunization was secondary to anti-D in 80 percent, anti-Kell in 12 percent, and anti-c in 5 percent. Approximately a fourth of afected fetuses had hydrops, and more than half also required exchange transfusion in the neonatal period. Among nearly 300 children aged 2 to 17 years who participated in neurodevelopmental testing, fewer than 5 percent had severe impairments. hese included severe developmental delay in 3 percent, cerebral palsy in 2 percent, and deafness in 1 percent.

• Prevention of Anti-D Alloimmunization

Anti-D immune globulin is one of the success stories of modern obstetrics. It has been used for nearly five decades to prevent D alloimmunization. In countries without access to anti-D immune globulin, up to 10 percent of D-negative pregnancies are complicated by hemolytic disease of the fetus and newborn (Zipursky, 2015). With immunoprophylaxis, however, the alloimmunization risk is reduced to <0.2 percent. Despite long-standing and widespread use, its mechanism of action is not completely understood.

As many as 90 percent of alloimmunization cases occur from fetomaternal hemorrhage at delivery. Routine postpartum administration of anti-D immune globulin to at-risk pregnancies within 72 hours of delivery lowers the alloimmunization rate by 90 percent (Bowman, 1985). Additionally, provision of anti-D immune globulin at 28 weeks' gestation reduces the third-trimester alloimmunization rate from approximately 2 percent to 0.1 percent (Bowman, 1988). Whenever there is doubt whether to give anti-D immunoglobulin, it should be given.

If not needed, it will not cause harm, but failure to provide it when needed can have severe consequences.

Current preparations of anti-D immune globulin are derived from human plasma donated by individuals with hightiter anti-D immunoglobulin D antibodies. Formulations prepared by cold ethanol fractionation and ultrailtration must be administered intramuscularly because they contain plasma proteins that could result in anaphylaxis if given intravenously. However, formulations prepared using ion exchange chromatography may be administered either intramuscularly or intravenously. his is important for treatment of significant fetomaternal hemorrhage, which is discussed subsequently. Both preparation methods efectively remove viral particles, including hepatitis and human immunodeiciency viruses. Depending on the preparation, the half-life of anti-D immune globulin ranges from 16 to 24 days, which is why it is given both in the third trimester and following delivery. he standard intramuscular dose of anti-D immune globulin-300 I-Lg or 1500 IU-will protect the average-sized mother from a fetal hemorrhage of up to 30 mL of fetal whole blood or 15 mL of fetal red cells.

In the United States, anti-D immune globulin is given prophylactically to all D-negative, unsensitized women at approximately 28 weeks' gestation, and a second dose is given after delivery if the newborn is D-positive (American College of Obstetricians and Gynecologists, 2017). Before the 28-week dose of anti-D immune globulin, repeat antibody screening is recommended to identiy individuals who have become alloimmunized (American Academy of Pediatrics, 2017). Following delivery, anti-D immune globulin should be given within 72 hours. Recognizing that 40 percent of neonates born to D-negative women are also D negative, administration of immune globulin is recommended only after the newborn is conirmed to be D positive (American College of Obstetricians and Gynecologists, 2017). If immune globulin is inadvertently not administered following delivery, it should be given as soon as the omission is recognized, because there may be some protection up to 28 days postpartum (Bowman, 2006). Anti-D immune globulin is also administered after pregnancyrelated events that could result in fetomaternal hemorrhage (see Table 15-2).

Anti-D immune globulin may produce a weakly positive-1: 1 to 1 :4-indirect Coombs titer in the mother. This is harmless and should not be confused with development of alloimmunization. Additionally, as the body mass index increases above 27 to 40 kg/m2, serum antibody levels decrease by 30 to 60 percent and may be less protective (MacKenzie, 2006; Woelfer, 2004). D-negative women who receive other types of blood products-including platelet transfusions and plasmapheresis-are also at risk of becoming sensitized, and this can be prevented with anti-D immune globulin. Rarely, a small amount of antibody crosses the placenta and results in a weakly positive direct Coombs test in cord and infant blood. Despite this, passive immunization does not cause signiicant fetal or neonatal hemolysis.

It is estimated that in 2 to 3 per 1000 pregnancies, the volume of fetomaternal hemorrhage exceeds 30 mL of whole blood (American College of Obstetricians and Gynecologists, 2017). A single dose of anti-D immune globulin would be insuicient in such situations. If additional anti-D immune globulin is considered only for women with risk factors such as those shown in Table 15-2, then hafof those who require additional immune globulin may be missed. For this reason, all D-negative women should be screened at delivery, typically with a rosette test, followed by quantitative testing if indicated (American College of Obstetricians and Gynecologists, 20i17).

he rosette test is a qualitative test that identiies whether fetal D-positive cells are present in the circulation of a D-negative woman. A sample of maternal blood is mixed with anti-D antibodies that coat any D-positive fetal cells present in the sample. Indicator red cells bearing the D-antigen are then added, and rosettes form around the fetal cells as the indicator cells attach to them by the antibodies. hus, if rosettes are visualized, there are fetal D-positive cells in that sample. In the setting of D incompatibility, or any time a large fetomaternal hemorrhage is suspected-regardless of antigen status, a Kleihauer-Betke test or flow cytometry test are used. These are discussed on page 307.

The dosage of anti-D immune globulin is calculated from the estimated volume of the fetal-to-maternal hemorrhage, as described on page 307. One 300-�g dose is given for each 15 mL of fetal red cells or 30 mL of fetal whole blood to be neutralized. If using an intramuscular preparation of anti-D immune globulin, no more than five doses may be given in a 24-hour period. If using an intravenous preparation, two ampules-totaling 600 �g-may be given every 8 hours. To determine if the administered dose was adequate, the indirect Coombs test may be performed. A positive result indicates that there is excess anti-D immunoglobulin in maternal serum, thus demonstrating that the dose was suicient. Alternatively, a rosette test may be performed to assess whether circulating fetal cells remain.

Formerly called D") these are the most common antigenic D variants in the United States and Europe. Serological weak D phenotypes have been further refined into two general categories using molecular analysis-RHD genotyping. Molecular weak D phenotypes carry reduced numbers of intact D antigens on the red cell surface. Those designated partial D types have protein deletions associated with abnormal D antigens that lack epitopes (Sandler, 2017). When this distinction is known, it can have clinical consequences in terms of sensitization risk and need for anti-D immune globulin.

Traditionally, serological weak D individuals have been considered to be D-positive or -negative depending on the clinical situation. For the purposes of blood donation, they are categorized as D-positive, whereas transfusion recipients with weak D are considered D-negative. In pregnancy, weak D has also been considered D-negative, so that individuals receive immune globulin and avoid potential sensitization (American College of Obstetricians and Gynecologists, 2017; Sandler, 2015).

Many non-Hispanic white Americans who test positive for weak D have weak D phenotypes 1, 2, or 3. Individuals with these phenotypes may be managed as though they are D-positive. Because they are not at risk for alloimmunization, anti-D immune globulin is not needed (Sandler 2015, 2017). In contrast, individuals with partial D antigens may be at risk for D-sensitization and do require immune globulin. Molecular RHD genotyping has been suggested for pregnant women with weak D phenotype, bur cost-benefit analysis of this strategy is presently lacking (American College of Obstetricians and Gynecologists, 2017). f molecular genetic testing has not been peormed in those with serologic weak D phenoype) D immunoprophylaxis should be administered to those with weak D phenotype.

A small amount of fetomaternal bleeding likely occurs in all pregnancies, and in two thirds, this may be suicient to provoke an antigen-antibody reaction. As shown in Figure 15-2, the incidence increases with advancing gestation and the 80 0.19 mL 70 )> 60;;)>C 50)C·uE 40

FIGURE 15-2 Incidence of fetal-to-maternal hemorrhage during pregnancy. The numbers at each data point represent total volume of fetal blood estimated to have been transferred into the maternal circulation. (Data from Choavaratana, 1997.) volume of fetal blood in the maternal circulation. Fortunately, a large blood loss-true fetomaternal hemorrhage-is rare. In one series of more than 30,000 pregnancies, fetomaternal hemorrhage ::150 mL occurred in 1 per 2800 births (de Almeida, 1994). he prevalence of fetomaternal hemorrhage of at least 30 mL-the volume of fetal blood covered by a standard 300 �g dose of anti-D immune globulin-is estimated to be 3 per 1000 pregnancies (Wylie, 2010).

Selected causes of fetomaternal hemorrhage are shown in Table 15-2. It also may occur with placenta previa, placental chorioangioma, or vasa previa (Giacoia 1997; Rubod, 2007). In each of these circumstances, however, fetomaternal hemorrhage is extremely uncommon if not rare. And, in more than 80 percent of cases, no cause is identified. With significant hemorrhage, the most common presenting complaint is decreased fetal movement (Bellussi, 2017; Wylie, 2010). A sinusoidal fetal heart rate pattern is infrequently seen but warrants immediate evaluation (Chap. 24, p. 464). Sonography may demonstrate elevated MCA peak systolic velocity, and indeed this is reported to be the most accurate predictor (Bellusi, 2017; Wylie, 2010). Hydrops is an ominous inding. If fetomaternal hemorrhage is suspected, an elevated MCA peak systolic velocity or sonographic evidence of hydrops prompts consideration of urgent fetal transfusion or delivery.

One limitation of quantitative tests for fetal cells in the maternal circulation is that they do not provide information regarding hemorrhage timing or chronicity (Wylie, 2010). In general, anemia developing gradually or chronically, as in alloimmunization, is better tolerated by the fetus than acute anemia. Chronic anemia may not produce fetal heart rate abnormalities until the fetus is moribund. In contrast, significant acute hemorrhage is poorly tolerated by the fetus and may cause profound fetal neurological impairment from cerebral hypoperfusion, ischemia, and infarction. In some cases, fetomaternal hemorrhage is identified during stillbirth evaluation (Chap. 35, p. 646).

FIGURE 15-3 Kleihauer-Betke test demonstrating massive fetalto-maternal hemorrhage. After acid-elution treatment, fetal red cells rich in hemoglobin F stain darkly, whereas maternal red cells with only very small amounts of hemoglobin F stain lightly.

Once fetomaternal hemorrhage is recognized, the volume of fetal blood loss should be estimated. he volume is essential to calculate the appropriate dose of anti D-immune globulin if the woman is D-negative, and it may inluence obstetrical management.

The most commonly used quantitative test for fetal red cells in the maternal circulation is the acid elution or Kleihauer-Betke (KB) test (Kleihauer, 1957). Fetal erythrocytes contain hemoglo bin F, which is more resistant to acid elution than hemoglobin

A. After exposure to acid, only fetal hemoglobin remains, such that after staining, the fetal erythrocytes appear red and adult erythrocytes appear as "ghosts" (Fig. 15-3). he fetal cells are then counted and expressed as a percentage of adult cells. he KB test is labor intensive. Importantly, there are two scenarios in which it may not be accurate: (1) maternal hemoglobinopathies such as �-thalassemia in which the fetal hemoglobin level is elevated and (2) pregnancies at or near term, when the fetus has already started to produce hemoglobin A.

he volume of fetomaternal hemorrhage is calculated from the KB test result using the following formula:

One method is to estimate the maternal blood volume (MBV) as 5000 mL for a normal-size, normotensive women at term. Thus, for 1.7 -percent positive KB-stained cells in a woman of average size with a hematocrit of 35 percent and whose fetus has a hematocrit of 50 percent: 5000 X 0.35 X 0.017 0.5 he fetal-placental blood volume at term approximates 125 mLlkg. For a 3000-g fetus, that would equate to 375 mL. Thus, this fetus lost approximately 15 percent (60 -375 mL) of the fetal-placental volume. Because the hematocrit is 50 percent in a term fetus, this 60 mL of whole blood represents 30 mL of red cells lost into the maternal circulation. This loss should be well tolerated hemodynamically but would require two 300-lLg doses of anti-D immunoglobulin to prevent alloimmunization. A more precise method to estimate the maternal blood volume includes a calculation based on the maternal height, weight, and anticipated physiological maternal blood volume accrual (Table 41-1, p. 756).

Fetomaternal hemorrhage can also be quantified using low cytometry, which uses monoclonal antibodies to hemoglobin F or to the D antigen, followed by quantiication of luorescence (Chambers, 2012; Welsh, 2016). Flow cytometry is an automated test that can analyze a greater number of cells than the KB test. Further, it is unafected by maternal levels of fetal hemoglobin or by fetal levels of hemoglobin A. Flow cytometry has been reported to be more sensitive and accurate than the KB test, however, it uses specialized technology not routinely available in many hospitals (Chambers, 2012; Corcoran, 2014; Fernandes, 2007).

This condition is also referred to as neonatal alloimmune throm cytopenia (FNAIT). Alloimmune thrombocytopenia (AIT) is the most common cause of severe thrombocytopenia among term newborns, with a frequency of 1 to 2 per 1000 births (Kamphuis, 2010; Pacheco, 2013; Risson, 2012). FNAIT is caused by maternal alloimmunization to paternally inherited fetal platelet antigens. he resulting maternal antiplatelet anti bodies cross the placenta in a manner similar to red cell allo immunization (p. 301). Unlike immune thrombocytopenia, the maternal platelet count is normal with FNAIT. And, unlike anti-D alloimmunization, severe sequelae may afect the initial at-risk pregnancy.

Maternal platelet alloimmunization is most often against human platelet antigen-1a (HPA-1a). It accounts for 80 to 90 percent of cases and is associated with the greatest severity (Bussel, 1997; Knight, 2011; Tiller, 2013). his is followed in order of frequency by HPA-5b, HPA-1b, and HPA-3a. Alloimmunization to other antigens accounts for only 1 percent of reported cases.

Approximately 85 percent of non-Hispanic white individuals are HPA-1a positive. Two percent are homozygous for HPA-1b and thus at risk for alloimmunization. Importantly, however, only 10 percent of homozygous HPA-1 b mothers who carry an HPA-1a fetus will produce anti-platelet antibodies. Approximately a third of afected fetuses or neonates will develop severe thrombocytopenia, and 10 to 20 percent of those with severe thrombocytopenia sustain an intracranial hemorrhage (ICH) (Kamphuis, 2010). As a result, population-based screening studies have identified FNAIT-associated ICH in 1 per 25,000 to 60,000 pregnancies (Kamphuis, 2010; Knight, 2011).

FNAIT may present in various ways. In some cases, neonatal thrombocytopenia may be an incidental finding or the newborn may manifest petechiae. In the other extreme, a fetus or neonate may develop devastating ICH-often before birth. Of 600 pregnancies with FNAIT identified through a large international registry, fetal or neonatal ICH complicated 7 percent of cases (Tiller, 2013). Hemorrhage afected the irst-born child in 60 percent and occurred before 28 weeks' gestation in half. A third of afected children died soon after birth, and 50 percent of survivors had severe neurological disabilities. Bussel and coworkers (1997) evaluated fetal platelet counts before therapy in 107 fetuses with FNAIT. Thrombocytopenia severity was predicted by a prior sibling with perinatal ICH, and 98 percent of cases were identiied this way. he initial platelet count was <20,000/�L in 50 percent. In cases in which the platelet count was initially >80,000/�L, they noted that it dropped by more than 1 O,OOO/�L each week in the absence of therapy.

Alloimmune thrombocytopenia is typically diagnosed following delivery of a neonate with severe and unexplained thrombocytopenia to a woman whose platelet count is normal. Rarely, the diagnosis is ascertained after identiYing fetal ICH. he condition recurs in 70 to 90 percent of subsequent pregnancies, is often severe, and usually develops earlier with each successive pregnancy. Traditionally, fetal blood sampling was performed to detect fetal thrombocytopenia and to tailor therapy, with transfusion of platelets if the fetal platelet count was < 50,000/�L. Because of procedure-related complications, however, experts recommend abandoning routine fetal platelet sampling in favor of empirical treatment with intravenous immune globulin (IVIG) and prednisone (Berkowitz, 2006; Pacheco, 2011).

herapy is stratified according to whether a prior afected pregnancy was complicated by perinatal ICH, and if so, at what gestational age (Table 15-3). Pioneering work by Bussel (1996) and Berkowitz (2006) and their colleagues demonstrated the eicacy of such treatment. In one series of 50 pregnancies with fetal thrombocytopenia secondary to FNAIT, IVIG raised the platelet count by approximately 50,000/�L, and no fetus developed ICH (Bussel, 1996). Among pregnancies at particularly high risk-based on a platelet count <20,000/�L or sibling with FNAIT-associated ICH-the addition of corticosteroids to IVIG increased the platelet count in 80 percent of cases (Berkowitz, 2006). Cesarean delivery has been recommended at or near term. A noninstrumental vaginal delivery is generally considered only if fetal blood sampling has demonstrated a platelet count > 100,000/�L (Pacheco, 2011).

Additional considerations include risks and costs associated with therapy. Side efects ofIVIG may include fever, headache, nausea/vomiting, myalgia, and rash. Maternal hemolysis also has been described (Rink, 2013). Costs for IVIG may exceed $70 per gram or nearly $10,000 for each weekly 2-g/kg infusion for an average-size pregnant woman (Pacheco, 2011).

lso known as immune or idiopathic thrombocytopenic 2urpura (ITP), this autoimmune disorder is characterized by antiplatelet IgG antibodies that attack platelet glycoproteins. In pregnancy, these antibodies may cross the placenta and cause fetal thrombocytopenia. Maternal ITP is discussed in Chapter 56 (p. 1086). Fetal thrombocytopenia is usually mild. However, neonatal platelet levels may fall rapidly after birth, with a nadir at 48 to 72 hours of life. Neither the maternal platelet count, identification of anti platelet antibodies, nor treatment with corticosteroids efectively predicts fetal or neonatal platelet counts (Hachisuga, 2014). Importantly, fetal platelet counts are usually adequate to allow vaginal delivery without an increased risk of ICH. In a recent review of more than 400 pregnancies

TABLE 15-3. Fetal-Neonatal Alloimmune Thrombocytopenia (FNAIT) Treatment Recommendations

Maternal anti-HPA antibody screening and cross-matching with paternal platelets at 12,s24, and 32 weeks' gestation; no treatment for negative test results

Beginning at 20 wks: IVIG 1 g/kg/wk and prednisone 0.5 mg/kg/d or IVIG 2 g/kg/wk

Beginning at 32 weeks: IVIG 2 g/kg/wk and prednisone 0.5 mg/kg/d.

Beginning at 12 wks: IVIG 1 g/kg/wk

Beginning at 20 wks: either increase IVIG to 2 g/kg/wk or add prednisone 0.5 mg/kg/d

Beginning at 28 wks: IVIG 2 g/kg/wk and prednisone 0.5 mg/kg/d.

Beginning at 12 wks: IVIG 2 g/kg/wk

Beginning at 20 wks: add prednisone 1 mg/kg/d Continue both until delivery

HPA human platelet antigen; ICH intracerebral hemorrhage; IVIG intravenous immunoglobulin G. Data from Pacheco, 2011s.

with ITP, there was no case of fetal or neonatal ICH and no infant with any central nervous system abnormality (Wyszynski, 2016). Fetal bleeding complications are considered rare, and fetal blood sampling is not recommended (Neunert, 201i1). Delivery mode is based on standard obstetrical indications.

This term refers to excessive accumulation of serous fluid. Strictly defined, hydrops etalis is edema of the fetus. Traditionally, the diagnosis was made after delivery of a massively edematous neonate, often stillborn (Fig. 1i5-4). With sonography, hydrops has become a prenatal diagnosis. It is deined as two or more fetal efusions-pleural, pericardial, or ascites-or one efusion plus anasarca. As hydrops progresses in severity, edema is invariably a component, and is usually accompanied by placentomegaly and hydramnios. Clinically significant edema is defined sonographically as skin thickness > 5 mm, and placentomegaly if the placenta thickness is at least 4 em in the second trimester or 6 em in the third trimester (Bellini, 2009; Society for Maternal-Fetal Medicine, 2015b). Hydrops may result from a wide range of conditions with varying pathophysiologies, each with the potential to make the fetus severely ill. It is divided into two categories. If found in association with red cell alloimmunization, it is termed immune, otherwise, it is nonimmune.

he incidence of immune hydrops has dramatically declined with the advent of anti-D immune globulin, MCA Doppler studies for detection of severe anemia, and prompt fetal transfusion when needed (p. 304). However, fewer than 10 percent of hydrops cases are caused by red cell alloimmunization (Bellini, 2012; Santolaya, 1992).

The pathophysiology underlying hydrops remains unknown. Immune hydrops is postulated to share several physiological abnormalities with nonimmune hydrops. As shown in

FIGURE 15-4 Hydropic, macerated stillborn infant and characteristically large placenta. The etiology was B1o9 parvovirus infection. (Used with permission from Dr. April Bleich.) 15-5, these include decreased colloid oncotic pres sure, increased hydrostatic (or central venous) pressure, and enhanced vascular permeability. Immune hydrops results from transplacental passage of maternal antibodies that destroy fetal red cells. The resultant anemia stimulates marrow erythroid hyperplasia and extramedullary hematopoiesis in the spleen and liver. The latter likely causes portal hypertension and impaired hepatic protein synthesis, which lowers plasma oncotic pressure (Nicolaides, 1985). Fetal anemia also may raise central venous pressure (Weiner, 1989). Finally, tissue hypoxia from anemia may increase capillary permeability, such that luid collects in the fetal thorax, abdominal cavity, andlor subcutaneous tissue.

he degree of anemia in immune hydrops is typically severe.

In a series of 70 pregnancies with fetal anemia from red cell alloimmunization, Mari and coworkers (2000) found that all those with immune hydrops had hemoglobin values <5 g/dL. As discussed on page 304, immune hydrops is treated with fetal blood transfusions.

At least 90 percent of cases of hydrops are nonimmune (Bellini, 2012; Santolaya, 1992). The prevalence estimate is 1 per 1500 second-trimester pregnancies (Heinonen, 2000). The number of specific disorders that can lead to nonimmune hydrops is extensive. Etiologies and the proportion of births within each hydrops category from a review of more than 6700 afected pregnancies are summarized in Table 1i5-4. A cause is identified in at least 60 percent prenatally and in more than 80 percent postnatally (Bellini, 2009; Santo, 2011). Currently, approximately 20 percent of cases remain idiopathic (Bellini, 2015). As shown in Figure 15-5, several diferent pathophysiological processes are proposed to account for the inal common pathway of hydrops fetalis.

Importantly, the etiology of non immune hydrops varies according to when in gestation it is identified. Of those diagnosed prenatally, aneuploidy accounts for approximately 20 percent, cardiovascular abnormalities for 15 percent, and infections for 14 percent-the most common of these being parvovirus B19 (Santo, 2011). Overall, only 40 percent of pregnancies with nonimmune hydrops result in a liveborn neonate, and of these, the neonatal survival rate is only about 50 percent. Sohan and colleagues (2001) reviewed 87 pregnancies with hydrops and found that 45 percent of those diagnosed before 24 weeks' gestation had a chromosomal abnormality. The most frequent aneuploidy was 45,X-Turner syndrome, and in such cases, the survival rate was <5 percent (Chap. 13, p. 259). If hydrops is detected in the irst trimester, the aneuploidy risk is nearly 50 percent, and most have cystic hygromas (Fig. 10-22, p. 198).

Although the prognosis of nonimmune hydrops is guarded, it is heavily dependent on etiology. In large series from Thailand and Southern China, aA-thalassemia is the predominant cause of nonimmune hydrops, accounting for 30 to 50 percent of cases and conferring an extremely poor prognosis (Liao, 2007; Ratanasiri, 2009; Suwanrath-Kengpol, 2005). In contrast, treatable etiologies such as parvovirus, chylothorax, and tachyarrhythmias, which each comprise about 10 percent of

Anemia Red cell alloimmunization Fetomaternal hemorrhage Hematological disorder Infection Selected fetal anomalies Placental abnormality Volume overload or Extramedullary hematopoiesis Impaired venous return Hepatic dysfunction, Metabolic disorders impaired protein synthesis Infection Tissue hypoxia ? Heart failure Increased hydrostatic pressure Lymphatic abnormality Decreased plasma oncotic pressure Increased capillary permeability Decreased lymphatic flow Increased interstitial fluid Hydrops fetalis

FIGURE 15�5 Proposed pathogenesis of immune and nonimmune hydrops fetalis. (Adapted from Bellini, 2009; Lockwood, 2009.) cases, can result in survival in two thirds of cases with fetal therapy (Sohan, 2001).

Hydrops is readily detected sonographically. As noted, two efusions or one efusion plus anasarca are required for diagnosis. Edema may be particularly prominent around the scalp, or equally obvious around the trunk and extremities. Efusions are visible as luid outlining the lungs, heart, or abdominal viscera (Fig. 15-6).

In many cases, targeted sonographic and laboratory evaluation will identiy the underlying cause of fetal hydrops. hese include cases due to fetal anemia, arrhythmia, structural abnormality, aneuploidy, placental abnormality, or complications of monochorionic twinning. Depending on the circumstances, initial evaluation includes the following: 1.

2.

Targeted sonographic fetal and placental examination, including:

A detailed anatomical survey to assess for the structural abnormalities listed in Table 15-4

MCA Doppler peak systolic velocity to assess for fetal anemia

Fetal echocardiography with M-mode evaluation 3.

Amniocentesis for fetal karyotype and for parvovirus B19, cytomegalovirus, and toxoplasmosis testing as discussed in Chapter 64. Consideration of chromosomal microarray analysis if fetal anomalies are present 4.

Kleihauer-Betke test for fetomaternal hemorrhage if anemia is suspected, depending on findings and test results 5.

Consideration of testing for alpha-thalassemia and/or inborn errors of metabolism.

Isolated Efusion or Edema. Although one efusion or anasarca alone is not diagnostic for hydrops, the above evaluation should be considered if these are encountered, as hydrops may develop. For example, an isolated pericardial eusion may be the initial finding in fetal parvovirus B19 infection (Chap. 64, p. 1217). n isolated pleural efusion may represent a chylothorax, which is amenable to prenatal diagnosis, and for which fetal therapy may be lifesaving if hydrops develops (Chap. 16, p. 324). Isolated ascites also may be the initial inding in fetal parvovirus B 19 infection, or it may result from a gastrointestinal

TABLE 15-4. Categories and Etiologies of Nonimmune Hydrops Fetalis

Structural defects: Ebstein anomaly, Fallot tetralogy with absent pulmonary valve, hypoplastic left or right heart, premature closure of ductus arteriosus, arteriovenous malformation (vein of Galen aneurysm)

Bradycardia, as may occur in heterotaxy syndrome with endocardial cushion defect or with anti-RolLa antibodies

Cystic hygroma, systemic lymphangiectasis, pulmonary lymphangiectasis

Parvovirus B19, syphilis, cytomegalovirus, toxoplasmosis, rubella, enterovirus, varicella, herpes simplex, coxsackievirus, listeriosis, leptospirosis, Chagas disease, Lyme disease

Skeletal dysplasia with very small thorax

Meconium peritonitis, gastrointestinal tract obstruction

Congenital (Finnish) nephrosis, Bartter syndrome, mesoblastic nephroma

Placental, Twin, and Cord Abnormalities 5

Placental chorioangioma, twin-twin transfusion syndrome, twin reversed arterial perfusion sequence, twin anemia polycythemia sequence, cord vessel thrombosis

Inborn errors of metabolism: Gaucher disease, galactosialidosis, GM1 gangliosidosis, sialidosis, mucopolysaccharidoses, mucolipidoses

Tumors: sacrococcygeal teratoma, hemangioendothelioma with Kassabach-Merritt syndrome apercentages reflect the proportion within each category from a systematic review of 6775 pregnancies with nonimmune hydrops.

Modified from Bellini, 2015.

FIGURE 15-6 Hydropic features. A. This profile of a 23-week fetus with nonimmune hydrops secondary to B 19 parvovirus infection depicts scalp edema (arrowheads) and ascites (*). B. This 34-week fetus had hydrops secondary to an arteriovenous malformation in the brain, known as a vein of Galen aneurysm. In this coronal image, prominent pleural effusions (*) outline the lungs (L). Fetal ascites is also pres- ent (arrows), as is anasarca. C. This axial (transverse) image depicts a pericardial effusion (arrows) in a 23-week fetus with hydrops from B1o9 parvovirus infection. The degree of cardiomegaly is impressive, and the ventricular hypertrophy raises concern for myocarditis, which can accompany parvovirus infection. D. This axial (transverse) image depicts fetal ascites (*) in a 15-week fetus with hydrops secondary to large cystic hygromas. Anasarca is also seen (bracket).

abnormality such as meconium peritonms. Finally, isolated edema, particularly involving the upper torso or the dorsum of the hands and feet, may be found in Turner or Noonan syndrome or may represent congenital lymphedema syndrome (Chap. 13, p. 259).

An association between fetal hydrops and development of maternal edema in which the fetus mirrors the mother is attributed to Ballantyne. He called the condition triple edema because the fetus, mother, and placenta all became edematous. he etiology of the hydrops is not related to development of mirror syndrome. It has been associated with hydrops from D alloimmunization, twin-twin transfusion syndrome, placental chorioangioma, and with fetal cystic hygroma, Ebstein anomaly, sacrococcygeal teratoma, chylothorax, bladder outlet obstruction, supraventricular tachycardia, vein of Galen aneurysm, and various congenital infections (Braun, 2010).

In a review of more than 50 cases of mirror syndrome, Braun (2010) found that approximately 90 percent of women had edema, 60 percent had hypertension, 40 percent had proteinuria, 20 percent had liver enzyme elevation, and nearly 15 percent had headache and visual disturbances. Based on these indings, it is reasonable to consider mirror syndrome a form of severe preeclampsia (Espinoza, 2006; Midgley, 2000). Others, however, have suggested that it is a separate disease process with hemodilution rather than hemoconcentration (Carbillon, 1997; Livingston, 2007).

Some reports describe the same imbalance of angiogenic and antiangiogenic factors that is observed with preeclampsia, and this suggests a common pathophysiology (Espinoza, 2006; Goa, 2013; Llurba, 2012). hese indings, which include elevated concentrations of soluble fms-like tyrosine kinase-1 (sFlt-l), decreased placental growth factor (PIG F) levels, and elevation of soluble vascular endothelial growth factor receptor-I (s VEG FR-1) concentrations, are discussed further Chapter 40 (p. 716).

In most cases with mirror syndrome, prompt delivery is indicated and followed by resolution of maternal edema and other findings (Braun, 2010). However, in isolated cases of fetal anemia, supraventricular tachycardia, hydrothorx, and bladder outlet obstruction, successful fetal treatment resulted in resolution of both fetal hydrops and maternal mirror syndrome (Goa, 2013; Livingston, 2007; Llurba, 2012; Midgley, 2000). Normalization of the angiogenic imbalance has also been described following fetal transfusion for parvovirus B 19 infection. Fetal therapy for these conditions is reviewed in Chapter 16. Given the parallels to severe preeclampsia, delaying delivery to efect fetal therapy should be considered only with caution. If the maternal condition deteriorates, delivery is recommended.

American Academy of Pediatrics, American College of Obstetricians and Gynecologists: Guidelines for Perinatal Care. 8th ed. Elk Grove Village, MP, 201

American College of Obstetricians and Gynecologists: Management of alloimmunization during pregnancy. Practice Bulletin No. 75, August 2006, Reairmed 2016

American College of Obstetricians and Gynecologists: Prevention ofRh 0 alloimmunization. Practice Bulletin No. 181, August 20o17 Bellini C, Hennekam RC: Non-immune hydrops fetalis: a short review of etiology and pathophysiology. Am] Med Genet 158A(3):597, 2012 Bellini C, Hennekam RC, Fulcheri E, et al: Etiology of nonimmune hydrops fetalis: a systematic review. Amo] Med Genet A 149A(5):844, 2009 Bellini C, Donarini G, Paladini 0, et al: Etiology of non-immune hydrops fetalis: an update. Am ] Med Genet 167 A: 1082, 2015 Bellussi F, Perolo A, Ghi T, et al: Diagnosis of severe fetomaternal hemorrhage with fetal cerebral Doppler: case series and systematic review. Fetal Diagn Ther 41(1):1,o2017 Berkowitz L, Kolb A, McFarland ]G, et al: Parallel randomized trials of risk-based therapy for fetal alloimmune thrombocytopenia. Obstet Gynecol 107(1):91,o2006 Bollason G, Hjartardottir H, Jonsson T, et al: Red blood cell alloimmunization in pregnancy during the years 1996-2015 in Iceland: a nation-wide population study. Transfusion 57(1o1):2578, 2017

Bowmano]: Rh-immunoglobulin: Rh prophylaxis. Best Pract Res Clin HaematoIo19(1):27,o2006

Bowman ]M: Controversies in Rh prophylaxis: who needs Rh immune globulin and when should it be given? Am ] Obstet Gynecol 151 :289, 1985 Bowman ]M: he prevention of h immunization. Transfus Med Rev 2: 129, 1988

Braun T, Brauer M, Fuchs I, et al: Mirror syndrome: a systematic review of fetal associated conditions, maternal presentation, and perinatal outcome. Fetal Diagn Ther 27(4):191,o2010

Bussel ]B, Berkowitz L, Lynch L, et al: Antenatal management of alloimmune thrombocytopenia with intravenous gamma-globulin: a randomized trial of the addition oflow-dose steroid to intravenous gamma-globulin. Am ] Obstet GynecoIo174(5):1414, 1996

Bussel ]B, Zabusky MR, Berkowitz L, et al: Fetal alloimmune thrombocytopenia. N Englo] Med 337:22, 1997

Carbillon L, Oury ]F, Guerin ]M, et al: Clinical biological features of Ballantyne syndrome and the role of placental hydrops. Obstet Gynecol Surv 52(5):310, 1997

Chambers E, Davies L, Evans S, et al: Comparison of haemoglobin F detection by the acid elution test, low cytometry and high-performance liquid chromatography in maternal blood samples analysed for fetomaternal haemorrhage. Transfus Med 22(3):199, 2012

Choavaratana R, Uer-Areewong S, Makanantakocol S: Fetomaternal transfusion in normal pregnancy and during delivery. ] Med Assoc Thai 80:96, 1997

Corcoran 0, Murphy 0, Donnelly], et al: The prevalence of maternal F cells in a pregnant population and potential overestimation of foeto-maternal haemorrhage as a consequence. Blood Transfus 12:570,o2014

Daniels G: Variants of RhO-current testing and clinical consequences. Br ] Haematol 161(4):461,o2013 de Almeida V, Bowman ]M: Massive fetomaternal hemorrhage: Manitoba experience. Obstet Gynecol 83:323, 1994 de Haas M, Thurik FF, Koelewijno]M et al: Haemolytic disease of the fetus and newborn. Vox Sang 109(2):99, 2015 de Haas M, Thurik FF, van der Ploeg CP, et al: Sensitivity of fetal RHO screening for safe guidance of targeted anti-D immunoglobulin prophylaxis: prospective cohort study of a nationwide programme in the Netherlands. BM] 89,o2016

Espinozao], Romero R, Nien ]K, et al: A role of the anti-angiogenic factor sVEGFR-1 in the "mirror syndrome" (Ballantyne's syndrome). ] Matern Fetal Neonatal Med 19(10):607,o2006

Fernandes B], von Dadelszen P, Fazal I, et al: Flow cytometric assessment of feto-maternal hemorrhage; a comparison with Betke-Kleihauer. Prenat Diagn 27(7):641, 2007

Garratty G, Glynn SA, McEntire R, et al: ABO and Rh(D) phenotype frequencies of diferent racial/ethnic groups in the United States. Transfusion 44(5):703, 2004

Giacoia GP. Severe fetomaternal hemorrhage: a review. Obstet Gynecol Surv 52:372, 1997

Giannina G, Moise K] ]r, Dorman K: A simple method to estimate the volume for fetal intravascular transfusion. Fetal Diagn Ther 13:94, 1998

Goa S, Mimura K, Kakigano A, et al: Normalisation of angiogenic imbalance after intra-uterine transfusion for mirror syndrome caused by parvovirus B19. Fetal Diagn her 6,o2013

Hachisuga K, Hidaka N, Fujita Y, et al: Can we predict neonatal thrombocytopenia in ofspring of women with idiopathic thrombocytopenic purpura? Blood 49(4):259,o2014

Hackney ON, Knudtson E], Rossi KQ, et al: Management of pregnancies complicated by anti-c isoimmunization. Obstet Gynecol 103:24, 2004 Heinonen S, Ruynamen M, Kirkinen P: Etiology and outcome of second trimes ter nonimmunological fetal hydrops. Scando] Obstet Gynecol 79: 15, 2000

Howard H, Mardew V, McFadyen I, et al: Consequences for fetus and neonate of maternal red cell allo-immunization. Arch Dis Child Fetal Neonat Ed 78:F62, 1998

Johnson ]A, MacDonald K, Clarke G, et al: No. 343-Routine non-invasive prenatal prediction of fetal RHO genotype in Canada: the time is here. ] Obstet Gynaecol Can 39(5):366, 2017

Kamphuis MM, Paridaans N, Porcelijn L, et al: Screening in pregnancy for fetal or neonatal alloimmune thrombocytopenia: systematic review. B]OG 117(1o1):1335,o2010

Kleihauer B, Braun H, Betke K: Demonstration of fetal hemoglobin in erythrocytes of a blood smear. Klin Wochenschr 35(12):637, 1957

Knight M, Pierce M, Allen 0, et al: The incidence and outcomes of fetomaternal alloimmune thrombocytopenia: a UK national study using three data sources. Br] HaematoIo152(4):460, 2011 Koelewijn ]M, Vrijkotte TG, van der Schoot CE, et al: Efect of screening for red cell antibodies, other than anti-D, to detect hemolytic disease of the fetus and newborn: a population study in the Netherlands. Transfusion 48:941,o2008

Lazar L, Harmath AG, Ban Z, et al: Detection of maternal deoxyribonucleic acid in peripheral blood of premature and mature newborn infants. Prenat Diagn 26(2):168, 2006

Liao C, Weio], Li Q, et al: Nonimmune hydrops fetal is diagnosed during the second half of pregnancy in Southern China. Fetal Diagn Ther 22(4):302,o2007 Liley A W: Liquor amnii analysis in management of pregnancy complicated by rhesus sensitization. Amo] Obstet GynecoIo82:1359, 1961 Lindenburg I, van Kamp I, van Zwet E, et al: Increased perinatal loss after intrauterine transfusion for alloimmune anaemia before 20 weeks of gestation. B]OG 120:847,o2013

Lindenburg IT, Smits-Wintjens VE, van Klink ]M, et al: Long-term neurodevelopmental outcome after intrauterine transfusion for hemolytic disease of the fetus/newborn: the LOTUS study. Amo] Obstet Gynecol 206:o141. e1,o2012

Livingston ]C, Malik M, Crombleholme TM, et al: Mirror syndrome: a novel approach to therapy with fetal peritoneal-amniotic shunt. Obstet Gynecol 110(2 Pt 2):540,o2007

Llurba E, Marsal G, Sanchez 0, et al: Angiogenic and antiangiogenic factors before and after resolution of maternal mirror syndrome. Ultrasound Obstet Gynecol 40(3):367, 2012

Lockwood q, Nadel AS, King ME, et al: A 32-year old pregnant woman with an abnormal fetal ultrasound study. Case 16-2009. N Englo] Med 360(21):2225,o2009

MacKenzie IZ, Roseman F, Findlayo], et al: he kinetics of routine antenatal prophylactic intramuscular injections of polyclonal anti-D immunoglobulin. B]OG 113:97, 2006

Mari G, Deter L, Carpenter RL, et al: Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. N Englo] Med 342:9, 2000

Martin ]A, Hamilton BE, Sutton PD, et al: Births: final data for 2003. Natl Vital Stat Rep 54(2): 1, 2005

Midgley DY, Hardrug K: The mirror syndrome. Euro] Obstet Gynecol Reprod Bioi 8:201, 2000

Moise K]: Fetal anemia due to non-Rhesus-D red-cell alloimmunization.

Semin Fetal Neonatal Med ,o2008

Moise K], Argoti PS: Management and prevention of red cell alloimmunization in pregnancy. A systematic review. Obstet Gynecol 120(5): 1132, 20o12

Moise K], Gandhi M, Boring NH, et al: Circulating cell-free DNA to determine the fetal RHD status in all three trimesters of pregnancy. Obstet Gynecol 128(6):1340, 2016

Neunert C, Lim W, Crowther M, et al: The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 11 (16):4190,o2011

Nicolaides KH, Warenski ]c, Rodeck CH: The relationship of fetal plasma protein concentration and hemoglobin level to the development of hydrops in rhesus isoimmunization. Am] Obstet Gynecol 152:341, 1985

Oepkes 0, Seaward PG, Vandenbussche FP, et al: Doppler ultrasonography versus amniocentesis to predict fetal anemia. N Engl] Med 355: 156, 2006

Pacheco LD, Berkowitz RL, Moise K], et a1: Fetal and neonatal alloimmune thrombocytopenia. A management algorithm based on risk stratification. Obstet Gynecol 118(5):1157,2011

Queenan ]T, Thomas PT, Tomai TP, et al: Deviation in amniotic fluid optical density at a wavelength of 450 nm in Rh isoimmunized pregnancies from 14 to 40 weeks' gestation: a proposal for clinical management. Am ] Obstet Gynecol 168:1370, 1993

Ratanasiri T, Komwilaisak R, Sittivech A, et al: Incidence, causes, and pregnancy outcomes of hydrops fetalis at Srinagarind Hospital, 1996-2005: a 10-year review.o] Med Assoc hai 92(5):594, 2009

Rink BD, Gonik B, Chmait RH, et al: Maternal hemolysis after intravenous immunoglobulin treatment in fetal and neonatal alloimmune thrombocytopenia. Obstet GynecoIo121o(2):47o1, 20o13

Risson DC, Davies MW, Williams BA: Review of neonatal alloimmune thrombocytopenia.o] Pediatr Child Health 48(9):816,o2012

Rubod C, Deruelle P, Le Gouef F, et al: Long-term prognosis for infants after massive fetomaternal hemorrhage. Obstet Gynecol 110(2 pt 1),o200

Sandler SG, Flegel WA, Westhof CM, et al: It's time to phase-in RHD genotyping for patients with a serological weak D phenotype. Transfusion 55(3):680,o2015

Sandler SG, Queenan ]T: A guide to terminology for Rh immunoprophylaxis.

Obstet Gynecol 130(3):633,o2017

Santo S, Mansour S, Thilaganathan B, et al: Prenatal diagnosis of non-immune hydrops fetalis: what do we tell the parents? Prenat Diagn 31: 186, 2011 Santolayao], Alley 0, Jafe R, et al: Antenatal classiication of hydrops fetalis.

Obstet 9:256, 1992

Society for Maternal-Fetal Medicine, Mari G, Norton ME, et a1: Society for Maternal-Fetal Medicine (SMFM) Clinical Guideline #8: he fetus at risk for anemia-diagnosis and management. Am] Obstet Gynecol 212(6):697, 20o15a

Society for Maternal-Fetal Medicine, Norton ME, Chauhan SP, et al: Society for Maternal-Fetal Medicine Clinical Guideline # : Nonimmune hydrops fetalis. Amo] Obstet Gynecol 212(2):127, 2015b

Sohan K, Carroll SG, De La Fuente S, et al: Analysis of outcome in hydrops fetalis in relation to gestational age at diagnosis, cause, and treatment. Acta Obstet Gynecol Scand 80(8):726, 2001

Storry]R, Castilho L, Daniels G, et a1: International Society of Blood Transfusion Working Party on red cell immunogenetics and blood group terminology: Cancun report (2012). Vox Sang 107(1): 90, 2014

Suwanrath-Kengpol C, Kor-anantakul 0, Suntharasaj T, et a1: Etiology and outcome of non-immune hydrops fetalis in southern Thailand. Gynecol Obstet Invest 59(3): 134, 2005

Tannirandorn Y, Rodeck CH: New approaches in the treatment of haemolytic disease of the fetus. Ballieres Clin Haematol 3(2):289, 1990

Tiller H, Kamphuis MM, Flodmark 0, et al: Fetal intracranial hemorrhages caused by fetal and neonatal alloimmune thrombocytopenia: an observational cohort study of 43 cases from an international multicentre registry. BM] 3:e002490, 20o13

Van den Veyver lB, Moise K]: Fetal RhO typing by polymerase chain reaction in pregnancies complicated by rhesus alloimmunization. Obstet Gynecol 88:1061, 1996

Van Kamp IL, lumper F], Bakkum RS, et al: he severity of immune fetal hydrops is predictive of fetal outcome after intrauterine treatment. Am ] Obstet Gynecol 185:668,o2001 Vivanti A, Benachi A, Huchet FX, et al: Diagnostic accuracy of fetal rhesus 0 genotyping using cell-free fetal DNA during the first trimester of pregnancy. Am] Obstet GynecoIo215:606.e1, 2016 Weiner CP, Pelzer GO, Heilskov], et al: he efect of intravascular transfusion on umbilical venous pressure in anemic fetuses with and without hydrops. Amo] Obstet Gynecol 161:1498, 1989

Weinstein L: Irregular antibodies causing hemolytic disease of the newborn: a continuing problem. Clin Obstet Gynecol 25(2):321, 1982

Welsh K], Bai Y, Education Committee of the Academy of Clinical Laboratory Physicians and Scientists: Pathology consultation on patients with a large h immune globulin dose requirement. Amo] Clin Pathol 145: 44, 2016

Woelfer B, Schuchter K, ]anisiw M, et al: Postdelivery levels of anti-D IgG prophylaxis in mothers depend on maternal body weight. Transfusion 44:512, 2004

Wylie B], D'Alton ME: Fetomaternal hemorrhage. Obstet Gynecol 115(5): 1039,o2010

Wyszynski OF, Carmen J, Cantor AB, et al: Pregnancy and birth outcomes among women with idiopathic thrombocytopenic purpura. ] Pregnancy 2016:8297407,o2016

Zimmerman R, Carpenter R] ]r, Durig P, et al: Longitudinal measurement of peak systolic velocity in the fetal middle cerebral artery for monitoring pregnancies complicated by red cell alloimmunization: a prospective multicenter trial with intention-to-treat. B]OG ):746,o2002

Zipursky A, Bhutani VK: Impact of Rhesus disease on the global problem of bilirubin-induced neurologic dysfunction. Semin Fetal Neonatal Med 20(1):2,o2015

Zwiers C, Lindenburg IT, Klumper F], et al: Complications of intrauterine intravascular blood transfusion: lessons learned ater 1678 procedures. Ultrasound Obstet Gynecol 50(2):180, 2017

MEDICAL THERAPY ....e.....e..e.... ...e......e...e..315

SURGICAL THERAPY ..e........e.... ...e....e..e..e... 318

OPEN FETAL SURGERY .....e....e..e.=...........e...319 FETOSCOPIC SURGERY ...........e.........e...... 321

PERCUTANEOUS PROCEDURESe. . .. .............. 324

EX-UTERO INTRAPARTUM TREATMENT ............e. 327

Minor grades of hydramnios rarey require active treatment. On the other han, when the abdomen is immensey distended and respiration is seriousy hampere, the termination of pregnancy is urgenty indicate. In such cases, the symptoms can be prompty relieved by peorating the membranes through the cervix, after which the amniotic luid drains of and labour pains set in.

-J. Whitridge Williams (1903) he concept of fetal therapy-even amniocentesis-was not considered by Williams in his irst edition. Aside from a few destructive procedures to aid vaginal delivery, any type of fetal treatment is not mentioned as even a remote possibility. Again, fast forward to this 25th edition, when interventions developed during the past three decades have dramatically altered the course of selected fetal anomalies and conditions. Reviewed in this chapter are fetal disorders amenable to treatment with either maternal medication or surgical procedures. he management of fetal anemia and thrombocytopenia is reviewed in Chapter 15, and treatment of some fetal infections is discussed in Chapters 64 and 65.

Fetal pharmacotherapy uses medications administered to the mother and then transported transplacentally to the fetus. s described here, it can be used to treat narray of serious conditions.

Fetal cardiac rhythm disturbances may be broadly categorized as tachyarrhythmias, heart ratesi> 180 beats per minute (bpm); bradyarrhythmia, heart rate < 110 bpm; and ectopy, typically premature atrial contractions. If these are identiied, fetal M-mode sonography is performed to measure the atrial and ventricular rates and to clariY the relationship between atrial and ventricular beats, thereby diagnosing the type of rhythm disturbance.

This is by far the most common arrhythmia and is identiied in 1 to 2 percent of pregnancies (Hahurij, 2011; Strasburger, 2010). Generally a benign inding, premature atrial contractions represent immaturity of the cardiac conduction system, and they typically resolve later in gestation or in the neonatal period. If the premature atrial contraction is conducted, it sounds like an extra beat when auscultated with handheld Doppler or fetoscope. However, premature atrial contractions are more commonly blocked and sound like dropped beats.

In general, premature atrial contractions are not associated with major structural cardiac abnormalities, although they sometimes occur with an atrial septal aneurysm. As shown in Figure 10-34 (p. 205), M-mode evaluation demonstrates that the dropped beat is a compensatory pause following the premature atrial contraction. They may occur as frequently as every other beat, known as blocked atrial bigeminy. This results in an auscultated fetal ventricular rate as low as 60 to 80 bpm. Unlike other causes of bradycardia, atrial bigeminy is benign and does not require treatment (Strasburger, 2010).

Approximately 2 percent of fetuses with premature atrial contractions are later found to have a supraventricular tachycardia (Copel, 2000; Srinivasan, 2008). Given the importance of identiying and treating supraventricular tachyarrhythmias, a fetus with premature atrial contractions is often monitored with heart rate assessment every 1 to 2 weeks until the ectopy resolves. This requires neither sonography nor fetal echocardiography, as the rate and rhythm may be easily ascertained with handheld Doppler.

The two most common tachyarrhythmias are supraventricular tachycardia (ST) and atrial lutter. SVT is characterized by an abrupt increase in the fetal heart rate to 180 to 300 bpm with 1: 1 atrioventricular concordance. he typical range is 200 to 240 bpm. ST may develop secondary to an ectopic focus or to an accessory atrioventricular pathway leading to a reentrant tachycardia. Atrial lutter is characterized by a much higher atrial rate, generally 300 to 500 bpm, with varying degrees of atrioventricular block. As a result, the ventricular rate in a fetus with atrial flutter may range from below normal to approximately 250 bpm (Fig. 16-1). In contrast, fetal sinus tachycardia typically presents with a gradual heart rate rise to a rate that is only slightly above normal. With this, readily discernible causes may be maternal fever or hyperthyroidism, or rarely, fetal anemia or infection.

If a fetal tachyarrhythmia is identified, it is important to determine whether it is sustained-deined as present for at least 50 percent of the time. It may be necessary to monitor the fetal heart rate for 12 to 24 hours upon initial detection, and then periodically to reassess (Srinivasan, 2008). Unsustained or intermittent tachyarrhythmias generally do not require treatment, provided that fetal surveillance is reassuring.

Sustained fetal tachyarrhythmia with ventricular rates exceeding 200 bpm impairs ventricular illing to a degree that the risk for hydrops is significant. With atrial flutter, lack of coordinated atrioventricular contractions may further compound this risk. Maternal administration of antiarrhythmic agents that cross the placenta may convert the rhythm to normal or lower the baseline heart rate to forestall heart failure. Therapy may require dosages at the upper end of the therapeutic adult range. Thus, a maternal electrocardiogram is obtained before and during therapy.

Antiarrhythmic medications most commonly used include digoxin, sotalol (Betapace), flecainide (Tambocor), and procainamide (Pronestyl). heir selection depends on the type of tachyarrhythmia as well as provider familiarity and experience with the drug. Traditionally, digoxin has been the initial preferred treatment, although it may poorly transfer to the fetus after hydrops has developed. Many centers now use lecainide or sotalol as first-line therapy Gaeggi, 2011; Shah, 2012). In many cases, additional agents are needed, particularly if hydrops has developed. SVT is generally more likely than atrial flutter to convert to a normal rhythm. With either arrhythmia, however, the overall neonatal survival rate now exceeds 90 percent (Ekman-Joelsson, 2015; Jaeggi, 2011; van der Heijden, 2013).

FIGURE 16-1 Atrial flutter. In this M-mode image at 28 weeks' gestation, calipers mark the ventricular rate, which is approximately 225 bpm. There are two atrial beats (A) for each ventricular beat (), such that the atrial rate is approximately 450 bpm with 2:1 atrioventricular block.

The most common etiology of pronounced fetal bradycardia is congenital heart block. Approximately 50 percent of cases occur in the setting of a structural cardiac abnormality involving the conduction system. hese include heterotaxy, in particular ltatrial isomerism; endocardial cushion deect; and less commonly corrected transposition of the great vessels (Srinivasan, 2008). he prognosis of heart block secondary to a structural cardiac anomaly is extremely poor, and fetal loss rates exceed 80 percent (Glatz, 2008; Strasburger, 2010).

In a structurally normal heart, 85 percent of atrioventricular block cases develop secondary to transplacental passage of maternal anti-SSA/Ro or anti-SSB/La antibodies (Buyon, 2009). Many of these women have, or subsequently develop, systemic lupus erythematosus or other connective tissue disease (Chap. 59, p. 1142). he risk of third-degree heart block with these antibodies is small-only about 2 percent. But, the risk may reach 20 percent if a prior infant has been afected. Immune-mediated congenital heart block confers a mortality rate of 20 to 30 percent, requires permanent pacing in two thirds of surviving children, and also poses a risk for cardiomyopathy (Buyon, 2009). If associated with efusions, bradyarrhythmias, or endocardial ibroelastosis, neonatal status may progressively worsen after birth (Cuneo, 2007).

Initial research eforts focused on maternal corticosteroid therapy to potentially reverse fetal heart block or forestall it.

Friedman and colleagues (2008, 2009) conducted a prospective multicenter trial of pregnancies with anti-SSA/Ro antibodies the PR Interval and Dexamethasone (PRIDE) study. Weekly sonographic surveillance was performed, and heart block was treated with maternal oral dexamethasone 4 mg daily. Unfortu nately, progression from second-to third-degree block was not prevented with maternal dexamethasone therapy, and third degree atrioventricular block was irreversible. In rare cases, there block. However, irst-degree block did not generally progress even without treatment. In a subsequent review of 156 preg nancies with isolated second-or third-degree fetal heart block, sion, need for pacemaker in the neonatal period, or overall sur vival rates (Izmirly, 2016). hus, dexamethasone use cannot be recommended for this indication.

More recent eforts have turned to potential therapy with hydroxychloroquine (Plaquenil), a mainstay of treatment for systemic lupus erythematosus (Chap. 59, p. 1142). In a multi center review of more than 250 pregnancies in women whose prior pregnancies had been complicated by neonatal lupus, recurrence of congenital heart block was signiicantly lower if the woman had been treated with hydroxychloroquine during pregnancy (Izmirly, 2012). Research in this area is ongoing.

Maternal terbutaline has also been given to increase the fetal heart rate in cases with sustained bradycardia of any cause in which the fetal heart rate is below 55 bpm. Reversal of hydrops with this therapy has been reported (Cuneo, 2007, 2010).

Several autosomal recessive enzyme deiciencies cause impaired fetal synthesis of cortisol from cholesterol by the adrenal cortex. his results in congenital adrenal hyperplasia (CAH). CAH is the most common etiology of androgen excess in females with 46,X disorders of sex development, formerly female pseudohermaphroditism (Chap. 3, p. 41). Lack of cortisol stimulates adrenocorticotrophic hormone (ACTH) secretion by the anterior pituitary, and the resulting androstenedione and testosterone overproduction leads to virilization of female fetuses. Sequelae may include formation of labioscrotal folds, persistence of a urogenital sinus, or even creation of a penile urethra and scrotal sac.

More than 90 percent ofCAH cases are caused by 21-hydroxylase deficiency, which is found in classic and nonclassic forms. he incidence of classic CAH approximates 1: 15000 births overall and is higher in selected populations. For example, it has been reported in approximately 1 :300 Yupik Eskimos (Nimkarn, 2010). Among those with classic CAH, 75 percent are at risk for salt-wasting adrenal crises and require postnatal treatment with mineralocorticoids and glucocorticoids to prevent hyponatremia, dehydration, hypotension, and cardiovascular collapse. The remaining 25 percent with classic CAH have the simple virilizing ype and also require glucocorticoid supplementation. As discussed in Chapter 32 (p. 614), all states mandate newborn screening for CAH.

he eicacy of maternal dexamethasone treatment to suppress fetal androgen overproduction and either obviate or ameliorate virilization of female fetuses has been recognized for more than 30 years (David, 1984; New, 2012). Prenatal corti costeroid therapy is considered successful in 80 to 85 percent of cases (Miller, 2013; Speiser, 2010). The alternative is con sideration of postnatal genitoplasty, a complex and somewhat controversial surgical procedure (Braga, 2009).

he tpical preventive regimen is oral dexamethasone given to the mother at a dosage of 20 Lg/kg/d-up to 1.5 mg per day, divided in three doses. The critical period for external genitlia development is 7 to 12 weeks' gestation, and treatment to pre vent virilization should be initiated by 9 wees-bore it is known whether the etus is at risk. Because this is n autosomal recessive condition, ffected females mke up only 1 in 8 at-risk conceptions.

Typically, carrier parents are identified after the birth of an afected child. Molecular genetic testing is clinically available, initially using sequence analysis of the CP21A2 gene, which encodes the 21-hydroxylase enzyme (Nimkarn, 2016). If this is uninformative, gene-targeted deletion/duplication analy sis is performed, and additional testing such as whole exome sequencing may be considered (Chap. 13, p. 272).

A goal of prenatal diagnosis is to limit dexamethasone expo sure in males and in unafected females. Prenatal diagnosis villi-at 10 to 12 weeks' gestation-or on amniocytes after 15 weeks. Cell-free DNA testing of maternal serum has potential to replace invasive tests such as chorionic villus sampling and amniocentesis for CAH (Chap. 13, p. 273). Determination of (Devaney, 2011). In the research setting, cell-free DNA testing using hybridization probes lanking the CP21A2 gene can be efective as early as 5617 weeks' gestation (New, 2014).

Maternal treatment with dexamethasone has become a topic of signiicant controversy. The Endocrine Society recommends that treatment be given only in the context of research protocols (Miller, 2013; Speiser, 2010). It should be noted that if therapy is initiated shortly before 9 weeks, the dose of dexamethasone used is not considered to have significant teratogenic potential because organogenesis of major organs has already taken place (McCullough, 2010). Ongoing concerns, however, focus on the potential efects of either excess endogenous androgens or excess exogenous dexamethasone on the developing brain. Although maternal dexamethasone has been used for many years to prevent virilization of female fetuses with CAH, longterm safety data are relatively limited.

Sonographically, this malformation is a well-circumscribed lung mass that may appear solid and echogenic or may have one or multiple variably sized cysts (Fig. 10-24, p. 199). Lesions with cysts � 5 mm are termed macrocystic, whereas microcystic lesions have smaller cysts or appear solid (Adzick, 1985). Also called congenital pulmonary airway malformation (CPAM), it represents a hamartomatous overgrowth of terminal bronchioles. Therapy for macrocystic congenital cystic adenomatoid malformation (CCAM) is discussed later (p. 324).

Occasionally, a microcystic CCAM may demonstrate rapid growth, generally between 18 and 26 weeks' gestation. he mass may become so large that it causes mediastinal shift, which may compromise cardiac output and venous return, resulting in hydrops (Cavoretto, 2008). A CCAM-volume ratio (CVR) has been used to quantiy size and risk for hydrops in these severe cases (Crombleholme, 2002). his ratio is an estimate of the CCAM volume (length X width X height X 0.52) divided by the head circumference. In a series of 40 pregnancies with microcystic CCAM, the mean CVR was 0.5 at 20 weeks' gestation, peaking in size at 1.0 at 26 weeks, followed by a pronounced decline prior to delivery (Macardle, 2016). A third of fetuses had no increase in mass size. In the absence of a dominant cyst, a CVR exceeding 1.6 is associated with a hydrops risk as high as 60 percent. However, CCAM growth resulting in hydrops develops in fewer than 2 percent of cases if the initial CVR is below 1.6 (Ehrenberg-Buchner, 2013; Peranteau, 2016). Importantly, a CVR in the range of 1.6 indicates that the mass essentially fills the thorax, and thus it is not unexpected that ascites or hydrops may develop.

If the CVR exceeds 1.6 or if signs of hydrops develop, corticosteroid treatment has been used in an efort to improve outcome. Regimens include dexamethasone-6.25 mg every 12 hours for four doses, or betamethasone-12.5 mg intramuscularly every 24 hours for two doses. Following a single course of corticosteroids, hydrops resolved in approximately 80 percent of cases, and 90 percent of treated fetuses survived (Loh, 2012; Peranteau, 2016). Recently, multiple courses of steroids-generally twohave been advocated for fetuses with large CCAM lesions and with persistent or worsening hydrops or ascites despite a single course of medication (Derderian, 2015; Peranteau, 2016).

Identification of fetal thyroid disease is rare and usually prompted by sonographic detection of a fetal goiter. If a goiter is found, determination of fetal hyper-or hypothyroidism is essential, and thyroid hormone levels may be measured in amnionic luid or fetal blood. Traditionally, fetal blood sampling, described in Chapter 14 (p. 294), is preferred to amniocentesis for guiding treatment, although data are limited (Abuhamad, 1995; Ribault, 2009). Goals of therapy are correction of the physiological abnormality and diminished goiter size. The goiter may compress the trachea and esophagus to such a degree that severe hydramnios or neonatal airway compromise may develop. Hyperextension of the fetal neck by a goiter can create labor dystocia.

Untreated fetal thyrotoxicosis may present with goiter, tachycardia, growth restriction, hydramnios, accelerated bone maturation, and even heart failure and hydrops (Huel, 2009; Peleg, 2002). The cause is usually maternal Graves disease with transplacental passage ofIgG thyroid-stimulating immunoglobulins. Fetal blood sampling may confirm the diagnosis (Duncombe, 2001; Heckel, 1997; Srisupundit, 2008). Conirmed fetal thyrotoxicosis is followed by maternal antithyroid treatment. During this, if the mother develops hypothyroidism, she is given supplementalilevothyroxine (Hui, 2011).

In a woman receiving medication for Graves disease, transplacental passage of methimazole or propylthiouracil may cause etal hypothyroidism (Bliddal, 2011 a). Other potential causes of fetal hypothyroidism resulting in goiter include transplacental passage of thyroid peroxidase antibodies, fetal thyroid dyshormonogenesis, and maternal overconsumption of iodine supple ments (Agrawal, 2002; Overcash, 2016).

Goitrous hypothyroidism may lead to hydramnios, neck hyperextension, and delayed bone maturation. If the mother is receiving antithyroid medication, discontinuation is generally recommended, along with intraamnionic levothyroxine injection. Numerous case reports describe intraamnionic levothyroxine treatment. However, optimal dosage and frequency have not been established, and reported dosages range from 50 to 800 �g every 1 to 4 weeks (Abuhamad, 1995; Bliddal, 2011b; Ribault, 2009) .

Also called maternaletal surgery, these procedures are ofered for selected congenital abnormalities in which the likelihood of fetal deterioration is so great that delaying treatment until after delivery would risk fetal death or substantially greater postnatal morbidity. Open fetal surgef) is a highly specialized intervention performed at relatively few centers in the United States and for only a few fetal conditions. Criteria for consideration of fetal surgery are listed in Table 16-1. In many cases, data regarding the safety and eicacy of these procedures are limited.

TABLE 16-1. Guiding Principles for Fetal Surgical Procedures

Accurate prenatal diagnosis for the defect is available, with staging if applicable

The defect appears isolated, with no evidence of other abnormality or underlying genetic syndrome that would significantly worsen survival or quality of life

The defect results in a high likelihood of death or irreversible organ destruction, and postnatal therapy is inadequate The procedure is technically feaSible, and a multidisciplinary team is in agreement regarding the treatment plan Maternal risks from the procedure are well documented and considered acceptable

There is comprehensive parental counseling It is recommended that there be an animal model for the defect and procedure

Data from Deprest, 201s0; Harrison, 1982; Vrecenak, 2013; Walsh, 201s1.

TABLE 16-2. Selected Fetal Abnormalities Amenable to Fetal Surgery

Twin-twin transfusion: laser of placental anastomoses Diaphragmatic hernia: fetal endoscopic tracheal occlusion

Posterior urethral valves: cystoscopic laser Congenital high airway obstruction: vocal cord laser Amnionic band release

Posterior-urethral valves/bladder outlet obstruction Pleural effusion: chylothorax or sequestration Dominant cyst in CCAM

Twin-reversed arterial perfusion (TRAP) sequence Monochorionic twins with severe anomaly in 1 twin Chorioangioma

Aortic or pulmonic valvuloplasty for stenosis Atrial septostomy for hypoplastic left heart with

EXIT-to-resection: resection of fetal thoracic or mediastinal mass

EXIT-to-extracorporeal membrane oxygenation (E(MO): congenital diaphragmatic hernia he Agency for Healthcare Research and Quality stresses that when considering fetal surgery, the overriding concern must be maternal and fetal safety. Accomplishing the fetal goals of the procedure is secondary (Walsh, 2011).

Some abnormalities amenable to fetal surgical treatment, antepartum or intrapartum, are shown in Table 16-2. An overview of these procedures, their indications, and complications is provided here to assist with initial patient evaluation and counseling. Additional content is also found in Cunningham and Gilstrap s Operative Obstetrics, 3rd edition.

These procedures require extensive preoperative counseling and multidisciplinary care. he mother must undergo general endotracheal anesthesia to suppress both uterine contractions and fetal responses. Using intraoperative sonographic guidance to avoid the placental edge, a low-transverse hysterotomy incision is made with a stapling device that seals the edges for hemostasis. To replace amnionic fluid losses, warmed luid is continuously infused into the uterus thorough a rapid infusion device. he fetus is gently manipulated to permit pulse oximetry monitoring and to establish venous access, in case luids or blood are emergently needed. The surgical procedure is then performed. After completion, the hysterotomy is closed and tocolysis begun. T ocolysis typically includes intravenous magnesium sulfate for 24 hours, oral indomethacin for 48 hours, and, at some centers, oral nifedipine until delivery (Wu, 2009). Prophylactic antibiotics are also administered and generally continued for 24 hours following the procedure. Cesarean delivery is needed later in gestation and for all future deliveries.

Morbidities associated with fetal surgery are well characterized. In a review of 87 open procedures, Golombeck and coworkers (2006) reported the following morbidities: pulmonary edema-28 percent, placental abruption-9 percent, blood transfusion-13 percent, premature rupture of membranes-52 percent, and preterm delivery-33 percent. Wilson and associates (2010) reviewed subsequent pregnancy outcomes following open fetal surgery and reported that 14 percent of women experienced uterine rupture and 14 percent had uterine dehiscence. Morbidities identiied in the recent Management of Myelomeningocele Study (MOMS) are shown in Table 16-3 (Adzick, 2011). Other potential risks include maternal sepsis and fetal death during or following the procedure, particularly if hydrops is present.

Even with postnatal repair, children with myelomeningocele generally have varying degrees of paralysis, bladder and bowel dys function, developmental delays, and brainstem dysfunction from the Arnold-Chiari II malformation (Chap. 10, p. 193). Damage is postulated to result from abnormal embryonic neurulation and from ongoing exposure of neural elements to amnionic luid (Adzick, 2010; Meuli, 1995, 1997). Fetal myelomeningocele meets the criteria listed in Table 16-1 and is the first nonlethal birth defect for which fetal surgery has been ofered (Fig. 16-2).

In preliminary reports, infants following antepartum defect repair were more likely to have reversal of the Arnold-Chiari II malformation and were less likely to require ventriculoperitoneal shunt placement (Bruner, 1999; Sutton, 1999). Spurred by this, the randomized, multicenter MOMS trial was conducted (Adzick, 2011). Criteria for trial participation included: (1) a singleton fetus at 19.0 to 25.9 weeks' gestation; (2) an upper myelomeningocele boundary between T1 and S 1 conirmed by fetal magnetic resonance (MR) imaging; (3) evidence of hindbrain herniation; and (4) a normal karyotype and no evidence of a fetal anomaly unrelated to the myelomeningocele. Women at risk for preterm birth or placental abruption, those with a contraindication to fetal surgery, and women with body mass indexi> 35 kg/m2 were excluded.

he MOMS indings demonstrated improved early childhood outcomes in the prenatal surgery cohort (see Table 16-3). Children who had undergone prenatal surgery were twice as likely to walk independently by 30 months. hey had signiicantly less hindbrain herniation and were only half

Composite developmental scorea,b

TABLE 16-3. Benefits and Risks of Fetal 68% 98% <0.001 40% 82% <0.001 149 ± 58 123 ± 57 0.007 64% 96% <0.001 20% 48% <0.001 42% 21% 0.01 6% 0 0.03 6% 0 0.03 9% 1% 0.03 21% 4% 0.001 34 ± 3 37 ± 1 <0.001 79% 15% <0.001 aEach primary outcome had two components. The perinatal death components of the primary outcomes as well as the Bayley Mental Development Index at 30 months did not differ between the two study cohorts.

bScore derived from Bayley Mental Development Index and difference between functional and anatomical level of lesion (30 months).

Data from Adzick, 201s1s.

FIGURE 16-2 Fetal myelomeningocele surgery. A. With the edges of both the laparotomy and hysterotomy incisions retracted, the skin around the defect is incised. Subsequently, the neural placode is sharply dissected from the arachnoid membrane. B. The dural membrane is reflected to the midline to cover the neural placode and is reapproximated using suture. In some cases a patch is needed (not shown). The fetal skin incision is subsequently sutured. Last, hysterotomy and laparotomy are then closed. (Reproduced with permission from Shamshirsaz AA, Ramin, SM, Belfort MA: Fetal therapy. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al: Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 201o7.) as likely to undergo ventriculoperitoneal shunting by the age of 1 year. A primary outcome was a composite score that was derived from the Bayley Mental Development Index and from the diference between the functional and anatomical level of the lesion at 30 months. This primary outcome was also signii cantly better in the prenatal surgery group.

When counseling prospective families, however, results are placed in perspective. For example, despite improvements in the proportion with independent ambulation, most children who received fetal surgery were not able to ambulate inde pendently, and nearly 30 percent were not able to ambulate at all. Prenatal surgery did not confer improvements in fetal or neonatal death rates or in the Bayley Mental Development

Index score at age 30 months. And, as shown in Table 16-3, surgery was associated with a small but significant risk for pla cental abruption and maternal pulmonary edema. Moreover, nearly half were delivered before 34 weeks, which signiicantly increased the risk for respiratory distress syndrome (Adzick, 201l). Long-term surveillance data have only recently become cele repair prior to the MOMS trial. At a median follow-up of 10 years, these children have higher rates of behavioral problems and adverse executive functioning compared with population norms (Danzer, 2016).

Since publication of the MOMS findings, fetal myelomeningocele surgery rates have grown. Expansion of centers ofering this procedure has raised concerns about the importance of training and ongoing experience, adherence to the MOMS research criteria, and need for a registry to ensure that future eforts have similar success rates (Cohen, 2014; Vrecenak, 20l3).

In the past, if hydrops developed in a fetus with a large pulmonary sequestration or cystic adenomatoid malformation without a dominant cyst, open fetal surgery with lobectomy was the only treatment available other than preterm delivery. Most thoracic masses are small and have a benign prognosis, and larger masses are generally treated with corticosteroids (p. 318). Fetal surgery is generally reserved for cases prior to 32 weeks in which hydrops is developing, and in selected cases, the survival rate following open lobectomy approximates 60 percent (Vrecenak, 20l3). Use of the ex-utero intrapartum treatment procedure in the treatment of fetal lung masses at delivery is discussed later on page 327.

This germ cell tumor has a prevalence of approximately 1 per 28,000 births (Derikx, 2006; Swamy, 2008). Sonographically, a sacrococcygeal teratoma (SCT) is a solid and/or cystic mass that arises from the anterior sacrum (Fig. 16-3). Fetal MR imaging can aid evaluation of the extent of the internal tumor component. he mass may grow rapidly, usually extending inferiorly and externally (Fig. 10-18, p. 196). Hydramnios is common, and hydrops may develop from high-output cardiac failure, either as a consequence of tumor vascularity or secondary to bleeding within the tumor and resultant anemia. Mirror syndrome-maternal preeclampsia developing along with fetal hydrops-may occur in this setting (Chap. 15, p. 312).

FIGURE 16-3 Fetal surgery for sacrococcygeal teratoma resection. Following laparotomy and hysterotomy, the caudal portion of the fetus has been delivered onto the surgical field. The tumor is held by the surgeon's hand. (Used with permission from Dr. Timothy M. Crombleholme.)

The perinatal mortality rate for cases of SCT diagnosed prenatally approximates 40 percent (Hedrick, 2004; Shue, 20l3). Poor prognostic factors include a solid component comprising more than 50 percent of the tumor mass and a tumor volume-to-fetal weight ratio (tumor volume divided by estimated fetal weight) exceeding 12 percent prior to 24 weeks' gestation (Akinkuotu, 2015). Fetal loss rates approach 100 percent if hydrops or placentomegaly develop (Vrecenak, 20l3). The group at the Children's Hospital of Philadelphia recommends consideration of open fetal surgery for SCT only in cases in which the tumor is completely external (Type I) and in which high cardiac output with early hydrops has developed in the second trimester (Vrecenak, 2013). For excision, hysterotomy is performed, and the external component is resected. he coccyx and any deep tumor are left in place for postnatal removal. Because tumor debulking interrupts the pathological vascular steal, normal fetal physiology may be restored.

As with open fetal surgeries, these procedures are performed at highly specialized centers, and some are considered investigational. To accomplish them, iberoptic endoscopes only 1 to 2 mm in diameter are used to penetrate the maternal abdominal wall, the uterine wall, and membranes. Instruments such as lasers fit through 3-to 5-mm cannulas that surround the endoscope. vIorbidities are generally lower than with open fetal surgery, but they still may be formidable, particularly if maternal laparotomy is required for access (Golombeck, 2006). Examples of some conditions treated by fetoscopy are listed in Table 16-2.

Indications and Technique. As discussed in Chapter 45 (p. 879), fetoscopic laser ablation of placental anastomoses is the preferred management for severe twin-twin transfusion syndrome (TTTS). It is generally performed between 16 and

FIGURE 16-4 Selective laser photocoagulation for twin-twin transfusion syndrome. The fetoscope is inserted into the recipienttwin sac and positioned over the vascular equator, which lies in between the two placental cord insertion sites. Arteriovenous anastomoses along the placental surface are individually photocoagulated using the laser. (Reproduced with permission from Shamshirsaz AA, Ramin, SM, Belfort MA: Fetal therapy. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al: Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 201o7.) 26 weeks' gestation for monochorionic-diamnionic twin pregnancies with stage II to stage IV TTTS. These categories of the Quintero Staging System are described in Chapter 45 (p. 879) (Quintero, 1999; Society for Maternal-Fetal Medicine, 2013).

For the procedure, a fetoscope is used to view the vascular equator that separates the placental cotyledons supplying each twin (Fig. 16-4). Arteriovenous anastomoses along the placental surface of the vascular equator are photocoagulated using a 600-�m diameter diode laser or a 400-�m neodymium:yttriumaluminum-garnet (Nd:YAG) laser (Fig. 16-5). he procedure is typically performed under epidural or local analgesia. At the end, amnioreduction is performed to decrease the single deepest pocket of amnionic luid to below 5 cm, and antibiotics are injected into the amnionic cavity.

With selective laser photocoagulation, anastomoses crossing between the twins along the vascular equator are individually coagulated (Ville, 1995). Unfortunately, residual anastomoses remain in up to a third of cases and may lead to TTTS recurrence or to the development of twin-anemia polycythemia sequence (TAPS). The latter is a feto-fetal transfusion characterized by large diferences in hemoglobin concentrations between a pair of monochorionic twins. To address these complications, the Solomon technique was developed. With this, after selective photocoagulation, the laser is used to coagulate the entire vascular equator, from one edge of the placenta to the other (Slaghekke, 2014a). he Solomon technique lowers the proportion of pregnancies with recurrent TTTS and TAPS in multiple trials. Also, placental dye-injection studies confirm a significant reduction in the number of residual anastomoses (Ruano, 2013; Slaghekke, 2014b).

Complications. Families should have reasonable expectations of procedural success and potential complications. Without treatment, the perinatal mortality rate for severe TTTS is 70 to 100 percent. Following laser therapy, the anticipated perinatal mortality rate approximates 30 to 50 percent, with a 5-to 20-percent risk for long-term neurological handicap (Society for Maternal-Fetal Medicine, 2013). Cystic periventricular leukomalacia and grade III to IV interventricular hemorrhage are identiied neonatally in up to 10 percent of laser-treated cases (Lopriore, 2006).

Procedure-related complications include preterm prematurely ruptured membranes in up to 25 percent, placental abruption in 8 percent, vascular laceration in 3 percent, amnionic band syndrome resulting from laser laceration of the membranes in 3 percent, and TAPS in 16 percent with photocoagulation and 3 percent with the Solomon modification (Habli, 2009; Robyr, 2006; Slaghekke, 2014b). Finally, most laser-treated TTTS pregnancies deliver before 34 weeks.

FIGURE 16-5 Fetoscopic photograph of laser photocoagulation for twin-twin transfusion syndrome. A. Vascular anastomoses (arrows) are shown before photocoagulation is performed. B. The ablation sites appear as blanched yellow-white areas (arrows). (Used with permission from Dr. Timothy M. Crombleholme.) he prevalence of congenital diaphragmatic hernia (CDH) is approximately 1 in 3000 to 4000 births, and the overall sur vival rate is 50 to 60 percent. Associated anomalies occur in 40 percent of cases and confer a considerably lower survival rate.

he main causes of mortality among those with isolated CDH are pulmonary hypoplasia and pulmonary hypertension. And, the major risk factor is liver herniation, which complicates at least half of cases and is associated with a 30-percent reduction in the survival rate (vfullassery, 2010, Oluyomi-Obi, 2017).

Because of maternal and fetal risks associated with fetal surgical intervention, eforts have focused on identiying those least likely to survive with postnatal therapy alone. Fetuses with associated anomalies are typically excluded, as are those with out liver herniation. Prediction is further hampered because of improvements in neonatal care for newborns with CDH. These include permissive hypercapnia, "gentle ventilation" to avoid barotrauma, and delayed surgery.

Lung-to-Head Ratio. This sonographic ratio was developed to improve prediction of survival in fetuses with isolated leftsided CDH diagnosed before 25 weeks' gestation (Metkus, 1996). he lung-to-head ratio (LHR) is a measurement of the right lung area, taken at the level of the four-chamber view of the heart, divided by the head circumference (Fig. 10-23, p. 198). Investigators found that the survival rate was 100 percent if the LHR wasi> 1.35, and there were no survivors if it was <0.6. Nearly three fourths of pregnancies had values between 0.6 and 1.35, and prediction was diicult in this large group because the overall survival rate approximated 60 percent (Metkus, 1996).

As of 2017, trials underway have selected a threshold LHR of < 1.0 or an observed-to-expected LHR <25 percent for study inclusion. An observed LHR is obtained sonographically from the afected fetus, whereas rhe expected LHR is an established reference value from normal fetuses (Peralta, 2005). In a recent metaanalysis, the odds ratio for survival with an LHR < 1.0 was only 0.14 (Oluyomi-Obi, 2017). Similarly, with an observed-to-expected LHR <25 percent, survival rates ranged from 13 to 30 percent. In contrast, an observed-to-expected LHR > 35 percent was associated with survival rates ranging from 65 to 88 percent.

Magnetic Resonance Imaging. This has been used to estimate the total volume of lung tissue, both ipsilateral and contralateral to the diaphragmatic hernia, which may then be compared with a gestational age-matched reference. Mayer and coworkers (2011) performed a metaanalysis of 19 studies involving more than 600 pregnancies in which isolated CDH was evaluated with feral MR imaging. Factors signiicantly associated with neonatal survival included the side of the defect, total fetal lung volume, observed-to-expected lung volume, and fetal liver position.

Fetal MR imaging has also been used to quantiy the volume of herniated liver (Fig. 10-57, p. 219). Two reasons underlie the rationale for assessing liver volume. First, liver herniation is perhaps the strongest predictor of outcome in fetuses with isolated CDH. Second, liver volume might be a more reliable predictor because lungs are inherently more compressible than liver. Indeed, these MR parameters-lung volumes and degree of liver herniation-correlate well with postnatal survival rates and may be more useful predictors than sonographic parameters (Bebbington, 2014; Ruano, 2014; Worley, 2009).

Tracheal Occlusion. Early attempts to treat severe diaphragmatic herniation used open fetal surgery to reposition the liver into the abdomen, which unfortunately kinked the umbilical vein and led to fetal demise (Harrison, 1993). Knowledge that lungs normally produce luid and that fetuses with upper airway obstruction develop hyperplastic lungs formed the rationale for tracheal occlusion. The idea was to "plug the lung until it grows" (Hedrick, 1994). Initial eforts focused on occluding the trachea with an external clip (Harrison, 1993). Subsequently, a detachable silicone balloon was placed within the trachea endoscopically (Fig. 16-6).

The balloon technique-termed etal endoscopic tracheal occlusion (FETO)-uses a 3-mm operating sheath and fetoscopes as small as 1 mm (Depresr, 2011; Ruano, 2012). he procedure is generally performed between 27 and 30 weeks' gestation, with the goal of removing the balloon at approximately 34 weeks, either through a second fetoscopic procedure or by ultrasound-guided puncture Gimenez, 2017). If these are unsuccessful, the balloon is removed during an ex-utero intrapartum treatment procedure at delivery (p. 327).

FIGURE 16-6 Fetoscopic tracheal occlusion (FETO). The endoscope enters the fetal oropharynx and advances down the trachea. Inset: The balloon is inflated to occlude the trachea, and then the endoscope is removed. (Reproduced with permission from Shamshirsaz AA, Ramin, SM, Belfort MA: Fetal therapy. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al: Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 2017.)

In 2003, a randomized trial of the FETO procedure in pregnancies with isolated CDH, liver herniation, and LHR < 1.4 did not identiY a benefit from fetal therapy (Harrison, 2003). Survival rates 90 days after birth were unexpectedly high in both groups and approximated 75 percent. Following this study, however, enthusiasm for the technique continued, particularly outside the United States. Using a lower LHR threshold of 1.0 in addition to liver herniation as prerequisites for inclusion, signiicantly higher postnatal survival rates have been reported. Rates improved from <25 percent with postnatal therapy to approximately 50 percent with FETO Gani, 2009; Ruano, 2012). In a recent metaanalysis of five trials that included 21i1 pregnancies, those treated with FETO were 13 times more likely to survive (Al-Maary, 2016). At present, FETO is available in the United States only in research trials.

After publication of the MOMS indings, research eforts focused on whether maternal morbidities associated with open fetal myelomeningocele repair might be mitigated if the procedure was accomplished endoscopically. Araujo Junior and associates (2016) conducted a systematic review that included 456 open cases and 84 endoscopic surgeries. he endoscopic procedures were generally performed by inserting instruments through the maternal abdominal wall and then through the uterine wall, with partial carbon dioxide insuiation of the uterus. he rate of maternal myometrial dehiscence or attenuation was only 1 percent following endoscopy compared with 26 percent following open procedures. However, endoscopy was associated with significantly increased rates of preterm delivery before 34 weeks-80 versus 45 percent, and of perinatal mortality-14 versus 5 percent.

Belfort and colleagues (2017) recently described their outcomes in 22 pregnancies with fetal myelomeningocele using a technique in which the maternal abdomen was opened, the uterus exteriorized, and the procedure then performed endoscopically using warmed carbon dioxide insuiation. In contrast with earlier endoscopic reports, most treated pregnancies were delivered at term, with no perinatal losses. Further, the proportion of infants requiring hydrocephalus treatment prior to 1 year of age-approximately 40 percent-was similar to that with open fetal surgery in the MOMS trial (Adzick, 2011; Belfort, 2017). Research eforts in this area will undoubtedly continue.

Sonographic guidance can be used to permit therapy with a shunt, radiofrequency ablation needle, or angioplasty catheter. With these procedures, desired instruments cross the maternal abdominal wall, uterine wall, and membranes to reach the amnionic cavity and fetus. Risks include maternal infection, preterm labor or prematurely ruptured membranes, and fetal injury or loss.

A shunt placed from the fetal pleural cavity into the amnionic cavity may be used to drain pleural luid (Fig. 16-7). A large efusion may cause a significant mediastinal shift, resulting in pulmonary hypoplasia or in heart failure and hydrops. he most common etiology of a primary efusion is chylothoraxcaused by lymphatic obstruction. Pleural efusions may also form secondary to congenital viral infection or aneuploidy, or they may be associated with a malformation such as pulmonary

FIGURE 16-7 Thoracoamnionic shunt placement. A. A large, right-sided fetal pleural effusion (asterisks) and ascites were identified at 18 weeks' gestation. The effusion was drained but rapidly reaccumulated. The xanthochromic fluid contained 95-percent lymphocytes, consistent with chylothorax. B. A double-pigtail shunt (arrow) was inserted under ultrasound gUidance. Following shunt placement, the efusion and ascites resolved.

FIGURE 16-8 Vesicoamnionic shunt placement. A. After amnioinfusion is performed, a trocar is inserted into the distended fetal bladder under sonographic guidance. The pigtail catheter is threaded into the trocar. B. The double-pigtail shunt has been deployed down the trocar, and the trocar has been removed. The distal end of the shunt is coiled within the fetal bladder, and the proximal end is draining into the amnionic cavity. (Reproduced with permission from Shamshirsaz AA, Ramin, SM, Belfort MA: Fetal therapy. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al: Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 201o7.) sequestration. Yinon and associates (2010) reported aneuploidy cent of cases.

Typically, the efusion is first drained using a 22-gauge needle with sonographic guidance. Tests for aneuploidy and infection are performed, as well as a cell count. A pleural-fluid cell count with greater than 80-percent lymphocytes, in the absence of infection, is diagnostic of chylothorax. If the luid reaccumulates, a trocar and cannula may be inserted through the fetal chest wall, and a double-pigtail shunt may be placed to drain the efusion. If the efusion is right-sided, the shunt is placed in the lower third of the chest to permit maximum expansion of the lung. If left-sided, the shunt is placed along the upper axillary line to allow the heart to return to normal position (Mann, 2010). he overall survival rate is 70 percent, and that for hydropic fetuses approximates 50 percent (Mann, 2010; Yinon, 2010). Shunt displacement into the amnionic cavity is not uncommon. If the shunt remains in place, it must be clamped immediately upon delivery of the newborn to avoid pneumothorax.

Shunts can also drain a dominant cyst in fetuses with macrocystic congenital cystic adenomatoid maormation. However, cysts rarely are large enough to pose a risk for hydrops or pulmonary hypoplasia. Shunt placement may improve survival to 90 percent in the absence of hydrops and to more than 75 percent with hydrops (Liwinska, 2017).

Vesicoamnionic shunts are used in selected fetuses with severe bladder-outlet obstruction in which diminished amnionic fluid portends a grim prognosis (Fig. 16-8). Distal obstruction of the urinary tract occurs more often in male fetuses. The most common etiology is posterior urethral valves, followed by urethral atresia and by prune bely syndrome, which is also called Eagle-Barrett syndrome. Sonographic indings include dilation of the bladder and proximal urethra, termed the "keyhole" sign, along with bladder wall thickening (Fig. 10-45, p. 210). Associated oligohydramnios before midpregnancy leads to pulmonary hypoplasia. Unfortunately, postnatal renal function may be poor even when amnionic fluid volume is normal.

Evaluation includes a careful search for concurrent anomalies, which may coexist in 40 percent of cases, and for aneuploidy, which has been reported in 5 to 8 percent of cases (Hayden, 1988; Hobbins, 1984; Mann, 2010). Fetal urine sampled at vesicocentesis may be used to perform genetic studies. As with other structural fetal abnormalities, chromosomal micro array analysis is recommended. Because visualization may be limited due to lack of amnionic fluid, counseling should include the increased likelihood that associated anomalies may be missed sonographically.

Potential candidates are fetuses without other severe anomalies or genetic syndromes and without sonographic features that confer poor prognosis, for example, renal cortical cysts. herapy is generally ofered only if the fetus is male, because in females, the underlying anomaly tends to be even more severe. Serial bladder drainage-vesicocentesis-performed under sonographic guidance at approximately 48-hour intervals is used to evaluate fetal urine electrolyte and protein content. Fetal urine is normally hypotonic due to tubular resorption of sodium and chloride, whereas isotonic urine in the setting of obstruction suggests renal tubular damage. Serial assessment permits classiication of the renal prognosis as good or poor and helps guide candidate selection (Table 16-4).

TABLE 16-4. Fetal Urinary Analyte Values with Bladder Outlet Obstruction

Good or poor prognosis is based on values from serial gestation, using the last specimen obtained.

Data from Mann, 2010.

Shunt placement allows urine to drain from the bladder into the amnionic cavity. When successful, this often prevents pulmonary hypoplasia, however, renal function is not reliably preserved. Before shunting, amnioinfusion of warmed lactated Ringer solution is generally performed to aid catheter placement. Amnioinfusion also aids sonographic evaluation of fetal anatomy. A small trocar and cannula are then inserted into the fetal bladder under sonographic guidance. he shunt is placed as low as possible within the bladder to avoid dislodgement after bladder decompression. A double-pigtail catheter is used. The distal end lies within the fetal bladder, and the proximal end drains into the amnionic cavity.

Complications include displacement of the shunt out of the fetal bladder in up to 40 percent of cases, urinary ascites in about 20 percent, and development of gastroschisis in 10 percent (Freedman, 2000; Mann, 2010). Preterm delivery is common, and neonatal survival rates range from 50 to 90 percent (Biard, 2005; Walsh, 201l). A third of surviving children have required dialysis or renal transplantation, and almost half have respiratory problems (Biard, 2005). In one randomized trial, vesicoamnionic shunt placement was compared with conservative management in 31 cases (Morris, 2013). hose receiving shunts had higher survival rates. However, only two children had normal renal function at age 2 years.

With this procedure, high-frequency alternating current is used to coagulate and desiccate tissue. Radiofrequency ablation (RFA) has become a favored modality for treatment of twin-reversed arterial peusion (TAP) sequence, also known as acardiac twin (Chap. 45, p. 880). Without treatment, the mortality rate for the normal or pump twin in severe TRAP sequence exceeds 50 percent. he procedure is also used for selective termination with other monochorionic twin complications (Bebbington, 2012).

Under sonographic guidance, a 17-to 19-9auge RF A needle is directed into the base of the umbilical cord of the acardiac twin and inserted into its abdomen. After a 2-cm area of coagulation is achieved, color Doppler sonography is applied to veriy absent low into the acardius. In several centers, survival rates for the normal twin following RF A have signiicantly improved (Lee, 2007; Livingston, 2007). RF A was performed at approximately 20 weeks' gestation in 98 pregnancies with TRAP sequence reported by the North American Fetal Therapy Network (NAFTNet). The median gestational age at delivery was 37 weeks, and the neonatal survival rate was 80 percent. The major complication was prematurely ruptured membranes and pre term birth. Twelve percent were delivered at approximately 26 weeks (Lee, 2013).

RFA has generally been ofered for TRAP sequence when the volume of the acardiac twin is large. In the NFTNet series cited above, the median size of the acardius relative to the pump twin was 90 percent (Lee, 2013). Considering procedure-related risks, expectant management with close fetal surveillance is instead considered if the estimated weight of the acardius is below 50 percent of the pump twin Jelin, 2010). Finally, acardiac twins are more likely to complicate monoamnionic gestations. In one recent series, pump twin survival following RFA was 88 percent in monochorionic diamnionic pregnancies but only 67 percent in monoamnionic pregnancies (Sugibayashi, 2016).

Selected fetal cardiac lesions may worsen during gestation, further complicating or even obviating options for postnatal repair. Severe narrowing of a cardiac outflow tract may result in progressive myocardial damage in utero, and a goal of fetal intervention is to permit muscle growth and preserve ventricular function (Walsh, 2011). These innovative procedures include aortic valvuloplasy for critical aortic stenosis; atrial septostomy for hypoplastic left heart syndrome with intact interatrial septum; and pulmonary valvuloplasy for pulmonary atresia with intact interventricular septum.

Fetal aortic valvuloplasty is the most commonly performed cardiac procedure, accounting for 75 percent of cases reported by the International Fetal Cardiac Intervention Registry (MoonGrady, 2015). It is ofered for selected cases of critical aortic stenosis in which the left ventricle is either normal sized or dilated. he goal is to prevent progression to hypoplastic left heart and to permit postnatal biventricular repair (McElhinney, 2009). Under sonographic guidance, an I8-gauge cannula is inserted through uterus and fetal chest wall and into the left ventricle. Although the procedure is ideally performed percutaneouslythrough the maternal abdominal wall-laparotomy may be needed if the fetal position is unfavorable. The cannula tip is positioned in front of the stenotic aortic valve, and a 2.5-to 4.5-mm balloon catheter is then guided into the aortic annulus and inlated. Fetal bradycardia requiring treatment complicates a third of cases, and hemopericardium requiring drainage afects approximately 20 percent (Moon-Grady, 2015).

From the first 100 cases at Boston Children's Hospital, 85 children survived, 38 of whom achieved biventricular circulation (Freud, 2014). Despite these successes, the mortality rate and risk for neurodevelopmental impairment in childhood appear to be similar to cases treated with postnatal repair (Laraja, 2017; Moon-Grady, 2015).

Fetal atrial septostomy, also using a percutaneous balloon catheter, is ofered in select cases of hypoplastic left heart with an intact or highly restrictive interatrial septum. This condition has a postnatal mortality rate of nearly 80 percent (Glantz, 2007). In an efort to ensure patency, atrial septal stent placement has

TABLE 16-5. Components of the Ex-Utero Intrapartum Treatment (EXIT) Procedure

Comprehensive preoperative evaluation: specialized sonography, fetal echocardiography, magnetic resonance imaging,

Uterine relaxation with deep general anesthesia and tocolysis

Intraoperative sonography to confirm placental margin and fetal position and to visualize vessels at uterine entry Placement of stay-sutures followed by use of uterine stapling device to decrease uterine entry bleeding

Maintenance of uterine volume during the procedure via continuous amnioinfusion of warmed physiological solution to help prevent placental separation Delivery of the fetal head, neck, and upper torso to permit access as needed Fetal injection of intramuscular vecuronium, fentanyl, and atropine Fetal peripheral intravenous access, pulse oximeter, and cardiac ultrasound Following procedure, umbilical lines placed prior to cord clamping Uterotonic agents administered as needed

Data from Moldenhauer, 2013.

also been performed. Of37 cases of atrial septostomy, survival to hospital discharge was almost 50 percent (Moon-Grady, 2015).

Fetal pulmonary valvuloplasty has been ofered in cases of pulmonary atresia with intact interventricular septum to prevent development of hypoplastic right heart syndrome. Although success is achieved in approximately two thirds of cases, it is not yet clear whether outcomes are improved compared with standard postnatal repair (Arzt, 2011; McElhinney, 2010).

This procedure allows the fetus to remain perfused by the placenta after being partially delivered, so that lifesaving treatment can be performed before completing the delivery. The technique was irst developed to obtain an airway with fetal tumors involving the oropharynx and neck (Catalano, 1992; Kelly, 1990; Langer, 1992). An ex-utero intrapartum treatment (EXIT) procedure is performed by a multidisciplinary team, which may include an obstetrician, maternal-fetal medicine specialist, pediatric surgeon(s), pediatric otolaryngologist, pediatric cardiologist, anesthesiologists for the mother and fetus, and neonatologists, as well as specially trained nursing personnel. Components of the procedure are shown in Table 16-5.

Selected indications are listed in Table 16-2. EXIT is the preferred procedure for intrapartum management oflarge venolymphatic malformations of the neck such as the one shown in Figure 16-9. At the Children's Hospital of Philadelphia, criteria for EXIT with a cervical venolymphatic malformation include compression, deviation, or obstruction of the airway by the mass, and also involvement of the floor of the mouth (Laje, 2015). In a review of 112 pregnancies with fetal cervical venolymphatic malformations, only about 10 percent met these criteria. Other indications for EXIT include severe micrognathia and congenital high airway obstruction sequence (CHAOS), which are discussed in Chapter 10 (Figs. 10-20 and 10-26, p. 197). Criteria for an EXIT procedure for micrognathia include a fetal jaw measurement below the 5th percentile along with indirect evidence of obstruction, such as hydramnios, an absent stomach bubble, or glossoptosis (Morris, 2009b). Case selection for EIT procedures is generally based on fetal 1R imaging findings (Chap. 10, p. 219).

FIGURE 16-9 Ex-utero intrapartum treatment (EXID procedure for a venolymphatic malformation. A. Upon delivery of the head, placental circulation was maintained and an airway was established over the course of 20 minutes by a team of pediatric subspecialists that included a surgeon, anesthesiologist, and otolaryngologist. B. Following a controlled intubation, the fetus was ready for delivery and transfer to the neonatal intensive care unit team. (Used with permission from Drs. Stacey Thomas and Patricia Santiago-Munoz.)

In some cases, an EIT procedure has been used as a bridge to other procedures. For example, resection of large thoracic masses may be accomplished by fetal thoracotomy performed with intact placental circulation. In a series of 16 fetuses with CCM volume ratiosi> 1.6 or hydrops, all of whom had mediastinal compression, Cass and colleagues (2013) reported that nine infants undergoing EIT-to-resection survived. In contrast, there were no survivors with urgent postnatal surgery alone. Similarly, Moldenhauer (2013) reported that 20 of 22 newborns treated with EXIT -to-resection for lung masses survived. he EIT procedure has also been used as a bridge to extracorporeal membrane oxygenation-EIT-to-ECMO-in pregnancies with severe congenital diaphragmatic hernia. However, it has not been found to clearly confer survival benefit in such cases (Morris, 2009a; Shieh, 2017; Stofan, 2012).

Counseling prior to an EIT procedure includes procedurerelated risks such as hemorrhage from placental abruption or uterine atony, need for cesarean delivery in future pregnancies, higher risk for subsequent uterine rupture or dehiscence, possible need for hysterectomy, and fetal death or permanent neonatal disability. Compared with cesarean delivery, the EIT procedure is associated with greater blood loss, a higher incidence of wound complications, and a longer operating time-approximately 40 minutes longer depending on the procedure (Noah, 2002).

Abuhamad Z, Fisher DA, Warsof SL, et al: Antenatal diagnosis and treatment of fetal goitrous hypothyroidism: case report and review of the literature. Ultrasound Obstet Gynecol 6:368, 1995

Adzick NS: Fetal myelomeningocele: natural history, pathophysiology, and in utero intervention. Semin Fetal Neonatal Med 15(1):9,o2010

Adzick NS, Harrison MR, Glick PL, et al: Fetal cystic adenomatoid malformation: prenatal diagnosis and natural history. ] Pediatr Surg 20:483, 1985 Adzick NS, Thon A, Spong CY, et al: A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Englo] Med 364(11):993, 2011 Agrawal P, Ogilvy-Stuart A, Lees C: Intrauterine diagnosis and management of congenital goitrous hypothyroidism. Ultrasound Obstet GynecoIo19:501, 2002

Akinkuotu Ae, Coleman A, Shue E, et al: Predictors of poor prognosis in prenatally diagnosed sacrococcygeal teratoma: a multiinstitutional review. ] Pediatr Surg 50(5):771,o2015

Al-Maary ], Eastwood MP, Russo FM, et al: Fetal tracheal occlusion for severe pulmonary hypoplasia in isolated congenital diaphragmatic hernia. A systematic review and meta-analysis of survival. Ann Surg 264(6):929,o2016

Araujo Junior A, Eggink A], van den Dobbelsteeno], et al: Procedure-related complications of open vs endoscopic fetal surgery for treatment of spina bifida in an era of intrauterine myelomeningocele repair: systematic review and meta-analysis. Ultrasound Obstet GynecoIo48(2):151, 2016

Arzt W, Tulzer G: Fetal surgery for cardiac lesions. Prenat Diagn 31 ( ):695, 2011 Bebbington M, Victoria T, Danzer E, et al: Comparison of ultrasound and magnetic resonance imaging parameters in predicting survival in isolated left-sided congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 43(6):670,o2014 Bebbington MW, Danzer E, Moldenhauer ], et al: Radiofrequency ablation vs bipolar umbilical cord coagulation in the management of complicated monochorionic pregnancies. Ultrasound Obstet GynecoIo40(3):319, 2012 Belfort MA, Whitehead E, Shamshirsaz A, et al: Fetoscopic open neural tube defect repair. Development and refinement of a two-port carbon dioxide insuiation technique. Obstet Gynecol 129(4):734,o201 Biard JM, Johnson MP, Carr Me, et al: Long-term outcomes in children treated by prenatal vesicoamniotic shunting for lower urinary tract obstruction. Obstet Gynecol 106:503,o2005

Bliddal S, Rasmussen AK, Sundberg K, et al: Antithyroid drug-induced fetal goitrous hypothyroidism. Nat Rev Endocrinol :396,o201o1a Bliddal S, Rasmussen AK, Sundberg K, et al: Graves' disease in two pregnancies complicated by fetal goitrous hypothyroidism: successful in utero treatment with levothyroxine.ohyroid 21(1):75, 2011b Braga LH, Pippi Salle ]L: Congenital adrenal hyperplasia: a critical reappraisal of the evolution of feminizing genitoplasty and the controversies surrounding gender reassignment. Eur] Pediatr Surg 19:203, 2009 Bruner JP, Tulipan N, Paschall L, et al: Fetal surgety for myelomeningocele and the incidence of shunt-dependent hydrocephalus. ]AMA 282(19): 1819, 1999 Buyon JP, Clancy M, Friedman DM: Autoimmune associated congenital heart block: integration of clinical and research clues in the management of the maternal/fetal dyad at risk. ] Intern Med 265(6):653, 2009

Cass DL, Olutoye 00, Cassady CI, et al: EXlT-to-resection for fetuses with large lung masses and persistent mediastinal compression near birth. ] Pediatr Surg 48(1):138,o2013

Catalano P], Urken ML, Alvarez M, et al: New approach to the management of airway obstruction in "high risk" neonates. Arch Otolaryngol Head Neck Surg 118:306, 1992

Cavoretto P, Molina F, Poggi S, et al: Prenatal diagnosis and outcome of echogenic fetal lung lesions. Ultrasound Obstet Gynecol 32:769, 2008

Cohen AR, Coutoo], Cummings JJ: Position statement on fetal myelomeningocele repair. Amo] Obstet GynecoIo21O(2):107, 2014 Copel JA, Liang RI, Demasio K, et al: he clinical significance of the irregular fetal heart rhythm. Am] Obstet Gynecol 182:813, 2000 Crombleholme TM, Coleman B, Hedrick H, et al: Cystic adenomatoid volume ratio predicts outcome in prenatally diagnosed cystic adenomatoid malformation of the lung.] Pediatr Surg 37(3):331,o2002 Cuneo BF, Lee M, Roberson 0, et al: A management strategy for fetal immune-mediated atrioventricular block. ] Matern Fetal Neonatal Med 23(12):1400,o2010 Cuneo BF, Zhao H, Strasburger ]F, et al: Atrial and ventricular rate response and patterns of heart rate acceleration during maternal-fetal terbutaline treatment offetal complete heart block. Am J Cardiol 100(4):661,o2007

Danzer E, homas NH, homas A, et al: Long-term neurofunctional outcome, executive functioning, and behavioral adaptive skills following fetal myelomeningocele surgery. Am] Obstet GynecoI214(2):269.e.l, 2014 David M, Forest MG: Prenatal treatment of congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency.] Pediatr 105(5):799, 1984 Deprest J, Nicolaides K, Done E, et al: Technical aspects of fetal endoscopic tracheal occlusion for congenital diaphragmatic hernia. ] Pediatr Surg 46(1): 22,o201o1 Deprest ]A, Flake A W, Gratacos E, et al: he making of fetal surgery. Prenat Diagn 30(7):653,o2010 Derderian SC, Coleman M, ]eanty C, et al: Favorable outcomes in high-risk congenital pulmonary airway malformations treated with multiple courses of maternal betamethasone. J Pediatr Surg 50(4):515,o2015 Derikx ]P, De Backer A, Van De Schoot L, et al: Factors associated with recurrence and metastasis in sacrococcygeal teratoma. Br ] Surg 93: 1543, 2006 Devaney SA, .Palomaki GE, Scott JA, et al: Noninvasive fetal sex determination using cell-free fetal DNA: a systematic review and meta-analysis. JAMA 306(6)o:627,o20o11 Duncombe GJ, Dickinson ]E: Fetal thyrotoxicosis after maternal thyroidectomy. Aust N Z J Obstet GynaecoIo41(2):224, 2001 Ehrenberg-Buchner S, Stapf M, Berman DR, et al: Fetal lung lesions: can we start to breathe easier? Am J Obstet Gynecol 208(2): 15l.el, 2013 Ekman-]oelsson B-M, Mellander M, Lagnefeldt L, et al: Foetal tachyarrhythmia treatment remains challenging even if the vast majority of cases have a favourable outcome. Acta Paediatr 104(11):1090, 2015 Freedman AL, Johnson MP, Gonzalez R: Fetal therapy for obstructive uropathy: past, present ... future? Pediatr N ephrol 14: 167, 2000 Freud LR, McElhinney DB, Marshall AC, et al: Fetal aortic valvuloplasty for evolving hypoplastic left heart syndrome. Postnatal outcomes of the irst 100 patients. Circulation 130(8):638,o2014 Friedman OM, Kim MY, Copel JA, et al: Prospective evaluation of fetuses with autoimmune associated congenital heart block followed in the PR interval and dexamethasone evaluation (PRIDE) study. Amo] Cardiol 103(8): 11 02, 2009 Friedman OM, Kim MY, Copel ]A: Utility of cardiac monitoring in fetuses at risk for congenital heart block: the PR Interval and Dexamethasone (PRIDE) Prospective Study. Circulation 117:485, 2008 Glantz ]A, Tabbutt S, Gaynor ]W, et al: Hypoplastic left heart syndrome with atrial level restriction in the era of prenatal diagnosis. Ann horac Surg 84:1633,o2007 Glatz Ae, Gaynor ]W, Rhodes A, et al: Outcome of high-risk neonates with congenital complete heart block paced in the first 24 hours after birth. J Thorac Cardiovasc Surg 136(3):767, 2008

Golombeck K, Ball RH, Lee H, et al: Maternal morbidity after maternal-fetal surgery. Am J Obstet Gynecol 194:834,o2006

Habli M, Bombtys A, Lewis 0, et al: Incidence of complications in twin-twin transfusion syndrome after selective fetoscopic laser photocoagulation: a single-center experience. Am J Obstet GynecoI201(4):417.e1, 2009

Hahurij NO, Blom NA, Lopriore E, et al: Perinatal management and longterm cardiac outcome in fetal arrhythmia. Early Hum Dev 87:83,o2011 Harrison MR, Filly RA, Golbus MS, et al: Fetal treatment. N Engl J Med 307:1651,o1982

Harrison MR, Keller RL, Hawgood SB, et al: A randomized trial of fetal endoscopic tracheal occlusion for severe fetal congenital diaphragmatic hernia. N Engl J Med 349: 1916,o2003

Harrison MR, Sydorak MR, Farrell JA, et al: Fetoscopic temporary tracheal occlusion for congenital diaphragmatic hernia: prelude to a randomized controlled trial. J Pediatr Surg 38:1012,o1993

Hayden SA, Russ PO, Pretorius DH, et al: Posterior urethral obstruction. Prenatal sonographic findings and clinical outcome in fourte�n cases. J Ultrasound Med 7(7):371, 1988

Heckel S, Favre R, Schlienger JL, et al: Diagnosis and successful in utero treatment of a fetal goitrous hyperthyroidism caused by maternal Graves disease. A case report. Fetal Diagn Ther 12(1):54, 1997

Hedrick HL, Flake A W, Crombleholme TM, et al: Sacrococcygeal teratoma: prenatal assessment, fetal intervention, and outcome. J Pediatr Surg 39(3):430, 2004

Hedrick MH, Estes JM, Sullivan M, et al: Plug the lung until it grows (PLUG): a new method to treat congenital diaphragmatic hernia in utero. J Pediatr Surg 29(5):612, 1994

Hobbins Jc, Robero R, Grannum P, et al: Antenatal diagnosis of renal anomalies with ultrasound: 1. Obstructive uropathy. Am J Obstet Gynecol 148:868, 1984

Huel C, Guibourdenche J, Vuillard E, et al: Use of ultrasound to distinguish between fetal hyperthyroidism and hypothyroidism on discovery of a goiter. Ultrasound Obstet Gynecol 33:412, 2009

Hui L, Bianchi OW: Prenatal pharmacotherapy for fetal anomalies: a 2011 update. Prenat Diagn 31:735, 2011 lzmirly PM, Costedoat-Chalumeau N, Pisoni C, et al: Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-ssal ro associated cardiac manifestations of neonatal lupus. Circulation 126(1):76,o2012 lzmirly PM, Saxena A, Sahl SK, et al: Assessment of fluorinated steroids to avert progression and mortality in anti-SSA/Ro-associated cardiac injury limited to the fetal conduction system. Ann Rheum Dis 75(6):1161, 2016

Jaeggi E, Carvalho JS, de Groot E, et al: Comparison of transplacental treatment of fetal supraventricular tachyarrhythmias with digoxin, lecainide, and sotalol. Results of a nonrandomized multicenter study. Circulation 124(16):1747,o2011

Jani ]C, Nicolaides KH, Gratacos E, et al: Severe diaphragmatic hernia treated by fetal endoscopic tracheal occlusion. Ultrasound Obstet Gynecol 34:304, 2009 ]elin E, Hirose S, Rand L, et al: Perinatal outcome of conservative management versus fetal intervention for twin reversed arterial perfusion sequence with a small acardiac twin. Fetal Diagn her 27:138,o2010

Jimenez JA, Eixarch E, DeKoninck P, et al: Balloon removal after fetoscopic endoluminal tracheal occlusion for congenital diaphragmatic hernia. Am ] Obstet GynecoIo217(1):78.e1, 2017 Kelly MF, Berenholz L, Rizzo A, et al: Approach for oxygenation of the newborn with aitway obstruction due to a cervical mass. Ann Otol Rhinol Laryngolo99(3 pt 1):179,o1990 Laje P, Peranteau WH, Hedrick HL, et al: Ex utero intrapartum treatment (EXIT) in the management of cervical lymphatic teratoma. J Pediatr Surg 50(2):311,o2015 Langer Jc, Tabb T, hompson P, et al: Management of prenatally diagnosed tracheal obstruction: access to the airway in utero prior to delivery. Fetal Diagn Ther 7(1):12,o1992

Laraja K, Sadhwani A, Tworetzky W, et al: Neurodevelopmental outcome in children after fetal cardiac intervention for aortic stenosis with evolving hypoplastic left heart syndrome. J Pediatr 184: 130, 2017

Lee H, Bebbington M, Crombleholme TM, et al: he North American Fetal Therapy Network Registry data on outcomes of radiofrequency ablation for twin-reversed arterial perfusion sequence. Fetal Diagn Ther 33(4):224,o2013

Lee H, Wagner A], Sy E, et al: Eicacy of radiofrequency ablation for twinreversed arterial perfusion sequence. Am J Obstet Gynecol 196:459, 2007

Litwinska M, Litwinska E, Janiak K, et al: horacoamniotic shunts in macrocystic lung lesions: case series and review of the literature. Fetal Diagn Ther 41(3):179,o201

Livingston Jc, Lim FY, Polzin W, et al: Intrafetal radiofrequency ablation for twin reversed arterial perfusion (TRAP): a single-center experience. Am J Obstet Gynecol 197:399, 2007

Loh K, Jelin E, Hirose S, et al: vIicrocystic congenital pulmonary airway malformation with hydrops fetalis: steroids vs. open fetal resection. J Pediatr Surg 47(1):36,o2012

Lopriore E, van Wezel-Meijler G, Middlethorp JM, et al: Incidence, origin, and character of cerebral injury in twin-to-twin transfusion syndrome treated with fetoscopic laser surgery. Am J Obstet GynecoIo194(5):1215, 2006

Macardle CA, Ehrenberg-Buchner S, Smith A. Surveillance of fetal lung lesions using the congenital pulmonary airway malformation volume ratio: natural history and outcomes. Prenat Diagn 36(3):282, 2016

Mann S, Johnson MP, Wilson RD: Fetal thoracic and bladder shunts. Semin Fetal Neonatal Med 15:28, 2010

Mayer S, Klaritsch P, Petersen S, et al: The correlation between lung volume and liver herniation measurements by fetal MRI in isolated congenital diaphragmatic hernia: a systematic review and meta-analysis of observational studies. Prenat Diagn 31(11):1086, 2011

McCullough LB, Chervenak FA, Brent L, et al: A case study in unethical transgressive bioethics: "Letter of Concern from Bioethicists" about the prenatal administration of dexamethasone. Am J Bioeth 10(9):35,2010

McElhinney DB, Marshall A, Wilkins-Haug LE, et l: Predictors of technical success and postnatal biventricular outcome after in utero aortic valvuloplasty for aortic stenosis with evolving hypoplastic left heart syndrome. Circulation 120(15):1482,o2009

McElhinney DB, Tworetsky W, Lock JE: Current status of fetal cardiac intervention. Circulation 121(10):1256,o2010

Metkus AP, Filly RA, Stringer MD, et al: Sonographic predictors of survival in fetal diaphragmatic hernia. J Pediatr Surg 31 (1): 148, 1996

Meuli M, Meuli-Simmen C, Hutchins GM, et al: In utero surgery rescues neurological function at birth in sheep with spina biida. Nat Med 1 (4) :342, 1995

Meuli M, Meuli-Simmen C, Hutchins GM, et al: he spinal cord lesion in human fetuses with myelomeningocele: implications for fetal surgery. J Pediatr Surg 32(3):448, 1997

Miller L, Witchel SF: Prenatal treatment of congenital adrenal hyperplasia: risks outweigh beneits. Am J Obstet GynecoIo208(5):354, 2013 Moldenhauer JS: Ex utero intrapartum therapy. Semin Pediatr Surg 22(1):44, 20o13

Moon-Grady AJ, Morris SA, Belfort M, et al: International Fetal Cardiac Intervention Registry. A worldwide collaborative description and preliminary outcomes.o] Am Coli CardioIo66(4):388, 2015

Morris LM, Lim FY, Crombleholme TM: Ex utero intrapartum treatment procedure: a peripartum management strategy in particularly challenging cases. J Pediatr 154(1):126, 2009a

Morris LM, Lim FY, Elluru RG, et al: Severe micrognathia: indications for EXIT-to-Aiway. Fetal Diagn Ther 26: 162, 2009b

Morris RK, Malin GL, Quinlan-Jones E, et al: Percutaneous vesicoamniotic shunting versus conservative management in fetal lower urinary tract obstruction (PLUTO): a randomized trial. Lancet 382(9903):1496,o2013 Mullassety 0, Ba'ath ME, Jesudason EC, et al: Value of liver herniation in prediction of outcome in fetal congenital diaphragmatic hernia: a systematic review and meta-analysis. Ultrasound Obstet Gynecol 35(5):609, 2010 New MI, Abraham M, Yuen T, et al: An update on prenatal diagnosis and treatment of congenital adrenal hyperplasia. Semin Reprod Med 30(5):396,

New MI, Tong K, Yuen T, et al: Noninvasive prenatal diagnosis of congenital adrenal hyperplasia using cell-free DNA in maternal plasma. J Clin Endocrinol Metab 99(6):E1022, 2014

Nimkan S, Gangishetti PK, Yau M, et al: 21-Hydroxylase deicient congenital adrenal hyperplasia. In Pagon RA, Adam MP, Ardinger HH, et al (eds):

GeneReviews. Seattle, University of Washington, 2016

Noah �IM, Norton ME, Sandberg P, et al: Short-term maternal outcomes that are associated with the EXIT procedure, as compared with cesarean delivery. Am J Obstet Gynecol 186(4):773,o2002

Overcash RT, Marc-Aurele KL, Hull AD, et l: Maternal iodine exposure: a case offetal goiter and neonatal hearing loss. Pediatrics 137(4):el, 2016

Oluyomi-Obi T, Kuret V, Puligandla P, et l: Antenatal predictors of outcome in prenatally diagnosed congenital diaphragmatic hernia (CDH). J Pediatr Surg 52(5):881, 2017

Peleg 0, Cada S, Peleg A, et al: he relationship between maternal serum thyroid-stimulating immunoglobulin and neonatal thyrotoxicosis. Obstet GynecoIo99(6):1040,o2002

Peralta CF, Cavoretto P, Csapo B, et al: Assessment of lung area in normal fetuses at 12-32 weeks. Ultrasound Obstet Gynecol 26(7):718, 2005 Peranteau H, Boelig MM, Khalek N, et al: Efect of single and multiple courses of maternal betamethasone on prenatal congenital lung lesion growth and fetal survival. J Pediatr Surg 51(1):28,o2016

Quintero RA, Morales J, Allen MH, et al: Staging of twin-twin transfusion syndrome. J Perinatol 19:550, 1999

Ribault V, Castanet M, Bertrand vI,et al: Experience with intraamniotic thyroxine treatment in nonimmune fetal goitrous hypothyroidism in 12 cases. J Clin Endocrinol Metab 94:3731, 2009

Robyr R, Lewi L, Salomon LJ, et al: Prevalence and management of late fetal complications following successful selective laser coagulation of chorionic plate anastomoses in twin-to-twin transfusion syndrome. Am J Obstet Gynecol 194(3):796,o2006

Ruano R, Lazar DA, Cass DL, et al: Fetal lung volume and quantification of liver herniation by magnetic resonance imaging in isolated congenital diaphragmatic hernia. Ultrasound Obstet GynecoIo43(6):662, 2014

Ruano R, Rodo C, Peiro JL, et al: Fetoscopic laser ablation of placental anastomoses in twin-twin transfusion syndrome using "Solomon technique." Ultrasound Obstet GynecoIo42(4):434, 2013

Ruano R, Yoshisaki CT, da Silva MM, et 1: A randomized controlled trial of fetal endoscopic tracheal occlusion versus postnatal management of severe isolated congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 39(1):20,

Shah A, Moon-Grady A, Bhogal N, et al: Efectiveness of sotalol as irstline therapy for fetal supraventricular tachyarrhythmias. Am J Cardiol 190(1o1):1614,o2012

Shamshirsaz A, Ramin, SM, Belfort A: Fetal therapy. In Yeomans ER, Hofman BL, Gilstrap LC III, et al: Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hill Education, 2017

Shieh HF, Wilson JM, Sheils CA, et a1: Does the ex utero intrapartum treatment to extracorporeal membrane oxygenation procedure change morbidity outcomes for high-risk congenital diaphragmatic hernia survivors? J Pediatr Surg 52(1):22,o2017

Shue E, Bolouri M, Jelin EB, et a1: Tumor metrics and morphology predict poor prognosis in prenatally diagnosed sacrococcygeal teratoma: a 25-year experience at a single institution. J Pediatr Surg 48(6):1225,o2013

Slaghekke F, Lewi L, Middeldorp JM, et al: Residual anastomoses in twintwin transfusion syndrome after laser: the Solomon randomized trial. Am J Obstet GynecoI211(3):285.el, 2014a

Slaghekke F, Lopriore E, Lewi L, et a1: Fetoscopic laser coagulation of the vascular equator versus selective coagulation for twin-to-twin transfusion syndrome: an open-label randomized controlled trial. Lancet 383(9935):2144, 2014b Society for Maternal-Fetal Medicine, Simpson LL: Twin-twin transfusion syndrome. Am J Obstet Gynecol 208(1):3, 2013

Speiser PW, Azziz, Baskin LS, et a1: Congenital adrenal hyperplasia due to steroid 21o-hydroxylase deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 95(9):4133, 2010

Srinivasan S, Strasburger J: Overview of fetal arrhythmias. Curr Opin Pediatr 20:522, 2008

Srisupundit K, Sirichotiyakul S, Tongprasent F, et al: Fetal therapy in fetal thyrotoxicosis: a case report. Fetal Diagn her 23(2):1o14,o2008

Stofan AP, Wilson J, Jennings RW, et al: Does the ex utero intrapartum treatment to extracorporeal membrane oxygenation procedure change outcomes for high-risk patients with congenital diaphragmatic hernia? J Pediatr Surg 47(6):1053,o2012

Strasburger JF, Wakai RT: Fetal cardiac arrhythmia detection and in utero therapy. Nat Rev (5):277,o2010

Sugibayashi R, Ozawa K, Sumie M, et a1: Forty cases of twin reversed arterial perfusion sequence treated with radio frequency ablation using the multistep coagulation method: a single-center experience. Prenat Diagn 36(5):437, 2016

Sutton LN, Adzick NS, Bilaniuk LT, et al: Improvement in hindbrain herniation demonstrated by serial fetal magnetic resonance imaging following fetal srgery for myelomeningocele. JAMA 282(19):1826, 1999

Swamy R, Embleton N, Hale J, et al: Sacrococcygeal teratoma over two decades: birth prevalence, prenatal diagnosis and clinical outcomes. Prenat Diagn 28: 1048, 2008

Van der Heijden LB, Oudijk MA, Manten GTR, et a1: Sotalol as irst-line treatment for fetal tachycardia and neonatal follow-up. Ultrasound Obstet GynecoIo42(3):285,o2013

Ville Y, Hyett J, Hecher K, et a1: Preliminary experience with endoscopic laser surgery for severe twin-twin transfusion syndrome. N Engl J Med 332(4):224, 1995

Vrecenak JD, Flake A W: Fetal surgical intervention: progress and perspectives.

Pediatr Surg Int 29(5):407,o2013

Walsh WF, Chescheir NC, Gillam-Krakauer M, et al: Maternal-fetal surgical procedures. Technical Brief No. 5. AHRQ Publication No.o1 0(1)-EHC059EF, Rockville, Agency for Healthcare Research and Quality, 201o1 Wilson RD, Lemerand K, Johnson MP, et a1: Reproductive outcomes in subsequent pregnancies after a pregnancy complicated by open maternal-fetal srgery (1996-2007). Am J Obstet Gynecol 203(3):209.el, 2010

Worley KC, Dashe JS, Barber RG, et al: Fetal magnetic resonance imaging in isolated diaphragmatic hernia: volume of herniated liver and neonatal outcome. Am J Obstet Gynecol 200:318.el, 2009

Wu D, Ball RH: The maternal side of maternal-fetal surgery. Clin Perinatol 36(2):247, 2009

Yinon Y, Grisaru-Granovsky S, Chaddha V, et al: Perinatal outcome following fetal chest shunt insertion for pleural efusion. Ultrasound Obstet Gynecol 36:58,o2010

FETAL MOVEMENTS............................ 331

FETAL BREATHING .............................. 333

CONTRACTION STRESS TESTING.................. 334

NONSTRESS TESTS .............................. 334 ACOUSTIC STIMULATION TESTS ................... 337 BIOPHYSICAL PROFILE.......................... 337 AMNIONIC FLUID VOLUME....................... 339 DOPPLERVELOCIMETRY......................... 339 ANTENATAL TESTING SUMMARY.................. 340

The rate of the oetal heart is subject to considerable variations, which aords us a airy reliable means of judging as to the well-being of the child. As a general rule, its lie should be considered in danger when the heart-beats all below 100 or exceed 160.

-J. Whitridge Williams (1903)

More than 100 years ago, the approach to fetal assessment was rather primitive. Since that time, and especially since the 1970s, technology to evaluate the health of the fetus has advanced remarkably. Techniques employed today to forecast fetal wellbeing focus on fetal biophysical indings that include heart rate, movement, breathing, and amnionic luid production. These indings aid antepartum fetal surveillance to prevent fetal death and avoid unnecessary interventions, which are stated goals of the American College of Obstetricians and Gynecologists and the American Academy of Pediatrics (2017).

Most fetuses will be healthy, and usually a negativethat is, normal-antepartum test result is highly reassuring, because fetal deaths within 1 week of a normal test are rare. Indeed, negative-predictive values-a true negative test-for most of the tests described are 99.8 percent or higher. In contrast, estimates of the positive-predictive values-a true positive test-for abnormal test results are low and range between 10 and 40 percent. Importantly, fetal surveillance is primarily based on circumstantial evidence. No deinitive randomized clinical trials have been conducted for obvious ethical reasons (American College of Obstetricians and Gynecologists, 2016).

commences as early as 7 weeks' gestation and becomes more sophisticated and coordinated by the end of pregnancy (Sajapala, 2017; Vindla, 1995). Indeed, beyond 8 menstrual weeks, fetal body movements are never absent for periods exceeding 13 minutes (DeVries, 1985). Between 20 and 30 weeks' gestation, general body movements become organized, and the fetus starts to show rest-activity cycles (Sorokin, 1982). Fetal movement maturation continues until approximately 36 weeks, when behavioral states are established in most normal fetuses. Nijhuis and colleagues (1982) described four fetal behavioral states:

State 1 F is a quiescent state-quiet sleep-with a narrow oscillatory bandwidth of the fetal heart rate.

State 2F includes frequent gross body movements, continuous eye movements, and wider oscillation of the fetal heart rate. This state is analogous to rapid eye movement (EM) or active sleep in the neonate.

State 3F includes continuous eye movements in the absence ofbody movements and no heart rate accelerations. he existence of this state is disputed (Pillai, 1990a).

State 4F is one ofvigorous body movement with continuous eye movements and heart rate accelerations. his state corresponds to the awake state in newborns.

Fetuses spend most of their time in states IF and 2F. For example, at 38 weeks, 75 percent of time is spent in these two states. hese behavioral states-particularly IF and 2F, which correspond to quiet sleep and active sleep-have been used to develop an increasingly sophisticated understanding offetal behavior. In a study offetal urine production, bladder volumes increased during state IF quiet sleep (Fig. 17-1). Duringstate 2F, the fetal heart rate baseline bandwidth increased appreciably, and bladder volume was signiicantly diminished due to decreased urine production and infrequent fetal voiding. These phenomena were interpreted to represent reduced renal blood flow during active sleep.

n important determinant of fetal activity appears to be sleep-awake cycles, which are independent of maternal ones. Fetal sleep cyclicity varies from approximately 20 minutes to as much as 75 minutes. In one study, the mean length of the quiet or inactive state for term fetuses was 23 minutes (TimorTritsch, 1978). Patrick and associates (1982) measured gross fetal body movements with real-time sonography for 24-hour periods in 31 normal pregnancies and found the longest period ofinactivity to be 75 minutes. Amnionicluid volume is another important determinant of fetal activity. Sherer and colleagues (1996) assessed the number of fetal movements in 465 pregnancies during biophysical profile testing in relation to amnionic luid volume. hey observed decreased fetal activity with diminished amnionic volumes and suggested that a restricted uterine space might physically limit fetal movements.

with fetal heart rate (FHR) variation recorded in relation to 1 F or 2F behavior states. State 1 F fetal heart rate has a narrow bandwidth consistent with quiet sleep. State 2F heart rate shows wide oscillation ofthe baseline consistent with active sleep. (Modified with permission from Oosterhof H, vd Stege JG, Lander M, et al: Urine production rate is related to behavioural states in the near term human fetus, Br J Obstet Gynaecol. 1993 Oct;l 00(1 0):920-922.) �E > 400 ..

._ 100

FIGURE 17-2 Graph depicts averages offetal movements counted during 12-hour periods (mean ± SEM). (Data from Sadovsky, 1979a.)

Sadovsky and coworkers (1979b) classiied fetal movements into three categories according to both maternal perceptions and independent recordings using piezoelectric sensors. Weak, strong, and rolling movements were described, and their relative contributions to total weekly movements throughout the last half of pregnancy were quantiied. As pregnancy advances, the rate of weak movements decreases, more vigorous movements increase for severalweeks, and then rates of these subside at term. Presumably, declining amnionic luid and space account for diminished activity at term.

Figure 1i7-2 shows fetal movements during the last half ofgestation in 127 pregnancies with normal outcomes. he mean number of weekly movements calculated from 12-hour daily recording periods rose from approximately 200 at 20 weeks' gestation to a maximum of 575 movements at 32 weeks. Fetal movements then declined to an average of 282 at 40 weeks. Normal weekly maternal counts of fetal movements ranged between 50 and 950. Count showed large daily variations, with included counts as low as 4 to 10 per 12-hour period in normal pregnancies.

Diminished fetal activity may be a harbinger ofimpending fetal death (Sadovsky, 1973). To quantiy fetal movement, clinical methods include use of a uterine contraction tocodynamometer, visualization with sonography, and maternal subjective perceptions.

Most, but not all, investigators report excellent correlation between maternally perceived fetal motion and movements documented by instrumentation. For example, Rayburn (1980) found that 80 percent of all movements observed during sonographic monitoring were perceived by the mother. In contrast, Johnson and colleagues (1992) reported that beyond 36 weeks, mothers perceived only 16 percent of fetal body movements. Fetal motions lasting more than 20 seconds were more likely to be identified than shorter episodes. Although several fetal-movement counting protocols have been used, neither the optimal number ofmovements nor the ideal duration for counting them has been defined. For example, in one method, perception of 10 fetal movements in up to 2 hours is considered normal (Moore, 1989). Commonly, women may present in the third trimester complaining of subjectively reduced fetal movement. Harrington and associates (1998) reported that 7 percent of nearly 6800 women presented with a complaint of decreased fetal movement. Fetal heart rate monitoring tests were employed if sonographic scans for fetal growth or Doppler velocimetry were abnormal. Pregnancy outcomes for women who complained of decreased fetal movement were not significantly diferent from those for women without this complaint. Scala and colleagues (2015) reported that 6 percent of women at term reported decreased fetal movements at 36 weeks or more. Women with two or more episodes of reduced fetal movements had greater risks of growth-restricted newborns and abnormal Doppler uterine artery low studies. However, stillbirth rates were not increased. Measurement ofthe myocardial performance index did not improve accuracy (Ho, 2017).

Grant and coworkers (1989) performed an unparalleled investigation of maternally perceived fetal movements and pregnancy outcome. More than 68,000 pregnancies were randomly assigned between 28 and 32 weeks' gestation. Women in the fetal movement arm of the study were instructed by specially employed midwives to record the time needed to feel 10 movements each day. his required an average of2.7 hours each day. Women in the control group were informally asked about movements during prenatal visits. Reports of decreased fetal motion were evaluated with tests of fetal well-being. Antepartum death rates for otherwise normal singleton fetuses were similar in the two study groups. Despite the counting policy, most stillborn fetuses were dead by the time the mothers reported for medical attention. Importantly, rather than concluding that maternal perceptions of fetal activity were meaningless, these investigators concluded that informal maternal perceptions were as valuable as formally recorded fetal movement.

Saastad and associates (2011) reported a total of 1076 women who were randomly assigned to standardized fetal movement counting from gestational week 28 versus no counting. Growth-restricted fetuses were identiied before birth signiicantly more often when fetal movement counting was used. he rate of I-minute Apgar scores :;3 was signiicant reduced (0.4 versus 2.3 percent) when counting was used. Also, Warrander and coworkers (2012) described placental pathology in pregnancies complicated by diminished fetal movements. Decreased movement was associated with various placental abnormalities including infarction.

After decades of uncertainty as to whether the fetus normally breathes, Dawes and coworkers (1972) showed small inward and outward flows of tracheal fluid in fetal sheep, indicating thoracic movement. These chest wall movements difered from those following birth in that they were discontinuous. Another interesting feature of fetal respiration was paradoxical chest wal movement (Fig. 17-3). In the newborn or adult, the opposite occurs. One interpretation of the paradoxical respiratory motion might be coughing to clear amnionic fluid debris. Although the physiological basis for the

FIGURE 17-3 Paradoxical chest movement with fetal respiration. During inspiration (A), the chest wall paradoxically col/apses and the abdomen protrudes, whereas during expiration (8), the chest wall expands. (Adapted from Johnson, 1988.) breathing relex is not completely understood, such exchange of amnionic fluid appears to be essential for normal lung development (Chap. 7, p. 133). Dawes (1974) identiied two types of respiratory movements. The irst are gasps or sighs, which occurred at a frequency of 1 to 4 per minute. The second, irregular bursts ofbreathing, occurred at rates up to 240 cycles per minute. hese latter rapid respiratory movements were associated with rapid eye movement. Badalian and associates (1993) studied the maturation of normal fetal breathing using color low and spectral Doppler analysis of nasal fluid low as an index of lung function. hey suggested that fetal respiratory rate declined in conjunction with increased respiratory volume at 33 to 36 weeks and coincidental with lung maturation.

Many investigators have examined fetal breathing movements using sonography to determine whether chest wall movements might reflect fetal health. Several variables in addition to hypoxia were found to afect fetal respiratory movements. These included hypoglycemia, sound stimuli, cigarette smoking, amniocentesis, impending preterm labor, gestational age, the fetal heart rate itself, and labor-during which it is normal for respiration to cease.

Because fetal breathing movements are episodic, interpretation of fetal health when respirations are absent may be tenuous. Patrick and associates (1980) performed continuous 24-hour observation using sonography to characterize fetal breathing patterns during the last 10 weeks of pregnancy. A total of 1224 hours of fetal observation in 51 pregnancies were collected, and ).>D

C)..=20

Time of day

FIGURE 17-4 The percentage of time spent breathing by 11 fetuses at 38 to 39 weeks. There is a significant increase in fetal breathing activity after breakfast. Breathing activity diminished during the day and reached its minimum between 20:00 and 24:00 hours. There was a significant increase in the percentage of time spent breathing between 04:00 and 07:00 hours, when mothers were asleep. (Adapted with permission from Patrick J, Campbell K, Carmichael L, et al: Patterns of human fetal breathing during the last 10 weeks of pregnancy, Obstet Gynecol. 1980 Jul;56(1 ):24-30.)

Figure 17-4 displays the percentages of time spent breathing near term. Clearly, there is diurnal variation, because breathing substantively diminishes during the night. In addition, breathing activity increases somewhat following maternal meals. Total absence of breathing was observed in some of these normal fetuses for up to 122 minutes, indicating that fetal evaluation to diagnose absent respiratory motion may require long periods of observation.

The potential for breathing activity to be an important marker of fetal health is unfulilled because of the multiplicity of factors that normally afect breathing. Most clinical applications have included assessment of other fetal biophysical indices, such as heart rate. As discussed subsequently, fetal breathing has become a component of the biophysical proile.

As amnionic luid pressure rises with uterine contractions, myometrial pressure exceeds collapsing pressure for vessels coursing through uterine muscle. his ultimately lowers blood flow to the intervillous space. Brief periods of impaired oxygen exchange result, and if utero placental pathology is present, these elicit late fetal heart rate decelerations (Chap. 24, p. 466). Contractions also may produce a pattern of variable decelerations as a result of cord compression, suggesting oligohydramnios, which is often a concomitant of placental insuiciency.

Ray and colleagues (1972) used this concept in 66 complicated pregnancies and developed the oytocin challenge test, which was later called the contraction stress test. Intravenous oxytocin is used to stimulate contractions, and the criterion for a positive test result, that is, an abnormal result, is uniform repetitive late fetal heart rate decelerations. These reflected the uterine contraction waveform and had an onset at or beyond the contraction acme. Such late decelerations could be the result of uteroplacental insuiciency. In their study, the tests were generally repeated on a weekly basis, and the investigators concluded that negative contraction stress test results, that is, normal results, forecasted fetal health. A major disadvantage is that the average contraction stress test requires 90 minutes to complete.

To perform the test, the fetal heart rate and uterine contractions are recorded simultaneously with an external monitor. If at least three spontaneous contractions of 40 seconds or longer are present in 10 minutes, no uterine stimulation is necessary (American College of Obstetricians and Gynecologists, 2016). Contractions are induced with either oxytocin or nipple stimulation if there are fewer than three in 10 minutes. For oxytocin use, a dilute intravenous inusion is initiated at a rate of 0.5 mU/min and doubled every 20 minutes until a satisfactory contraction pattern is established (Freeman, 1975). The results of the contraction stress test are interpreted according to the criteria shown in Table

Nipple stimulation to induce uterine contractions is usually successful for contraction stress testing (Huddleston, 1984). One method involves a woman rubbing one nipple through her clothing for 2 minutes or until a contraction begins. This 2-minute nipple stimulation ideally will induce a pattern of three contractions per 10 minutes. If not, after a 5-minute interval, she is instructed to retry nipple stimulation to achieve the desired pattern. If this is unsuccessful, then dilute oxytocin may be used. Advantages include reduced cost and shortened testing times. Some have reported unpredictable uterine hyperstimulation and fetal distress, whereas others did not find excessive activity to be harmful (Frager, 1987; Schellpfefer, 1985).

Freeman (1975) and Lee and colleagues (1975) introduced the nonstress test to describe fetal heart rate acceleration in response to fetal movement as a sign of fetal health. This test involved the use of Doppler-detected fetal heart rate acceleration coincident with fetal movements perceived by the mother. By the end of the 1970s, the nons tress test had become the primary method of testing fetal

TABLE 17-1. Criteria for Interpretation of the Contraction Stress Test

Negative: no late or significant variable decelerations Positive: late decelerations following 50% or more of contractions (even if the contraction frequency is fewer than three in 10 minutes) Equivocal-suspicious: intermittent late decelerations or significant variable decelerations Equivocal-hyperstimulatory: fetal heart rate decelerations that occur in the presence of contractions more frequent than every 2 minutes or lasting longer than 90 seconds Unsatisfactory: fewer than three contractions in 10 minutes or an uninterpretable tracing health. he nonstress test was easier to perform, and normal results were used to urther discriminate false-positive contraction stress tests. Simplistically, the nonstress test is primarily a test ofetal condition, and it difers from the contraction stress test, which is considered a test of uteropacentalonction. Currently, nonstress testing is the most widely used primary testing method for assessment of fetal well-being. It has lso been incorporated into the biophysical profile testing system, subsequently discussed.

Autonomic inluences are mediated by sympathetic or para sympathetic impulses from brainstem centers to normally raise or slow the fetal heart rate. Beat-to-beat variability is also under the control ofthe autonomic nervous system (Matsuura, 1996).

Consequently, pathological loss of fetal heart rate acceleration may be seen in conjunction with signiicantly decreased beat to-beat variability (Chap. 24, p. 462). Loss of such reactivity, however, is most commonly associated with sleep cycles. It also rette smoking Oansson, 2005).

The nonstress test is based on the hypothesis that the heart rate of a fetus that is not acidemic as a result of hypoxia or to fetal movement. Fetal movements during testing are identi ied by maternal perception and recorded. As hypoxia develops, these fetal heart rate accelerations diminish (Smith, 1988).

Gestational age inluences acceleration or reactivity ofthe fetal heart rate. Pillai and James (1990b) studied the development of fetal heart rate acceleration patterns during normal pregnancy. The percentage of body movements that is accompanied by accelerations and the amplitude of these accelerations both increase with gestational age (Fig. 17-5). Guinn and colleagues (1998) studied nonstress test results between 25 and 28 weeks' gestation in 188 normal fetuses. Only 70 percent of these normal fetuses demonstrated the required 15 beats per minute (bpm) or more of heart rate acceleration. Lesser degrees of acceleration, that is, 10 bpm, occurred in 90 percent ofthe fetuses.

The National Institute of Child Health and Human Development Fetal Monitoring Workshop defined normal acceleration based on gestational age (Macones, 2008). In fetuses at or beyond 32 weeks' gestation, the acceleration acme is 15 bpm or more above the baseline rate, and the acceleration lasts 15 seconds or longer but less than 2 minutes. Before 32 weeks, normal accelerations are defined as having an acme that is 10 bpm or more above baseline for 10 seconds or longer. Cousins and associates (2012) compared the Workshop criteria recommended before 32 weeks, that is, 10 bpm/10 seconds, with standard 15 bpm/15 seconds criteria in a randomized trial of 143 women. They found no diferences in perinatal outcomes.

):J=20

FIGURE 17-5 Percentage offetuses tlith at least one acceleration of 15 bpm sustained for 15 seconds concurrent with fetal movement. (Redrawn from Pillai M, James 0: The development offetal heart rate patterns during normal pregnancy, Obstet Gynecol. 1990 Nov;76(5 Pt 1):812-816.)

Criteria to define normal nonstress test results difer. They vary regarding the number, amplitude, and duration of accelerations and the test duration. he definition recommended by the American College of Obstetricians and Gynecologists (2016) requires two or more accelerations peaking at 15 bpm or more above baseline, each lasting 15 seconds or more, and all occurring within 20 minutes of beginning the test (Fig. 17-6). It is also recommended that accelerations with or without fetal movements be accepted, and that a 40-minute or longer tracing-to account for fetal sleep cycles-should be performed before concluding that fetal reactivity is insuicient. Miller and coworkers (1996b) reviewed outcomes in fetuses with nons tress tests considered as nonreactive because there was only one acceleration. hey concluded

FIGURE 17-6 Reactive nonstress test. In the upper panel, notice the increase offetal heart rate by more than 15 beats/min for longer than 15 seconds following fetal movements, which are indicated by the vertical marks (lower panen.

that one acceleration was just as reliable as two in predicting healthy fetal status. Although a normal number and amplitude of accelerations seems to reflect fetal well-being, their absence does 60 not invariably predict fetal compromise. Indeed, some investigators have reported 90-percent or higher false-positive rates (Devoe, 1986). Because healthy fetuses may not move for periods of up to 75 minutes, some have considered that a longer duration of nonstress testing might increase the positive-predictive value of an abnormal, that is, nonreactive, test (Brown, 1981). In this scheme, either the test became reactive during a period up to 80 minutes or the test remained nonreactive for 120 minutes, which indicated that the fetus was very ill.

Not only do deinitions of normal nonstress test results difer, but the reproducibility ofinterpretations is problematic (Hage, 1985). Thus, although nons tress testing is popular, the reliability of test interpretation needs improvement.

Based on the foregoing, an abnormal nons tress test is not always ominous and can be seen with a sleeping fetus. Also, an abnormal test can revert to normal as the fetal condition changes, such as the example shown in

Figure 17-7. Importantly, a normal nonstress test can become abnormal if the fetal condition deteriorates.

There are abnormal patterns that reliably forecast severe fetal jeopardy (Fig. 17-8). Devoe and coworkers (1985) concluded that nonstress tests that were nonreactive for 90 minutes were almost invariably-93 percent-associated with significant perinatal pathology. Hammacher and coworkers (1968) described tracings with what they termed a silent oscillatoy pattern that he considered dangerous. his pattern consisted of a fetal heart rate baseline that oscillated less than 5 bpm and presumably indicated absent acceleration and beat-to-beat variability.

Visser and associates (1980) described a terminal cardiotocoram, which included: (1) baseline oscillation ofless than 5 bpm, (2) absent accelerations, and (3) late decelerations with spontaneous uterine contractions. hese results were similar to experiences from Parkland Hospital in which absence of accelerations during an 80-minute recording period in 27 fetuses was associated consistently with evidence of uteroplacental pathology (Leveno, 1983). he latter included fetal-growth restriction in 75ipercent, oligohydramnios in 80 percent, fetal acidemia in 40 percent, meconium in 30 percent, and placental infarction in 93 percent.

FIGURE 17-7 Two antepartum fetal heart rate (FHR) tracings in a 28-week pregnant woman with diabetic ketoacidosis. A. FHR tracing (upper panel) and accompanying contraction tracing (second panen. Tracing, obtained during maternal and fetal acidemia, shows absence of accelerations, diminished variability, and late decelerations with weak spontaneous contractions. B. Fetal heart rate tracing shows return of normal accelerations and variability of the fetal heart rate following correction of maternal acidemia.

Set originally rather arbitrarily at 7 days, the interval between tests appears to have been shortened as experience evolved with nonstress testing. According to the American College of Obstetricians and Gynecologists (2016), more frequent testing is advocated by some investigators for women with postterm pregnancy, multifetal gestation, pregestational diabetes, fetalgrowth restriction, or pregnancy hypertension. In these circumstances, some investigators perform twice-weekly tests, with additional testing completed for maternal or fetal deterioration regardless of the time elapsed since the last test. Others perform nonstress tests daily or even more frequently, such as with severe preeclampsia remote from term.

Fetal movements commonly produce heart rate decelerations. Timor-Tritsch and associates (1978) reported this during nonstress testing in half to two thirds of tracings, depending on the vigor of the fetal motion. This high incidence of decelerations inevitably makes interpretation of their signiicance problematic. Indeed, Meis and coworkers (1986) reported that variable fetal

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FIGURE 17-8 Nonreactive nonstress test (left side of tracing) followed by contraction stress test showing mild, late decelerations (right side of tracing). Cesarean delivery was performed, and the severely acidemic fetus could not be resuscitated.

heart rate decelerations during nonstress tests were not a sign of fetal compromise. he American College of Obstetricians and Gynecologists (2016) has concluded that variable decelerations, if nonrepetitive and brief-less than 30 seconds-do not indicate fetal compromise or the need for obstetrical intervention. In contrast, repetitive variable decelerations-at least three in 20 minutes-even if mild, have been associated with a greater risk of cesarean delivery for fetal distress. Decelerations lasting 1 minute or longer have been reported to have an even worse prognosis (Bourgeois, 1984; Druzin, 1981; Pazos, 1982).

Hoskins and associates (1991) attempted to reine interpretation of testing that shows variable decelerations by adding sonographic estimation of amnionic luid volume. The incidence of cesarean delivery for intrapartum fetal distress progressively rose concurrently with the severity of variable decelerations and decline of amnionic luid volume. Severe variable decelerations during a nonstress test plus an amnionic luid index (AFI) ;5 em resulted in a 75-percent cesarean delivery rate. Fetal distress in labor, however, also frequently developed in those pregnancies with variable decelerations but with normal amounts of amnionic luid. Similar results were reported by Grubb and Paul (1992).

Smith and associates (1987) performed a detailed analysis of the causes of fetal death within 7 days of normal nons tress tests. The most common indication for testing was postterm pregnancy. he mean interval between testing and death was 4 days, with a range of 1 to 7 days. he single most common autopsy inding was meconium aspiration, oten associated with some type of umbilical cord abnormality. They concluded that an acute asphyxial insult had provoked fetal gasping. hey also concluded that nonstress testing was inadequate to preclude such an acute asphyxial event and that other biophysical characteristics might be beneicial. Importantly, assessment of amnionic luid volume was considered valuable. Other ascribed frequent causes of fetal death included intrauterine infection, abnormal cord position, malformations, and placental abruption.

Loud external sounds have been used to startle the fetus and thereby provoke heart rate acceleration-an acoustic stimulation nonstress test. A commercially available acoustic stimulator is positioned on the maternal abdomen, and a stimulus of 1 to 2 seconds is applied (Eller, 1995). his may be repeated up to three times for up to 3 seconds (American College of Obstetricians and Gynecologists, 2016). A positive response is deined as the rapid appearance of a qualiYing acceleration following stimulation (Devoe, 2008). In a randomized trial of 113 women undergoing nonstress testing, vibroacoustic stimulation shortened the average time of testing from 24 to 15 minutes (Perez-Delboy, 2002). Similar results were reported by Turitz and coworkers (2012). Laventhal and colleagues (2003) reported that fetal tachyarrhythmia could be provoked with vibroacoustic stimulation.

Manning and colleagues (1980) proposed the combined use of ive fetal biophysical variables as a more accurate means of assessing fetal health than a single element. Typically, these tests require 30 to 60 minutes of examiner time. Shown in

Table 1i7-2 are the ive fetal biophysical components assessed: (1) heart rate acceleration, (2) breathing, (3) movements, (4) tone, and (5) amnionic luid volume. Normal variables were assigned a score of 2 each, and abnormal variables were given a score of O. Thus, the highest score possible for a normal fetus is 10. Maternal medications such as narcotics and sedatives can signiicantly lower the score (Kopecky, 2000). Ozkaya and associates (2012) found that biophysical test scores were higher if a test was performed in late evening-20:00 to 22:00 hours-compared with 08:00 to 10:00 hours.

TABLE 17-2. Components and Scores for the Biophysical Profile

Nonstress testa :2 accelerations of : 15 beats/min for : 15 sec within 20-40 min Fetal breathing : 1 episode of rhythmic breathing lasting ::30 sec within 30 min Fetal movement ::3 discrete body or limb movements within 30 min Fetal tone ::1 episode of extremity extension and subsequent retun to fiexion Amnionic fluid A pocket of amnionic fluid that measures at least 2 cm in two volumeb planes perpendicular to each other (2 x 2 cm pocket) o or 1 acceleration within 20-40 min <30 sec of breathing within 30 min <3 discrete movements o extension/flexion events Largest single vertical pocket :;2 cm aMay be omitted if all four sonographic components are normal.

bFurther evaluation warranted, regardless of biophysical composite score, if largest vertical amnionic fluid pocket :;2 cm.

Manning and colleagues (1987) tested more than 19,000 pregnancies using the biophysical profile interpretation and management shown in Table 17-3. More than 97 percent of the pregnancies tested had normal test results. They reported a false-normal test rate-defined by an antepartum death of a structurally normal fetus-of approximately 1 per 1000. he most common identiiable causes of fetal death after a normal biophysical profile include fetomaternal hemorrhage, umbilical cord accidents, and placental abruption (Dayal, 1999).

Manning and coworkers (1993) published a remarkable description of 493 fetuses in which biophysical scores were performed immediately before measurement of umbilical venous blood pH values obtained via antepartum cordocentesis. Approximately 20 percent of tested fetuses had growth restriction, and the remainder had alloimmune hemolytic anemia. As shown in Figure 17-9, a biophysical score of 0 was almost invariably associated with significant fetal acidemia, whereas a normal score of 8 or 10 was associated with normal pH. An equivocal test result-a score of 6-was a poor predictor of abnormal outcome. As the abnormal score dropped from 2 or 4 down to 0, this decline was a more accurate predictor of abnormal fetal outcome. hus overall, these scores provide poor sensitivity to predict cord blood pH.

Similar studies have substantiated these findings. Salvesen and associates (1993) concluded that the biophysical proile was of limited value in the prediction of fetal pH. Weiner and coworkers (1996) assessed 135 overtly growth-restricted fetuses and came to a similar conclusion. Kaur and colleagues (2008) performed daily biophysical proiles to ascertain the optimal delivery time in 48 growth-restricted preterm fetuses that weighed less than 1000 g. Despite scores of 8 in 27 fetuses and 6 in 13, there were six deaths and 21 acidemic fetuses. Lalor and associates (2008) performed a Cochrane review and concluded that there is insuicient evidence to support the use of the biophysical proile as a fetal well-being test in high-risk pregnancies.

Because the biophysical proile is labor intensive and requires a person trained in sonography, Clark and coworkers (1989) used an abbreviated biophysical proile as a irst-line screening test in 2628 singleton pregnancies. Speciically, a vibroacoustic nons tress test was performed twice weekly and combined with

TABLE 17-3. Interpretation of Biophysical Profile Score 10 Normal, nonasphyxiated fetus 8/10 (Normal AFV) Normal, nonasphyxiated fetus 8/8 (NST not done) 8/10 (Decreased AFV) Chronic fetal asphyxia suspected 6 Possible fetal asphyxia o to 2 Almost certain fetal asphyxia

If amnionic fluid volume abnormal, deliver

If normal fluid at >36 weeks with favorable cervix, deliver If repeat test :;6, deliver

If repeat test >6, observe and repeat per protocol

Repeat testing same day; if biophysical profile score :;6, deliver Deliver

AFV = amnionic fluid volume; NST = nonstress test.

Reproduced with permission from Manning FA, Morrison I, Harman CR, et al: Fetal assessment based on fetal biophysical profile scoring: experience in 19,221 referred high-risk pregnancies. II. An analysis of false-negative fetal deaths, Am J Obstet Gynecol. 1987 Oct;157(4 Pt 1 ):880-884.

I.

):J0 downstream impedance (Chap. 10, p. 213). For growth 7.30 7.25 0E:J

E:J= 7.20 7.10 7.05

FIGURE 17-9 Mean umbilical vein pH (±2 SD) obtained by cordocentesis in relation to fetal biophysical profile score category. (Data from Manning, 1993.)

API determination for which �5 cm was considered abnormal (Chap. 11, p. 230). his abbreviated biophysical proile required approximately 10 minutes to perform, and they concluded that it was a superb antepartum surveillance method because there were no unexpected fetal deaths.

Nageotte and colleagues (1994) also combined biweely nons tress tests with the AFI and considered measures �5 cm to be abnormal. They performed 17,429 modiied biophysical proiles in 2774 women and concluded that such testing was an excellent fetal surveillance tool. Miller and associates (1996a) reported results with more than 54,000 modiied biophysical profiles performed in 15,400 high-risk pregnancies. They described a false-negative rate of 0.8 per 1000 and a falsepositive rate of 1.5 percent.

The American College of Obstetricians and Gynecologists (2016) has concluded that the modiied biophysical proile test is as predictive of fetal well-being as other approaches to biophysical fetal surveillance.

he importance of amnionic fluid volume estimation is indicated by its inclusion into virtually all schemes in which fetal health is assessed (Ff0en, 2008). This is based on the rationale that diminished utero placental perfusion may lead to lower fetal renal blood low, decreased urine production, and ultimately, oligohydramnios (Chap. 11, p. 231). The American College of Obstetricians and Gynecologists (2016) concludes that data available from randomized trials indicate that the use of the deepest vertical pocket measurement, as opposed to the AFI, to diagnose oligohydramnios is associated with a reduction in unnecessary interventions without an increase in adverse perinatal outcomes (Nabhan, 2008; Reddy, 2014).

restricted fetuses, several fetal vascular circuits including the umbilical artery, middle cerebral artery, and ductus venosus have been evaluated as diagnostic tools for fetal well-being (Chap. 44, p. 854). Maternal uterine artery Doppler velocimetry has also been assessed as a modality to predict placental dysfunction, with the goal to balance stillbirth against the risks of preterm delivery (Ghidini, 2007). Even the efects of sildenail in pregnant sheep have been evaluated using Doppler velocimetry (Alanne, 2017). he rationale is that sildenafil would improve placental blood low in the presence of placental insuiciency. This proved untrue, as sildenail was associated with detrimental efects on fetal cardiovascular dynamics.

Waveforms were irst studied in the umbilical arteries late in pregnancy, and abnormal waveforms correlated with placental villous hypovascularity. Of the small placental arterial channels, 60 to 70 percent need to be obliterated before the umbilical artery Doppler waveform becomes abnormal. Such extensive placental vascular pathology has a major efect on fetal circulation. According to Trudinger (2007), because more than 40 percent of the combined fetal ventricular output is directed to the placenta, obliteration of placental vascular channel increases aterload and leads to fetal hypoxemia. This in turn leads to ventricular dilation and redistribution of middle cerebral artery blood low. Ultimately, pressure rises in the ductus venosus due to afterload in the right side of the fetal heart (Baschat, 2004). Clinically, abnormal Doppler waveforms in the ductus venosus are a late inding in the progression of fetal deterioration due to chronic hypoxemia.

he umbilical artery systolic-diastolic (SID) ratio is considered abnormal if it is >95th percentile for gestational age or if diastolic low is either absent or reversed (Chap. 10, p. 213). Absent or reversed end-diastolic low signiies greater impedance to umbilical artery blood low (Fig. 44-8, p. 854). It is reported to result from poorly vascularized placental villi and is seen in extreme cases of fetal-growth restriction (T odros, 1999). According to Zelop and colleagues (1996), the perinatal mortali ty rate for absent end-diastolic flow was about 10 percent, and for reversed end-diastolic low, it approximated 33 percent.

Spinillo and associates (2005) studied neurodevelopmental outcome at 2 years of age in 266 growth-restricted fetuses delivered between 24 and 35 weeks' gestation. Of infants who had shown absent or reversed umbilical artery low, 8 percent had evidence of cerebral palsy compared with 1 percent of those in whom Doppler low had been normal.

Doppler ultrasound of the umbilical artery has been subjected to more extensive assessment with randomized controlled trials than has any previous test of fetal health. Williams and colleagues (2003) randomized 1360 high-risk women to either nons tress testing or Doppler velocimetry. hey found a significantly higher incidence of cesarean delivery for fetal distress in the nonstress test group compared with that for those tested with Doppler velocimetry-8.7 versus 4.6 percent, respectively. One interpretation of this finding is that the nonstress test more frequently identiied fetuses in jeopardy. Conversely, Gonzalez and associates (2007) found that abnormal umbilical artery Doppler indings in a cohort of growth-restricted fetuses were the best predictors of perinatal outcomes.

he utility of umbilical artery Doppler velocimetry was reviewed by the American College of Obstetricians and Gynecologists (2016). They concluded that no beneit has been demonstrated other than in pregnancies with suspected fetal-growth restriction. Similarly, velocimetry has not proved valuable as a screening test for fetal compromise in the general obstetrical population.

Various other fetal-maternal Doppler indices have been studied, including the fetal middle cerebral artery and ductus venosus and the uterine arteries. The American College of Obstetricians and Gynecologists (2016) concluded that Doppler investigations of other blood vessels besides the umbilical artery have not been shown to improve perinatal outcome.

As discussed, at this time, Doppler velocimetry interrogation of the middle cerebral artery (MCA) to detect fetal compromise is not recommended. Still, the technology has received particular attention because of observations that the hypoxic fetus attempts brain sparing by reducing cerebrovascular impedance and thus increasing blood flow. Such brain sparing in growthrestricted fetuses has been documented to undergo reversal (Konje, 2001). Investigators reported that 8 of 17 fetuses with this reversal died. Ott and coworkers (1998) randomized 665 women undergoing modified biophysical proile evaluation to either the profile alone or combined with middle cerebral and umbilical artery velocity low assessment. Pregnancy outcomes between these two study groups did not difer significantly.

Middle cerebral artery Doppler velocimetry has proven valuable to detect severe fetal anemia in 165 fetuses with D-antigen alloimmunization. Oepkes and colleagues (2006) prospectively compared serial amniocentesis for measurement of bilirubin levels with Doppler measurement of peak systolic velocity in the middle cerebral artery. These investigators concluded that Doppler could safely replace amniocentesis in the management of alloimmunized pregnancies. And as discussed in Chapter 15 (p. 303), this technique has been reported to be useul for detection and management of fetal anemia of any cause (Moise, 2008).

Doppler ultrasound has also been used to assess the fetal venous circulation. Bilardo and colleagues (2004) prospectively studied umbilical artery and ductus venosus Doppler velocimetry in 70 growth-restricted fetuses at 26 to 33 weeks' gestation. hey concluded that ductus venosus velocimetry was the best predictor of perinatal outcome. Importantly, negative or reversed low in the ductus venosus was a late finding because these fetuses had already sustained irreversible multiorgan damage due to hypoxemia. Also, gestational age at delivery was a major determinant of perinatal outcome independent of ductus venosus flow. Specifically, 36 percent of growth-restricted fetuses delivered between 26 and 29 weeks' gestation succumbed compared with only 5 percent delivered from 30 to 33 weeks.

Baschat and coworkers (2007) studied 604 growth-restricted fetuses using umbilical artery, middle cerebral artery, and ductus venosus Doppler velocimetry and reached similar conclusions. Speciically, absent or reversed flow in the ductus venosus was associated with profound generalized fetal metabolic collapse. hey too reported that gestational age was a powerful cofactor in ultimate perinatal outcome for growth-restricted fetuses delivered before 30 weeks. Put another way, by the time severely abnormal low is seen in the ductus venosus, it is too late because the fetus is already near death. Conversely, earlier delivery puts the fetus at risk for death due to preterm delivery. Ghidini (2007) concluded that these reports do not support routine use of ductus venosus Doppler in the monitoring of growth-restricted fetuses and recommended further study.

Vascular resistance in the uterine circulation normally decreases in the irst half of pregnancy due to invasion of maternal uterine vessels by trophoblastic tissue (Chap. 5, p. 92). This process can be detected using Doppler flow velocimetry, and uterine artery Doppler may be most helpful in assessing pregnancies at high risk of utero placental insuiciency (Abramowicz, 2008). Persistence or development of high-resistance patterns has been linked to various pregnancy complications (Lees, 2001; Yu, 2005). In a study of 30,519 unselected British women, Smith and colleagues (2007) assessed uterine artery velocimetry at 22 to 24 weeks' gestation. The risk of fetal death before 32 weeks, when associated with abruption, preeclampsia, or fetal-growth restriction, was significantly linked to high-resistance flow. This has led to suggestions for continued research of uterine artery Doppler velocimetry as a screening tool to detect pregnancies at risk for stillbirth (Reddy, 2008). Sciscione and Hayes (2009) reviewed the use of uterine artery Doppler flow studies in obstetrical practice. Because standards for the study technique and criteria for an abnormal test are lacking, they noted that uterine artery Doppler studies should not be considered standard practice in either low-or high-risk populations.

Antenatal forecasts of fetal health have clearly been the focus of intense interest, and several themes emerge. First, despite a continuous evolution of testing options, the precision or eicacy of any given method is limited. Second, the wide range of normal biological fetal variation makes interpretation of test results challenging. Last, despite the invention of increasingly complex testing methods, abnormal results are seldom reliable, prompting many clinicians to use antenatal testing to forecast fetal welness rather than ilness.

Platt and coworkers (1987) reviewed the eicacy of antenatal testing between 1971 and 1985 at Los Angeles County Hospital. During this 15-year period, more than 200,000 pregnancies were managed, and nearly 17,000 of these women underwent antepartum testing of various types. Fetal surveillance rose from < 1 percent of pregnancies in the early 1970s to 15 percent in the mid-1980s. hese authors concluded that such testing was clearly beneicial because the fetal death rate was signiicantly less in the tested high-risk pregnancies compared with the rate in those not tested. he study, however, did not consider other innovations incorporated into practice during those 15 years. Preliminary results from Ghana suggest that nonstress testing may be beneicial in low-resource countries (Lawrence, 2016). In an observational study of 316 pregnancies complicated by gestational hypertension, women undergoing nons tress testing had a nonsignificant decreased risk for stillbirth compared with those not tested-3.6 versus 9.2 percent, respectively.

The beneits of antenatal fetal testing have not been suficiently evaluated in randomized controlled trials according to hacker and Berkelman (1986). This was concluded after reviewing 600 reports, which included only four randomized trials that were not powered to permit detection of important beneits. From their review, Enkin and colleagues (2000) concluded that "despite their widespread use, most tests of fetal well-being should be considered of experimental value only rather than validated clinical tools." nother important and unanswered question is whether antepartum fetal surveillance identiies fetal asphyxia early enough to prevent brain damage. Manning and coworkers (1998) studied the incidence of cerebral palsy in 26,290 high-risk pregnancies managed with serial biophysical proile testing. These outcomes were compared with those of 58,657 low-risk pregnancies in which antepartum testing was not performed. The rate of cerebral palsy was 1.3 per 1000 in tested pregnancies compared with 4.7 per 1000 in untested women. Todd and coworkers (1992) attempted to correlate cognitive development in infants up to age 2 years following either abnormal umbilical artery Doppler velocimetry or nons tress test results. Only abnormal nonstress tests were associated with marginally poorer cognitive outcomes. These investigators concluded that by the time fetal compromise is diagnosed with antenatal testing, fetal damage has already been sustained. Low and associates (2003) reached a similar conclusion.

According to the American College of Obstetricians and Gynecologists (2016), a normal antepartum fetal test result is , highly reassuring that a stillbirth will not occur within 1 week. This conclusion was reached after an analysis of reports of stillbirth rates associated with the various antepartum fetal heart rate tests (Table 17-4). Note that these results are corrected to remove lethal anomalies and unpredictable catastrophes such

TABLE 17-4. Stillbirth Rates within 1 Week of a Normal Antepartum Fetal Surveillance Test

Nonstress test 1s.9 5861 Contraction stress test OJ 12,656 Biophysical profile 0.8 44,828 Modified biophysical profile 0.8 54,61s7 aCorrected fot lethal anomalies and unpredictable causes of fetal death such as abruption or cord accident.

as placental abruption or cord accidents. The most important consideration in deciding when to begin antepartum testing is the prognosis for neonatal survival.

The severity of maternal disease is another. In general, with most high-risk pregnancies, testing begins by 32 to 34 weeks' gestation. P�egnancies with severe complications might require testing as early as 26 to 28 weeks. he frequency for repeating tests has been arbitrarily set at 7 days, but more frequent testing is often done.

Abramowicz JS, Sheiner E: Ultrasound of the placenta: a systemic approach.

Part II: function assessment (Doppler). Placenta 29(11):921,o2008

Alanne L, Hofren J, Haapsamo M, et al: Efect of sildenail citrate on fetal central hemodynamics and placental volume blood low during hypoxemia in a chronic sheep model. Abstract No. 25. Presented at the 37th Annual Meeting of the Society for Maternal-Fetal Medicine. January 23-28, 2017

American Academy of Pediatrics and American College of Obstetricians and Gynecologists: Guidelines for perinatal care, 8th ed. Elk Grove Village, AAP,o2017

American College of Obstetricians and Gynecologists: Antepartum fetal surveillance. Practice Bulletin No. 145, July 2014, Reairmed 2016

Badalian 55, Chao CR, Fox HE, et al: Fetal breathing-related nasal fluid flow velocity in uncomplicated pregnancies. Am J Obstet Gynecol 169:563, 1993

Baschat AA: Opinion and review: Doppler application in the delivery timing in the preterm growth-restricted fetus: another step in the right direction. Ultrasound Obstet Gynecol 23: 11o8, 2004

Baschat AA, Cosmi E, Bilardo C, et al: Predictors of neonatal ourcome in earlyonset placental dysfunction. Obstet Gynecol 109:253, 200

Bilardo CM, Wolf H, Stigter RH, et al: Relationship between monitoring parameters and perinatal outcome in severe, early intrauterine growth restriction. Ultrasound Obstet Gynecol 23: 199, 2004

Bourgeois FJ, Thiagarajah 5, Harbert GM J r: The signiicance of fetal heart rate decelerations during nonstress testing. Am J Obstet Gynecol 150:213, 1984 Brown R, Patrick J: he nonstress test: how long is enough? Am J Obstet

Gynecol 141:646, 1981

Clark SL, Sabey P, Jolley K: Nonstress testing with acoustic stimulation and amnionic luid volume assessment: 5973 tests without unexpected fetal death. Am J Obstet Gynecol 160:694, 1989

Cousins LM, Poelder DM, Faron 5, et al: Nonstress testing at ;32.0 weeks' gestation: a randomized trial comparing diferent assessment criteria. Am J Obstet (4):311.e1, 2012

Dawes GS: Breathing before birth in animals and man. An essay in medicine.

Physiol Med 290:557, 1974

Dawes GS, Fox HE, Leduc BM, et al: Respiratory movements and rapid eye movement sleep in the foetal lamb. J Physiol 220: 119, 1972

Dayal AK, Manning FA, Berek DJ, et al: Fetal death after normal biophysical proile score: an eighteen year experience. m J Obstet Gynecol 181:o1231, 1999

Devoe LD: Antenatal fetal assessment: contraction stress test, nonstress test, vibroacoustic stimulation, amniotic fluid volume, biophysical proile, and modified biophysical profile-an overview. Semin Perinatol 32(4):247, 2008

Devoe LD, Castillo A, Sherline DM: The nonstress test as a diagnostic test: a critical reappraisal. Am J Obstet GynecoIo152:1047, 1986

Devoe LD, McKenzie J, Searle NS, et al: Clinical sequelae of the extended nonstress test. m J Obstet GynecoIo151:1074, 1985

DeVries J1, Visser GH, Prechd NF: The emergence of fetal behavior. II. Quantitative aspects. Early Hum Dev 12:99, 1985

Druzin ML, Gratacos J, Keegan A, et al: Antepartum fetal heart rate testing, 7. The signiicance of fetal bradycardia. m J Obstet Gynecol 139: 194, 1981

Eller DP, Scardo JA, Dillon E, et al: Distance from an intrauterine hydrophone as a factor afecting intrauterine sound pressure levels produced by the vibroacoustic stimulation test. Am J Obstet Gynecol 173:523, 1995

Enkin M, Keirse MJ, Renfrew M, et al: A Guide to Efective Care in Pregnancy and Childbirth, 3rd ed. New York, Oxford University Press, 2000

Frager NB, Miyazaki FS: Intrauterine monitoring of contractions during breast stimulation. Obstet Gynecol 69:767, 1987

Freeman RK: The use of the oxytocin challenge test for antepartum clinical evaluation of utero placental respiratory function. Am J Obstet Gynecol 121:481, 1975

Fr0en JF, Tviet

JV, Saastad E, et a1: Management of decreased fetal movements. Semin ,r2008

Ghidini A: Doppler of the ductus venosus in severe preterm fetal growth restriction. A test in search of a purpose? Obstet Gynecol 109:250, 200

Gonzalez JM, Stamilio OM, Ural S, et al: Relationship between abnormal fetal testing and adverse perinatal outcomes in intrauterine growth restriction. Am J Obstet Gynecol 196:e48, 2007

Grant A, Elbourne 0, Valentin L, et al: Routine formal fetal movement counting and risk of antepartum late death in normally formed singletons. Lancet 2:345, 1989

Grubb OK, Paul RH: Amnionic luid index and prolonged antepartum fetal heart rate decelerations. Obstet Gynecol 79:558, 1992

Guinn DA, Kimberlin KF, Wigton TR, et al: Fetal heart rate characteristics at 25 to 28 weeks gestation. Am J Perinatol 15:507, 1998

Hage ML: Interpretation of nonstress tests. Am J Obstet Gynecol 153:490, 1985

Hammacher K, Huter A, Bokelmann J, et al: Foetal heart frequency and perinatal condition of the foetus and newborn. Gynaecologia 166:349, 1968

Harrington K, Thompson 0, Jorden L, et al: Obstetric outcomes in women who present with a reduction in fetal movements in the third trimester of pregnancy. J Perinat Med 26:77, 1998

Ho 0, Wang J, Homann Y, et a1: Use of the myocardial performance index in decreased fetal movement assessment: a case-control study. Fetal Diagn Ther June 15, 2017 [Epub ahead of print]

Hoskins IA, Frieden FJ, Young BK: Variable decelerations in reactive nonstress tests with decreased amnionic luid index predict fetal compromise. Am J Obstet Gynecol 165: 1094, 1991

Huddleston JF, Surlif JG, Robinson 0: Contraction stress test by intermittent nipple stimulation. Obstet Gynecol 63:669, 1984

Jansson LM, DiPietro J, Elko A: Fetal response to matenal methadone administration. Am J Obstet Gynecol 193:611,2005

Johnson MJ, Paine LL, Mulder HH, et al: Population diferences of fetal biophysical and behavioral characteristics. Am J Obstet Gynecol 166: 138, 1992

Kaur S, Picconi JL, Chadha R, et al: Biophysical proile in the treatment of intrauterine growth-restricted fetuses who weigh < 1000 g. Am J Obstet Gynecol 199:264.el, 2008

Konje JC, Bell SC, Taylor DT: Abnormal Doppler velocimetry and blood low volume in the middle cerebral artery in very severe intrauterine growth restriction: is the occurrence of reversal of compensatory low too late? BJOG 108:9 3,r2001

Kopecky EA, Ryan ML, Barrett JFR, et a1: Fetal response to maternally administered morphine. Am J Obstet Gynecol 183:424,r2000

Lalor JG, Fawole B, Alirevic Z, et al: Biophysical proile for fetal assessment in high risk pregnancies. Cochrane Database Syst Rev I :CD000038, 2008 Laventhal NT, Dildy GA III, Belfort MA: Fetal tachyarrhythmia associated with vibroacoustic stimulation. Obstet Gynecol 101: 116, 2003

Lawrence ER, Quarshie EL, Lewis KF, et al: Introduction of cardiotocograph monitoring improves birth outcomes in women with preeclampsia in Ghana. IntJ Gynaecol Obstet 132(1):103,r2016

Lee CY, DiLoreto Pc, O'Lane JM: A study of fetal heart rate acceleration patterns. Obstet GynecoIr45:142,

Lees C, Parra M, Missfelder-Lobos H, et al: Individualized risk assessment for adverse pregnancy outcome by uterine artery Doppler at 23 weeks. Obstet Gynecol 98:369, 2001

Leveno KJ, Williams ML, DePalma RT, et al: Perinatal outcome in the absence of antepartum fetal heart rate acceleration. Obstet Gynecol 61 :347, 1983 Low JA, Killen H, Derrick EJ: Antepartum fetal asphyxia in the preterm preg nancy. Am J Obstet Gynecol 188:461, 2003

Macones GA, Hankins GO, Spong CY, et al: The 2008 National Institute of Child Health and Human Development workshop report on electronic fetal monitoring: update on deinitions, interpretation, and research guidelines. Obstet Gynecol 112:661, 2008

Manning FA, Bondagji N, Harman CR, et 1: Fetal assessment based on fetal biophysical proile scoring VIII: the incidence of cerebral palsy in tested and untested perinates. Am J Obstet Gynecol 178:696, 1998

Manning FA, Morrison 1, Harman CR, et a1: Fetal assessment based on fetal biophysical proile scoring: experience in 19,221 referred high-risk pregnancies, 2. n analysis of false-negative fetal deaths. Am J Obstet Gynecol 15 :880, 1987

Manning FA, Platt LD, Sipos L: Antepartum fetal evaluation: development of a fetal biophysical proile. Am J Obstet Gynecol , 1980 Manning FA, Snijders R, Harman CR, et al: Fetal biophysical proile score,

VI. Correlation with antepartum umbilical venous fetal pH. Am J Obstet GynecoIr169:755, 1993

Matsuura M, Murata Y, Hirano T, et al: he efects of developing autonomous nervous system on FHR variabilities determined by the power spectral analysis. Am J Obstet Gynecol 174:380, 1996

Meis PJ, Ureda JR, Swain M, et a1: Variable decelerations during nonstress tests are not a sign of fetal compromise. Am J Obstet Gynecol 154:586, 1986 Miller DA, Rabello YA, Paul RH: The modiied biophysical proile: antepar tum testing in the 1990s. Am J Obstet GynecoIr174:812, 1996a

Miller F, Miller 0, Paul R, et al: Is one fetal heart rate acceleration during a nons tress test as reliable as two in predicting fetal status? Am J Obstet 4:337, 1996b

Moise KJ Jr: he usefulness of middle cerebral artery Doppler assessment in the treatment of the fetus at risk for anemia. Am J Obstet Gynecol 198: 161. e1,r2008

Moore TR, Piaquadio K: A prospective evaluation of fetal movement screening to reduce the incidence of antepartum fetal death. Am J Obstet Gynecol 160: 1075, 1989

Nabhan AF, Abdelmoula YA: Amniotic luid index versus single deepest vertical pocket as a screening test for preventing adverse pregnancy outcome. Cochran Database Syst Rev 3:CD006593, 2008

Nageotte MP, Towers CV, Asrat T, et al: Perinatal outcome with the modiied biophysical proile. Am J Obstet Gynecol 170: 2, 1994 Nijhuis JG, Prechtl HF, Martin CB J r, et al: Are there behavioural states in the human fetus? Early Hum Dev 6: , 1982 Oepkes 0, Seaward PG, andenbussche FP, et al: Doppler ultrasonography versus amniocentesis to predict fetal anemia. N Engl J Med 355: 156, 2006 Oosterhof H, vd Stege JG, Lander M, et al: Urine production rate is related to behavioural states in the near term human fetus. BJOG 100:920, 1993 Ott ('], Mora G, Arias F, et al: Comparison of the modiied biophysical proile to a "new" biophysical proile incorporating the middle cerebral artery to umbilical artery velocity low systolic/diastolic ratio. Am J Obstet Gynecol 178:1346,r1998 Ozkaya E, Baser E, Cinar M, et al: Does diurnal rhythm have an impact on fetal biophysical profile? J Maten Fetal Neonatal Med 25(4):335, 2012 Patrick J, Campbell K, Carmichael L, et al: Patterns of gross fetal body movements over 24-hour observation intervals during the last 10 weeks of pregnancy. Am J Obstet Gynecol 142:363, 1982 Patrick J, Campbell K, Carmichael L, et al: Patterns of human fetal breathing during the last 10 weeks of pregnancy. Obstet Gynecol 56:24, 1980 Pazos R, Vuolo K, Aladjem S, et al: Association of spontaneous fetal heart rate decelerations during antepartum nonstress testing and intrauterine growth retardation. Am J Obstet Gynecol 144:574, 1982 Perez-Oelboy A, Weiss J, Michels A, et al: A randomized trial of vibroacoustic stimulation for antenatal fetal testing. Am J Obstet Gynecol 187:S 146, 2002 Pillai M, James 0: Behavioural states in normal mature human fetuses. Arch Dis Child 65:39, 1990a Pillai M, James 0: The development of fetal heart rate patterns during normal pregnancy. Obstet Gynecol 6:812, 1990b Platt LD, Paul RH, Phelan J, et al: Fifteen years of experience with antepartum fetal testing. Am J Obstet Gynecol 156:1509, 198 Ray M, Freeman R, Pine S, et al: Clinical experience with the oxytocin challenge test. Am J Obstet Gynecol 1r14: 1, 2 Raybun WF: Clinical signiicance of perceptible fetal motion. Am J Obstet Gynecol 138:210, 1980 Reddy UM, Abuhamad Z, Levine 0, et al: Fetal imaging: executive summary of a joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Sociery for Maternal-Fetal Medicine, American Institute of Ultrasound in Medicine, American College of Obstetricians and Gynecologists, American College of Radiology, Society for Pediatric Radiology, and Society of Radiologists in Ultrasound Fetal Imaging Workshop. Obstet Gynecol 123(5):10 0,r2014 Reddy UM, Filly A, Copel JA, et al: Prenatal imaging: ultrasonography and magnetic resonance imaging. Obstet Gynecol 112(1):145,r2008 Saastad E, Winje BA, Stray Penderson B, et al: Fetal movement counting improved identiication of fetal growth restriction and perinatal outcomesa multi-centre, randomized, controlled trial. PLoS One 6(12):e28482, 2011 Sadovsky E, Evron S, Weinstein 0: Daily fetal movement recording in normal pregnancy. Riv Obstet Ginecol Practica Med Perinatal 59:395, J 9a Sadovsky E, Laufer N, Allen JW: he incidence of diferent types of fetal movement during pregnancy. BJOG 86:10, 1979b Sadovsky E, Yafe H: Daily fetal movement recording and fetal prognosis. Obstet Gynecol 41:845,r1973

Sajapala S, AboElIail MA, Kanenshi K, et a1: 40 ultrasound study of fetal movement early in the second trimester of pregnancy. J Perinat Med 45(6):737,r2017 Salvesen DR, Freeman J, Brudenell JM, et al: Prediction of fetal acidemia in pregnancies complicated by maternal diabetes by biophysical scoring and fetal heart rate monitoring. BJOG , 1993 Scala C, Bhide A, Familiari A, et al: Number of episodes of reduced fetal movement at term: association with adverse perinatal outcome. Am J Obstet Gynecol 213(5):678.el, 2015

Schell pfefer MA, Hoyle 0, Johnson JWC: Antepartum uterine hypercontractiliry secondary to nipple stimulation. Obstet Gynecol 65:588, 1985 Sciscione AC, Hayes EJ: Uterine artery Doppler low studies in obstetric practice. Am J Obstet Gynecol 20r1(2):121, 2009

Sherer DM, Spong CY, Ghidini A, et al: In preterm fetuses decreased amniotic luid volume is associated with decreased fetal movements. Am J Obstet Gynecol 174:344, 1996

Smith CV, Nguyen HN, Kovacs B, et al: Fetal death following antepartum fetal heart rate testing: a review of 65 cases. Obstet Gynecol 70: 18, 1987 Smith Gc, Yu CK, Papageorghiou AT, et al: Maternal uterine artery Doppler low velocimetry and the risk of stillbirth. Obstet Gynecol 109: 144, 2007

Smith JH, Anand KJ, Cotes PM, et al: Antenatal fetal heart rate variation in relation to the respiratory and metabolic status of the compromised human fetus. BJOG 95:980, 1988

Sorokin Y, Bottoms SF, Dierker CJ, et al: he clustering of fetal heart rate changes and fetal movements in pregnancies berween 20 and 30 weeks gestation. Am J Obstet Gynecol 143:952, 1982

Spinillo A, Montanari L, Bergante C, et al: Prognostic value of umbilical artery Doppler studies in unselected preterm deliveries. Obstet Gynecol 105:613, 2005 hacker SB, Berkelman RL: Assessing the diagnostic accuracy and eicacy of selected antepartum fetal surveillance techniques. Obstet Gynecol Surv 41:121,r1986

Timor-Tritsch IE, Dierker LJ, Hertz RH, et al: Studies of antepartum behavioral state in the human fetus at term. Am J Obstet Gynecol 132:524, 1978 Todd AL, Tridinger BJ, Cole MJ, et al: Antenatal tests of fetal welfare and development at age 2 years. Am J Obstet Gynecol 167:66, 1992

Todros T, Sciarrone A, Piccoli E, et al: Umbilical Doppler waveforms and placental villous angiogenesis in pregnancies complicated by fetal growth restriction. Obstet Gynecol 93:499, 1999

Trudinger B: Doppler: more or less? Ultrasound Obstet Gynecol29 (3):243, 2007

Turitz AL, Bastek JA, Sam mel MD, et al: Can vibroacoustic stimulation improve the eiciency of a tertiary care antenatal testing unit? J Matern Fetal Neonatal Med 25(12):2645,r2012

VindJa S, James 0: Fetal behavior s a test oHetl well-being. BJOG 102:597, 1995

Visser GHA, Redman CWG, Huisjes HJ, et al: Nonstressed antepartum heart rate monitoring: implications of decelerations after spontaneous contractions. Am J Obstet Gynecol 138:429, 1980

Warrander LK, Batra G, Bernatavicius G, et al: Maternal perception of reduced fetal movements is associated with altered placental structure and function. PLoS One 7(4):e34851, 2012

Weiner Z, Divon MY, Katz N, et al: Multi-variant analysis of antepartum fetal test in predicting neonatal outcome of growth retarded fetuses. Am J Obstet Gynecol 174:338, 1996

Williams KP, Farquharson OF, Bebbington M, et al: Screening for fetal wellbeing in a high-risk pregnant population comparing the nonstress test with umbilical artery Doppler velocimetry: a randomized controlled clinical trial. Am J Obstet Gynecol 188: 1366, 2003

Yu CK, Smith GC, Papageorghiou AT, et al: An integrated model for the prediction of preeclampsia Llsing maternal factors and uterine artery Doppler velocimetry in unselected low-risk women. Am J Obstet Gynecol 193:429,r2005

Zelop CM, Richardson OK, Hefner LJ: Outcomes of severely abnormal umbilical artery Doppler velocimetry in structurally normal singleton fetuses. Obstet Gynecol 8 :434, 1996

NOMENCLATUREe. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346

FIRST-TRIMESTER SPONTANEOUS ABORTION .e.e.e347

SPONTANEOUS ABORTION CLINICAL CLASSIFICATION .e348

RECURRENT MISCARRIAGE ..e......... ....e.. ..e352

MIDTRIMESTER ABORTIONe. . . . . . . . . . . . . . . . . . . . . . . 353

CERVICAL INSUFFICIENCY ..e..e..... . .... ....... 354

INDUCED ABORTION .e.. ....e.e...e..e...e...e...e. 357

FIRST-TRIMESTER ABORTION METHODS ..........e. 358

SECOND-TRIMESTER ABORTION METHODS .. .... . 362

In the eary months of pregnancy spontaneous expulsion of the ovum is neary always preceded by the death of the oetus. For this reason the consideration of the aetioloy of abortion practicaly resolves itsef into determining the cause of oetal death. In the later months, on the other han, the oetus is frequenty born alive, and other actors must be looked or to explain its expulsion.

-J. Whitridge Williams (1903)

In early pregnancy, miscarriage is a common event. Most early losses stem from genetic abnormalities or yet unidentified reasons. Thus, the opportunity for prevention is currently small. Women with later miscarriage or with recurrent miscarriage more likely have a repetitive cause that may be modiied. In contrast to these spontaneous losses, pregnancy termination may be elected. For both induced abortion and miscarriage, management has evolved to include surgical or medical options, and providers should have an understanding of these techniques and their potential complications.

Abortion is defined as the spontaneous or induced termination of pregnancy before fetal viability. It thus is appropriate that miscarriage and abortion are terms used interchangeably. However, popular use of abortion by laypersons implies intended pregnancy termination, and many prefer miscarriage for spontaneous loss. In contrast, induced abortion describes surgical or medical termination of a live fetus that has not reached viability.

Terms used to define fetal viability and thus an abortus vary among authoritative organizations. The National Center for Health Statistics, the Centers for Disease Control and Prevention, and the World Health Organization all deine abortion as pregnancy termination or loss before 20 weeks' gestation or with a fetus delivered weighing <500 g. hese criteria, however, are somewhat contradictory because the mean birthweight of a 20-week fetus is 320 g, whereas 500 g is the mean for 22 to 23 weeks (Moore, 1977). Further confusion may derive from criteria set by state laws that deine abortion even more widely.

Technological developments have added to current abortion terminology. For example, precise measurement of serum human chorionic gonadotropin (hCG) concentrations can identiY extremely early pregnancies. Also, transvaginal sonography allows greater inspection of failed pregnancies, but recommendations vary as to terms for: (1) early conceptions in which no products are seen sonographically, (2) pregnancies that display a gestational sac but no embryo, and (3) those in which a dead embryo is seen (Kolte, 2015; Silver, 2011). Further, incongruity exists for the term eary pregnancy loss itsel. Currently, the American College of Obstetricians and Gynecologists (2017 c) deines this as a nonviable, intrauterine pregnancy (IUP) with either an empty gestational sac or a ges activity within the irst 126' weeks of gestation. Of other clini cal terms, spontaneous abortion includes threatened, inevitable, incomplete, complete, and missed abortion. Septic abortion is used to further classiy any of these that are complicated further by infection. Recurrent pregnancy loss is variably deined but is meant to identiy women with repetitive miscarriage.

pic gestations. he term pregnancy of unknown location (PUL) confirmed sonographic location. In this context, ive categories are proposed for early pregnancies: definite ectopic pregnancy, probable ectopic, PUL, probable IUP, and definite IUP (Barn hart, 2011). Diagnostic and management options for ectopic gestation are described in Chapter 19 (p. 373).

More than 80 percent of spontaneous abortions occur within the irst 12 weeks of gestation. With irst-trimester losses, demise of the embryo or fetus nearly always precedes spontaneous expulsion. Death is usually accompanied by hemorrhage into the decidua basalis. This is followed by adjacent tissue necrosis that stimulates uterine contractions and expulsion. An intact gestational sac is usually filled with luid. An anembryonic miscarriage contains no identifiable embryonic elements. Less accurately, the term blighted ovum may be used (Silver, 201l). The others are embyonic miscarriages, which often display a developmental abnormality of the embryo, fetus, yolk sac, and, at times, the placenta. In contrast, in later pregnancy losses, the fetus usually does not die before expulsion, and other sources for abortion are sought.

Rates for miscarriage vary according to the study population. In pregnancies aged 5 to 20 weeks' gestation, the incidence ranges from 11 to 22 percent and is higher in earlier weeks (Ammon Avalos, 2012). To evaluate rates starting at conception, Wilcox and colleagues (1988) studied 221 healthy women trying to conceive through 707 menstrual cycles and found a miscarriage rate of 31 percent. This study found that two thirds of these losses are early and clinicaly silent. Currently, certain factors are known to inluence clinicaly apparent miscarriage. However, it is unknown if these same factors also afect clinically silent pregnancy loss.

Of all miscarriages, approximately half are euploid abortions, that is, carrying a normal chromosomal complement. The other half has a chromosomal abnormality. Initially determined by tissue karyotyping, this percentage appears to persist even when implementing newer cytogenetic techniques Qenderny, 2014). Notably, the American College of Obstetricians and Gynecologists (20 16d) does not recommend routine use of chromosomal microarray testing of irst-trimester fetal tissues. However, these organizations, and the American Society for Reproduc tive Medicine (2012), recognize its value if cytogenetic analysis alters future care.

Both abortion and chromosomal anomaly rates decline with advancing gestational age (Ammon Avalos, 2012; Eiben, 1990).

Kajii and associates (1980) noted that 75 percent of chromo somally abnormal abortions occurred by 8 weeks' gestation. Of chromosomal abnormalities, 95 percent are caused by maternal gametogenesis errors, and 5 percent by paternal errors Qacobs, 1980). Most common abnormalities are trisomy, found in 50 to 60 percent; monosomy X, in 9 to 13 percent; and triploidy, in 11 to 12 percent (Eiben, 1980; Jenderny, 2014).

Trisomies typically result from isolated nondisjunction, rates of which rise with maternal age (Bow§, 1975). Trisomies of chromosomes 13, 16, 18, 21, and 22 are most common. In contrast, balanced structural chromosomal rearrangements may originate from either parent and are found in 2 to 4 percent of couples with recurrent pregnancy loss.

Monosomy X (45,X) is the single most frequent specific chro mosomal abnormality. his is Turner syndrome, which usually results in abortion, but liveborn females are described in Chap ter 13 (p. 259). Conversely, autosomal monosomy is rare and incompatible with life.

Triploidy is often associated with hydropic or molar placental degeneration (Chap. 20, p. 389). The fetus within a partial hydatidiform mole frequently aborts early, and the few carried longer are all grossly deformed. Advanced maternal and paternal ages do not increase the incidence of triploidy. Tetraploid fetuses most often abort early in gestation, and they are rarely liveborn.

In chromosomally normal pregnancy losses, maternal influences play a role. The causes of euploid abortions are poorly understood, but various medical disorders, environmental conditions, and developmental abnormalities have been implicated.

Euploid pregnancies abort later than aneuploid ones. Specifically, the rate of euploid abortion peaks at approximately 13 weeks (Kajii, 1980). In addition, the incidence of euploid abortion rises dramatically after maternal age exceeds 35 years (Stein, 1980).

Some common viruses, bacteria, and parasites that invade the normal human can infect the fetoplacental unit by blood-borne transmission. Others may infect locally through genitourinary infection or colonization. However, despite the numerous infections acquired in pregnancy and discussed in Chapters 64 and 65, these uncommonly cause early abortion.

Some disorders are possibly linked with higher rates of early pregnancy loss and are discussed in their respective chapters. Prominent risks are associated with poorly controlled diabetes mellitus, obesity, thyroid disease, and systemic lupus erythematosus. In these and others, inflammatory mediators may be an underlying theme (Kalagiri, 2016; Sjaarda, 2017). Although thrombophilias were initially linked to various pregnancy outcomes, most putative associations have been refuted (American College of Obstetricians and Gynecologists (2017e).

herapeutic doses of radiation are undeniably abortifacient. Doses that cause abortion are not precisely known, but suggested parameters are found in Chapter 46 (p. 906). Similarly, the efects of chemotherapy exposure in causing abortion are not well deined (Chap. 12, p. 242). Particularly worrisome are women with an ongoing pregnancy after early exposure to methotrexate, described later (p. 361). Of cancer survivors, those who were treated with abdominopelvic radiotherapy or chemotherapy may later be at greater risk for miscarriage, as discussed in Chapter 63 (p. 1192).

The risk of miscarriage caused by surgery is not well studied. But, as discussed in Chapter 46 (p. 901), uncomplicated surgical procedures performed during early pregnancy are unlikely to increase the abortion risk (Mazze, 1989). Of indications, ovarian tumors can generally be resected without inciting miscarriage. An important exception involves early removal of the corpus luteum or the ovary in which it resides. If performed before 10 weeks' gestation, supplemental progesterone should be given, and supplementation is enumerated in Chapter 63 (p.i1198).

Trauma seldom causes first-trimester miscarriage, and although Parkland Hospital is a busy trauma center, this is an infrequent association. Major trauma-especially abdominalcan cause fetal loss, but is more likely as pregnancy advances (Chap. 47, p. 925).

Sole deficiency of one nutrient or moderate deiciency of all does not appear to increase risks for abortion. Even in extreme cases-for example, hyperemesis gravidarum-abortion is rare. Dietary quality may play a role, as miscarriage risk may be reduced in women who consume a diet rich in fruits, vegetables, whole grains, vegetable oils, and ish (Gaskins, 2015). With regard to maternal weight, underweight is not associated with a greater miscarriage risk (Balsells, 2016). However, as noted in Chapter 48 (p. 938), obesity does raise pregnancy loss rates.

Lifestyle choices reputed to be associated with a higher miscarriage risk are most often related to chronic and especially heavy use oflegal substances. he most commonly used is alcohol, with its potent teratogenic efects discussed in Chapter 12 (p. 239). That said, an increased miscarriage risk is only seen with regular or heavy use (Avalos, 2014; Feodor Nilsson, 2014).

Approximately 10 percent of pregnant women admit to cigarette smoking (Centers for Disease Control and Prevention, 2016). It seems intuitive that cigarettes could cause early pregnancy loss (Pineles, 2014). Adverse efects of illicit drugs areidiscussed in Chapter 12 (p. 249).

Excessive cafeine consumption-not well defined-has been associated with a higher abortion risk. Reports link heavy intake of approximately ive cups of cofee per dayabout 500 mg of cafeine-with a slightly greater abortion risk (Cnattingius, 2000; Klebanof, 1999). Studies of "moderate" intake-less than 200 mg daily-did not indicate increased risk (Savitz, 2008; Weng, 2008). In contrast, in one prospective cohort of more than 5100 gravidas, cafeine was linked to miscarriage but not in a dose-response relationship (Hahn, 2015). Currently, the American College of Obstetricians and Gynecologists (2016e) has concluded that moderate consumption likely is not a major abortion risk and that any associated risk with higher intake is unsettled.

Environmental toxins suggested to have a possible link to miscarriage include bisphenol A, phthalates, polychlorinated biphenyls, and dichlorodiphenyltrichloroethane (DDT) (Krieg, 2016). Even fewer studies implicate occupational exposures. In a follow-up of the Nurses Health Study II, Lawson and associates (2012) reported slightly increased miscarriage risks in nurses exposed to sterilizing agents, x-rays, and antineoplastic drugs. Also, a higher miscarriage risk was found for dental assistants exposed to more than 3 hours of nitrous oxide daily if there was no gas-scavenging equipment (Boivin, 1997).

Increasing paternal age is signiicantly associated with an greater risk for abortion (de La Rochebrochard, 2003). In the Jerusalem Perinatal Study, this risk was lowest before age 25 years, after which it progressively increased at 5-year intervals (Kleinhaus, 2006). The etiology of this association is not well studied, but chromosomal abnormalities in spermatozoa likely play a role (Sartorius, 2010).

his diagnosis is presumed when bloody vaginal discharge or bleeding appears through a closed cervical os during the first 20 weeks. This bleeding in early pregnancy must be diferentiated from that with implantation, which some women have at the time of their expected menses. Aside from this, almost one fourth of women develop bleeding during early gestation that may persist for days or weeks. It may be accompanied by suprapubic discomfort, mild cramps, pelvic pressure, or persistent low backache. Of symptoms, bleeding is by far the most predictive risk factor for pregnancy loss.

Even if miscarriage does not follow threatened abortion, rates of later adverse pregnancy outcomes are increased as shown in Table

Of these, highest risks are for preterm delivery. Weiss and coworkers (2004) noted greater risks for adverse outcomes in later pregnancy if early bleeding was heavy rather than light. Compared with those without bleeding, women with first-trimester bleeding in an initial pregnancy have higher recurrence rates in their second (Lykke, 2010).

TABLE 18-1. Adverse Outcomes That Are Increased in Women with Threatened Abortion

Placenta previa Preterm ruptured membranes Placental abruption Preterm birth Manual removal of placenta Low-birthweight infant Cesarean delivery Fetal-growth restriction

From Lykke, 2010; Saraswat, 2010; Weiss, 2004; Wijesiriwardana,s2006.

Every woman with an early pregnancy, vaginal bleeding, and pain should be evaluated. he primary goal is prompt diagnosis of ectopic pregnancy, and serial quantitative serum S-hCG levels and transvaginal sonography are integral tools. Because these are not 100-percent accurate to confirm early embryo death or location, repeat evaluations are often necessary. With a robust uterine pregnancy, serum S-hCG levels should rise at least 53 to 66 percent every 48 hours (Barnhart, 2004c; Kadar, 1982). Although a less-used marker, serum progesterone concentrations <5 ng/mL suggest a dying pregnancy. Values >20 ng/mL support the diagnosis of a healthy one (Daily, 1994).

Transvaginal sonography is used to locate the pregnancy and determine viability. If this cannot be done, then a PUL is diagnosed, and serial surveillance is implemented for clinically stable women. The gestational sac-an anechoic fluid collection that represents the exocoelomic cavity-may be seen by 4.5 weeks (Fig. 9-3, p. 159). At this same time, S-hCG levels generally measure 1500 to 2000 mIU/mL (Barnhart, 1994; Timor-Tritsch, 1988). Connolly and colleagues (2013) observed that this value could be as low as 390 mIU/mL. However, they also noted that a threshold as high as 3500 mIU/mL may be needed to identiY the gestational sac in some cases that ultimately yield a viable singleton IUP.

Another caveat is that a gestational sac may appear similar to other intrauterine fluid accumulations-the so-called pseudogestational sac (Fig. 19-4, p. 375). his pseudosac may be blood derived from a bleeding ectopic pregnancy and is easier to exclude once a yolk sac is seen. Typically, the yolk sac is visible by 5.5 weeks and with a mean gestational-sac diameter of 10 mm. Thus, the diagnosis of an IUP should be made cautiously if the yolk sac is not yet seen (American College of Obstetricians and Gynecologists, 20 16h).

For management of threatened abortion, observation is the norm. Acetaminophen-based analgesia will help relieve discomfort from cramping. Bed rest is often recommended but does not improve outcomes. The hematocrit and blood type is determined. If anemia or hypovolemia is signiicant, then pregnancy evacuation is generally indicated. In cases in which there is a live fetus, some instead may choose transfusion and further observation.

During abortion, bleeding follows partial or complete placental separation and dilation of the cervical os. Before 10 weeks' gestation, the fetus and the placenta are frequently expelled together, but later, they deliver separately. hus, tissue may remain entirely within the uterus or partially extrude through the cervix. Products lying loosely within the cervical canal can be easily extracted with ring forceps. In contrast, with incom plete expulsion, three management options include curettage, expectant management, or misoprostol (Cytotec), which is prostaglandin EI (PGEI) (Kim, 2017). he last two are deferred in clinically unstable women or those with uterine infection.

Each option has its own risks and benefits. With all three, infection and need for transfusion are uncommon. However, misoprostol and expectant care are associated with unpredictable bleeding, and some women will undergo unscheduled curettage. Expectant management of spontaneous incomplete abortion has failure rates that approximate 25 percent in randomized trials (Nadarajah, 2014; Nielsen, 1999; Trinder, 2006). Some observational studies have shown failure rates of 10 to 15 percent (Blohm, 2003; Casikar, 2012; Luise, 2002). Medical therapy carries failure rates of 5 to 30 percent (Dao, 2007; Shochet, 2012; Trinder, 2006). In many studies for this, an oral misoprostol dose of 600 1g has been used (American College of Obstetricians and Gynecologists, 2009). Alternatively, an 800-l1g vaginal or a 400-1g oral or sublingual misoprostol dose is suitable. Last, curettage usually results in a quick resolution that is 95-to 100-percent successful. However, it is invasive and not necessary for all women.

At times, complete expulsion of the entire pregnancy may ensue, and the cervical os subsequently closes. A history of heavy bleeding, cramping, and passage of tissue is typical. Patients are encouraged to bring in passed tissue, in which a complete gestation should be discerned from blood clots or a decidual cast. he latter is a layer of endometrium in the shape of the uterine cavity that when sloughed can appear as a collapsed sac (Fig. 19-2, p. 373).

If an expelled complete gestational sac is not identified, transvaginal sonography is performed to diferentiate a complete abortion from threatened abortion or ectopic pregnancy. Characteristic findings of a complete abortion include a minimally thickened endometrium without a gestational sac. However, this does not guarantee a recent uterine pregnancy. Condous and associates (2005) described 152 women with heavy bleeding, an empty uterus with endometrial thickness < 15 mm, and a diagnosis of completed miscarriage. Six percent were subsequently found to have an ectopic pregnancy. Thus, a complete abortion cannot be surely diagnosed unless: (1) true products of conception are seen grossly or (2) unless sonography confidently documents first an intrauterine pregnancy and then later an empty cavity. In unclear settings, serial serum hCG level measurements aid clariication. With complete abortion, these levels drop quickly (Table 18-2).

This describes dead products of conception that have been retained for days or weeks in the uterus with a closed cervical os. Diagnosis is imperative prior to intervention and avoids interruption of a potentially live IUP. Transvaginal sonography is the primary tool.

TABLE 18-2. Percentage Decline of Initial Serum

FIGURE 18-1 Transvaginal sonogram displays a large anechoic sac consistent with an anembryonic gestation. Calipers measure uterine length and anteroposterior thickness in a sagittal plane.

aThe percentage decline is given as the expected decline.

The minimum expected decline in parentheses is the 95th percentile value. Declines less than this minimum may reflect retained either intrauterine or extrauterine trophoblast.

Data from Barnhart, 2004a; Chung, 2006.

At 5 to 6 weeks' gestation, a 1-to 2-mm embryo adjacent to the yolk sac can be seen (Daya, 1993). As listed in Table 18-3, absence of an embryo in a sac with a mean sac diameter (MSD) ::25 mm signiies a dead fetus (Fig. 18-1). Fetal cardiac activity can typically be detected at 6 to 6.5 weeks with a crown-rump length (CL) of 1 to 5 mm and an MSD of 13 to 18 mm (Goldstein, 1992; Levi, 1990). A threshold CL ::7 mm with absent cardiac activity is also used to diagnose nonviability (Doubilet, 2013). Preisler and associates (2015) implemented the guidelines in Table 18-3 and conirmed' these CL and MSD thresholds. However, for cases in which a gestational sac had no embryo or yolk sac and measured < 12 mm, they

TABLE 18-3. Guidelines for Early Pregnancy Loss Diagnosisa

CRL ::7 mm and no heartbeat MSD ::25 mm and no embryo An initial US scan shows a gestational sac with yolk sac, and after ::11 days no embryo with a heartbeat is seen An initial US scan shows a gestational sac without a yolk sac, and after ::2 weeks no embryo with a heatbeat is seen

Transvaginal preferable to transabdominal US

M-mode imaging used to document and measure heartbeat Doppler US not used to evaluate a normal early embryo aFrom the Society of Radiologists in Ultrasounds; American College of Radiology.

CRL = crown-rump length; MSD = mean sac diameter; US = ultrasound.

From Doubilet,

Lane, 2013.

recommended that to diagnose nonviability after 2 weeks, in addition to the lack of an embryo with a heartbeat, the MSD should have failed to double.

During scanning, because of theoretical temperature elevation in tissues exposed to pulsed Doppler beam, this modality is applied only when needed for additional diagnostic purposes. M-mode should be used to document cardiac activity and measure the rate (Lane, 2013). Finding of an IUP and cardiac activity lowers subsequent miscarriage rates (Siddiqi, 1988).

In addition to the diagnostic parameters of Table 18-3, other softer sonographic markers may portend early pregnancy failure. Values for yolk sac diameters (measured inner-to-inner ring) for each gestational week in normal pregnancy have been established. Yolk sac diameters ::6 mm in pregnancies < 10 weeks' gestation are suspicious for pregnancy failure (Berdahl, 2010; Lindsay, 1992). The fetal heart rate in the irst trimester rises from 110 to 130 beats per minute (bpm) at 6 weeks' gestation to 160 to 170 bpm at 8 weeks (Achiron, 1991; Rauch, 2009). A slower heart rate is unfavorable, especially those <85 bpm (Laboda, 1989; Stefos, 1998). Even with cardiac activity, fetuses with a small MSD may presage embryonic loss. Speciically, a diference <5 mm between the MSD and CRL values raises concern (Bromley, 1991; Dickey, 1992). Last, subchorionic hematoma, that is, blood collected between the chorion and uterine wall, often accompanies threatened miscarriage. Studies are contradictory as to its association with ultimate pregnancy loss (Pedersen, 1990; Stabile, 1989; Tuuli, 2011). Bennett and associates (1996) noted that miscarriage risk correlated with larger hematoma size, older maternal age, and bleeding at a gestational age :;8 weeks.

With rapid confirmation of embryonic or fetal death, surgicalior medical evacuation or expectant observation is an option. As with induced abortion, nonsurgical options balance their noninvasiveness against heavier procedural bleeding, longer completion times, and lower success rates. Of options, expectant care underperforms medical or surgical options, and failure rates range from 15 to 50 percent (Luise, 2002; Trinder, 2006; Zhang, 2005). Also, weeks may pass between pregnancy failure diagnosis and actual spontaneous miscarriage.

Alternatively, misoprostol can be given to hasten uterine evacuation. A single 800-l-1g dose vaginally is a common stan dard (American College of Obstetricians and Gynecologists, 20 16c). It may be repeated in 1 to 2 days, and one large trial reported that 22 percent of women required a second dose (Zhang, 2005). Overall, failure rates range from 15 to 40 per cent (Petersen, 2014; Trinder, 2006). Unlike induced abortion, adding mifepristone does not add value (Stockheim, 2006).

Contraindications mirror those listed in the section describing induced abortion (p. 361).

Confirmation of completion may include a history of heavy bleeding, cramping, and tissue passage followed by ebbing flow; ping serum hCG levels. That said, there is no consensus on intervention.

Pre term premature rupture of membranes (PPRO\1) at a pre viable gestational age complicates 0.5 percent of pregnancies (Hunter, 2012). Rupture may be spontaneous or may follow an invasive procedure such as amniocentesis or fetal surgery.

Risks for spontaneous rupture at a previable gestation are prior

PPROM, prior second-trimester delivery, and tobacco use (Kilpatrick, 2006).

A gush of vaginal fluid that is seen pooling during sterile speculum examination confirms the diagnosis. In suspect cases, amnionic luid will fern on a microscope slide or will have a pH >7, or oligohydramnios will be seen on sonography (Sugibayashi, 2013). lso, amnionic fluid proteins placental alpha microglobulin-1 and insulin growth factor binding protein-I, described in Chapter 22 (p. 235), can be assayed (Doret, 2013).

In iatrogenic cases, defects are typically higher in the uterus and tend to self seal. Also, an occlusive plug-termed an amniopatch-can be created by intraamnionic instillation of autologous platelets and cryoprecipitate. Considered investigational, it is used to seal some surgical leaks (Richter, 2013).

Spontaneous rupture in the first trimester is nearly always followed by either uterine contractions or infection, and termination is typical. In some second-trimester cases not associated with pain, fever, or bleeding, fluid may have collected previously between the amnion and chorion. If this is documented, then diminished activity with observation is reasonable. After 48 hours, if no additional amnionic luid has escaped and if there is no bleeding, cramping, or fever, then a woman may resume ambulation and pelvic rest at home.

However, more typically with second-trimester spontaneous PPROM at a previable age, 40 to 50 percent of women will deliver within the first week, and 70 to 80 percent will do so after 2 to 5 weeks (American College of Obstetricians and Gynecologists, 2016f). Average latency is 2 weeks (Hunter, 2012; Kibel, 2016). Significant maternal complications attend previable PPROM and include chorioamnionitis, endometritis, sepsis, placental abruption, and retained placenta (Waters, 2009). With bleeding, cramping, or fever, abortion is considered inevitable, and the uterus is evacuated.

Without these complications, expectant management is an option in the well-counseled patient (American College of

Obstetricians and Gynecologists, 20 17). Many will choose ter mination due to the just-described maternal risks and tenuous neonatal outcomes. In contemporary cohorts with PPROM at <24 weeks' gestation, only approximately 20 percent of fetuses survive until hospital discharge (Esteves, 2016; Everest, 2008;

Muris, 2007). Of surviving infants, 50 to 80 percent sufer long-term sequelae (Miyazaki, 2012; Pristauz, 2008). Further stratification of outcomes by gestational age is described in

Chapter 42 (p. 806). Overall, prognosis is improved if previa ble PPROM occurred at a later gestation, latency is longer, and oligohydramnios is absent. Neonatal mortality predominantly stems from pulmonary dysfunction, which has higher rates when oligohydramnios persists (Winn, 2000). Fetal deforma tions may also result from scant amnionic luid. Amnioinfusion has been investigated but is currently investigational (Roberts, 20i14).

If expectant care is elected, management is described in

Chapter 42 (p. 807). Antibiotics are considered and given for 7 days to extend latency. Other topics include lung-maturing corticosteroids, magnesium sulfate neuroprophylaxis, group

B streptococcus antibiotic prophylaxis, tocolytics, and neo natal resuscitation eforts. After initial hospitalization, the patient may be discharged home, with instruction for careful surveillance for complications until viability, at which time readmission is usual (American College of Obstetricians and

Gynecologists, 20 16). In subsequent pregnancies, the risk for recurrent preterm birth is great, and in one cohort study, the rate neared 50 percent (Monson, 2016).

With abortion legalization, horriic infections and maternal deaths associated previously with criminal septic abortions are now rare. Still, with spontaneous or induced abortion, organisms may invade myometrial tissues and extend to cause parametritis, peritonitis, and septicemia. Most bacteria causing septic abortion are part of the normal vaginal lora. Particularly worrisome are severe necrotizing infections and toxic shock syndrome caused by group A streptococcus-S pyogenes (Daif, 2009).

Rare but severe infections with otherwise low-virulence organisms can complicate medical or spontaneous abortions. Deaths have been reported from toxic shock syndrome due to Clostridium peringens (Centers for Disease Control and Prevention, 2005). Similar infections are caused by Clostridium sordellii and have clinical manifestations that begin within a few days after an abortion. Women may be afebrile when first seen with severe endothelial injury, capillary leakage, hemoconcentration, hypotension, and a profound leukocytosis. Maternal deaths from these clostridial species approximate 0.58 per 100,000 medical abortions (Meites, 2010).

Management of clinical infection includes prompt administration of broad-spectrum antibiotics as discussed in Chapter 37 (p. 668). If there are retained products, then suction curettage is also performed. Most women respond to this treatment within 1 to 2 days and are discharged when afebrile. Follow-up oral antibiotic treatment is likely unnecessary (Savaris, 2011). In a very few women, severe sepsis syndrome develops, and intensive supportive care is essential. Although rare, clinical decline in the patient and widespread peritonitis despite curettage should raise concerns. Imaging that shows free air or air within the uterine wall typically prompts laparotomy (Eschenbach, 2015). If the uterus is necrotic, hysterectomy is indicated.

With spontaneous miscarriage, 2 percent of h D-negative women will become alloimmunized if not provided passive isoimmunization. With an induced abortion, this rate may reach 5 percent. The American College of Obstetricians and Gynecologists (2017g) recommends anti-Rho (D) immunoglobulin given as 300 �g intramuscularly (IY!) for all gestational ages. Doses may also be graduated, with 50 �g given Hvl for pregnancies :;12 weeks and 300 �g for ::13 weeks. This is administered immediately following surgical evacuation. For planned medical or expectant management, the injection is given within 72 hours of pregnancy failure diagnosis.

With threatened abortion, immunoglobulin prophylaxis is controversial because of sparse evidence-based data (Hannafin, 2006). hat said, it is reasonable to administer anti-D immunoglobulin for a threatened abortion and a live fetus, and this is our practice.

Afecting approximately 1 percent of fertile couples, recurrent pregnancy loss (RPL) is classically deined as three or more consecutive pregnancy losses <20 weeks' gestation or with a fetal weight < 500 g. Mindful of this threshold, data from two large studies showed the risk for a subsequent miscarriage to be similar whether following two or three prior pregnancy losses (Bhattacharya, 2010; Brigham, 1999). And, the American Society for Reproductive Medicine (2013) now deines RPL as two or more failed pregnancies conirmed by sonographic or histopathological examination. Primary PL refers to multiple losses in a woman who has never delivered a liveborn, and secondary PL refers to multiple pregnancy losses in a patient with a prior live birth. Remarkably, the chances for a successful pregnancy arei> 50 percent even after five losses (Table 18-4).

TABLE 18-4. Predicted Success Rate of Subsequent Pregnancy According to Age and Number of Previous Miscarriages

No. of Previous 2 3 4 5 Miscarriages at Predicted Success of Subsequent

Evaluation for RPL addresses the major etiologies, described next (American Society for Reproductive Medicine, 2012). Treatment considerations reach beyond the scope of this book, and interested readers are referred to Chapter 6 in Wiliams Gynecoloy, 3rd edition (Halvorson, 2016).

hree widely accepted causes of RPL are parental chromosomal abnormalities, antiphospholipid antibody syndrome, and structural uterine abnormalities. First-trimester losses in PL have a signiicantly lower incidence of genetic abnormalities than sporadic miscarriage (Stephenson, 2002; Sullivan, 2004).

The timing of recurrent loss can ofer clues, and in some women, each miscarriage may occur near the same gestational age (Heuser, 2010). Genetic factors usually result in early embryonic losses, whereas autoimmune or uterine anatomical abnormalities more likely cause second-trimester losses (Schust, 2002). Approximately 40 to 50 percent of women have idiopathic RPL (Li, 2002; Stephenson, 1996).

Although these account for only 2 to 4 percent of RPL cases, karyotyping of both parents is considered by many to be essential. Of abnormalities, reciprocal translocations are most common and followed by robertsonian translocations (Fan, 2016). heir genesis and reproductive sequelae are discussed in Chapter 13 (p. 261).

After thorough genetic counseling, couples with an abnormal karyotype can be ofered in vitro fertilization (IVF) followed by preimplantation genetic diagnosis (American Society for Reproductive Medicine, 2012; Society for Assisted Reproductive Technology, 2008). This technique is described in Chapter 14 (p. 295). However, in couples with RPL who are chromosomaly normal, PGD is not currently recommended.

Several genital tract abnormalities have been implicated in RPL and other adverse pregnancy outcomes (Reichman, 2010). According to Devi Wold and colleagues (2006), 15 percent of women with three or more consecutive miscarriages will be found to have a congenital or acquired uterine anomaly.

Of acquired abnormalities, uterine synechiae-Asherman syndrome-usually result from destruction of large areas of endometrium. This can follow uterine curettage, hysteroscopic surgeries, or uterine compression sutures (Conforti, 2013; Rathat, 2011). Characteristic multiple illing defects are seen with hysterosalpingography or saline-infusion sonography. Treatment is hysteroscopic adhesiolysis. In many, this lowers miscarriage rates and improves live birth rates (Yu, 2008).

Uterine leiomyomas are common and may cause miscarriage, especially iflocated near the placental implantation site. That said, data indicating them to be a significant cause ofRPL are not con 77 73 68 62 vincing (Saravelos, 2011). Uterine cavity distortion is apparently 69 64 58 52 not requisite for bad outcomes (Sunkara, 2010). But in women undergoing IVF, pregnancy outcomes are adversely afected by

Data fror Brigham, 1999 submucous but not subserosal or intramural leiomyomas a un,

TABLE 18-5. Clinical and Laboratory Criteria for Diagnosis of Antiphospholipid Antibody Syndromea

Obstetric:

One or more unexplained deaths of a morphologically normal fetus at or beyond 10 weeks,

Severe preeclampsia or placental insufficiency necessitating delivery before 34 weeks,

Vascular: One or more episodes of arterial, venous, r small vessel thrombosis in any tissue or organ

Presence of lupus anticoagulant according to guidelines of the International Society on Thrombosis and Hemostasis,

Medium or high serum levels of IgG or IgM anticardiolipin antibodies,

IgG = immunoglobulin G; igM = immunoglobulin M.

Modified from Branch, 2010; ETkan, 201s1; Miyakis, 2006.

2001; Ramzy, 1998). s discussed in Chapter 63 (p. 1197), most agree that excision of submucosal leiomyomas in women with RPL can be considered.

Congenital genital tract anomalies often originate from abnormal mlillerian duct formation. These have an overall incidence of approximately 1 in 200 women (Nahum, 1998). Depending on their anatomy, some may raise risks for early miscarriage, whereas others may cause midtrimester abortion or preterm delivery. Unicornuate, bicornuate, and septate uteri are associated with all three types of loss (Reichman, 2010). A fuller discussion of these anatomical abnormalities and their reproductive efects is found in Chapter 3 (p. 41).

Miscarriages are more common in women with systemic lupus erythematosus (Clowse, 2008). Many of these women, as well as some without lupus, carry antiphospholipid antibodies, a family of autoantibodies that bind to phospholipid-binding plasma proteins (Erkan, 201 1). Women with RPL have a higher frequency of these antibodies compared with normal controls (Branch, 2010). As shown in 1 able 18-5, the antiphospholipid antibody syndrome APS) is deined by these antibodies in combination with various forms of reproductive loss and substantively increased risks for venous thromboembolism (American College of Obstetricians and Gynecologists, 20 17b,i). Mechanisms that cause pregnancy loss are discussed along with treatment in Chapter 59 (p. 1144).

Regarding alloimmunity, one provocative theory suggests that normal pregnancy requires formation of blocking factors that avert maternal rejection of foreign fetal antigens that are paternally derived (Chap. 5, p. 95). Factors that prevent this tolerance may underlie RPL (Berger, 2010). However, proposed therapies using paternal or third-party leukocyte immunization or intravenous immunoglobulin (IlG) have not proved beneicial in aAt least one clinical and one laboratory criteria must be present for diagnosis. bThese tests must be positive on two or more occasions at least 12 weeks apart.

women with idiopathic RPL (Christiansen, 2015; Stephenson, 2010).

According to Arredondo and Noble (2006), 8 to 12 percent of recurrent miscarriages are caused by endocrine factors. Studies to evaluate these have been inconsistent and generally underpowered. Two examples, both controversial, are progesterone deficiency caused by a luteal-phase dect and poycystic ovarian syndrome (Bukulmez, 2004; Cocksedge, 2008).

In contrast, the well-known abortifacient action of uncontrolled diabetes mellitus is detailed in Chapter 57 (p. 1099). Optimal periconceptional glycemic control will mitigate many of these losses.

Likewise, the efects of overt hypothyroidism and severe iodine deficiency on early pregnancy failure are well known and discussed in Chapter 58 (p. 1124). Correction with supplementation reverses these actions. Also, the influence of subclinical hypothyroidism and antithyroid antibodies are sporadic, and thus any efects on recurrent miscarriage rates have been debated (Garber, 2012). That said, two metaanalyses reported convincingly positive associations between these antibodies and a greater risk for sporadic and recurrent miscarriages (Chen, 2011; Thangaratinam, 2011). One ongoing randomized trial regarding potential beneits of treatment will help guide future management (Vissenberg, 2015).

he timespan that deines a mid trimester fetal loss extends from the end of the first trimester until the fetus weighs < 500 g or gestational age reaches 20 weeks. Less than in the irst trimester,

TABLE 18-6. Some Causes of Midtrimester Spontaneous

Abruption, previa the spontaneous loss rate in the second ranges from 1.5 to 3 percent and, after 16 weeks, is only 1 percent (Simpson, 2007; Wyatt, 2005). Unlike earlier miscarriages that frequently are caused by chromosomal aneuploidies, these later fetal losses are due to a multitude of causes (Table 18-6). One frequently overlooked factor is that many second-trimester abortions are medically induced because of fetal abnormalities detected by prenatal screening programs for chromosome aneuploidy and structural defects.

.Midtrimester abortions are classified similarly to first-trimester miscarriages (p. 348). Management is similar in many regards to that used for second-trimester induced abortion, described later (p. 362). One exception is cervical cerclage, which may be employed for cervical insuiciency.

Also known as incompetent cervix, this is a discrete obstetrical entity characterized classically by painless cervical dilatation in the second trimester. It can be followed by prolapse and ballooning of membranes into the vagina, and ultimately, expulsion of an immature fetus. his sequence oten repeats in uture pregnancies.

Although the cause of insuiciency is obscure, previous cervical trauma has been implicated. One Norwegian cohort study of more than 15,000 women with prior cervical conization found a fourfold risk of pregnancy loss before 24 weeks' gestation (lbrechtsen, 2008). However, cerclage is not beneicial for women solely with this risk and without a preterm birth history (Zeisler, 199 ). Of other surgeries, dilation and evacuation carries a 5-percent risk of cervical injury, but neither it nor dilation and extraction raises the likelihood of cervical insuiciency (Chasen, 2005). In other instances, abnormal cervical development, including that following in utero exposure to diethylstilbestrol (DES), may playia role (Hoover, 2011).

Last, cervical ripening changes, such as altered hyaluronan or collagen content, discussed in Chapter 21 (p. 409), may be contributory (Eglinton, 2011; Sundtoft, 2017).

For women with an unequivocal history of second-trimester painless delivery, prophylactic cerclage placement is an option and reinforces a weak cervix by an encircling suture. However, some women have a history and clinical findings that make it diicult to veriy-classic cervical insuiciency. In one randomized trial of almost 1300 women with an atypical history, cerclage was found to be only marginally beneicial-13 versus 17 percent-to prolong pregnancy past 33 weeks (MacNaughton, 1993). It seems likely that many of these women instead had preterm labor.

In addition to history, the physical inding of early dilation of the internal cervical os may be an indicator of insuiciency. In a systematic review, cerclages that were placed based on this finding provided superior perinatal outcomes compared with expectant management (Ehsanipoor, 2015).

Transvaginal sonography is yet another tool, and cervical length and the presence offunneling are sought. he latter is ballooning of the membranes into a dilated internal os, but with a closed external os. In women with these findings, early randomized trials were inconclusive in proving the clinical value of cerclage to prevent preterm birth (Rust, 2001; To, 2004). A multicenter randomized trial of 302 high-risk women with cervical length <25 mm reported that cerclage prevented birth before viability but not birth before 34 weeks (Owen, 2009). Subsequently, however, Berghella and coworkers (201i1) included ive trials in a metaanalysis and showed that cerclage for these high-risk women signiicantly reduced preterm birth before 24, 28, 32, 35, and 37 weeks.

Cervical length screening is now recommended by both the American College of Obstetricians and Gynecologists (2016b) and the Society for Maternal-Fetal Medicine (2015) for women with prior preterm birth. Between 16 and 24 weeks' gestation, sonographic cervical measurement is completed every 2 weeks. If an initial or subsequent cervical length is 25 to 29 mm, then a weekly interval is considered. If the cervical length measures <25 mm, cerclage is ofered to this group of women. Notably, for women without a history of preterm birth but with a short cervix incidentally identiied sonographically, progesterone therapy is ofered instead of cerclage.

With twin gestations, one retrospective analysis found no improved outcomes in women with a cervical length <25 mm (Stoval, 2013). he College (2016b) does not recommend the use of cerclage in twin pregnancies.

Contraindications to cerclage usually include bleeding, contractions, or ruptured membranes, which substantially raises the likelihood of failure. Thus, prophylactic cerclage before dilatation is preferable. Surgery between 12 and 14 weeks' gestation allows this early intervention yet avoids surgery in a woman with a irst-trimester pregnancy destined for spontaneous loss.

Preoperatively, screening for aneuploidy and obvious malformation is completed. Cervical secretions are tested for gonorrhea and chlamydial infection. hese and obvious cervical infections are treated.

At times, the cervix instead is found to be dilated, efaced, or both, and an emergent rescue cerclage is performed. However, there is debate as to how late this should be performed. The conundrum is that the more advanced the pregnancy, the greater the risk that surgical intervention will stimulate preterm labor or membrane rupture. At Parkland Hospital, cerclage procedures are generally not done once supposed fetal viability is reached after 23 to 24 weeks. Others, however, recommend placement later than this (Caruso, 2000; Terkildsen, 2003).

When outcomes of cerclage are evaluated, women with similar clinical presentations are ideally compared. For example, in the study of elective cerclage by Owen and associates (2009), approximately a third of women delivered before 35 weeks, and complications were few. By contrast, in a 10-year review of 75 women undergoing rescue cerclage procedures, Chasen and Silverman (1998) reported that only half were delivered after 36 weeks. Importantly, only 44 percent of those with bulging membranes at the time of cerclage reached 28 weeks. Terkildsen and associates (2003) had similar experiences. Caruso and coworkers (2000) described rescue cerclage done in 23 women with a dilated cervix and protruding membranes from 17 to 27 weeks' gestation. There were 11 liveborn neonates, and these researchers concluded that success was unpredictable. Our experiences at Parkland Hospital are that rescue cerclages have a high failure rate, and women are counseled accordingly.

If the clinical indication for cerclage is questionable, a woman may instead be observed. Most undergo cervical examinations weekly or every 2 weeks to assess efacement and dilatation. Unfortunately, rapid efacement and dilation can develop despite such precautions (Witter, 1984).

Of the two vaginal cerclage operations, most use the simpler procedure developed by McDonald (1963) and shown in

Figure 1i8-2. The more

FIGURE 18-2 McDonald cerclage procedure for incompetent cervix. A. Start of the cerclage procedure with a no. 2 monofilament suture being placed in the body of the cervix very near the level of the internal os. B. Continuation of suture placement in the body of the cervix so as to encircle the os. C. Encirclement completed. D. The suture is tightened around the cervical canal sufficiently to reduce the diameter of the canal to 5 to 10 mm, and then the suture is tied. The efect of the suture placement on the cervical canal is apparent. A second suture placed somewhat higher may be of value if the first is not in close proximity to the internal os.

complicated operation is a modification of the procedure described by Shirodkar (1955) and shown in Figure 18-3. When either technique is performed prophylactically, women with a classic history of cervical incompetence have excellent outcomes (Caspi, 1990; Kuhn, 1977). For either vaginal or abdominal cerclage, there is insuicient evidence to recommend perioperative antibiotic prophylaxis (American College of Obstetricians and Gynecologist, 2016b,i). Thomason and coworkers (1982) found that perioperative tocolytics failed to arrest most labor. Regional analgesia is suitable and preferred. Ater this, the woman is placed in standard dorsal lithotomy position. he vagina and perineum are surgically prepared, and the bladder is drained. Some operators do not use potentially irritating antiseptic solution on the exposed amnionic membranes and instead use warm saline (Pelosi, 1990). Although steps are described subsequently, a thorough and illustrated review of cerclage technique is provided by Hawkins (2017). For suturing, options include a no. 1 or 2 nylon or polypropylene monoilament suture or 5-mm Mersilene tape. During placement, the suture is placed as high as possible and into the dense cervical stroma. Two cerclage sutures do not appear more efective than one (Giraldo-Isaza, 2013).

FIGURE 18-3 Modified Shirodkar cerclage for incompetent cervix. A. A transverse incision is made in the mucosa overlying the anterior cervix, and the bladder is pushed cephalad. B. A 5-mm Mersilene tape on a swaged-on or Mayo needle is passed anterior to posterior. C. The tape is a cerclage in place with labor contractions. T ransvaginally placed cerclages are typically removed even with cesarean delivery to avoid rare long-term foreign-body complications (Hawkins, 2014). With scheduled cesarean delivery, the cerclage may be removed at 37 weeks or deferred until the time of regional analgesia and delivery. Again, the risk of labor ensuing before delivery must be considered. During extraction, particularly with a Shirodkar cerclage or a cerclage using Mersilene tape, analgesia helps ensure patient comfort

B and adequate visualization.

At times, suture placed at the uterine isthmus can be used and left until completion of childbearing. Because of significantly greater risks of bleeding and complications during placement, this approach is reserved for selected instances of severe cervical anatomical defects or prior transvagi c nal cerclage failure.

Placement of a cervicoisthmic cerclage was originally described using laparotomy, but several reports additionally detail lapa then directed posterior to anterior on the other side of the cervix. Allis clamps are placed so as to bunch the cervical tissue. This diminishes the distance that the needle must travel submucosally cervicoisthmic cerclages. Steps are and aids tape placement. D. The tape is snugly tied anteriorly, after ensuring that all slack has been taken up. The cervical mucosa is then closed with continuous stitches of chromic suture. summarizedin Figure 18-4. Tulandi

Rescue cerclage with a thinned dilated cervix is more diicult and risks tissue tearing and membrane puncture. Replacement of the prolapsed amnionic sac back into the uterus will usually aid suturing (Locatelli, 1999). Options include steep Trendelenburg or filling the bladder with 600 mL of saline through an indwelling Foley catheter. However, these steps may carry the cervix cephalad and away from the operating field. Membrane reduction can also be achieved by pressure from a wide moist swab or by placing a Foley catheter through the cervix and inlating the 30-mL balloon to deflect the amnionie sac cephalad. The balloon is then deflated gradually as the cerclage suture is tightened around the catheter tubing, which is then removed. Simultaneous outward traction created by ring forceps placed on the cervical edges may be helpful. In some women with bulging membranes, transabdominal amnionic fluid aspiration to decompress the sac may be considered. If this is done, bacterial cultures of the luid should be obtained.

For uncomplicated pregnancies without labor, the cerclage is usually cut and removed at 37 weeks' gestation. This balances the risk of preterm birth against that of cervical laceration from and coworkers (2014) evaluated 16 studies involving 678 pregnancies. Placement before pregnancy and during pregnancy was similar, whether performed laparoscopically or by laparotomy.

Zaveri and associates (2002) reviewed 14 observational studies in which a prior transvaginal cerclage had failed to prevent preterm delivery. The risk of perinatal death or delivery before 24 weeks' gestation was only slightly lower following transabdominal cerclage compared with the risk following repeat transvaginal cerclage-6 versus 13 percent, respectively. Importantly, 3 percent of women who underwent transabdominal cerclage had serious operative complications, whereas there were none in the transvaginal group. Whittle and coworkers (2009) described 31 women in whom transabdominal cervico isthmic cerclage was done laparoscopieally between 10 and 16 weeks. he procedure was converted to laparotomy in 25 percent, and there were four failures due to chorioamnionitis. Overall, fetal survival rate approximated 80 percent.

Principal among these are membrane rupture, preterm labor, hemorrhage, infection, or combinations thereof. All are

FIGURE 18-4 Transabdominal cervicoisthmic cerclage. Following incision and sharp dissection in the vesicouterine space, the blad der is mobilized caudally. At the level of the internal os, a window is made in free space medial to the uterine vessels. This avoids vessel compression by the tightened cerclage. Care is also taken to avoid the ureter, which is lateral and posterior. The suture is passed anterior to posterior or vice versa. In this case, the knot is tied anteriorly, and the vesicouterine peritoneum is closed with absorbable suture in a running fashion. (Reproduced with permission from Hawkins JS: Lower genital tract procedures. In Yeomans ER, Hofman BL, Gilstrap LC III, et al: Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 2017.) uncommon with prophylactic cerclage. In the multicenter study by Owen and colleagues (2009), of 138 procedures, there was one instance each of ruptured membranes and bleeding. In the trial by MacNaughton and associates (1993), membrane rupture complicated only 1 of more than 600 procedures done before 19 weeks. In our view, clinical infection mandates immediate removal of the suture with labor induced or augmented. Similarly, ¥lith imminent abortion or delivery, the suture should be removed at once because uterine contractions can tear through the uterus or cervix.

Following cerclage, if subsequent cervical thinning is detected by sonographic assessment, then some consider a reinforcement cerclage. In one retrospective study, however, reinforcing cerclage sutures placed later did not significantly prolong pregnancy (Contag, 2016).

Membrane rupture during suture placement or within the irst 48 hours following surgery is considered by some to be an indication for cerclage removal because of the likelihood of serious fetal or maternal infection (Kuhn, 1977). That said, the range of management options includes observation, removal of the cerclage and observation, or removal of the cerclage and labor induction (O'Connor, 1999).

he term induced abortion is defined as the medical or surgical termination of pregnancy before the time of fetal viability.

Deinitions used to evaluate these statistically include: (1) abortion ratio-the number of abortions per 1000 live births, and (2) abortion rate-the number of abortions per 1000 women aged 15 to 44 years. Overall, abortions most likely are underreported in the United States because clinics inconsistently list medically induced abortions. For example, the Guttmacher Institute found that 926,000 procedures were performed in 2014 Oones, 2017). But for 2013, only about 664,400 elective abortions were reported to the Centers for Disease Control and Prevention Oatlaoui, 2016). Of these, 66 percent were pregnancies aged ;8 weeks' gestation, and 92 percent of abortions were completed beforei; 13 weeks. he abortion ratio was 200 per 1000 live births, and the abortion rate was 12.5 per 1000 women.

herapeutic abortion refers to termination of pregnancy for medical indications. Inclusive medical and surgical disorders are diverse and discussed throughout this text. In cases of rape or incest, many consider termination. The most frequent indi cation currently is to prevent birth of a fetus with a signiicant anatomical, metabolic, or mental deformity.

the interruption of pregnancy before viability at the request of the woman, but not for medical reasons. Most abortions done today are elective, and thus, it is one of the most frequently performed medical procedures.

• Abortion in the United States

The legality of elective abortion was established by the United States Supreme Court in the case ofRoe v. Wae. The Court defined the extent to which states might regulate abortion and ruled that firsttrimester procedures must be let to the medical judgment of the physician. ter this, the state could regulate abortion procedures in ways reasonably related to maternal health. Finally, subsequent to viability, the state could promote its interest in the potential of human life and regulate and even proscribe abortion, except for preservation of the life or health of the mother.

Other legislation soon followed. he 1976 Hyde Amendment forbids use of federal funds to provide abortion services except in case of rape, incest, or life-threatening circumstances. The Supreme Court in 1992 reviewed Planned Parenthood v. Casy and upheld the fundamental right to abortion, but established that regulations before viability are constitutional as long as they do not impose an "undue burden" on the woman. Subsequently, many states introduced counseling requirements, waiting periods, parental consent for minors, facility requirements, and funding restrictions. Such limits are often called targeted regulation of abortion providers (TRAP) laws. One major choice-limiting decision was the 2007 Supreme Court decision that reviewed Gonales v. Carhart and upheld the 2003 Partial-Birth Abortion Ban Act. This was problematic because there is no medically approved definition of partial-birth abortion according to the American College of Obstetricians and Gynecologists (20 14a). In 2016, some TAP laws were dialed back by the Supreme

Court ruling in the case of Who/� Woman 5 Health v. Helerstedt. With this, the justices noted that abortion laws must confer health safety benefits that outweigh burdens on access.

The American College of Obstetricians and Gynecologists (2014a, 2017 d) supports the legal right of women to obtain an abortion prior to fetal viability and advocates for improved access. he College also (2017 a) supports abortion training, and the Accreditation Council for Graduate Medical Education mandates that obstetrics and gynecology residency education must include access to experience with induced abortion. The Kenneth J. Ryan Residency Training Program was established in 1999 to work with residency programs to improve abortion and contraceptive training. Moreover, postresidency training in these techniques is available in formal 2-year Family Planning fellowships.

Other residency programs are less codified, but teach residents technical aspects through their management of early spontaneous abortions and pregnancy interruption for fetal death, severe fetal anomalies, and life-threatening medical or surgical disorders.

he College (2016g) respects the need and responsibility of health-care providers to determine their individual positions on induced abortion. It also advocates for counseling and timely referral if providers have individual beliefs that preclude pregnancy termination. hree basic choices available to a woman considering an abortion are: (1) continued pregnancy with its risks and parental responsibilities; (2) continued pregnancy with arranged adoption; or (3) termination of pregnancy with its risks. Knowledgeable and compassionate counseling should objectively describe and provide information regarding these choices to permit informed decision-making (Templeton, 2011).

Pregnancy termination can be performed either medically or surgically by several methods. In the absence of serious maternal medical disorders, abortion procedures do not require hospitalization (Guiahi, 2012). However, outpatient surgical facilities should have the ability to provide emergency resuscitation and immediate transfer to a hospital (American College of Obstetricians and Gynecologists, 20 14b).

Surgical evacuation is performed transvaginally through an appropriately dilated cervix. For this, preoperative cervical ripening is favored by many and is typically associated with less manual intraoperative cervical dilation, a technically easier procedure, less pain, and shorter operative times (Kapp, 2010; Webber, 2015). On balance, cervical preparation adds a surgical delay and potential side efects. In a selective approach, some recommend cervical priming for irst-trimester suction curettage only for those at greater risk of complications from intraoperative cervical dilation, such as those with cervical stenosis and adolescents (Allen, 2016). Of note, surgical steps presented here apply to both induced abortion and miscarriage, discussed earlier (p. 347).

FIGURE 18-5 Hygroscopic dilators. With each type, the dry unit (left) expands exponentially when exposed to water (right) as in the endocervical canal. A. Laminaria. B. Dilapan-S.

For ripening, hygroscopic dilators, also called osmotic dilators, are devices that draw water from surrounding tissues and expand to gradually dilate the endocervical canal. One type is derived from various species of Laminaria algae that are harvested from the ocean floor (Fig. 18-5). hese come in diferent diameters, which allow the number of inserted devices, also called tents, to be customized to a given cervix. Another device is Dilapan-S, which is composed of an acrylic-based gel. Each type expands to an ultimate diameter three to four times that of its dry state. However, Dilapan-S achieves this in 4 to 6 hours, which is faster than the 12 to 24 hours needed for laminaria (Fox, 2014).

With hygroscopic dilators, shallow insertion yields insuicient internal os dilation or tent expulsion, but deep placement risks dislodgement into the uterine cavity (Fig. 18-6). Accordingly, the numbers of sponges and dilators inserted are carefully counted and recorded in the patient's chart. Once tents are inserted, several gauze sponges at the external os help prevent spontaneous tent expulsion. Patients can ambulate, void, or stool without limitation.

FIGURE 18-6 Insertion of laminaria before dilatation and curettage. A. Laminaria immediately after being appropriately placed with its upper end just through the internal os. B. Several hours later the laminaria is now swollen, and the cervix is dilated and softened.

C. Laminaria inserted too far through the internal os; the laminaria may rupture the membranes.

Schneider and associates (1991) described 21 cases in which women who had a hygroscopic dilator placed changed their minds. Of 17 women who chose to continue their pregnancy, there were 14 term deliveries, two preterm deliveries, and one miscarriage 2 weeks later. None sufered infection-related morbidity, including three untreated women with cervical cultures positive for Chlamydia trachomatis. In similar circumstances with four second-trimester terminations, Siedhof and Cremer (2009) described two preterm and two term deliveries.

Instead of hygroscopic dilators, misoprostol is often used for cervical ripening. he typical dose is 400 �g administered sublingually, buccally, or placed into the posterior vaginal fornix 3 to 4 hours prior to surgery. Instead, oral administration proves less efective and may take longer (Allen, 2016). Another efective cervical-ripening agent is the antiprogestin mifepristone, 200 mg given orally 24 to 48 hours before surgery (Ashok, 2000). Its cost and greater delay to the procedure, however, typically favor misoprostol use instead.

In comparing hygroscopic dilators and misoprostol for ripening, randomized studies show equal or slightly greater dilation with hygroscopic dilators. Other surgical parameters do not vary significantly (Bartz, 2013; Burnett, 2005; Macisaac, 1999). Hygroscopic dilators extend procedure time and can be uncomfortable, whereas misoprostol introduces fever, bleeding, and gastrointestinal side efects.

If not done as part of early prenatal care, hemoglobin level and h status are assessed. Screening for gonorrhea, for syphilis, and for human immunodeficiency virus, hepatitis B, and chlamydial infections is also completed. Obvious cervical infections are treated and resolved before elective procedures. To prevent postabortal infection after a first-or second-trimester surgical evacuation, prophylactic doxycycline, 100 mg orally 1 hour before and then 200 mg orally after, is provided (Achilles, 2011; American College of Obstetricians and Gynecologists, 20 16a). Prophylaxis specifically for infective endocarditis prevention in those with valvular heart disease is not required in the absence of active infection (Nishimura, 2017). No recommendations speciically address venous thromboembolism prophylaxis for suction curettage in low-risk gravidas. At our hospital, we encourage early ambulation.

lso called suction dilation and curettage or suction curettage, vacuum aspiration is a transcervical approach to surgical abortion. he cervix is first dilated and then products of conception are evacuated. For this, a rigid cannula is attached either to an electric-powered vacuum source or to a handheld GO-mL syringe for its vacuum source. hese are electric vacuum aspiration (EVA) or manual vacuum aspiration (MVA), respectively. Sharp dilation and curettage (D -C) in which contents are mechanically scraped out soley by a sharp curette is currently not recommended for pregnancy evacuation due to greater blood loss, pain, and procedural time (National Abortion Federation, 2016; World Health Organization, 2012). Importantly, this practice is distinguished from brief sharp curettage following initial aspiration. In one survey, this combination is employed by nearly 50 percent of abortion providers (O'Connell, 2009).

After bimanual examination is performed to determine uterine size and orientation, a speculum is inserted, and the cervix is swabbed with povidone-iodine or equivalent solution. he anterior cervical lip is grasped with a toothed tenaculum. The cervix, vagina, and uterus are richly supplied by nerves of Frankenhauser plexus, which lies within connective tissue lateral to the uterosacral and cardinal ligaments. Thus, vacuum aspiration at minimum requires intravenously or orally administered sedatives or analgesics, and some add a paracervical or intracervical blockade with lidocaine (llen, 2009; Renner, 2012). For local blocks, 5 mL of 1-or 2-percent lidocaine is most efective if placed immediately lateral to the insertion of the uterosacral ligaments into the uterus at 4 and 8 o'clock. An intracervical block with 5-mL aliquots of I-percent lidocaine injected at 12, 3, 6, and 9 o'clock was reported to be equally efective (Mankowski, 2009). Alternatively, general or regional anesthesia may be elected.

Uterine sounding measures the depth and inclination of the cavity before other instrument insertion. If required, the cervix

FIGURE 18-7 Dilatation of cervix with a Hegar dilator. Note that the fourth and fifth fingers rest against the perineum and buttocks, lateral to the vagina. This maneuver is an important safety measure because if the cervix relaxes abruptly, these fingers prevent a sudden and uncontrolled thrust of the dilator, a common cause of uterine perforation.

is further dilated with Hegar, Hank, or Pratt dilators until a suction cannula of the appropriate diameter can be inserted. he degree of required cervical dilation roughly approximates gestational age. Hegar sizes reflect their diameter in millimeters. Pratt and Hank dilators are sized in French units, which can be converted to millimeters by dividing the French number by three.

With dilation, the fourth and fifth ingers of the hand introducing the dilator should rest on the perineum and buttocks as the instrument is pushed through the internal os (Fig. 18-7). his technique minimizes forceful expansion and provides a safeguard against uterine perforation.

Following dilation, for most first-trimester aspiration procedures, an 8-to 12-mm Karman cannula is appropriate. Small cannulas carry the risk of leaving retained intrauterine tissue postoperatively, whereas large cannulas risk cervical injury and more discomfort. To begin, the cannula is slowly moved toward the fundus until resistance is met. Suction is then activated. he cannula is gradually pulled back toward the os and is slowly turned circumferentially to cover the entire surface of the uterine cavity (Fig. 18-8). his is repeated until no more tissue is aspirated. A gentle sharp curettage can follow to remove any remaining tissue fragments (Fig. 18-9). Strong and consistent evidence supports high eicacy, safety, and patient acceptability for both MVA and EVA (Lichtenberg, 2013).

For abortion done at $6 weeks' gestation, a distinct drawback is that the pregnancy may be small and missed by the curette. To identiy placenta, the aspirated contents are rinsed in a strainer to remove blood, and then placed in a clear plastic container with saline and examined with back lighting (MacIsaac, 2000). Placental tissue macroscopically appears soft, luy, and feathery. A magniying lens, colposcope, or microscope can augment visualization. With gestations $7 weeks, the failed abortion rate approximates 2 percent (Kaunitz, 1985;

FIGURE 18-8 A suction curette has been placed through the cervix into the uterus. The figure shows the rotary motion used to aspirate the contents. (Reproduced with permission from Hoffman BL, Corton MM: Surgeries for benign gynecologic disorders. In Hofman BL, Schorge JO, Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGraw-Hili Education, 2016.)

Paul, 2002). hus, if products are not clearly identiied, serial serum heG levels can be informative (Dean, 2015).

In women undergoing abortion, complication rates rise with gestational age. Of these, uterine perforation and lower-genitaltract laceration are uncommon but potentially serious. In one

FIGURE 18-9 A sharp curette is advanced into the uterine cavity while the instrument is held with the thumb and forefinger as shown in Figure 18-7. In the movement of the curette, only the strength of these two fingers should be used. (Reproduced with permission from Hofman BL, Corton MM: Surgeries for benign gynecologic disorders. In Hofman BL, Schorge JO, Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGraw-Hili Education, 2016.) systematic review of irst-trimester abortion, the uterine per foration rate was � 1 percent, as was the cervical or vaginal laceration rate (White, 2015). Perforation is usually recognized when the instrument passes without resistance deep into the pelvis. isk factors include operator inexperience, prior cervi cal surgery or anomaly, adolescence, multiparity, and advanced gestational age (llen, 2016; Grimes, 1984). If the uterine per foration is small and fundal, as when produced by a uterine sound or narrow dilator, observation of vital signs and for uter ine bleeding is usually su.cient.

If a suction cannula or sharp curette passes into the peritoneal cavity, considerable intraabdominal damage can ensue. In these cases, laparotomy or laparoscopy to thoroughly examine the abdominal contents is oten the safest course. Uterine perforation is not a contraindication to completing the curettage under direct guidance during laparoscopy or laparotomy (Owen, 2017).

Following curettage, uterine synechiae may form, and the risk of synechiae increases with the number of procedures. Most cases are mild and of unclear reproductive significance (Hooker, 2014). However, of Asherman syndrome cases, one series found that two thirds were linked to first-trimester curettage (Schenker, 1982).

Other irst-trimester abortion complications are hemorrhage, incomplete removal of products, and postoperative infections, and these are germane to both surgical and medical abortion techniques. Hemorrhage with abortion is variably defined. One supported by the Society for Family Planning is bleeding that prompts a clinical response or bleeding in excess of 500 mL (Kerns, 2013). For irst-trimester surgical abortions, hemorrhage complicates �1 percent (White, 2015). Atony, abnormal placentation, and coagulopathy are frequent sources, whereas surgical trauma is a rare cause. With medical abortion, bleeding is more common. In one study of more than 42,000 Finnish women undergoing pregnancy termination with pregnancies less 63 days, hemorrhage complicated 15 percent of medical abortion but only 2 percent of surgical cases (Niinimaki, 2009).

Infection is another risk. One review of surgical abortion found a cumulative rate of 0.5 percent in those given prophylaxis compared with 2.6 percent in those given placebo (Achilles, 2011). In another review of nearly 46,000 irst-trimester abortions, the postoperative infection rate was <0.3 percent for either surgical or medical methods (Upadhyay, 2015).

Incomplete abortion may require reevacuation. For medical abortion, this neared 5 percent in one systematic review (Raymond, 2013). Reaspiration rates following surgical abortion are typically <2 percent (Ireland, 2015; Niinimaki, 2009).

In sum, first-trimester surgical abortion ofers higher e.cacy rates (96 to 100 percent) than medical abortion (83 to 98 percent). Medical abortion also carries a greater cumulative risk of complications, although diferences are small (Lichtenberg, 2013). hese are balanced against the greater privacy of medical abortion and the more invasive steps of curettage.

In appropriately selected women, outpatient medical abortion is an acceptable option for pregnancies with a menstrual age <63 days (American College of Obstetricians and Gynecolo gists (20 16c). Although suitable at later gestational ages, success rates are lower.

gestation, one third are completed medically in the United

States Qatlaoui, 2016). hree medications are used alone or in combination: mifepristone, methotrexate, and misoprostol. Of these, mifepristone augments uterine contractility by reversing progesterone-induced myometrial quiescence, whereas misopro scol directly stimulates the myometrium. Both also ripen the cervix (Mahajan, 1997; Tang, 2007). Methotrexate acts on tro phoblast and halts implantation. It is used less frequently now due to current availability of the more efective mifepristone.

Contraindications to medical abortion have evolved from exclusion criteria that were used in initial clinical trials. Cau tions include current intrauterine device; severe anemia, coagu lopathy, or anticoagulant use; long-term systemic corticosteroid liver, renal, pulmonary, or cardiovascular disease; or uncon trolled hypertension (Guiahi, 2012). Of note, misoprostol is suitable for early pregnancy failure in those with prior uterine surgery (Chen, 2008).

Methotrexate and misoprostol are both teratogens. Thus there must be a commitment to completing the abortion once these drugs are given (Aufret, 2016; Hyoun, 2012; Kozma, 2011). With mifepristone, for women who choose to continue their preg nancies after exposure, the ongoing pregnancy rate ranges from 10 to 46 percent (Grossman, 2015). The associated major mal formation rate was 5 percent in one series of 46 exposed preg nancies (Bernard, 2013).

Several dosing schemes are efective, and some are shown in Table 18-7. Because of its greater e.cacy, mifepristonel misoprostol combinations are favored. Presently, for gestations up to 63 days, the most widely accepted regimen is mifepristone, 200 mg given orally on day 0 and followed in 24 to 48 hours by misoprostol 800 �g, administered by a vaginal, buccal, or sublingual route (American College of Obstetricians and Gynecologists, 2016c). Another earlier regimen used a 600-mg oral mifepristone dose followed in 48 hours by a 400-�g oral misoprostol dose (Spitz, 1998). If desired, mifepristone and misoprostol may be self-administered at home (Chong, 2015). At Planned Parenthood clinics, for irst-trimester medical abortion, doxycycline 100 mg is taken orally daily for 7 days and begins with abortifacient administration (Fjerstad, 2009). he woman is then discharged home and appointed to return in 1 to 2 weeks.

Symptoms following misoprostol are common within 3 hours and include vomiting, diarrhea, fever, and chills. Bleeding and cramping with medical termination typically is signiicantly worse than with menses. Thus, adequate analgesia, usually including a narcotic, is provided. If bleeding soaks two or more pads per hour for at least 2 hours, the woman is instructed to contact her provider to determine whether she needs to be seen .

At the follow-up appointment, routine postabortal sonographic examination is typically unnecessary (Clark, 2010). Instead, assessment of the clinical course along with bimanual pelvic examination is recommended. If sonography is indicated

TABLE 18-7. Various Regimens for Medical Termination of Pregnancy aMifepristone, 200-600 mg orally; followed in 24-48 hr by: bMisoprostol, 200-600 �g orally or 400-800 �g vaginally, buccally, or sublingually

Methotrexate/Misoprostol dMethotrexate, 50 mg/m2 BSA intramuscularly or orally; followed in 3-7 days by: eMisoprostol, 800 �g vaginally. Repeat if needed 1 week after methotrexate initially given

Mifepristone, 200 mg orally; followed in 24-48 hr byj

Misoprostol, 400 �g vaginally or buccally every 3 hr up to 5 doses

Misoprostol, 600-800 �g vaginally; followed by 400 �g vaginally or buccally every 3 hr up to 5 doses 50 units oxytocin in 500 mL of normal saline infused during 3 hr; then 1-hr diuresis (no oxytocin); then escalate sequentially in a similar fashion through 150,200,250, and finally 300 units oxytocin each in 500 mL normal saline aOoses of 200 versus 600 mg similarly effective. bOral route may be less effective and have more nausea and diarrhea. Sublingual route has more side effects than vaginal route.

3-12 hours given vaginally; 3-4 hours given sublingually. dEficacy similar for routes of administration. eSimilar efficacy when given on day 3 versus day 5. BSA = body surface area. Pymar, 2001; Raghavan, 2009; Schaff, 2000; Shannon, 2006; von Hertzen, 2003, 2007, 2009, 2010; Winikof, 2008.

due to concern for failed abortion or for bleeding, unnecessary surgery can be avoided if scans are interpreted appropriately. Specifically, if no gestational sac is seen and there is no heavy bleeding, then intervention is unnecessary. This is true even when, as is common, the uterus contains sonographically evident debris (Paul, 2000). vleasurements < 15 mm and < 30 mm have been used as thresholds to signal evacuation success (Nielsen, 1999; Zhang, 2005). Another study reported that a multilayered sonographic pattern indicated a successful abortion (Tzeng, 2013). Last, hCG values may be informative. Compared with preprocedural levels, Barnhart and coworkers (2004b) found declines of 88 percent at day 3 and 82 percent at day 8 following misoprostol administration correlated with a 95-percent rate of successful abortion completion.

In the second trimester, fetal anomaly or death, maternal health complications, inevitable abortion, or desired termination may be indications for uterine evacuation. As in the irst trimester, available options are medical or surgical. But, in the second trimester, dilation and evacuation (D & E) rather than suction D & C is dictated because of fetal size and bony structure.

Of options, D & E is a common means of second-trimester induced abortion in the United States. Of legally obtained abortions in 2013, 9 percent were performed by D & E at gestational agesi> 13 weeks Oarlaoui, 2016). Many of the surgical and medical steps for second-trimester abortion mirror those in the irst trimester, and diferences are emphasized here.

With D & E, wide mechanical cervical dilation precedes evacuation of fetal parts. he degree needed rises with fetal gestational age, and inadequate dilatation risks cervical trauma, uterine perforation, or tissue retention (Peterson, 1983). Thus, presurgical cervical preparation is advised, and main options include hygroscopic dilators or misoprostol.

With laminaria, overnight preparation ofers optimal cervical dilation (Fox, 2014). Uncommonly, laminaria may fail to adequately dilate the cervix, and serialilaminaria insertion with an increasing number of tents over several days is one option (Stubblefield, 1982). Supplementing laminaria with misoprosrol or mifeprisrone is another choice (Ben-Ami, 201i5).

Dilapan-S is also suitable for cervical preparation. It may be preferable for same-day procedures as this device achieves its maximal efect in 4 to 6 hours (Newmann, 2014).

Misoprostol can be used instead of hydroscopic dilators for cervical preparation. The typical dose is 400 1g given vaginally or buccally 3 to 4 hours prior to D & E. Randomized trials vary regarding the ability of misoprostol to achieve results equal to that with hydroscopic dilators (Bartz, 2013; Goldberg, 2005; Sagiv, 2015). vIisoprostol added to laminaria ofers small increases in dilation but also greater side efects (Edelman, 2006).

Fewer studies have evaluated mifepristone for cervical ripening. In one, mifepristone alone provided less dilation than hydroscopic dilators (BO'gatta, 2012). In another trial, mifepristone added 48 hours before misoprostol created greater cervical dilation compared with misoprostol alone (Carbonell, 2007). Last, Goldberg and associates (2015) compared hygroscopic dilation with or without added mifepristone. They found no diferences for gestations < 19 weeks, but the combination aided procedures for later ages.

In sum, hygroscopic dilators are consistently efective for cervical preparation before D & E. For those desiring same-day procedures, Dilapan-S alone or misoprostol alone may ofer advantages. Layering agents may be most helpful for later gestations or for an inadequate response from initial hygroscopic dilators alone. Yet, layering adds cost and potential side efects (Shaw, 2016).

With elective abortion, some choose to induce fetal demise prior to D & E to avert a live birth or to avoid violating the Partial Birth Abortion Ban Act, cited later (Diedrich, 2010). For this, an intracardiac potassium chloride injection or a 1-mg intraamnionic or intrafetal digoxin injection is frequently used prior to cervical ripening (Sfakianaki, 2014; White, 2016).

During D & E, sonography can be used as an adjunct in all cases or selectively in more challenging ones. Perioperative antibiotic prophylaxis mirrors that for first-trimester procedures (p. 359). To reduce postprocedure bleeding, vasopressin, 2 to 4 units in 20 mL of saline or anesthetic, can be injected intracervically or as part of a paracervical block (Kerns, 2013; Schulz, 1985). Once adequate cervical dilation is achieved, the initial surgical step drains amnionic fluid with an 11-to 16-mm suction cannula or with amniotomy and gravity. his reduces the risk of amnionic fluid embolism and brings the fetus into the lower uterine segment for removal (Owen, 2017; Prager, 2009).

For pregnancies beyond 16 weeks, the fetus is extracted, usually in parts, using Sopher forceps or other destructive instruments. With complete removal of the fetus, a large-bore vacuum curette is used to remove the placenta and remaining tissue.

Major complications are infrequent with D & E, and rates range from 0.2 to 2 percent in large series (Cates, 1982; Lederie, 2015; Peterson, 1983). These include uterine perforation, cervical laceration, uterine bleeding, and postabortal infection. Rare complications include disseminated intravascular coagulopathy or amnionic luid embolism (Ray, 2004; York,i2012).

Placenta previa or the accrete syndromes can raise D & E risks.

Once diagnosed, placenta accreta typically prompts hysterec tomy (Matsuzaki, 2015). For placenta previa, D & E is preferred to quickly evacuate the placenta, but the ability to transfuse present (American College of Obstetricians and Gynecologists, 2017h; Perriera, 2017). Medical induction may be elected, but the risk for transfusion is greater than with D & E (Nakayama, 2007; Ruano, 2004). Data are few, but predelivery uterine artery embolization may lower bleeding risks (Pei, 2017).

Prior cesarean delivey is not a contraindication for 0 & E and may be preferred over prostaglandins for those with multiple prior hysterotomies (Ben-Ami, 2009; Schneider, 1994). During medical abortion, the uterine rupture rate is 0.4 percent with one prior cesarean delivery (Berghella, 2009). From fewer data, the rate may reach 2.5 percent with two or more prior cesarean deliveries (Andrikopoulou, 2016). If a medical agent is elected in those with prior cesarean hysterotomy, misoprostol is an option. Prostaglandin E2 (PGE2) appears to pose similar risk (Ie Roux, 2001; Reichman, 2007).

Of these, dilation and extraction (D & ) is similar to 0 & E except that a suction cannula is used to evacuate the intracranial contents after delivery of the fetal body through the dilated cervix. This aids extraction and minimizes uterine or cervical injury from large instruments or fetal bones. 0 & X is also called an intact D & . In political parlance, this procedure has been termed partial birth abortion.

In some women with second-trimester pregnancies who desire sterilization, hysterotomy with tubal ligation is reason able. If there is signiicant uterine disease, then hysterectomy may provide ideal treatment. In some cases of a failed second trimester medical induction, either of these may be considered.

Principal among noninvasive methods is a mifepristone plus misoprostol regimen or misoprostol alone (see Table 18-7). Of these two options, the combined regimen yields a shorter termination duration (Kapp, 2007; Ngoc, 201l). Hygroscopic dilators may speed the time to delivery with this combined regimen (Mazouni, 2009; Vincienne, 2017). In selecting misoprostol routes, oral administration leads to a longer time to delivery compared with vaginal or sublingual routes (Dickinson, 2014). Prophylactic antibiotics are not typically given, and infection surveillance during labor is instead applied (Achilles, 2011).

Another induction agent, PGE2, shows similar eicacy and side efects compared with misoprostol Gain, 1994; Jansen, 2008). Simultaneous administration of an antiemetic such as metoclopramide (Reglan), an antipyretic such as acetaminophen, and an antidiarrheal such as diphenoxylate/atropine (Lomotil) will help prevent or treat symptoms. Dinoprostone (Prostin) is an available PGE2 in the United States. However, its greater cost and poor pharmacologic stability at room temperature may make it less attractive than misoprostol.

Of other agents, high-dose intravenous oxytocin in saline will result in second-trimester abortion in 80 to 90 percent of cases (see Table 18-7). However, by comparison, misoprostol leads to higher successful induction rates and faster delivery times (Alavi, 2013).

Rarely used, ethacridine lactate is an organic antiseptic that activates myometrial mast cells to release prostaglandins (Olund, 1980). Placed extraovularly, that is, extraamnionically, it is associated with longer times to delivery and greater complication rates compared with misoprostol (Boza, 2008).

For second-trimester gestations, D & E or medical induction is suitable clinically and psychologically. Thus, patient input and clinical indication guide selection (Burgoine, 2005; Kerns, 2012). Once delivered, viewing and holding the fetus mayior may not be desired by the patient (Sloan, 2008).

Evaluation of a stillborn fetus is described in Chapter 35 (p. 646). One component is autopsy, which can also be valuable for second-trimester losses or terminations due to anomaly. For example, in a stud) of 486 women of all ages with secondtrimester miscarriage, fetal malformations were identiied in 13 percent 000, 2009). In another, a third of otherwise normal fetuses had associated chorioamnionitis that was judged to have preceded labor (Allanson, 2010). Indeed, according to Srinivas and associates (2008), 95 percent of placentas in midtrimester miscarriages are abnormal. Other abnormalities are vascular thromboses and infarctions.

With either surgical or medical abortion, subsequent autopsy can yield information, but fragmented D & E specimens may provide less information than intact fetuses (Gawron, 2013; Lal, 2014). Karyotyping can be performed on samples from either method (Bernick, 1998).

Legally induced abortion in the United States has a low associated mortality rate, and from 2008 to 2012, the rate was < 1 death per 100,000 procedures Oatlaoui, 2016). Earlyiabortions are safer. For example, Zane and coworkers (2015) found a mortality rate of 0.3 deaths per 100,000 procedures at;8 weeks' gestation; a rate of2.5 at 14 to 17 weeks; and 6.7 at ::18 weeks. As emphasized by Raymond and Grimes (2012), mortality rates are 14-fold greater for pregnancies that are continued.

Data relating abortion to overall maternal health and to subsequent pregnancy outcome are limited. From studies, there is no evidence for excessive mental disorders (Biggs, 2017; Munk-Olsen, 2011). here are few data regarding subsequent reproductive health, although the rates of infertility or ectopic pregnancy are not increased. Exceptions may stem from postabortal infections, especially those caused by C trachomatis. Of subsequent adverse pregnancy outcomes, several studies note an approximate 1.5-fold greater incidence of preterm delivery following surgical evacuation (Lemmers, 2016; Makhlouf, 2014; Saccone, 2016). his risk accrues with the number of terminations (Hardy, 2013; Klemetti, 2012). Subsequent pregnancy outcomes are similar regardless of whether a prior induced abortion was completed medically or surgically (Mannisto, 2013; Virk, 2007).

After medical or surgical management of an early pregnancy termination or loss, ovulation na) resume as early as 8 days, but the average time is 3 weeks (Lahteenmaki, 1978; Stoddard, 2011). Thus, unless another pregnancy is imminently desired, efective contraception is initiated to help lower the unintended pregnancy rate, which was 45 percent in 2011 in the United States (Finer, 2016). In suitable candidates described in Chapter 38 (p. 685), an intrauterine device can be inserted after the procedure or medical abortion is completed (Bednarek, 2011; Korjamo, 2017). Alternatively, any of the various forms of hormonal contraception can be initiated at this time (Curtis, 2016).

For women who desire another pregnancy, conception need not be delayed. Specifically, Wong and colleagues (2015) found similar live-birth rates in groups conceiving within 3 months of first-trimester pregnancy loss compared with groups with later conception. Others have found similarly reassuring results using an interval-to-conception threshold of 6 months (Kangatharan, 2017; Love, 2010).

Achilles SL, Reeves MF, Society of Family Planning: Prevention of infection after induced abortion: release date October 2010: SFP guideline 20102. Contraception 83(4):295, 201r1

Achiron R, Tadmor 0, Mashiach S: Heart rate as a predictor of first-trimester spontaneous abortion after ultrasound-proven viability. Obstet Gynecol 78(3 Pt 1):330

Alavi A, Rajaei M, mirian M, et al: Misoprostol versus high dose oxytocin and laminaria in termination of pregnancy in second-trimester pregnancies. Electron Physician 5(4):713, 2013

Albrechtsen S, Rasmussen S, Thoresen S, et al: Pregnancy outcome in women before and after cervical conization: population based cohort study. BMJ 18:337,r2008

Allanson B, Jennings B, Jacques A, et al: Infection and fetal loss in the midsecond trimester of pregnancy. Aust N Z J Obstet Gynaecol 50(3):221, 2010

Allen RH, Fitzmaurice G, Liford L, et al: Oral compared with intravenous sedation for first-trimester surgical abortion: a randomized controlled trial. Obstet Gynecol 113(2 Pt 1):276, 2009

Allen RH, Goldberg AB: Cervical dilation before first-trimester surgical abortion « 14 weeks' gestation). Contraception 93(4):277, 2016

American College of Obstetricians and Gynecologists: Misoprostol for postabortion care. Committee Opinion No. 427, February 2009

American College of Obstetricians and Gynecologists: Abortion policy. College Statement of Policy. January 1993, Reairmed 2014a

American College of Obstetricians and Gynecologists: Induced abortion. In Guidelines for Women's Health Care, 4th ed. Washington, 2014b

American College of Obstetricians and Gynecologists: Antibiotic prophylaxis for gynecologic procedures. Practice Bulletin No. 104, May 2009, Reaffirmed 2016a

American College of Obstetricians and Gynecologists: Cerclage for management of cervical insuiciency. Practice Bulletin No. 142, February 2014, Reairmed 2016b

American College of Obstetricians and Gynecologists: Medical management of irst-trimester abortion. Practice Bulletin No.143, March 2014, Reairmed 2016c American College of Obstetricians and Gynecologists: Microarray and next generation sequencing technology: the use of advanced genetic diagnostic tools in obstetrics and gynecology. Committee Opinion No. 682, December 2016d American College of Obstetricians and Gynecologists: Moderate cafeine consumption during pregnancy. Committee Opinion No. 462, August 2010, Reairmed 2016e

American College of Obstetricians and Gynecologists: Premature rupture of membranes. Practice Bulletin No. 172, October 2016f

American College of Obstetricians and Gynecologists: he limits of conscientious refusal in reproductive medicine. Committee Opinion No. 385, November 2007, Reairmed 2016g

American College of Obstetricians and Gynecologists: Ultrasound in pregnancy. Practice Bulletin No. 175, December 2016h

American College of Obstetricians and Gynecologists: Use of prophylactic antibiotics in labor and delivery. Practice Bulletin No. 120, June 2011, Reaffirmed 2016i

American College of Obstetricians and Gynecologists: Abortion training and education. Committee Opinion No. 612, November 2014, Reairmed 2017a

American College of Obstetricians and Gynecologists: Antiphospholipid syndrome. Practice Bulletin No. 132, December 2012, Reairmed 2017b American College of Obstetricians and Gynecologists: Early pregnancy loss.

Practice Bulletin No. 150, May 2015, Reairmed 2017c

American College of Obstetricians and Gynecologists: Increasing access to abortion. Committee Opinion No. 613, November 2014, Reairmed 2017d

American College of Obstetricians and Gynecologists: Inherited thrombophilias in pregnancy. Practice Bulletin No. 138, September 2013, Reairmed 2017e

American College of Obstetricians and Gynecologists: Periviable birth. Obstetric Care Consensus No.r6, October 2017f

American College of Obstetricians and Gynecologists: Prevention of h D alloimmunization. Practice Bulletin No. 181, August 2017g

American College of Obstetricians and Gynecologists: Second-trimester abortion. Practice Bulletin No. 135, June 2013, Reairmed 2017h

American College of Obstetricians and Gynecologists: hromboembolism in pregnancy. Practice Bulletin No. 123, September 2011, Reairmed 2017i American Society for Reproductive Medicine: Definitions of infertility and recurrent pregnancy loss. Fertil Steril 99:63, 2013

American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril 98: 1103, 2012

Ammon Avalos L, Galindo C, Li OK: A systematic review to calculate background miscarriage rates using life table analysis. Birth Defects Res A Clin Mol TeratoIr94(6):417, 2012

Andrikopoulou M, Lavery JA, Ananth CV, et al: Cervical ripening agents in the second trimester of pregnancy in women with a scarred uterus: a systematic review and metaanalysis of observational studies. Am J Obstet Gynecol 215(2):177,r2016

Arredondo F, Noble LS: Endocrinology of recurrent pregnancy loss. Semin Reprod Med 1 :33, 2006

Ashok PW, Flett GM, Templeton A: Mifepristone versus vaginally administered misoprostol for cervical priming before irst-trimester termination of pregnancy: a randomized, controlled study. Am J Obstet Gynecol 183(4):998,r2000

Aufret M, Bernard-Phalippon N, Dekemp J, et al: Misoprostol exposure during the first trimester of pregnancy: is the malformation risk varying depending on the indication? Eur J Obstet Gynecol Reprod Bioi 20 : 188, 2016

Avalos LA, Roberts SC, Kaskutas LA, et al: Volume and type of alcohol during early pregnancy and the risk of miscarriage. Subst Use Misuse 49: 1437,r2014

Balsells M, Garcia-Patterson A, Corcoy R: Systematic review and meta-analysis on the association of prepregnancy underweight and miscarriage. Eur J Obstet Gynecol Reprod Bioi 207:73, 2016

Barnhart K, Mennuti MT, Benjamin I, et al: Prompt diagnosis of ectopic pregnancy in an emergency department setting. Obstet GynecoI84(6): 1010, 1994

Barnhart K, Sammel MD, Chung K, et al: Decline of serum human chorionic gonadotropin and spontaneous complete abortion: deining the normal curve. Obstet Gynecol 104:975, 2004a

Barnhart K, van Mello NM, Bourne T, et al: Pregnancy of unknown location: a consensus statement of nomenclature, deinitions, and outcome. Fertil Steril 95(3):857,r201r1 Barnhart KT, Bader T, Huang X, et al: Hormone pattern after misoprostol administration for a nonviable irst-trimester gestation. Fertil Steril 81(4):1099,r2004b

Barnhart KT, Sammel MD, Rinaudo PF: Symptomatic patients with an early viable intrauterine pregnancy: hCG curves redeined. Obstet Gynecol 104:50, 2004c

Bartz 0, Maurer R, llen RH, et al: Buccal misoprostol compared with synthetic osmotic cervical dilator before surgical abortion: a randomized controlled trial. Obstet GynecoIr122(1):57, 2013

Bednarek PH, Creinin MD, Reeves MF, et al: Immediate versus delayed IUD insertion after uterine aspiration. N Engl J Med 364(21):2208, 2011 Ben-Ami I, Schneider D, Svirsky R, et al: Safety of late second-trimester pregnancy termination by laminaria dilatation and evacuation in patients with previous multiple cesarean sections. Am J Obstet Gynecol 201 (2): 154.e1, 2009

Ben-Ami I, Stern S, Vaknin Z, et al: Prevalence and risk factors of inadequate cervical dilation following laminaria insertion in second-trimester abortioncase control study. Contraception 91(4):308, 2015

Bennett GL, Bromley B, Lieberman E, et al: Subchorionic hemorrhage in irsttrimester pregnancies: prediction of pregnancy outcome with sonography. Radiology 200(3):803, 1996

Berdahl DM, Blaine J, Van Voorhis B, et al: Detection of enlarged yolk sac on early ultrasound is associated with ad-verse pregnancy outcomes. Fertil Sterilr94(4):1535,r2010

Berger OS, Hogge WA, Barmada MM, et al: Comprehensive analysis ofHLA

G: implications for recurrent spontaneous abortion. Reprod Sci 17(4):331, 2010

Berghella V, Airoldi J, O'Neill M, et al: Misoprostol for second trimester pregnancy termination in women with prior caesarean: a systematic review. BJOG 116(9):1151,2009

Berghella V, Mackeen D: Cervical length screening with ultrasound-indicated cerclage compared with history-indicated cerclage for prevention of preterm birth: a meta-analysis. Obstet GynecoIr118(1):148, 2011

Bernard N, Elefant E, Carlier P, et al: Continuation of pregnancy after irsttrimester exposure to mifepristone: an observational prospective study. BJOG 120(5):568,r2013

Bernick BA, Ufberg DD, Nemirof R, et al: Success rate of cytogenetic analysis at the time of second-trimester dilation and evacuation. Am J Obstet Gynecol 179(4):957, 1998

Bhattacharya S, T own end J, Bhattacharya S: Recurrent miscarriage: are three miscarriages one too many? Analysis of a Scottish population-based database of 151,021 pregnancies. Eur J Obstet Gynecol Reprod Bioi 150:24, 2010

Biggs MA, Upadhyay UD, McCulloch CE, et al: Women's mental health and well-being 5 years after receiving or being denied an abortion: a prospective, longitudinal cohort study. JAMA Psychiatry 74(2):169,2017

Blohm F, Friden B, Platz-Christensen J], et al: Expectant management of irst-trimester miscarriage in clinical practice. Acta Obstet Gynecol Scand ):654, 2003

Boivin JF: Risk of spontaneous abortion in women occupationally exposed to anaesthetic gases: a meta-analysis. Occup Environ Med 54:541, 1997

Borgatta L, Roncari D, Sonalkar S, et al: Mifepristone vs. osmotic dilator insertion for cervical preparation prior to surgical abortion at 14-16 weeks: a randomized trial. Contraception 86(5):567, 2012

Boue J, Bou A, Lazar P: Retrospective and prospective epidemiological studies of 1500 karyotyped spontaneous human abortions. Teratology 12(1):11, 1975

Boza AV, de Leon RG, Castillo LS, et al: Misoprostol preferable to ethacridine lactate for abortions at 13-20 weeks of pregnancy: Cuban experience. Reprod Health Matters 16(31 Suppl):189, 2008

Branch DW, Gibson M, Silver M: Recurrent miscarriage. N Engl J Med 363:18,r2010

Brigham SA, Conlon C, Farquhason RG: A longitudinal study of pregnancy outcome following idiopathic recurrent miscarriage. Hum Reprod 14(11):2868, 1999

Bromley B, Harlow BL, Laboda LA, et al: Small sac size in the irst trimester: a predictor of poor fetal outcome. Radiology 178(2):375,r1991

Bukulmez 0, Arici A: Luteal phase defect: myth or reality. Obstet Gynecol Clin North Am 31:727, 2004

Burgoine GA, Van Kirk SD, Romm J, et al: Comparison of perinatal grief after dilation and evacuation or labor induction in second trimester terminations for fetal anomalies. Am J Obstet GynecoIr192(6):1928, 2005

Burnett MA, Corbett CA, Gertenstein RJ: A randomized trial of laminaria tents versus vaginal misoprostol for cervical ripening in irst trimester surgical abortion. J Obstet Gynaecol Can 27(1):38, 2005

Carbonell JL, Gallego FG, Llorente MP, et al: \ aginal vs. sublingual misoprostol with mifepristone for cervical priming in second-trimester abortion by dilation and evacuation: a randomized clinical trial. Contraception 75(3):230, 2007 Caruso A, Trivellini C, De Carolis S, et al: Emergency cerclage in the presence of protruding membranes: is pregnancy outcome predictable? Acta Obstet Gynecol Scand 79:265, 2000

Casikar I, Lu C, Oates J, et al: The use of power Doppler colour scoring to predict successful expectant management in women with an incomplete miscarriage. Hum Reprod 2 (3):669,r2012

Caspi E, Schneider DF, Mor Z, et al: Cervical internal os cerclage: description of a new technique and comparison with Shirodkar operation. Am J Perinatol 7:347, 1990

Cates W Jr, Schulz KF, Grimes DA, et al: Dilatation and evacuation procedures and second-trimester abortions. The role of physician skill and hospital setting. JAMA 248(5):559, 1982

Centers for Disease Control and Prevention: Clostridium sordelii roxic shock syndrome after medical abortion with mifepristone and intravaginal misoprostol-United States and Canada, 2001-2005. MMWR 54(29):724, 2005 Centers for Disease Control and Prevention: Tobacco use and pregnancy. 2016. Available at: https:!lwww.cdc.govlreproductivehealth/maternalinfanthealth/tobaccousepregnancy.l Accessed May 2, 2016

Chasen ST, Kalish RB, Gupta , et al: Obstetric outcomes after surgical abortion atr> or = 20 weeks' gestation. m J Obstet Gynecol 193:1161,r2005 Chasen ST, Silverman NS: Mid-trimester emergent cerclage: a ten year single institution review. J Perinatol 18:338, 1998

Chen BA, Reeves MF, Creinin MD, et al: Misoprostol for treatment of early pregnancy failure in women with previous uterine surgery. Am J Obstet Gynecol 198:626.el, 2008

Chen L, Hu R: hyroid autoimmuniry and miscarriage: a meta-analysis. Clin Endocrinol 74:513, 2011

Chong E, Frye LJ, Castle J, et al: A prospective, nonrandomized study of home-use of mifepristone for medical abortion in the U.S. Contraception 92:215,r2015

Christiansen OB, Larsen EC, Egerup P, et al: Intravenous immunoglobulin treatment for secondary recurrent miscarriage: a randomised, double-blind, placebo-controlled trial. BJOG 122(4):500,2015 Chung K, Sammel M, Zhou L, et al: Deining the curve when initial levels of human chorionic gonadotropin in patients with spontaneous abortions are low. Ferril Steril 85(2): 508, 2006 Clark W, Bracken H, T anenhaus J, et al: lternatives to a routine follow-up visit for early medical abortion. Obstet Gynecol 115(2 Pt 1):264,r2010 C10wse ME, Jamison M, Myers E, et al: A national study of the complications of lupus in pregnancy. Am J Obstet Gynecol 199: 127.el, 2008 Cnattingius S, Signorello LB, Anneren G, et al: Cafeine intake and the risk of irst-trimester spontaneous abortion. N Engl J Med 343: 1839, 2000 Cocksedge A, Li TC, Saravelos SH, et a1: A reappraisal of the role of polycystic ovary syndrome in recurrent miscarriage. Reprod Biomed Online 17:151,r2008 Condous G, Okaro E, Khalid A, et al: Do we need to follow up complete miscarriages with serum human chorionic gonadotrophin levels? BJOG 112:827, 2005 Conforti A, lviggi C, Mollo A, et al: he management of Asherman syndrome: a review of literature. Reprod BioI Endocrinol 11: 118, 2013 Connolly A, Ryan DH, Stuebe AM, et al: Reevaluation of discriminatory and threshold levels for serum j-hCG in early pregnancy. Obstet Gynecol 121(1):65,r2013 Contag SA, Woo J, Schwartz DB, et al: Reinforcing cerclage for a short cevix at follow-up after the primary cerclage procedure. J Matern Fetal Neonatal Med 29(15):2423, 2016 Curtis M, Tepper NK, Jatlaoui TC, et al: U.S. medical e1igibiliry criteria for contraceptive use, 2016. MMWR 65(3):1, 2016 DaifJL, Levie M, ChudnofS, et al: Group A streptococcus causing necrotizing fasciitis and toxic shock syndrome after medical termination of pregnancy. Obstet Gynecol 113(2 Pt 2):504, 2009 Daily CA, Laurent SL, Nunley WC J r: The prognostic value of serum progesterone and quantitative beta-human chorionic gonadotropin in early human pregnancy. Am J Obstet Gynecol 171 (2):380, 1994 Dao B, Blum J, Thieba B, et al: Is misoprostol a safe, efective and acceptable alternative to manual vacuum aspiration for postabortion care? Results from a randomized trial in Burkina Faso, West Africa. BJOG 114(11): 1368, 2007 Daya S: Accuracy of gestational age estimation by means of fetal crown-rump length measurement. Am J Obstet Gynecol 168(3 Pt 1):903, 1993 Dean G, Colarossi L, Porsch L, et al: Manual compared with electric vacuum aspiration for abortion at less than 6 weeks of gestation: a randomized controlled trial. Obstet Gynecol 125(5):1121,2015 de La Rochebrochard E, honneau P: Paternal age >or = 40 years: an important risk factor for infertiliry. Am J Obstet Gynecol 189(4):901,2003 Devi Wold AS, Pham N, Arici A: Anatomic factors in recurrent pregnancy loss. Semin Reprod Med 1 :25, 2006 Dickey RP, Olar TT, Taylor SN, et al: Relationship of small gestational saccrown-rump length diferences to abortion and abortus karyorypes. Obstet Gynecol 79(4):554, 1992 Dickinson JE, Jennings BG, Doherry DA: Mifepristone and oral, vaginal, or sublingual misoprostol for second-trimester abortion: a randomized controlled trial. Obstet Gynecol 123(6):1162,2014 Diedrich J, Drey E, Sociery of Family Planning: Induction of fetal demise before abortion. Contraception 81r(6):462, 2010 Doret M, Cartier R, Miribel J, et al: Premature preterm rupture of the membrane diagnosis in early pregnancy: PAMG-l and IGFBP-l detection in amniotic fluid with biochemical tests. C1in Biochem 46(18):1816, 2013

Doubilet PM, Benson CB, Bourne T, et al: Diagnostic criteria for nonviable pregnancy early in the irst trimester. N Engl J Med 369: 1443, 2013

Edelman AB, Buckmaster JG, Goetsch MF, et al: Cervical preparation using laminaria with adjunctive buccal misoprostol before second-trimester dilation and evacuation procedures: a randomized clinical trial. Am J Obstet Gynecol 194(2):425,r2006

Eglinton GS, Heway C, Skupski OW, et al: Endocervical hyaluronan and ultrasound-indicated cerclage. Ultrasound Obstet GynecoI37(2):214, 2011

Ehsanipoor RM, Seligman NS, Saccone G, et 1: Physical examinationindicated cerclage: a systematic review and meta-analysis. Obstet Gynecol 126(1):125,r2015

Eiben B, Bartels I, Bahr-Prosch S, et al: Cytogenetic analysis 50 spontaneous abortions with the direct-preparation method of chorionic villi and its implications for studying genetic causes of pregnancy wastage. Am J Hum Genet 47:656, 1990

Erkan 0, Kozora E, Lockshin MD: Cognitive dysfunction and white matter abnormalities in antiphospholipid syndrome. Pathophysiology 18(1):93, 201r1

Eschenbach DA: Treating spontaneous and induced septic abortions. Obstet Gynecol 125(5):1042,r2015

Esteves JS, de Sa A, de Carvalho PR, et al: Neonatal outcome in women with preterm premature rupture of membranes (PPROM) between 18 and 26 weeks. J Matern Fetal eonatal Med 29(7):1108, 2016

Everest NJ, Jacobs SE, Davis PG, et a1: Outcomes following prolonged preterm premature rupture of the membranes. Arch Dis Child Fetal Neonatal Ed 93(3):F207, 2008

Fan HT, Zhang M, Zhan P, et al: Structural chromosomal abnormalities in couples in cases of recurrent spontaneous abortions in Jilin Province, China. Genet v101 Res 15 (1): 1, 2016

Feodor Nilsson S, Andersen PK, Strandberg-Larsen K, et a1: Risk factors for miscarriage from a prevention perspective: a nationwide follow-up study. BJOG 121:13 5,r2014

Finer LB, Zolna MR: Declines in unintended pregnancy in the United States, 2008-2011r. N Engl J Med 374(9):843, 2016

Fjerstad M, Trussell J, Sivin 1, et al: Rates of serious infection after changes in regimens for medical abortion. N Engl J Med 361:145, 2009

Fox MC, Krajewski CM: Cervical preparation for second-trimester surgical abortion prior to 20 weeks' gestation: SFP Guideline #201r3-4. Contraception 89(2):75, 2014

Garber J, Cobin R, Gharib H, et a1: Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. hyroid 22 (12):1200,r2012

Gaskins AJ, Toth TL, Chavarro JE: Prepregnancy nutrition and early pregnancy outcomes. Curr Nutr Rep 4(3):265,2015

Gawron LM, Hammond C, Ernst LM: Perinatal pathologic examination of non intact, second-trimester fetal demise specimens: the value of standardization. Arch Pathol Lab Med 137(8):1083,r2013

Giraldo-Isaza A, Fried GP, Hegarry SE, et al: Comparison of 2 stitches vs 1 stitch for transvaginal cervical cerclage for preterm birth prevention. Am J Obstet Gynecol 208:209.el, 2013

Goldberg AB, Drey EA, Whitaker AK: Misoprostol compared with laminaria before early second-trimester surgical abortion: a randomized trial. Obstet Gynecol 106:234, 2005

Goldberg AB, Fortin JA, Drey EA, et al: Cervical preparation before dilation and evacuation using adjunctive misoprostol or mifeprisrone compared with ovenight osmotic dilators alone: a randomized controlled trial. Obstet Gynecol 126(3):599,r2015

Goldstein SR: Signiicance of cardiac activiry on endovaginal ultrasound in very early embryos. Obstet Gynecol 80(4):670, 1992

Grimes DA, Schulz KF, Cates WJ Jr: Prevention of uterine perforation during curettage abortion. JAvIA 251 (16):21 08, 1984

Grossman D, White K, Harris L, et al: Continuing pregnancy after mifepristone and "reversal" of irst-trimester medical abortion: a systematic review. Contraception 92(3):206, 2015

Guiahi M, Davis A, Sociery of Family Planning: First-trimester abortion in women with medical conditions: release date October 2012 SFP guideline #20122. Contraception 86(6):622, 2012

Hahn A, Wise A, Rothman KJ, et al: Cafeine and cafeinated beverage consumption and risk of spontaneous abortion. Hum Reprod 30(5): 1246, 2015

Halvorson LM: First-trimester abortion. In Hofman BL, Schorge JO, Bradshaw KO, et al (eds): Williams Gynecology, 3rd ed. McGraw-Hill Education, New York, 2016

Hannain B, Lovecchio F, Blackburn P: Do Rh-negative women with irst trimester spontaneous abortions need Rh immune globulin? Am J Obstet Gynecol 24:487, 2006

Hardy G, Benjamin A, Abenhaim HA: Efect of induced abortions on early preterm births and adverse perinatal outcomes. J Obstet Gynaecol Can 35(2):138,r2013

Hawkins E, NimarofM: Vaginal erosion of an abdominal cerclage 7 years after laparoscopic placement. Obstet Gynecol 123(2 Pt 2 Suppl 2):420, 2014

Hawkins JS: Lower genital tract procedures. In Yeomans ER, Hofman BL, Gilstrap LC III, et al: Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hill Education, 201

Heuser e, Dalton J, Macpherson C, et al: Idiopathic recurrent pregnancy loss recurs at similar gestational ages. Am J Obstet Gynecol 203(4):343.e1, 2010

Hofman BL, Corton MM: Surgeries for benign gynecologic disorders. In Hofman BL, Schorge JO, Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGraw-Hill Education, 2016

Hooker AB, Lemmers M, Thurkow AL, et al: Systematic review and metaanalysis of intrauterine adhesions after miscarriage: prevalence, risk factors and long-term reproductive outcome. Hum Reptod Update 20(2):262, 2014

Hoover RN, Hyer M, PheifFer RM, et al: Adverse health outcomes in women exposed in utero to diethylstilbestrol. N Engl J Med 365(14): 1304,r2011

Hunter TJ, Byrnes MJ, Nathan E, et al: Factors inluencing survival in previable preterm premature rupture of membranes. J Matern Fetal Neonatal Med 25(9):1755,r2012

Hyoun SC, Obiean SG, Scialli AR: Teratogen update: methotrexate. Birth Defects Res A Clin Mol Teratol 94(4):18 ,r2012

Ireland LD, Gatter M, Chen AY: Medical compared with surgical abortion for efective pregnancy termination in the irst trimester. Obstet Gynecol 126(1):22,r2015

Jacobs PA, Hassold TJ: The origin of chromosomal abnormalities in spontaneous abortion. In Porter IH, Hook EB (eds): Human Embryonic and Fetal Death. New York, Academic Press, 1980, p 289

Jain JK, Mishell DR: Comparison of intravaginal misoprostol with prostaglandinE2 for termination of 2nd-trimester pregnancy. N EnglJ Med 331:290,r1994

Jansen NE, Pasker-De Jong PC, Zondervan HA: Mifepristone and misoprostol versus Dilapan and sulprostone for second trimester termination of pregnancy. J Matern Fetal Neonatal 21(1l):847, 2008

Jatlaoui Te, Ewing A, Mandel MG, et al: Abortion surveillance-United States, 2013. MMWR 65(12):1,r2016

Jenderny J: Chromosome aberrations in a large series of spontaneous miscarriages in the German population and review of the literature. Mol Cytogenet 7:38,r2014

Jones RK, Jerman J: Abortion incidence and service availability in the United States, 2014. Perspect Sex Reprod Health 49(1):17, 2017

Joo JG, Beke A, Berkes E, et al: Fetal pathology in second-trimester miscarriages. Fetal Diagn her 25(2): 186, 2009

Jun SH, Ginsburg ES, Racowsky C, et al: Uterine leiomyomas and their efect on in vitro fertilization outcome: a retrospective study. J Assist Reprod Genet 18:139,r2001

Kadar N, DeCherney AH, Romero R: Receiver operating characteristic (ROC) curve analysis of the relative eicacy of single and serial chorionic gonadotropin determinations in the early diagnosis of ectopic pregnancy. Fertil Steril 37:542, 1982

Kajii T, Ferrier A, Niikawa N, et al: Anatomic and chromosomal anomalies in 639 spontaneous abortions. Hum Genet 55:87, 1980

Kalagiri RR, Carder T, Choudhuty S, et al: Inlammation in complicated pregnancy and its outcome. Am J Perinatol 33(14):1337, 2016

Kangatharan C, Labram S, Bhattacharya S: Interpregnancy interval following miscarriage and adverse pregnancy outcomes: systematic review and metaanalysis. Hum Reprod Update 23(2):221, 201

Kapp N, Borgatta L, Stubbleield PG, et al: Mifepristone in midtrimester medical abortion: a randomized controlled trial. Obstet Gynecol 110: 1304, 2007 Kapp N, Lohr PA, Ngo TO, et al: Cervical preparation for irst trimester surgi cal abortion. Cochrane Database Syst Rev 2:CDOO 20 , 2010 Kaunitz M, Rovira EZ, Grimes DA, et al: Abortions that fai\. Obstet Gynecol 66(4):533, 1985

Kerns J, Steinauer J: Management of postabortion hemorrhage: release date November 2012 SFP Guideline #20131. Contraception 87(3):331, 2013

Kerns J, Vanjani R, Freedman L, et al: Women's decision making regarding choice of second trimester termination method for pregnancy complications. Int J Gynaecol Obstet 116(3):244, 2012

Kibei M, Asztalos E, Barrett J, et al: Outcomes of pregnancies complicated by preterm premature rupture of membranes between 20 and 24 weeks of gestation. Obstet Gynecol 128(2):313,r2016

Kilpatrick SJ, Patil R, Connell J, et al: Risk factors for previable premature rupture of membranes or advanced cervical dilation: a case control study. Am J Obstet Gynecol 194(4): 1168,r2006

Kim C, Barnard 5, Neilson JP, et al: Medical treatments for incomplete miscarriage. Cochrane Database Syst Rev 1 :CD007223, 2017

KlebanofMA, Levine RJ, DerSimonian R, et al: \laternal serum paraxanthine, a cafeine metabolite, and the risk of spontaneous abortion. N Engl J Med 341:1639,r1999

Kleinhaus K, Perrin M, Friedlander Y, et al: Paternal age and spontaneous abortion. Obstet Gynecol 108:369, 2006

Klemetti R, Gissler M, Niinimaki M, et al: Birth outcomes after induced abortion: a nationwide register-based study of irst births in Finland. Hum Reprod 27(11):3315, 2012

Kolte AM, Bernardi A, Christiansen OB, et al: Terminology for pregnancy loss prior to viability: a consensus statement from the ESHRE early pregnancy special interest group. Hum Reprod 30(3):495, 2015

Korjamo R, Mentula M, Heikinheimo 0: Immediate versus delayed initiation of the levonorgestrel-releasing intrauterine system following medical termination of pregnancyB1 year continuation rates: a randomised controlled trial. BJOG June 26, 2017 [Epub ahead ofprintJ

Kozma e, Ram aseth u J: Methotrexate and misoprostol teratogenicity: further expansion of the clinical manifestations. Am J Med Genet A 15 5A(7): 1723, 2011 Krieg SA, Shahine LK, Lathi RB: Environmental exposure to endocrine disrupting chemicals and miscarriage. Fertil Steril 106(4):941,r2016

Kuhn RPJ, Pepperell RJ: Cervical ligation: a review of 242 pregnancies. Aust N ZJ Obstet GynaecoIr 17:79, 19 7 Laboda LA, Estrof JA, Benacerraf BR: First trimester bradycardia. A sign of impending fetal loss. J Ultrasound Med 8(10):561, 1989

Lahteenmaki P, Luukkainen T: Return of ovarian function after abortion. Clin EndocrinoIr2:123, 19 8

Lal AK, Kominiarek vlA, Sprawka NM: Induction of labor compared to dilation and evacuation for postmortem analysis. Prenat Diagn 34(6):547, 2014 Lane BF, Wong-You-Cheong J], Javitt MC, et al: ACR Appropriateness Criteria irst trimester bleeding. Ultrasound Q 29(2):91,2013

Lawson Ce, Rocheleau CM, Whelan A, et al: Occupational exposures among nurses and risk of spontaneous abortion. AmJ Obstet Gyneco1206:32 .e1,2012

Lederle L, Steinauer JE, Montgomety A, et al: Obesity as a risk factor for complications after second-trimester abortion by dilation and evacuation. Obstet Gynecol 126(3):585,r2015

Lemmers M, Verschoor MA, Hooker AB, et al: Dilatation and curettage increases the risk of subsequent preterm birth: a systematic review and metaanalysis. Hum Reprod 31(1):34,r2016

Ie Roux PA, Pahal GS, Hofman L, et al: Second trimester termination of pregnancy for fetal anomaly or death: comparing mifepristone/misoprostol to gemeprost. Eur J Obstet Gynecol Reprod Bioi 95(1):52, 2001

Levi CS, Lyons EA, Zheng XH, et al: Endovaginal US: demonstration of cardiac activity in embryos of less than 5.0 mm in crown-rump length. Radiology 176(1): 1,r1990

Li Te, Iqbal T, Anstie B, et al: An analysis of the pattern of pregnancy loss in women with recurrent miscarriage. Fertil Steril 78(5):1100,r2002 Lichtenberg ES, Paul M, Society of Family Planning: Surgical abortion prior to 7 weeks of gestation. Contraception 88(1):7, 2013

Lindsay OJ, Lovett IS, Lyons EA, et al: Yolk sac diameter and shape at endovaginal US: predictors of pregnancy outcome in the irst trimester. Radiology 183(1):115, 1992

Locatelli A, Vergani P, Bellini P, et al: Amnioreduction in emergency cerclage with prolapsed membranes: comparison of two methods for reducing the membranes. Am J Perinatol 16:73, 1999

Love ER, Bhattacharya 5, Smith NC, et al: Efect of interpregnancy interval on outcomes of pregnancy after miscarriage: retrospective analysis of hospital episode statistics in Scotland. BMJ 341 :c3967, 2010

Luise C, Jermy K, May C, et al: Outcome of expectant management of spontaneous irst trimester miscarriage: observational study. BvlJ 324:873, 2002 Lykke JA, Dideriksen L, Lidegaard 0, et al: First-trimester vaginal bleeding and complications later in pregnancy. Obstet Gynecol 115:935,r2010 MacIsaac L, Darney P: Early surgical abortion: an altenative to and backup for medical abortion. Am J Obstet Gynecol 183:S76, 2000

MacIsaac L, Grossman 0, Balistreri E, et al: A randomized controlled trial of laminaria, oral misoprostol, and vaginal misoprostol before abortion. Obstet Gynecol 93(5 Pt 1):766, 1999

MacNaughton Me, Chalmers IG, Dubowitz V, et al: Final report of the Medical Research Council/Royal College of Obstetricians and Gynaecologists Multicentre Randomized Trial of Cervical Cerclage. BJOG 100:516, 1993

Mahajan OK, London SN: Mifepristone (RU486): a review. Ferti! Steril 68(6):967, 1997

Makhlouf MA, Clifton RG, RobertS JM, et al: Adverse pregnancy outcomes among women with prior spontaneous or induced abortions. Am J Perinatol 31(9):765,r2014

Mankowski JL, Kingston J, Moran T, et al: Paracervical compared with intracervical lidocaine for suction curettage: a randomized controlled trial. Obstet Gynecol 113:1052,r2009

Mannisto J, Mentula M, Bloigu A, et al: Medical versus surgical termination of pregnancy in primigravid women-is the next delivery diferently at risk? A population-based register study. BJOG 120(3):331,2013 tvfatsuzaki S, Matsuzaki S, Ueda Y, et al: A case report and literature review of midtrimester termination of pregnancy complicated by placenta previa and placenta accreta. AJP Rep 5(1):e6, 2015

Mazouni C, Vejux N, Menard JP, et al: Cervical preparation with laminaria tents improves induction-to-delivery interval in second-and third-trimester medical termination of pregnancy. Contraception 80( 1): 1 0 1, 2009 vfazze l, Kallen B: Reproductive outcome after anesthesia and operation during pregnancy: a registry study of 5405 cases. Am J Obstet Gynecol 161:1178,r1989

McDonald A: Incompetent cervix as a cause of recurrent abortion. J Obstet Gynaecol Br Commonw 70:105,r1963

Meites E, Zane S, Gould C: Fatal lostridium sordeLiii infections after medical abortions. N Engl J Med 363(14):1382, 2010

Monson A, Gibbons KJ, Esplin MS, et al: Pregnancy outcomes in women with a history of previable, preterm prelabor rupture of membranes. Obstet GynecoIr128(5):976,r2016

Moore L: he Developing Human: Clinically Oriented Embryology. 2nd ed.

Philadelphia, WB Saunders, 1977

Munk-Olsen T, Laursen T, Pedersen C, et al: Induced first-trimester abortion and risk of mental disorder. N Engl J Med 364(4):332, 2011

Muris C, Girard B, Creveuil C, et al: Management of premature rupture of membranes before 25 weeks. Eur J Obstet Gynecol Reprod Bioi 131(2):163, 2007

Miyakis S, Lockshin MD, Atsumi T, et al: International consensus statement on an update of the classiication criteria for definite anti phospholipid syndrome (APS). J hromb Haemost 4(2):295, 2006

Miyazaki K, Furuhashi M, Yoshida K, et al: Aggressive intervention of previable preterm premature rupture of membranes. Acta Obstet Gynecol Scand 91(8):923,r2012

Nadarajah R, Quek YS, Kuppannan K, et al: A randomised controlled trial of expectant management versus surgical evacuation of early pregnancy loss. Eur J Obstet Gynecol Reprod Bioi 178:35, 2014

Nahum GG: Uterine anomalies. How common are they, and what is their distribution among subtypes? J Reprod Med 43(10):877, 1998

Nakayama D, Masuzaki H, Miura K, et al: Efect of placenta previa on blood loss in second-trimester abortion by labor induction using gemeprost. Contraception 75(3):238, 2007

National Abortion Federation: 2016 Clinical policy guidelines. 2016. Available at: https://prochoice.org/wp-content/uploads/20 16-CPGs-web. pdf. Accessed April 23, 2017

Newmann SJ, Sokolof A, haryil M, et al: Same-day synthetic osmotic dilators compared with overnight laminaria before abortion at 14-18 weeks of gestation: a randomized controlled trial. Obstet Gynecol 123:271, 2014

Ngoc NT, Shochet T, Raghavan S, et al: Mifepristone and misoprostol compared with misoprostol alone for second-trimester abortion. Obstet Gynecol 118(3):601,r2011

Nielsen S, Hahlin M, Platz-Christensen J: Randomised trial comparing expectant with medical management for first trimester miscarriages. BJOG 106(8):804, 1999

Niinimaki M, Pouta A, Bloigu A, et al: Immediate complications after medical compared with surgical termination of pregnancy. Obstet Gynecol 114:795, 2009 Nishimura A, Otto CM, Bonow RO, et al: 2017 AHA/ACC Focused Update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/ American Heart Association Task Force on Clinical Practice Guidelines. Circulation 135(25):el159, 2017 O'Connell K, Jones HE, Simon M, et al: First-trimester surgical abortion practices: a survey of National Abortion Federation members. Contraception 79(5):385, 2009 O'Connor S, Kuller JA, McMahon MJ: Management of cervical cerclage ater preterm premature rupture of membranes. Obstet Gynecol Surv 54:391, 1999 Olund A, Kindahl H, Oliw E, et al: Prostaglandins and thromboxanes in amniotic fluid during rivanol-induced abortion and labour. Prostaglandins 19(5):791, 1980 Owen J: First-and second-trimester pregnancy termination. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hill Education, 2017 Owen J, Hankins G, lams J, et al: Multicenter randomized trial of cerclage for preterm birth prevention in high-risk women with shortened midtrimester cervical length. Am J Obstet Gynecol 201(4):375, 2009 Paul M, SchafE, Nichols M: he roles of clinical assessment, human chorionic gonadotropin assays, and ultrasonography in medical abortion practice. Am J Obstet Gynecol 183(2 Suppl):S34, 2000

Paul ME, Mitchell CM, Rogers AJ, et al: Early surgical abortion: eicacy and safety. Am J Obstet Gynecol 187:407, 2002

Pedersen JF, Mantoni M: Prevalence and signiicance of subchorionic hemorrhage in threatened abortion: a sonographic study. AJR Am J Roentgenol 154(3):535, 1990

Pei R, Wang G, Wang H, et al: Eicacy and safety of prophylactic uterine artery embolization in pregnancy termination with placenta previa. Cardiovase Intervent RadioIr40(3):375, 2017

Pelosi A: A new technique for reduction of prolapsed fetal membranes for emergency cervical cerclage. Obstet Gynecol 75(1):143, 1990 Perriera LK, Arslan M, Masch R: Placenta praevia and the risk of adverse outcomes during second trimester abortion: a retrospective cohort study. Aust N ZJ Obstet GynaecoI57(l):99, 2017

Petersen SG, Perkins A, Gibbons K, et al: Can we use a lower intravaginal dose of misoprostol in the medical management of miscarriage? A randomised controlled study. Aust N Z J Obstet Gynaecol 53(1):64, 2013

Peterson WF, Berry FN, Grace MR, et al: Second-trimester abortion by dilatation and evacuation: an analysis of 47 cases. Obstet GynecoI62(2): 185, 1983

Pineles BL, Park E, Samet JM: Systematic review and meta-analysis of miscarriage and maternal exposure to tobacco smoke during pregnancy. Am J Epidemiol 179(7):807, 2014

Prager SW, Oyer DJ: Second-trimester surgical abortion. Clin Obstet Gynecol 52(2): 179, 2009

Preisler J, Kopeika J, Ismail L, et al: Deining safe criteria to diagnose miscarriage: prospective observational multicentre study. BMJ 351 :h4579, 2015

Pristauz G, Bauer M, Maurer-Fellbaum U, et al: Neonatal outcome and twoyear follow-up after expectant management of second trimester rupture of membranes. Int J Gynaecol Obstet 101(3):264, 2008

Pymar HC, Creinin MD, Schwartz JL: Mifepristone followed on the same day by vaginal misoprostol for early abortion. Contraception 64:87,r2001 Raghavan S, Comendant R, Digol I, et al: Two-pill regimens of misoprostol after mifepristone medical abortion through 63 days' gestational age: a randomized controlled trial of sublingual and oral misoprostol. Contraception 79(2):84, 2009 Ramzy AM, Sattar M, Amin Y, et al: Uterine myomata and outcome of assisted reproduction. Hum Reprod 13: 198, 1998 Rauch ER, Schattman GL, Christos PJ, et al: Embryonic heart rate as a predictor of irst-trimester pregnancy loss in infertility patients after in vitro fertilization. Fertil Steril 91 (6):2451, 2009 Rathat G, Do Trinh P, Mercier G, et al: Synechia ater uterine compression sutures. Fertil Sterilr95(1):405, 201r1 Ray BK, Vallejo Me, Creinin MD, et al: Amniotic fluid embolism with second trimester pregnancy termination: a case report. Can J Anaesth 51 (2): 139, 2004

Raymond E, Grimes D: he comparative safety of legal induced abortion and childbirth in the United States. Obstet Gynecolr119(2, Part 1):215,r2012 Raymond EG, Shannon C, Weaver MA, et al: First-trimester medical abortion with mifepristone 200 mg and misoprostol: a systematic review. Contraception 87:26, 2013 Reichman DE, Laufer MR: Congenital uterine anomalies afecting reproduction. Best Pract Res Clin Obstet GynecoIr24(2):193, 2010 Reichman 0, Cohen M, Beller U: Prostaglandin E2 mid-trimester evacuation of the uterus for women with a previous cesarean section. Int J Gynaecol Obstet 96(1):32, 2007 Renner M, Nichols MD, Jensen JT, et al: Paracervical block for pain control in first-trimester surgical abortion. Obstet Gynecol 119:r1030,r2012 Richter J, Henry A, Ryan G, et al: Amniopatch procedure after previable iatrogenic rupture of the membranes: a two-center review. Prenat Diagn 33(4):391,r2013 Roberts D, \ ause S, Martin W, et al: Amnioinfusion in very early preterm prelabor rupture of membranes (AMIPROM): pregnancy, neonatal and maternal outcomes in a randomized controlled pilot study. Ultrasound Obstet GynecoIr43(5):490, 2014 Ruano R, Dumez Y, Cabrol 0, et al: Second-and third-trimester therapeutic terminations of pregnancy in cases with complete placenta previa-does feticide decrease postdelivery maternal hemorrhage? Fetal Diagn Ther 19(6):475,r2004 Rust OA, Atlas RO, Reed J, et al: Revisiting the short cervix detected by transvaginal ultrasound in the second trimester: why cerclage may not help. Am J Obstet Gyneco1r185:1098, 2001

Saccone G, Perriera L, Berghella V: Prior uterine evacuation of pregnancy as independent risk factor for preterm birth: a systematic review and metaanalysis. Am J Obstet Gynecol 214(5):572, 2016 Sagiv R, Mizrachi Y, Glickman H, et al: Laminaria vs. vaginal misoprostol for cervical preparation before second-trimester surgical abortion: a randomized clinical trial. Contraception 91 (5) :406, 2015

Saraswat L, Bhattacharya S, Maheshwari A, et al: Maternal and perinatal outcome in women with threatened miscarriage in the irst trimester: a systematic review. B]OG 117:245,2010

Saravelos SH, Yane], Rehmani H, et al: he prevalence and impact of ibroids and their treatment on the outcome of pregnancy in women with recurrent miscarriage. Hum Reprod 26:3274,e20e11

Sartorius GA, Nieschlag E: Paternal age and reproduction. Hum Reprod Update 16(1):65, 2010

Savaris F, Silva de Moraes G, Cristovam A, et al: Are antibiotics necessary ter 48 hours of improvement in infected/septic abortions? A randomized controlled trial followed by a cohort study. Am] Obstet GynecoIe204:301.e1, 2011

Savitz DA, Chan L, Herring AH, et al: Cafeine and miscarriage risk. Epidemiology 19:55, 2008

Schaf A, Fielding SL, Westhof C, et al: Vaginal misoprostol administered 1, 2, or 3 days after mifepristone for early medical abortion. A randomized trial.e]AMA 284:1948,e2000

Schenker ]G, Margalioth E]: Intrauterine adhesions: an updated appraisal.

Ferti! Steri!e37(5):593, 1982e

Schneider D, Bukovsky I, Caspi E: Safery of midtrimester pregnancy termination by laminaria and evacuation in patients with previous cesarean section. Ame] Obstet GynecoIe171(2):554, 1994

Schneider D, Golan A, Langer R, et al: Outcome of continued pregnancies after first and second trimester cervical dilatation by laminaria tents. Obstet Gynecol 78:1121, 1991

Schulz F, Grimes DA, Christensen DD: Vasopressin reduces blood loss from second-trimester dilatation and evacuation abortion. Lancet 2:353, 1985 Schust D, Hille]: Recurrent pregnancy loss. In Bereke] (ed): Novak's Gynecol ogy, 13th ed. Philadelphia, Lippincott Williams & Wilkins, 2002

Sfakianaki AK, Davis K], Copel ]A, et al: Potassium chloride-induced fetal demise: a retrospective cohort study of eicacy and safety. ] Ultrasound Med 33(2):337,e2014

Shannon C, Wiebe E, Jacot F: Regimens of misoprostol with mifepristone for early medical abortion: a randomized trial. B]OG 113:621,e2006

Shaw A, Lerma K: Update on second-trimester surgical abortion. Curr Opin Obstet GynecoIe28(6):51O, 2016

Shirodkar N: A new method of operative treatment for habitual abortions in the second trimester of pregnancy. Antiseptic 52:299, 1955

Shochet T, Diop A, Gaye A, et al: Sublingual misoprostol versus standard surgical care for treatment of incomplete abortion in five sub-Saharan African countries. BMC Pregnancy Childbirth 12:127,e2012

Siddiqi TA, Caligaris ]T, Miodovnik M, et al: Rate of spontaneous abortion after irst trimester sonographic demonstration of fetal cardiac activity. Am ] Perinatol 5(1):1, 1988

Siedhof M, Cremer ML: Pregnancy outcomes after laminaria placement and second-trimester removal. Obstet Gynecol 114(2 Pt 2):456,e2009

Silver M, Branch DW, Goldenberg R, et al: Nomenclature for pregnancy outcomes. Obstet GynecoIe118(6):1402, 2011

Simpson]L: Causes offetal wastage. Clin Obstet GynecoIe50(1):10, 2007 Sloan EP, Kirsh S, et al: Viewing the fetus following termination of pregnancy for fetal anomaly.e] Obstet Gynecol Neonatal Nurs 37(4):395, 2008 Society for Assisted Reproductive Technology: Preimplantation genetic testing: a Practice Committee opinion. Fertil Steril 90(5 Suppi):S136, 2008

Society for Maternal-Fetal Medicine: Cervical cerclage for the woman with prior adverse pregnancy outcome. Reairmed 2015. Available at: https://ww.smfm.org/ p u blications/ 9 8-cervical-cerclage-fo r-the-woman -wi thprior-adverse-pregnancy-outcome. Accessed May 12, 201

Spitz 1M, Bardin CW, Benton L, et al: Early pregnancy termination with mifepristone and misoprostol in the United States. N Engle] Med 338(18):1241,e1998

Srinivas SK, Ernst LM, Edlow AG, et al: Can placental pathology explain second-trimester pregnancy loss and subsequent pregnancy outcomes? Am ] Obstet Gynecol 199:402.e1, 2008

Stabile I, Campbell S, Grudzinskas ]G: hreatened miscarriage and intrauterine hematomas. Sonographic and biochemical studies. ] Ultrasound Med 8(6):289, 1989

Stefos TI, Lolis DE, Sotiriadis A], et al: Embryonic heart rate in early pregnancy.e] Clin Ultrasound 26(1):33, 1998

Stein Z, Kline ], Susser E, et al: Maternal age and spontaneous abortion. In Porter IH, Hook EB (eds): Human Embryonic and Fetal Death. New York, Academic Press, 1980, p 107

Stephenson MD: Frequency offactors associated with habitual abortion in 197 couples. Fertil Steril 66(1):24, 1996

Stephenson MD, Awartani A, Robinson P: Cytogenetic analysis of miscarriages from couples with recurrent miscarriage: a case-control study. Hum Reprod 17(2):446, 2002

Stephenson MD, Kutteh WH, Purkiss S, et al: Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: a multicentered randomized placebo-controlled trial. Hum Reprod 25(9):2203,e2010

Stockheim D, Machtinger R, Wiser A, et al: A randomized prospective study of misoprostol or mifepristone followed by misoprostol when needed for the treatment of women with early pregnancy failure. Fertil Steril 86:956, 2006

Stoddard A, Eisenberg DL: Controversies in family planning: timing of ovulation after abortion and the conundrum of postabortion intrauterine device insertion. Contraception 84(2):119, 2011

Stoval N, Sibai B, Habli M: Is there a role for cerclage in twin gestation with short cervical length (CL)? Single center experience. Abstract No. 143, Am ] Obstet Gynecole208(1 Suppl):S73, 2013

Stubbleield PG, Altman M, Goldstein SP: Randomized trial of one versus two days of laminaria treatment prior to late midtrimester abortion by uterine evacuation: a pilot study. Am] Obstet GynecoI143(4):481, 1982

Sugibayashi S, Aeby T, Kim D, et al: Amniotic luid arborization in the diagnosis of previable preterm premature rupture of membranes. ] Reprod Med 57(3-4):136,e2012

Sullivan E, Silver M, LaCoursiere DY, et al: Recurrent fetal aneuploidy and recurrent miscarriage. Obstet Gynecol 104:784,e2004

Sundtoft I, Langhof-Roos ], Sandager P, et al: Cervical collagen is reduced in non-pregnant women with a history of cervical insuiciency and a short cevix. Acta Obstet Gynecol Scand 96(8):984, 2017

Sunkara SK, Khairy M, EI-Toukhy T, et al: he efect of intramural ibroids without uterine cavity involvement on the outcome of IVF treatment: a systematic review and meta-analysis. Hum Reprod 25(2):418, 2010

Tang OS, Gemzell-Danielsson K, Ho PC: Misoprostol: pharmacokinetic proiles, efects on the uterus and side-efects. Inte] Gynaecol Obstet 99 Suppl 2:S 160, 2007

Templeton A, Grimes D: A request for abortion. N Engl] Med 365(23):2198, 2011

Terkildsen MFC, Parilla BV, Kumar P, et al: Factors associated with success of emergent second-trimester cerclage. Obstet Gynecol 101 :565, 2003

Thangaratinam S, Tan A, Knox E, et al: Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. BM] 342:d2616,e2011 homason ]L, Sampson MB, Beckman CR, et al: he incompetent cevix: a 1982 update.e] Reprod Med 27:187, 1982

Timor-Tritsch IE, Farine D, Rosen MG: A close look at early embryonic development with the high-frequency transvaginal transducer. Am J Obstet GynecoIe159(3):676, 1988

To MS, Alirevic Z, Heath VCF, et al: Cervical cerclage for prevention of preterm delivery in women with short cervix: randomised controlled trial. Lancet 363:1849,e2004

Trinder ], Brocklehurst P, Porter R, et al: Management of miscarriage: expectant, medical, or surgical? Results of randomized controlled trial (miscarriage treatment (MIST) trial). BM] 332(7552):1235, 2006

Tulandi T, lghanaim N, Hakeem G, et al: Pre and post-conceptional abdominal cerclage by laparoscopy or laparotomy. ] Minim Invasive Gynecol 21(6):987,e2014

Tuuli MG, Norman SM, Odibo AO, et al: Perinatal outcomes in women with subchorionic hematoma: a systematic review and meta-analysis. Obstet GynecoIe117(5):1205,e2011

Tzeng CR, Hwang ]L, Au HK, et al: Sonographic patterns of the endometrium in assessment of medical abortion outcomes. Contraception 88(1):153,e2013

Upadhyay UD, Desai S, Zlidar V, et al: Incidence of emergency department visits and complications after abortion. Obstet Gynecol 125(1): 175, 2015

Vincienne M, Anselem 0, Cordier AG, et al: Comparison of the induction-todelivery interval in terminations of pregnancy with or without Dilapan-S. Fetal Diagn her March 29, 201 [Epub ahead of print]

Virk], Zhang], Olsen]: Medical abortion and the risk of subsequent adverse pregnancy outcomes. N Engle] Med 357:648, 2007

Vissenberg R, van Dijk MM, Fliers E, et al: Efect oflevothyroxine on live birth rate in euthyroid women with recurrent miscarriage and TPO antibodies (T4-LIFE study). Contemp Clin Trials 44:134,e2015 von Hertzen H, Honkanen H, Piaggio G, et al: WHO multinational study of three misoprostol regimens after mifepristone for early medical abortion. I: Eicacy. B]OG 110:808,e2003 von Hertzen H, Huong NTM, Piaggio G, et al: Misoprostol dose and route after mifepristone for early medical abortion: a randomized controlled noninferiority tril. B]OG 117(10):1186,e2010 von Hertzen H, Piaggio G, Huong NT, et al: Eicacy of two intervals and two routes of administration of misoprostol for termination of early pregnancy: a randomized controlled equivalence trial. Lancet 369: 1938, 2007 von Hertzen H, Piaggio G, Wojdyla D, et al: Two mifepristone doses and two intervals of misoprostol administration for termination of early pregnancy: a randomized factorial controlled equivalence trial. B]OG 116(3):381, 2009

Waters TP, Mercer BM: he management of preterm premature rupture of the membranes near the limit of fetal viability. Am 1 Obstet Gynecol 201(3):230,r2009

Webber K, Grivell M: Cervical ripening before irst trimester surgical evacuation for non-viable pregnancy. Cochrane Database Syst Rev 11 :CD009954, 2015

Weiss lL, Malone FD, Vidaver 1, et al: hreatened abortion: a risk factor for poor pregnancy outcome, a population-based screening study. Am 1 Obstet Gynecol 190(3):745,r2004

Weng X, Odouki R, Li DK: Maternal cafeine consumption during pregnancy and the risk of miscarriage: a prospective cohort study. Am 1 Obstet Gynecol 198:279.e1,r2008

White K, Carroll E, Grossman D: Complications from irst-trimester aspiration abortion: a systematic review of the literature. Contraception 92(5):422, 2015

White KO, Nucatola DL, Westhof C: Intra-fetal compared with intraamniotic digoxin before dilation and evacuation: a randomized controlled trial. Obstet GynecoIr128(5):1071, 2016

Whittle L, Singh SS, Allen L, et al: Laparoscopic cervico-isthmic cerclage: surgical technique and obstetric outcomes. Am 1 Obstet Gynecol 201:364. e1, 2009

Wijesiriwardana A, Bhattachatya S, Shetty A, et al: Obstetric outcome in women with threatened miscarriage in the irst trimester. Obstet Gynecol 107:557,r2006

Wilcox AF, Weinberg CR, O'Connor IF, et al: Incidence of early loss of pregnancy. N Engl 1 Med 319:189, 1988

WinikofB, Dzuba IG, Creinin MD, et al: Two distinct oral routes of misoprostol in mifepristone medical abortion: a randomized controlled trial. Obstet GynecoIr112(6):1303,2008

Winn HN, Chen M, Amon E, et al: Neonatal pulmonaty hypoplasia and perinatal mortality in patients with mid trimester rupture of amniotic membranes-a critical analysis. Am 1 Obstet GynecoIr182:1638, 2000

Witter FR: Negative sonographic indings followed by rapid cervical dilatation due to cervical incompetence. Obstet Gynecol 64: 136, 1984

Wong LF, Schliep KC, Silver RM, et al: The efect of a very short interpregnancy interval and pregnancy outcomes following a previous pregnancy loss. Am 1 Obstet Gynecol 212(3):375.e1, 2015

World Health Organization: Safe Abortion: Technical and Policy Guidance for Health Systems, 2nd ed. Geneva, WHO, 2012

Wyatt PR, Owolabi T, Meier C, et al: Age-speciic risk of fetal loss observed in a second trimester serum screening population.r·Am 1 Obstet Gynecol 192:240,r2005

York S, Lichtenberg ES: Characteristics of presumptive idiopathic disseminated intravascular coagulation during second-trimester induced abortion. Contraception 85(5):489, 2012

Yu D, Wong YM, Cheong Y, et al: Asherman syndrome-one century later.

Fertil Steril 89(4):759, 2008

Zane S, Creanga A, Berg Cl, et al: Abortion-related mortality in the United States: 1998-2010. Obstet GynecoIr126(2):258, 2015

Zaveri V, Aghajafari F, Amankwah K, et al: Abdominal versus vaginal cerclage after a failed transvaginal cerclage: a systematic review. Am 1 Obstet Gynecol 187:868,r2002

Zeisler H, laura A, Bancher-Todesca D, et al: Prophylactic cerclage in pregnancy. Efect in women with a history of conization. 1 Reprod Med 42(7):390, 1997

Zhang 1, Gilles 1M, Barnhart K, et al: A comparison of medical management with misoprostol and surgical management for early pregnancy failure. N Engll Med 353:761,r2005

TUBAL PREGNANCY. .e..e.....e..e....e...e....e....e..e.371

CLINICAL MANIFESTATIONS ........e.......e.e..e..e.372

MUL TIMODALITY DIAGNOSIS .e...........e... ...373

MEDICAL MANAGEMENT ........e..e..e....e...e..... 377

SURGICAL MANAGEMENT ..e...e....e.e....e....e..e... 378

INTERSTITIAL PREGNANCY .e.e..e.....e..e....e. ...e.380

CESAREAN SCAR PREGNANCYe. . . . . . . ............. 381

CERVICAL PREGNANCY. . . . . . . . . . . . . ............. 382

ABDOMINAL PREGNANCY . . . . . . . . . . ............. 383

OVARIAN PREGNANCYe. . . . . . . . . . . . . ............. 384

As soon as an unruptured extra-uterine pregnancy is positivey diagnosed, its immediate removal by laparotomy is urgenty indicate, since rupture may occur at any time and the patient die rom haemorrhage bore operative aid can be obtaine.

-J. Whitridge Williams (1903)

Following fertilization and fallopian tube transit, the blastocyst normally implants in the endometrial lining of the uterine cavity. Implantation elsewhere is considered ectopic and accounts for 0.5 to 1.5 percent of all irst-trimester pregnancies in the United States (Hoover, 2011; Stulberg, 2014). his small proportion disparately accounts for 3 percent of all pregnancyrelated deaths (Creanga, 2017). Fortunately, urine and serum beta-human chorionic gonadotropin (�-hCG) assays and transvaginal sonography allow earlier diagnosis. As a result, both maternal survival rates and conservation of reproductive capacity are improved.

Nearly 95 percent of ectopic pregnancies are implanted in the various segments of the fallopian tube. hese segments are shown in Chapter 2 (Fig. 2-14, p. 29). he ampulla (70 percent) is the most frequent site, followed by isthmic (12 percent), imbrial (1i1 percent), and interstitial tubal pregnancies (2 percent) (Bouyer, 2002). The remaining 5 percent of nontubal ectopic pregnancies implant in the ovary, peritoneal cavity, cervix, or prior cesarean scar. Occasionally, a multifetal pregnancy contains one conceptus with normal uterine implantation that coexists with one implanted ectopically. he natural incidence of these heterotopic pregnancies approximates 1 per 30,000 pregnancies (Reece, 1983). However, with assisted reproductive technologies (ART), their incidence is 9 in 10,000 pregnancies (Perkins, 2015). Rarely, twin tubal pregnancy with both embryos in the same tube or with one in each tube has been reported (Eze, 2012; Goswami, 2015).

Regardless of location, D-negative women with an ectopic pregnancy who are not sensitized to D-antigen are given IgG anti-D immunoglobulin (American College of Obstetricians and Gynecologists, 2017). In irst-trimester pregnancies, a 50-�g or 300-�g dose is appropriate, whereas a standard 300-�g dose is used for later gestations (Chap. 15, p. 305).

Abnormal fallopian tube anatomy underlies many cases of tubal ectopic pregnancy. Surgeries for a prior tubal pregnancy, for fertility restoration, or for sterilization confer the highest risk. After one previous ectopic pregnancy, the chance of another is increased ivefold (Bhattacharya, 2012). Prior sexually transmitted disease or other tubal infection, which can distort normal tubal anatomy, is another factor. Speciically, one episode of salpingitis can be followed by a subsequent ectopic pregnancy in up to 9 percent of women (Westrom, 1992). Peritubal adhesions subsequent to salpingitis, appendicitis, or endometriosis can also increase chances. Sapingitis isthmica nodosa, which is a condition in which epithelium-lined diverticula extend into a hypertrophied muscularis layer, is another (Bolaji, 2015). Finally, congenital fallopian tube anomalies, especially those secondary to in utero diethylstilbestrol exposure, can predispose (Hoover, 2011).

Infertility, as well as the use of ART to overcome it, is linked to substantively increased risks for ectopic pregnancy (Clayton, 2006). With ART, the ectopic pregnancy rate in the United States between 2001 and 2011 was 1.6 percent (Perkins, 2015). And "atypical" implantations-cornual, abdominal, cervical, ovarian, and heterotopic pregnancy-are more frequent. Smoking is another known association, although the underlying mechanism is unclear (Hyland, 2015). Last, with any form of contraception, the absolute number of ectopic pregnancies is decreased because pregnancy occurs less often. However, with some contraceptive method failures, the relative number of ectopic pregnancies is increased. Examples include tubal sterilization, copper and progestin-releasing intrauterine devices (IUDs), and progestin-only contraceptives (Chap. 38, p. 680).

With tubal pregnany, because the fallopian tube lacks a submucosalilayer, the fertilized ovum promptly burrows through the epithelium. he zygote comes to lie near or within the muscularis, which is invaded by rapidly proliferating trophoblast. The embryo or fetus in an ectopic pregnancy is oten absent or stunted.

Outcomes of ectopic pregnancy include tubal rupture, tubal abortion, or pregnancy failure with resolution. With rupture, the invading expanding conceptus and associated hemorrhage can tear rents in the fallopian tube (Fig. 19-1). Tubal ectopic pregnancies usually burst spontaneously but may occasionally rupture following coitus or bimanual examination.

FIGURE 19-1 Ruptured ampullary early tubal pregnancy. (Used with permission from Dr. Togas Tulandi.) lternatively, the pregnancy may pass out the distal fallopian tube. Tubal abortion frequency depends in part on the initial implantation site, and distal implantations are favored. Subsequently, hemorrhage may cease and symptoms eventually disappear. But bleeding can persist as long as products remain in the tube. Blood slowly trickles from the tubal fimbria into the peritoneal cavity and typically pools in the rectouterine cul-de-sac. If the fimbriated extremity is occluded, the fallopian tube may gradually become distended by blood, forming a hematosalpinx. Uncommonly, an aborted fetus will implant on a peritoneal surface and become an abdominal pregnancy, which is discussed on page 383.

Last, an unknown number of ectopic pregnancies spontaneously fail and are reabsorbed. This may be documented now more regularly with the advent of sensitive 3-hCG assays.

Distinctions beween "acute" ectopic pregnancy just described and "chronic" ectopic pregnancy can be drawn. The more common acute ectopic pregnancies are those with a high serum 3hCG level and rapid growth, leading to a timely diagnosis. hese carry a higher risk of tubal rupture (Barnhart, 2003c). With chronic ectopic pregnancy, abnormal trophoblast dies early, and thus negative or low, static serum 3-hCG levels are found (Brennan, 2000). Chronic ectopic pregnancies typically rupture late, if at all, but commonly form a complex pelvic mass, which oten is the reason prompting diagnostic surgery (Cole, 1982; Ugur, 1996).

Earlier patient presentation and more precise diagnostic technology typically allow identiication before rupture. In these cases, symptoms and signs of ectopic pregnancy are often subtle or even absent. The woman does not suspect tubal pregnancy and assumes that she has a normal early pregnancy or is having a miscarriage.

With later diagnosis, the classic triad is delayed menstruation, pain, and vaginal bleeding or spotting. With tubal rupture, lower abdominal and pelvic pain is usually severe and frequently described as sharp, stabbing, or tearing. Abdominal palpation elicits tenderness. Bimanual pelvic examination, especially cervical motion, causes exquisite pain. The posterior vaginal fornix may bulge from blood in the rectouterine cul-de-sac, or a tender, boggy mass may be felt beside the uterus. The uterus can also be slightly enlarged due to hormonal stimulation. Symptoms of diaphragmatic irritation, characterized by neck or shoulder pain, especially on inspiration, develop in perhaps half of women with sizable hemoperitoneum.

Some degree of vaginal spotting or bleeding is reported by 60 to 80 percent of women with tubal pregnancy. Although profuse vaginal bleeding suggests an incomplete abortion, such bleeding occasionally is seen with tubal gestations. Moreover, tubal pregnancy can lead to signiicant intraabdominal hemorrhage. Responses to moderate bleeding include no change in vital signs, a slight rise in blood pressure, or a vasovagal response with bradycardia and hypotension. Blood pressure will fall and pulse will rise only if bleeding continues and hypovolemia

FIGURE 19-2 This decidual cast was passed by a patient with a tubal ectopic pregnancy. The cast mirrors the shape of the endometrial cavity, and each arrow marks the portion of decidua that lined the cornua.

becomes significant. Vasomotor disturbances develop, ranging from vertigo to syncope.

Even after substantive hemorrhage, hemoglobin or hematocrit readings may at irst show only a slight reduction. Hence, after an acute hemorrhage, a trending decline in hemoglobin or hematocrit levels over several hours is a more valuable index of blood loss than is the initial level. In approximately half of women with a ruptured ectopic pregnancy, varying degrees of leukocytosis up to 30,000/�L may be documented.

Decidua is endometrium that is hormonally prepared for pregnancy, and the degree to which the endometrium is converted with ectopic pregnancy is variable. Thus, in addition to bleeding, women with ectopic tubal pregnancy may pass a decidual cast. his is the entire sloughed endometrium that takes the form of the endometrial cavity (Fig. 19-2). Importantly, decidual sloughing may also occur with uterine abortion. hus, tissue is carefully evaluated visually by the provider and then histologically for evidence of a conceptus. If no clear gestational sac is seen or if no villi are identified histologically within the cast, then the possibility of ectopic pregnancy must still be considered.

he diferential diagnosis for abdominal pain coexistent with pregnancy is extensive. Pain may derive from uterine conditions such as miscarriage, infection, degenerating or enlarging leiomyomas, or round-ligament pain. Adnexal disease may include ectopic pregnancy; hemorrhagic, ruptured, or torsed ovarian masses; salpingitis; or tuboovarian abscess. Last, appendicitis, cystitis, renal stone, and gastroenteritis are more common nongynecological sources of lower abdominal pain in early pregnancy.

Several algorithms have been proposed to identiY ectopic pregnancy. Most include these key components: physical indings, transvaginal sonography (TVS), serum 3-hCG level measurement-both the initial and the subsequent pattern of rise or decline, and diagnostic surgery, which includes dilation and curettage (D&C), laparoscopy, and occasionally, laparotomy (Fig. 19-3). Algorithm use applies only to hemodynamically stable women, and those with presumed rupture undergo prompt surgical therapy. For a suspected unruptured ectopic pregnancy, all diagnostic strategies involve trade-ofs. Strategies that maximize detection of ectopic pregnancy may result in termination of a normal intrauterine pregnancy (IUP). Conversely, those that reduce the potential for normal pregnancy interruption will delay ectopic pregnancy diagnosis. Patient desires for the index pregnancy are also discussed and may inluence these trade-ofs.

apid and accurate determination of pregnancy is essential to iden tiY an ectopic pregnancy. Current pregnancy tests use enzyme linked immunosorbent ssays (ELISAs) for the beta subunit of hCG. With these assays, lower limits of detection are 20 to 25 mIU/mL for urine and :;5 mIU/mL for serum (Greene, 2015).

With bleeding or pain and a positive pregnancy test result, an initial TVS is typically performed to identiY gestation loca tion. If a yolk sac, embryo, or fetus is identiied within the uterus or the adnexa, then a diagnosis can be made. In many cases, however, TVS is nondiagnostic, and tubal pregnancy is still a possibility. In these cases in which neither intrauterine nor extrauterine pregnancy is identiied, the term pregnancy of unknown location (PUL) is used until additional clinical infor mation allows determination of pregnancy location.

Levels above the Discriminatory Zone. Several investigators ure to visualize a uterine pregnancy indicates that the pregnancy either is not alive or is ectopic (Barnhart, 1994). Some institu tions set their discriminatory threshold at ::1500 mIU/mL, whereas others use ::2000 mIU/mL. Connolly and associates (2013) suggested an even higher threshold. hey noted that with live uterine pregnancies, a gestational sac was seen 99 percent of the time with a discriminatory level of >3510 mIU/mL.

If the initial 3-hCG level exceeds the set discriminatory level and no evidence for an IUP is seen with TVS, then ectopic pregnancy is a concern. The diagnosis is narrowed in most cases to a failing IUP, a recent complete abortion, or an ectopic pregnancy. Early multifetal gestation also remains a possibility. Without clear evidence for ectopic pregnancy, serial 3-hCG level assessment is reasonable, and a level is checked 48 hours later. This averts unnecessary methotrexate administration and avoids harming an early normal multifetal pregnancy. With greater concern for an ectopic gestation, D&C is another option to distinguish an ectopic from a failing IUP. Importantly, patient factors greatly influence these decisions.

Levels below the Discriminatoy Zone. If the initial 3-hCG level is below the set discriminatory value, pregnancy location is often not technically discernible with TVS. With these PULs, serial 3-hCG level assays are done to identiY patterns that indicate either a growing or failing IUP. Levels that rise or fall outside these expected parameters increase the concern for ectopic pregnancy. hus, appropriately selected women with a possible ectopic pregnancy, but whose initial 3-hCG level is below the discriminatory threshold, are seen 2 days later for further evaluation. Trends in levels aid diagnosis.

IUP t Prenatal care FIGURE 19-3 One suggested algorithm for evaluation of a woman with a suspected ectopic pregnancy. aExpectant management, D&C, or medical regimens are suitable options. bMay consider repeat 3-hCG level if normal IUP suspected. 3-hCG = beta human chorionic gonadotropin; D&C = dilatation and curettage; IUP = intrauterine pregnancy; VS

Nondiagnostic t D&Cb Chorionic villi Absent t Treat ectopic pregnancy Present = transvaginal sonography.

With early normal progressing IUPs, Barnhart and coworkers (2004b) reported a 53-percent 48-hour minimum rise with a 24-hour minimum rise of 24 percent. Seeber and associates (2006) found an even more conservative minimal 35-percent 48-hour rise in normal IUPs. With multifetal gestation, this same anticipated rate of rise is expected (Chung, 2006). Despite these guidelines, Silva and colleagues (2006) caution that a third of women with an ectopic pregnancy will have a 53-percent rise at 48 hours. They further reported that no single pattern characterizes ectopic pregnancy and that approximately half of ectopic pregnancies will show decreasing �-hCG levels, whereas the other half will have increasing levels. Also, despite a declining �-hCG level, a resolving ectopic pregnancy may rupture.

With a failing IUP, patterned rates of �-hCG level decline can also be anticipated. Following spontaneous abortion, rates decline by 21 to 35 percent at 48 hours and 68 to 84 percent at 7 days. Of note, these ranges relect that �-hCG percentages drop faster if the initial �-hCG level is higher (Barnhart, 2004a). With resolving PULs, Butts and coworkers (2013) found greater rates of decline that ranged from 35 to 50 percent at 48 hours and 66 to 87 percent at 7 days for starting hCG values between 250 and 5000 mIU/mL.

In pregnancies without these expected rises or falls in �-hCG levels, distinction between a nonliving IUP and an ectopic pregnancy may be aided by additional �-hCG levels (Zee, 2014). Again delay is balanced against the risk from rupture. D&C is an option and provides a quicker diagnosis balanced against normal pregnancy interruption. Before curettage, a second TVS examination may be indicated and may display new informative indings.

A single serum progesterone measurement may clariy the diagnosis in a few cases (Stovall, 1989, 1992). A value exceeding 25 ng/mL excludes ectopic pregnany with 92-percent sensitivity (Lipscomb, 1999a; Pisarska, 1998). Conversely, values <5 ng/mL are found in only 0.3 percent of normal progressing IUPs (Mol, 1998; Verhaegen, 2012). hus, values <5 ng/mL suggest either a nonliving IUP or an ectopic pregnancy. Because in most ectopic pregnancies, progesterone levels range between 10 and 25 ng/mL, the clinical utility of this practice is limited. One caveat is that pregnancy achieved with assisted reproductive technology may be associated with higher than usual progesterone levels (Perkins, 2000).

Endometrial Findings. In a woman in whom ectopic pregnancy is suspected, TVS is performed to look for findings indicative of uterine or ectopic pregnancy. During endometrial cavity evaluation, an intrauterine gestational sac is usually visible between 4Y2 and 5 weeks. The yolk sac appears between 5 and 6 weeks, and a fetal pole with cardiac activity is irst detected at 5Y2 to 6 weeks (Fig. 9-3, p. 159). With transabdominal sonography, these structures are visualized slightly later.

In contrast, with ectopic pregnancy, a trilaminar endometrial pattern can be diagnostic (Fig. 19-4). Its speciicity is 94 percent, but with a sensitivity of only 38 percent (Hammoud, 2005). In addition, Moschos and Twickler (2008b) determined sac within the endometrial cavity. Its cavity-conforming shape and central location are characteristic of these anechoic fluid col lections. Distal to this fluid, the endometrial stripe has a trilaminar pattern, which is a common finding with ectopic pregnancy.

(Reproduced with permission from Gala RB: Ectopic pregnancy. In

Hoffman BL, Schorge JO, Bradshaw KD, et al: Williams Gynecology, 3rd ed. New York, McGraw-Hili Education; 2016. Photo contributor:

Dr. Elysia Moschos.) in women with a pregnancy of unknown location at presenta tion that no normal IUPs had a stripe thickness <8 mm.

Anechoic luid collections, which might normally suggest an early intrauterine gestational sac, may also be seen with ectopic pregnancy. These include pseudogestational sac and decidual cyst. First, a pseudosac is a fluid collection between the endometrial layers and conforms to the cavity shape (see Fig. 19-4). If a pseudosac is noted, the risk of ectopic pregnancy is increased (Hill, 1990; Nyberg, 1987). Second, a decidual cyst is identiied as an anechoic area lying within the endometrium but remote from the canal and often at the endometrial-myometrial border. Ackerman and colleagues (1993 b) suggested that this finding represents early decidual breakdown and precedes decidual cast formation.

hese two indings contrast with the intradecidual sign seen with uterine pregnancies. With this, an early gestational sac is seen as an anechoic sac eccentrically located within one of the endometrial stripe layers (Dashefsky, 1988). The American College of Obstetricians and Gynecologists (2016) advises caution in diagnosing an IUP in the absence of a deinite yolk sac or embryo.

Adnexal Findings. he sonographic diagnosis of ectopic pregnancy rests on visualization of an adnexal mass separate from the ovary (Fig. 19-5). If fallopian tubes and ovaries are visualized and an extrauterine yolk sac, embryo, or fetus is identified, then an ectopic pregnancy is conirmed. In other cases, a hyperechoic halo or tubal ring surrounding an anechoic sac is seen (Nadim, 2017). Alternatively, an inhomogeneous adnexal mass is usually caused by hemorrhage within the ectopic sac. Overall, approximately 60 percent of ectopic pregnancies are seen as an inhomogeneous mass adjacent to the ovary; 20 percent appear as a hyperechoic ring; and 13 percent have an obvious gestational sac with a fetal pole (Condous, 2005). Importantly, not all adnexal masses represent an ectopic pregnancy, and integration of sonographic findings with other clinical information is necessary.

adnexal mass. In this last image, color Doppler shows a classic "ring

FIGURE 19-5 Various transvaginal sonographic findings with ectopic tubal pregnancies. For sonographic diagnosis, an ectopic mass should be seen in the adnexa separate from the ovary and may be seen as: (A) a yolk sac (shown here) and/or fetal pole with or without cardiac activity within an extrauterine sac, (B) an empty extrauterine sac with a hyperechoic ring, or (C) an inhomogeneous of fire," which reflects increased vascularity typical of ectopic pregnancies. LT OV = left ovary; SAG LT AD = sagittal left adnexa; UT = uterus.

Placental blood low within the periphery of the complex adnexal mass-the ring ofire-can be seen with transvaginal color Doppler imaging. Although this can aid diagnosis, this finding can also be seen with a corpus luteum cyst, and differentiation can be challenging.

Hemoperitoneum. In afected women, blood in the peritoneal cavity is most often identified using sonography, but assessment can also be made by culdocentesis (Fig. 19-6). Sonographically, anechoic or hypoechoic luid initially collects in the dependent retrouterine cul-de-sac, and then additionally surrounds the uterus as it fills the pelvis. As much as 50 mL of blood can be seen in the cul-de-sac using TVS, and transabdominal imaging then is used to assess the hemoperitoneum extent. Importantly, however, a small amount of peritoneal luid is physiologically normal. With signiicant intraabdominal hemorrhage, blood will track up the pericolic gutters to fill Morison pouch near the liver. Free luid in this pouch typically is not seen until accumulated volumes reach 400 to 700 mL (Branney, 1995; Rodgerson, 2001; Rose, 2004). Diagnostically, peritoneal fluid in conjunction with an adnexal mass is highly predictive of ectopic pregnancy (Nyberg, 1991). Ascites from ovarian or other cancer is a notable mimic.

Culdocentesis is a simple technique used commonly in the past. The cervix is pulled ourward and upward toward the symphysis with a tenaculum, and a long 18-gauge needle is inserted through the posterior vaginal fornix into the retrouterine culde-sac. If present, fluid can be aspirated. However, a failure to do so is interpreted only as unsatisfactory entry into the culde-sac. Fluid containing fragments of old clots or bloody fluid that does not clot suggests hemoperitoneum. In contrast, if the blood sample clots, it may have been obtained from an adjacent blood vessel or from a briskly bleeding ectopic pregnancy. Several studies have challenged its usefulness, and culdocentesis has been largely replaced by TVS (Glezerman, 1992; Vermesh, 1990).

Several endometrial changes accompany ectopic pregnancy, and all lack coexistent trophoblast. Decidual reaction is found in 42 percent of samples, secretory endometrium in 22 percent, and proliferative endometrium in 12 percent (Lopez, 1994). Some recommend that the absence of trophoblastic tissue be confirmed by D&C before methotrexate treatment is given (Chung, 201i1; Shaunik, 201l). Investigators found that the presumptive diagnosis of ectopic pregnancy is inaccurate in nearly 40 percent of cases without histological exclusion of a spontaneous pregnancy loss. Nevertheless, the risks of D&C are weighed against the limited maternal risks of methotrexate.

Endometrial biopsy with a Pipelle catheter was studied as an alternative to D&C and found inferior (Barnhart, 2003b; Ries, 2000). By comparison, frozen section of curettage fragments to identiY products of conception is accurate in more than 90 percent of cases (Barak, 2005; Li, 2014b).

Direct visualization of the fallopian tubes and pelvis by laparoscopy ofers a reliable diagnosis in most cases of suspected

FIGURE 19-6 Techniques to identiy hemoperitoneum. A.Transvaginal sonography of an anechoic fluid collection (arrow) in the retrouterine cul-de-sac. B. Culdocentesis: with a 16-to 18-gauge spinal needle attached to a syringe, the cul-de-sac is entered through the posterior vaginal fornix as upward traction is applied to the cervix with a tenaculum. (B, Reproduced with permission from Gala RB: Ectopic pregnancy. In Hofman BL, Schorge JO, Bradshaw KD, et al: Williams Gynecology, 3rd ed. New York, McGraw-Hili Education, 2016.) ectopic pregnancy. This also permits a ready transition to definitive operative therapy, which is discussed on page 378.

Medical therapy traditionally involves the antimetabolite methotrexate (MTX). This drug is a folic acid antagonist. It tightly binds to dihydrofolate reductase, blocking the reduction of dihydrofolate to tetrahydrofolate, which is the active form of folic acid. As a result, de novo purine and pyrimidine synthesis is halted, which leads to arrested DNA, RNA, and protein synthesis. Thus, MTX is highly efective against rapidly proliferating tissue such as trophoblast. Overall, ectopic tubal pregnancy resolution rates approximate 90 percent with its use. The drawbacks, however, are that bone marrow, gastrointestinal mucosa, and respiratory epithelium can also be harmed. It is directly toxic to hepatocytes and is renally excreted. MTX is also a potent teratogen, and MTX embryopathy is notable for craniofacial and skeletal abnormalities and fetal-growth restriction (N urmohamed, 201i1). In addition, MTX is excreted into breast milk and may accumulate in neonatal tissues and interfere with neonatal cellular metabolism (American Academy of Pediatrics, 2001; Briggs, 2015). Based on all these findings, a list of contraindications and pre therapy laboratory testing is found in Table

TABLE 19-1. Medical Treatment Protocols for Ectopic Pregnancy

Sensitivity to MTX Tubal rupture Breastfeeding One dose; repeat if necessary

Days 1 (baseline), 4, and 7 If seru m �-hCG level does not decline by 15% from day 4 to day 7 Less than 15% decline during

Up to four doses of both drugs until serum �-hCG declines by 15% 1 mg/kg, days 1,s3,5, and 7 0.1 mg/kg days 2, 4, 6, and 8 Days 1 (baseline), 3, 5, and 7

If serum �-hCG level declines < 15%, give additional dose; repeat serum �-hCG in 48 hours and compare with previous value; maximum four doses

Once 15% decline achieved, then weekly serum �-hCG levels until undetectable

Intrauterine pregnancy Immunodeficiency Peptic ulcer disease Hepatic, renal, or hematologic dysfunction Active pulmonary disease

BSA = body surface area; �-hCG =�-human chorionic gonadotropin; MTX = methotrexate; NA = not applicable. Data from American Society for Reproductive Medicine, 2013.

Of precautions, MTX is bound primarily to albumin, and its displacement by other medications such as phenytoin, tetracyclines, salicylates, and sulfonamides can increase MTX serum drug levels. Moreover, renal clearance of MTX may be impaired by nonsteroidal antiinlammatory drugs including aspirin, probenecid, or penicillins (Stika, 2012). Last, vitamins containing folic acid may lower MTX eicacy.

For ease and eicacy, intramuscular MTX administration is used most often for ectopic pregnancy medical resolution, and single-dose and multidose MTX protocols are available (see Table 19-1). As noted, MTX can lead to bone marrow depression. his toxicity can be blunted by early administration of leucovorin, which is olinic acid and has activity equivalent to folic acid. Thus, leucovorin, which is given within the multidose protocol, allows for some purine and pyrimidine synthesis to bufer side efects.

In comparing these two protocols, trade-ofs are recognized.

For example, single-dose therapy ofers simplicity, less expense, and less intensive posttherapy monitoring and does not require leucovorin rescue. However, some but not all studies report a higher success rate for the multidose regimen (Alleyassin, 2006; Barnhart, 2003a; Lipscomb, 2005). At our institution, we use single-dose MTX.

The best candidate for medical therapy is the woman who is asymptomatic, motivated, and compliant. With medical therapy, some classic predictors of success include a low initial serum 3-hCG level, small ectopic pregnancy size, and absent fetal cardiac activity. Of these, initial serum 3-hCG level is the single best prognostic indicator of successful treatment with single-dose MTX. Speciically, reported failure rates are 1.5 percent if the initial serum 3-hCG concentration is < 1000 mID/mL; 5.6 percent at 1000 to 2000 mID/mL; 3.8 percent at 2000 to 5000 mID/mL; and 14.3 percent when levels range between 5000 and 10,000 mID/mL (Menon, 2007). Interestingly, the initial serum 3-hCG value is not a valid indicator of the number of doses needed for successful resolution (NowakMarkwitz, 2009).

Many early trials also used "large size" as an exclusion criterion, although these data are less precise. Lipscomb and colleagues (1998) reported a 93-percent success rate with single-dose MTX when the ectopic mass was <3.5 cm. This compared with success rates between 87 and 90 percent when the mass wasi> 3.5 cm. Last, failure rates rise if cardiac activity is seen, with an 87 -percent success rate in such cases.

hese regimens are associated with minimal laboratory changes and symptoms, although occasional toxicity may be severe. Kooi and Kock (1992) reviewed 16 studies and reported that adverse efects resolved by 3 to 4 days ater MTX was discontinued. he most common were liver involvement-12 percent; stomatitis6 percent; and gastroenteritis-1 percent. One woman had bone marrow depression. Fortunately, MTX treatment does not diminish ovarian reserve (Boots, 2016; Dyar, 2013). Moreover, conceptions within the irst 6 months after MTX treatment for this indication are not associated with elevated rates of miscarriage or fetal malformations and growth restriction (Svirsy, 2009).

Importantly, 65 to 75 percent of women initially given MTX will have increasing pain beginning several days ater therapy. Thought to relect separation of the ectopic pregnancy from the tubal wall, this "separation pain" generally is mild and relieved by analgesics. In a series of 258 MTX-treated women by Lipscomb and colleagues (1999b), 20 percent had pain that merited evaluation in a clinic or emergency room. Dltimately, 10 of these 53 underwent surgical exploration. Said another way, 20 percent of women given single-dose MTX will have significant pain, and about 20 percent of these will require laparoscopy.

As shown in Table 19-1, monitoring single-dose therapy calls for serum 3-hCG determinations at days 4 and 7 following initial injection on day 1. After single-dose MTX, mean serum 3-hCG levels may rise or fall during the first 4 days and then gradually decline. If the level fails to drop more than 15 percent between days 4 and 7, then a second dose of MTX is required. This is necessary in 15 to 20 percent of women treated with single-dose therapy (Cohen, 2014a; Kirk, 2007).

With multi dose MTX, levels are measured at 48-hour intervals until they fall more than 15 percent. D p to four doses may be given to one patient if required (Stovall, 1991).

Once appropriately dropping levels are achieved in either regimen, serum 3-hCG determinations are then measured weekly until undetectable. Outpatient monitoring is preferred, but if patient safety or compliance is questioned, the woman is hospitalized during initial surveillance. Lipscomb and colleagues (1998) used single-dose MTX to successfully treat 287 women and reported that the average time to resolutiondeined as a serum 3-hCG level < 15 mID/mL, was 34 days. Importantly, the longest time was 109 days.

Failure is judged when the 3-hCG level plateaus or rises or the tube ruptures. Importantly, tubal rupture can occur even with declining 3-hCG levels. Lipscomb and associates (1998) described a 14-day mean time to rupture, but one woman had tubal rupture 32 days after single-dose MTX.

From one metaanalysis, the overall success rate for treatment with MX is 89 percent. The success for the multidose regiment is 92.7 percent, whereas that for single-dose is 88.1 percent (Barnhart, 2003a). Despite this diference, the single dose is more frequently used because of its simplicity and convenience.

Studies have compared laparotomy with laparoscopic surgery for ectopic pregnancy (Lundorf, 1991; Murphy, 1992; Vermesh, 1989). Overall, tubal patency and number of subsequent uterine pregnancies do not difer between these routes. hus, laparoscopy is the preferred surgical treatment for ectopic pregnancy unless a woman is hemodynamically unstable. As experience has accrued, cases previously managed by laparotomy-for example, ruptured tubal pregnancies with hemoperitoneum-can safely be managed laparoscopically by those with suitable expertise (Cohen, 2013; Sagiv, 2001). hat said, the lowered venous return and cardiac output associated with the pneumoperitoneum of laparoscopy must be factored into the decision to select mini mally invasive surgery for hypovolemic women.

Before surgery, future fertility desires are discussed. In women desiring permanent sterilization, the unafected tube can be ligated or removed concurrently with salpingectomy for the afected fallopian tube.

Two procedures-salpingostomy or salpingectomy-are options. Two multicenter, randomized controlled trials have compared laparoscopic outcomes between the two procedures in women with a normal contralateral fallopian tube. he European Surgery in Ectopic Pregnancy (ESEP) study randomized 23i1 women to salpingectomy and 215 to salpingostomy. After surgery, subsequent rates of ongoing pregnancy by natural conception did not difer significantly between groups-56 versus 61 percent, respectively (Mol, 2014). Again, in the DEMETER trial, the subsequent 2-year rate for achieving a uterine pregnancy did not difer between groups-64 versus 70 percent, respectively (Fernandez, 2013). In women with an abnormalappearing contralateral tube, salpingostomy is a conservative option for fertility preservation.

his procedure is typically used to remove a small unruptured pregnancy. A 10-to 15-mm linear incision is made on the anti mesenteric border of the fallopian tube over the pregnancy. The products usually will extrude from the incision. These can be carefully removed or flushed out using high-pressure irrigation that more thoroughly removes the trophoblastic tissue (Al-Sunaidi, 2007). Small bleeding sites are controlled with needlepoint electrocoagulation, and the incision is left unsutured to heal by secondary intention. Serum 3-hCG levels are used to monitor response to both medical and surgical therapy. After linear salpingostomy, serum 3-hCG levels decline rapidly over days and then more gradually, with a mean resolution time of approximately 20 days.

Seldom performed today, salpingotomy is essentially the same procedure except that the incision is closed with delayedabsorbable suture. According to T ulandi and Guralnick (1991), prognosis does not difer with or without suturing, and laparoscopic suturing adds surgical time.

Tubal resection may be used for both ruptured and unruptured ectopic pregnancies. To minimize the rare recurrence of pregnancy in the tubal stump, complete excision of the fallopian tube is advised. With one laparoscopic technique, the afected fallopian tube is lifted and held with atraumatic grasping forceps (Thompson, 2016). One of several suitable bipolar grasping devices is placed across the fallopian tube at the uterotubal junction. Once desiccated, the tube is cut. The bipolar device is then advanced across the most proximal portion of mesosalpinx. Similarly, current is applied, and the desiccated tissue cut. This process moves serially from the proximal mesosalpinx to its distal extent under the tubal ampulla. Alternatively, an endoscopic suture loop can be used to encircle and ligate the knuckle of involved fallopian tube and its underlying vascular supply within the mesosalpinx. Two consecutive suture loops are placed, and the tube distal to these ligatures is then cut free with scissors. Salpingectomy during laparotomy is shown in Chapter 39 (p. 704).

Most tubal ectopic pregnancies are small and pliant. Accord ingly, they can be held firmly by grasping forceps and drawn up into one of the accessory site cannulas. Larger tubal ectopic pregnancies may be placed in an endoscopic sac to prevent frag mentation as they are removed through the laparoscopic port site. Importantly, to remove all trophoblastic tissue, the pelvis and abdomen should be irrigated and suctioned free of blood and tissue debris. Slow and systematic movement of the patient from Trendelenburg to reverse Trendelenburg positioning dur ing irrigation can also assist in dislodging stray tissue and luid.

hese should be suctioned and removed from the peritoneal cavity.

After surgery, 3-hCG levels usually fall quickly and approxi mate 10 percent of preoperative values by day 12 (Hajenius, 1995; Vermesh, 1988). Persistent trophoblast is rare following salpingectomy, but complicates 5 to 15 percent of salpingos tomies (Kayatas, 2014; Pouly, 1986; Seifer, 1993). Rates are lower for laparotomy versus laparoscopic procedures (Hajenius, 1995). Other risk factors are debatable but may include greater serum 3-hCG levels and smaller ectopic size (Rabischong, 2010; Seifer, 1997). Bleeding caused by retained trophoblast is the most serious complication.

Incomplete removal of trophoblast can be identiied by stable or rising 3-hCG levels. v1onitoring approaches are not codified. One scheme measures serum 3-hCG levels on postoperative day 1, and values dropping < 50 percent of the preoperative value relect risk for persistent trophoblast (Spandorfer, 1997). Another measures weekly levels (Mol, 2008). With stable or increasing 3-hCG levels, additional surgical or medical therapy is necessary. Without evidence for tubal rupture, standard therapy for this is single-dose MTX, 50 mg/m2 X body surface area (BSA). Rupture and bleeding require surgical intervention.

Several randomized trials have compared methotrexate treatment with laparoscopic surgery. One multicenter trial compared a multidose MTX protocol with laparoscopic salpingostomy and found no diferences for tubal preservation and primary treatment success (Hajenius, 1997). In this same study group, however, health-related quality-of-life factors such as pain, posttherapy depression, and decreased perception of health were significantly impaired after systemic MX compared with laparoscopic salpingostomy (Nieuwkerk, 1998). In their randomized controlled trial, Fernandez and coworkers (2013) compared multidose medical therapy against salpingostomy and found that medical and conservative surgery provided similar 2-year rates of attaining a uterine pregnancy.

Evidence is conlicting when single-dose MTX is compared with surgical intervention. In two separate studies, single-dose MTX was overall less successful in resolving pregnancy than laparoscopic salpingostomy, although tubal patency and subsequent uterine pregnancy rates were similar between both groups (Fernandez, 1998; Sowter, 2001). Women treated with MTX had significantly better physical functioning immediately following therapy, but there were no diferences in psychological functioning. Krag NIoeller and associates (2009) reported the results from their randomized trial that had a median surveillance period of 8.6 years during which future pregnancy rates were evaluated. Ectopic-resolution success rates were not significantly diferent between those managed surgically and those treated with MTX. Moreover, cumulative spontaneous uterine pregnancy rates were not diferent between the MTX group (73 percent) and the surgical group (62 percent).

Based on these studies, we conclude that women who are hemodynamically stable and in whom there is a small tubal diameter, no fetal cardiac activity, and serum �-hCG concentrations <5000 mIU/mL have similar outcomes with medicalior surgical management. Despite lower success rates with medical therapy for women with larger tubal size, higher serum �-hCG levels, and fetal cardiac activity, medical management can be ofered to the motivated woman who understands the risks.

In select cases, it is reasonable to observe very early tubal pregnancies that are associated with stable or falling serum �-hCG levels. Mavrelos and coworkers (2013) noted that almost one third of 333 tubal ectopic pregnancies measuring <3 cm and with �-hCG levels < 1500 mIU/mL resolved without intervention. Cohen and associates (20 14b) similarly followed 674 women with declining �-hCG levels to successul resolution. hese findings have been supported by smaller randomized trials Qurkovic, 2017; van Mello, 2013).

With expectant management, subsequent rates of tubal patency and intrauterine pregnancy are comparable with surgical or medical management. That said, compared with the established safety of medical and surgical therapy, the prolonged surveillance and risks of tubal rupture support the practice of expectant therapy only in appropriately selected and counseled women.

An interstitial pregnancy is one that implants within the proximal tubal segment that lies within the muscular uterine wall (Fig. 19-7). Incorrectly, they may be called cornual pregnancies, but this term describes a conception that develops in the rudimentary horn of a uterus with a miillerian anomaly (Moawad, 2010). Risk factors are similar to others discussed for tubal ectopic pregnancy, although previous ipsilateral salpingectomy is a specific risk factor for interstitial pregnancy (Lau, 1999). Undiagnosed interstitial pregnancies usually rupture following 8 to 16 weeks of amenorrhea, which is later than for more distal pregnancies. his is due to greater distensibility of the myometrium covering the interstitial fallopian tube segment. Because of the proximity of these pregnancies to the uterine and ovarian arteries, hemorrhage can be severe and associated with mortality rates as high as 2.5 percent (Tulandi, 2004).

With transvaginal sonography and serum �-hCG assays, interstitial pregnancy can now be diagnosed early in many cases, but diagnosis can be challenging. hese pregnancies sonographically can appear similar to an eccentrically implanted uterine pregnancy, especially in a uterus with a miillerian anomaly. Criteria that may aid diferentiation include: an empty uterus, a gestational sac seen separate from the endometrium and > 1 cm away from the most lateral edge of the uterine cavity, and a thin, < 5-mm myometrial mantle surrounding the sac (Timor-Tritsch, 1992). Moreover, an echo genic line, known as the "interstitial line sign," extending from the gestational sac to the endometrial cavity most likely represents the interstitial portion of the fallopian tube and is highly sensitive and specific (Ackerman, 1993a). In unclear cases, three-dimensional (3-D) sonography, magnetic resonance (MR) imaging, or diagnostic laparoscopy can help clariy anatomy (Parker, 2012; Tanaka, 2014). Laparoscopically, an enlarged protuberance is found lying outside the round ligament and coexistent with a normal distal fallopian tube and ovary.

FIGURE 19-7 Interstitial ectopic pregnancy. A.This parasagittal view using transvaginal sonography shows an empty uterine cavity and a mass that is cephalad and lateral to the uterine fundus (calipers). B. Intraoperative photograph during laparotomy and before cornual resection of the same ectopic pregnancy. In this frontal view, the bulging right-sided interstitial ectopic pregnancy is lateral to the round ligament insertion and medial to the isthmic portion of the fallopian tube. (Used with permission from Drs. David Rogers and Elaine Duryea.)

Surgical management with either cornual resection or cornuostomy may be performed via laparotomy or laparoscopy, depending on patient hemodynamic stability and surgeon expertise (Hofman, 2016; Zuo, 2012). With either approach, intraoperative intramyometrial vasopressin injection may limit surgical blood loss, and 3-hCG levels should be monitored postoperatively to exclude remnant trophoblast. Cornual resection removes the gestational sac and surrounding cornual myometrium by means of a wedge excision (Fig. 19-8). Alternatively, cornuostomy involves incision of the cornua and suction or instrument extraction of the pregnancy. Both instances require myometrial closure.

With early diagnosis, medical management may be considered. But because of the low incidence, consensus regarding methotrexate regimens is lacking. In their small series, J ermy and associates (2004) reported a 94-percent success with systemic MTX using a dose of 50 mg/m2 X BSA. Others have described direct MTX injection into the gestational sac (Framarino-dei-Malatesta, 2014). Importantly, because these women typically have higher initial serum 3-hCG levels, longer surveillance is usually needed.

The risk of uterine rupture with subsequent pregnancies following either medical or surgical management is unclear. hus, careful observation of these women during pregnancy, along with strong consideration of elective cesarean delivery, is warranted.

FIGURE 19-8 During cornual resection, the pregnancy, surrounding myometrium, and ipsilateral fallopian tube are excised en bloc. The incision is angled inward as it is deepened. This creates a wedge shape into the myometrium, which is then closed in layers with delayed-absorbable suture. The serosa is closed with subcuticular style suturing. (Reproduced with permission from Hofman BL, Corton MM: Surgeries for benign gynecologic conditions. In Hofman BL, Schorge JO, Bradshaw KD, et al: Williams Gynecology, 3rd ed. New York, McGraw-Hili Education, 2016.)

Distinct from interstitial pregnancy, the term angular pregnany describes implantation within the endometrial cavity but at one cornu and medial to the uterotubal junction and round ligament. An angular pregnancy displaces the round ligament upward and outward, whereas an interstitial tubal pregnancy does not shift it (Arleo, 2014). This distinction is important because angular pregnancies can sometimes be carried to term but with increased risk of abnormal placentation and its consequences Qansen, 1981).

This term describes implantation within the myometrium of a prior cesarean delivery scar. Its incidence approximates 1 in 2000 normal pregnancies and has increased along with the cesarean delivery rate (Ash, 2007; Rotas, 2006). he pathogen esis of cesarean scar pregnancy (CSP) has been likened to that rhage (Timor-Tritsch, 2014a,b). It is unknown if the incidence increases with multiple cesarean deliveries or if it is afected by either one-or two-layer uterine incision closure during cesarean.

Women with CSP usually present early, and pain and bleed ing are common. Still, up to 40 percent of women are asymp tomatic, and the diagnosis is made during routine sonographic examination (Rotas, 2006). Sonographically, diferentiating be diicult (Moschos, 2008a; Timor-Tritsch, 2016). According to Godin (1997), four sonographic criteria should be satisied for the diagnosis and are described in Figure 19-9. Although TVS is the typical first-line imaging tool, MR imaging is useful when sonography is inconclusive (Huang, 2014; Osborn, 2012).

Treatment standards are lacking, and several options are available. Expected management is an option, and live birth rates were 57 percent in one review (Maheux-Lacroix, 2017). However, hemorrhage, placenta accreta, and uterine rupture are risks. Thus, hysterectomy is an acceptable initial choice in those desiring sterilization. It is sometimes necessary with heavy uncontrolled bleeding. Fertility-preserving options include systemic or locally injected methotrexate, either alone or combined with conservative surgery (Birch Petersen, 2016; Cheung, 2015). Surgical procedures include visually guided suction curettage, hysteroscopic removal, or isthmic excision done abdominally or vaginally. hese are completed solely or with adjunctive MTX Qurkovic, 2016; Li, 2014a; Wang, 2014; Yang, 2009). Often uterine artery embolization (UE) is used preoperatively to minimize hemorrhage risk (Zhang, 2012; Zhuang, 2009). Foley balloon catheter placement can be another option for procedure-associated bleeding (TimorTritsch,i2015a).

Following conservative treatment, subsequent pregnancies have good outcomes, but placenta accreta and recurrent CSP are risks (Gao, 2016; Wang, 2015). Uterine arteriovenous malformations are a potential long-term complication (TimorTritsch,i2015b).

FIGURE 19-9 Cesarean scar pregnancy. A. Transvaginal sonogram of a uterus with a cesarean scar pregnancy (CSP) in a sagittal plane. An empty uterine cavity is identified by a bright hyperechoic endometrial stripe (long, white arrow). An empty cervical canal is similarly identified (short, white arrow). Last, an intrauterine mass is seen in the anterior part of the uterine isthmus (red arrows). Myometrium between the bladder and gestational sac is absent or thinned (1 to 3 mm). Photo contributor: Dr. Elysia Moschos.) B. Hysterectomy specimen containing a cesarean scar pregnancy. C. This same hysterectomy specimen is transversely sectioned at the level of the uterine isthmus and through the gestational sac. The uterine body lies to the left, and the cervix is on the right. A metal probe is placed through the endocervical canal to show the eccentric development of this gestation. Only a thin layer of myometrium overlies this pregnancy, which pushes anteriorly through the uterine wall. (Reproduced with permission from Gala RB: Ectopic pregnancy. In Hoffman BL, Schorge JO, Bradshaw KD, et al: Williams Gynecology, 3rd ed. New York, McGraw-Hili Education; 2016. Photo contributors: Drs. Sunil Balgobin, Manisha Sharma, and Rebecca Stone.) his rare ectopic pregnancy is defined by cervical glands noted histologically opposite the placental attachment site and by all or part of the placenta found below the entrance of the uterine vessels or below the peritoneal relection on the anterior uterus. In a typical case, the endocervix is eroded by trophoblast, and the pregnancy develops in the fibrous cervical wall. Predisposing risks include ART and prior uterine curettage (Ginsburg, 1994; Jeng, 2007).

Painless vaginal bleeding is reported by 90 percent of women with a cervical pregnancy-a third of these have massive hemorrhage (Ushakov, 1997). As pregnancy progresses, a distended, thin-walled cervix with a partially dilated external os may be evident. Above the cervical mass, a slightly enlarged uterine fundus can be felt. Identification of cervical pregnancy is based on speculum examination, palpation, and TVS. Sonographic indings typical of cervical pregnancy are shown and described in Figure 19-10. MR imaging and 3-D sonography have also been used to confirm the diagnosis Q ung, 2001; Sherer, 2008).

Cervical pregnancy may be treated medically or surgically. Conservative management strives to minimize hemorrhage, resolve the pregnancy, and preserve fertility. In many centers, including ours, methotrexate has become the first-line therapy in stable women, and administration follows protocols listed in Table 19-1 (Verma, 2011; Zakaria, 2011). he drug has also been injected directly into the gestational sac, alone or with systemic doses Qeng, 2007; 1urji, 2015). Others describe MTX infusion combined with uterine artery embolization"chemoembolization" (Xiaolin, 2010).

FIGURE 19-10 Cervical pregnancy. Transvaginal sonographic findings may include: (1) an hourglass uterine shape and ballooned cervical canal; (2) gestational tissue at the level of the cervix (black arrow); (3) absent intrauterine gestational tissue (white arrows); and (4) a portion of the endocervical canal seen interposed between the gestation and the endometrial canal. (Used with permission from Dr. Elysia Moschos.)

With MTX regimens, resolution and uterine preservation are achieved for gestations < 12 weeks in 91 percent of cases (Kung, 1997). In selecting appropriate candidates, Hung and colleagues (1i996) noted higher risks of systemic MTX treat ment failute in those with a gestational age >9 weeks, �-hCG levels > 10,000 mIU/mL, crown-rump length > 10 mm, and fetal cardiac activity. For this reason, many induce fetal death with intracardiac or intrathoracic injection of potas sium chloride. With a single-dose intramuscular protocol, an

MTX dose between 50 and 75 mg/m2 X BSA is typical. To resolve fetal cardiac activity, a sonographically guided fetal intracardiac injection of 2 mL (2 mEq/mL) potassium chlo ride solution can be given (Verma, 2009). Song and associ ates (2009) described management of 50 cases and observed regression.

As an adjunct to medical or surgical therapy, uterine artery embolization has been described either as a response to bleeding or as a preprocedural preventive tool (Hirakawa, 2009; Zakaria, 2011). Also, in the event of hemorrhage, a 26F Foley catheter with a 30-mL balloon can be placed intracervically and inlated to efect hemostasis by vessel tamponade and to monitor uterine drainage. The balloon remains inlated for 24 to 48 hours and is gradually decompressed over a few days (Ushakov, 1997).

Although conservative management is feasible for many women with cervical pregnancies, suction curettage or hysterectomy may be selected. Moreover, hysterectomy may be required with bleeding uncontrolled by conservative methods. Because of the close proximity of the ureters to the ballooned cervix, urinary tract injury rates are a concern during hysterectomy.

If cervical curettage is planned, intraoperative bleeding may be lessened by preoperative UAE, by intracervical vasopressin injection, or by a cerclage placed at the internal cervical os to compress feeding vessels (Chen, 2015; Fylstra, 2014; Wang, 2011). Also, cervical branches of the uterine artery can efectively be ligated with vaginal placement of hemostatic cervical sutures on the lateral aspects of the cervix at 3 and 9 o'clock (Bianchi, 2011). Following curettage, a Foley balloon can be placed to tamponade bleeding and is managed as described earlier. Suction curettage may be especially favored in rare cases of a heterotopic pregnancy composed of a cervical and a desired uterine pregnancy (Tsakos, 2015).

hese rare ectopic pregnancies are defined as an implantation in the peritoneal cavity exclusive of tubal, ovarian, or intraligamentous implantations. Although a zygote can traverse the tube and implant primarily in the peritoneal cavity, most abdominal pregnancies are thought to follow early tubal rupture or abortion with reimplantation. In cases of advanced extrauterine pregnancy, it is not unusual for the placenta to be still at least partially attached to the uterus or adnexa.

Diagnosis may be diicult. First, symptoms may be absent or vague. Laboratory tests are typically uninformative, although maternal serum alpha-fetoprotein levels can be elevated. Clinically, abnormal fetal positions may be palpated, or the cervix is displaced (Zeck, 2007). Sonographically, the diagnosis is often missed (Costa, 1991). Oligohydramnios is common but nonspecific. Other clues include a fetus seen separate from the uterus or eccentrically positioned within the pelvis; lack of myometrium beween the fetus and the maternal anterior abdominal wall or bladder; extrauterine placental tissue; or bowel loops surrounding the gestational sac (Allibone, 1981; Chukus, 2015). If additional anatomical information is needed, MR imaging can help confirm the diagnosis and provide maximal information concerning placental implantation (Bertrand, 2009; Mittal, 2012).

Treatment of an abdominal pregnancy depends on the ges tational age at diagnosis. Conservative management carries a maternal risk for sudden and dangerous hemorrhage. Moreover, in 20 percent. Thus, we believe that termination generally is indicated when the diagnosis is made. Certainly, before 24 weeks, conservative treatment rarely is justified. Despite this, some have described waiting until fetal viability with close sur veillance (Kim, 2013; Marcellin, 2014).

Once placental implantation has been assessed, several options to control intraoperative hemorrhage mimic those used for placenta accrete syndrome (Chap. 41, p. 792). he principal surgical objectives involve delivery of the fetus and careful assessment of placental implantation without provoking hemorrhage. Unnecessary exploration is avoided because the anatomy is commonly distorted and surrounding areas are extremely vascular. Importantly, placental removal may precipitate torrential hemorrhage because the normal hemostatic mechanism of myometrial contraction to constrict hypertrophied blood vessels is lacking. If it is obvious that the placenta can be safely removed or if there is already hemorrhage from its implantation site, then removal begins immediately. When possible, blood vessels supplying the placenta should be ligated irst.

Some advocate leaving the placenta in place as the lesser of two evils. It decreases the chance of immediate life-threatening hemorrhage, but at the expense of long-term sequelae. If let in the abdominal cavity, the placenta commonly becomes infected, with subsequent formation of abscesses, adhesions, intestinal or ureteral obstruction, and wound dehiscence (Bergstrom, 1998; Martin, 1988). In many of these cases, surgical removal becomes inevitable. If the placenta is let, its involution may be monitored using sonography and serum �-hCG levels (France, 1980; Martin, 1990). Color Doppler sonography can be used to assess changes in blood low. In some cases, and usually depending on its size, placental function rapidly declines, and the placenta is resorbed. But placental resorption may take years (Roberts, 2005; Valenzano, 2003).

If the placenta is left in place, postoperative methotrexate use is controversial. It has been recommended to hasten involution but has been reported to cause accelerated placental destruction with accumulation of necrotic tissue and infection with abscess formation (Rahman, 1982). It is diicult to envision a supporting role for the use of an antimetabolite for a senescent organ (Worley, 2008).

Ectopic implantation of the fertilized egg in the ovary is rare and is diagnosed if four clinical criteria are met. hese were outlined by Spiegelberg (1878): (1) the ipsilateral tube is intact and distinct from the ovary; (2) the ectopic pregnancy occupies the ovary; (3) the ectopic pregnancy is connected by the uteroovarian ligament to the uterus; and (4) ovarian tissue can be demonstrated histologically amid the placental tissue. Risk factors are similar to those for tubal pregnancies, but ART or IUD failure seems to be disproportionately associated (Zhu, 2014). Presenting complaints and findings mirror those for tubal ectopic pregnancy. Although the ovary can accommodate the expanding pregnancy more easily than the fallopian tube, rupture at an early stage is the usual consequence (Melcer, 2016).

Transvaginal sonography use has resulted in a more frequent diagnosis of unruptured ovarian pregnancies. Sonographically, an internal anechoic area is surrounded by a wide echogenic ring, which in turn is surrounded by ovarian cortex (Comstock, 2005). In their review of 49 cases, Choi and associates (2011) noted that the diagnosis may not be made until surgery, as many cases are presumed tubal ectopic pregnancy. Moreover, at surgery, an early ovarian pregnancy may be considered to be a hemorrhagic corpus luteum.

Evidence-based management accrues mainly from case reports (Hassan, 2012; Scutiero, 2012). Classically, management for ovarian pregnancies has been surgical. Small lesions can be managed by ovarian wedge resection or cystectomy, whereas larger lesions require oophorectomy (Elwell, 2015; Melcer, 2015). With conservative surgery, 3-hCG levels should be monitored to exclude remnant trophoblast.

Pregnancy implanted toward the mesosalpinx may rupture into a space formed between the broad ligament leaves and become an intraligamentous or broad ligament pregnancy. Rents in prior cesarean sca's serve as another conduit (Rudra, 2013). hese are rare, and information accrues from case reports. Clinical indings and management mirror those for abdominal pregnancy. Although laparotomy is required in most instances, a few case reports describe laparoscopic excision of early small pregnancies (Apantaku, 2006; Cormio, 2006).

Ectopic placental implantations in less expected sites have been described in case reports and include the omentum, liver, and retroperitoneum, among others (Brouard, 2015; Liang, 2014; Watrowski, 2015). Also, intramural uterine implantations at sites other than a cesarean scar have been noted in women with prior uterine surgeries, ART, or adenomyosis (Memtsa, 2013; Wu, 2013). Although laparotomy is preferred by many for these ectopic sites, laparoscopic excision by those with suitable skills is gaining acceptance.

Ackerman TE, Levi CS, Dashefsky SM, et al: Interstitial line: sonographic finding in interstitial (cornual) ectopic pregnancy. Radiology 189(1):83, 1993a Ackerman TE, Levi CS, Lyons A, et al: Decidual cyst: endovaginal sono graphic sign of ectopic pregnancy. Radiology 189(3):727, 1993b

Alleyassin A, Khademi A, Aghahosseini M, et al: Comparison of success rates in the medical management of ectopic pregnancy with single-dose and multiple-dose administration of methotrexate: a prospective, randomized clinical trial. Fertil Steril 85(6): 1661, 2006

Allibone GW, Fagan CJ, Porter SC: The sonographic features of intra-abdominal pregnancy. J Clin Ultrasound 9(7):383, 1981

Al-Sunaidi M, Tulandi T: Surgical treatment of ectopic pregnancy. Semin Reprod Med 25(2): 117, 2007

American Academy of Pediatrics Committee on Drugs: Transfer of drugs and other chemicals into human milk. Pediatrics 108(3):776,o2001

American College of Obstetricians and Gynecologists: Prevention ofRh D alloimmunization. Practice Bulletin No. 181, August 201

American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine: Ultrasoound in pregnancy. Practice Bulletin No. 175, December 2016

American Society for Reproductive Medicine: Medical treatment of ectopic pregnancy: a committee opinion. Fertil Sterilo100(3):638, 2013

Apantaku 0, Rana P, Inglis T: Broad ligament ectopic pregnancy following invitro fertilization in a patient with previous bilateral salpingectomy. J Obstet Gynaecol 26(5):474, 2006

Arleo EK, DeFilippis EM: Cornual, interstitial, and angular pregnancies: clariying the terms and a review of the literature. Clin Imaging 38(6):763, 2014

Ash A, Smith A, Maxwell D: Caesarean scar pregnancy. BJOG 114:253,2007 Barak S, Oettinger M, Perri A, et al: Frozen section examination of endometrial curettings in the diagnosis of ectopic pregnancy. Acta Obstet Gynecol Scand 84(1):43, 2005 Barnhart K, Mennuti MT, Benjamin I, et al: Prompt diagnosis of ectopic pregnancy in an emergency department setting. Obstet GynecoIo84:o1010, 1994 Barnhart KT, Gosman G, Ashby R, et al: The medical management of ectopic pregnancy: a meta-analysis comparing "single dose" and "multidose" regimens. Obstet Gynecol 101:778, 2003a Barnhart KT, Gracia CR, Reindl B, et al: Usefulness of Pipelle endometrial biopsy in the diagnosis of women at risk for ectopic pregnancy. Am J Obstet Gynecol 188:906, 2003b Barnhart KT, Rinaudo P, Hummel A, et al: Acute and chronic presentation of ectopic pregnancy may be two clinical entities. Fertil Steril 80: 1345, 2003c

Barnhart KT, Sammel MD, Chung K, et al: Decline of serum hCG and spontaneous complete abortion: defining the normal curve. Obstet Gynecol 104:975,o2004a Barnhart KT, Sammel MD, Rinaudo PF, et al: Symptomatic patients with an early viable intrauterine pregnancy: hCG cuves redeined. Obstet Gynecol 104:50,o2004b

Bergstrom R, Mueller G, Yankowitz J: A case illustrating the continued dilemmas in treating abdominal pregnancy and a potential explanation for the high rate of postsurgical febrile morbidity. Gynecol Obstet Invest 46:268, 1998 Bertrand G, Le Ray C, Simard-Emond L, et al: Imaging in the management of abdominal pregnancy: a case report and review of the literature. J Obstet Gynaecol Can 31(1):57, 2009 Bhattacharya S, McLernon DJ, Lee AJ, et al: Reproductive outcomes following ectopic pregnancy: register-based retrospective cohort study. PLoS Med 9(6):el001243,o2012 Bianchi P, Salvatori MM, Torcia F, et al: Cervical pregnancy. Fertil Steril 95(6):2123.e3,o2011 Birch Petersen K, Hofmann E, Rifbjerg Larsen C, et al: Cesarean scar pregnancy: a systematic review of treatment studies. Fertil Steril 105(4):958, 20o16 Bolaji II, Oktaba M, Mohee K, et al: n odyssey through salpingitis isthmica nodosa. Eur J Obstet Gynecol Reprod BioI 184:73, 2015 Boots CE, Hill MJ, Feinberg EC, et al: Methotrexate does not afect ovarian reserve or subsequent assisted reproductive technology outcomes. J Assist Reprod Genet 33(5):647,o2016 Bouyer J, Coste J, Fernandez H, et al: Sites of ectopic pregnancy: a 10 year population-based study of 1800 cases. Hum Reprod 17(12):3224,o2002 Branney SW, Wolfe E, Moore EE, et al: Quantitative sensitivity of ultrasound in detecting free intraperitoneal fluid. J Trauma 40(6):1052, 1995 Brennan DF, Kwatra S, Kelly M, et al: Chronic ectopic pregnancy-two cases of acute rupture despite negative beta hCG. J Emerg Med 19(3):249,2000 Briggs GG, Freeman RK (eds): Drugs in Pregnancy and Lactation. Philadelphia, Wolters Kiuwer, 2015

Brouard KJ, Howard BR, Dyer A: Hepatic pregnancy suspected at term and successful delivery of a live neonate with placental attachment to the right lobe of the liver. Obstet GynecoIo126(1):207, 2015

Butts SF, Guo W, Cary MS, et al: Predicting the decline in human chorionic gonadotropin in a resolving pregnancy of unknown location. Obstet Gynecol 122(2 Pt 1):33, 2013

Chen H, Yang S, Fu J, et al: Outcomes of bilateral uterine artery chemoembolization in combination with surgical evacuation or systemic methotrexate for cervical pregnancy. J Minim Invasive GynecoIo22(6):1029, 2015

Cheung Y: Local methotrexate injection as the first-line treatment for cesarean scar pregnancy: review of the literature. J Minim Invasive Gynecol 22(5):753,o2015

Choi HJ, 1m KS, Jung HJ, et al: Clinical analysis of ovarian pregnancy: a report of 49 cases. Eur J Obstet Gynecol Reprod Bioi 158(1):87,2011

Chukus A, Tirada N, Restrepo R, et al: Uncommon implantation sites of ectopic pregnancy: thinking beyond the complex adnexal mass. Radiographies 35(3):946,o2015

Chung K, Chandavarkar U, Opper N, et al: Reevaluating the role of dilation and curettage in the diagnosis of pregnancy of unknown location. Fertil Steril 96(3):659, 2011

Chung K, Sammel MD, Coutifaris C, et al: Defining the rise of serum HCG in viable pregnancies achieved through use ofIVF. Hum Reprod 21(3):823, 2006

Clayton HB, Schieve A, Peterson HB, et al: Ectopic pregnancy risk with assisted reproductive technology procedures. Obstet Gynecol 107(3):595, 2006

Cohen A, Almog B, Satel A, et al: Laparoscopy versus laparotomy in the management of ectopic pregnancy with massive hemoperitoneum. Int J Gynaecol Obstet 123(2):139, 2013

Cohen A, Bibi G, lmog B, et al: Second-dose methotrexate in ectopic pregnancies: the role of beta human chorionic gonadotropin. Fertil Steril 102(6):1646,o2014a

Cohen A, Zakar L, Gil Y, et al: Methotrexate success rates in progressing ectopic pregnancies: a reappraisal. m J Obstet GynecoI211(2):128.e1, 2014b Cole T, Corlett RC Jr: Chronic ectopic pregnancy. Obstet Gynecol 59(1):63,

Comstock C, Huston K, Lee W: he ultra-sonographic appearance of ovarian ectopic pregnancies. Obstet Gynecol 105:42, 2005

Condous G, Okaro E, Khalid A, et al: he accuracy of transvaginal ultrasonography for the diagnosis of ectopic pregnancy prior to surgery. Hum Reprod 20(5): 1404, 2005

Connolly A, Ryan DH, Stuebe AM, et al: Reevaluation of discriminatory and threshold levels for serum 3-hCG in early pregnancy. Obstet Gynecol 121(1):65,o2013

Cormio G, Ceci 0, Loverro G, et al: Spontaneous left broad ligament pregnancy after ipsilateral salpingo-oophorectomy. J Minim Invasive Gynecol 13(2):84,o2006

Costa SO, Presley J, Bastert G: Advanced abdominal pregnancy. Obstet Gynecol Surv 46:515, 1991 Creanga A, Syverson C, Seed K et al: Pregnancy-related mortaliry in the United States, 2011-2013. Obstet GynecoIo130(2):366, 2017 Dashefsky SM, Lyons EA, Levi CS, et al: Suspected ectopic pregnancy: endovaginal and transvesical US. Radiology 169: 181, 1988 Elwell E, Sailors JL, Denson PK, et al: Unruptured second-trimester ovarian pregnancy. J Obstet Gynaecol Res 41(9):1483,o2015 Eze IN, Obuna JA, Ejikeme BN: Bilateral tubal ectopic pregnancies: a report of rwo cases. Ann Afr Med 11 (2): 112, 2012 Fernandez H, Capmas P, Lucot JP, et al: Fertiliry after ectopic pregnancy: the DEMETER randomized trial. Hum Reprod 28(5):1247,o2013 Fernandez H, Yves Vincent SCA, Pauthier S, et al: Randomized trial of conservative laparoscopic treatment and methotrexate administration in ectopic pregnancy and subsequent fertiliry. Hum Reprod 13:3239, 1998

Framarino-dei-Malatesta M, Piccioni MG, Derme M, et al: Transabdominal ultrasound-guided injection of methotrexate in the treatment of ectopic interstitial pregnancies. J Clin Ultrasound 42(9):522,o2014

France JT, Jackson P: Maternal plasma and urinary hormone levels during and after a successful abdominal pregnancy. BJOG 87:356, 1980

Fylstra DL: Cervical pregnancy: 13 cases treated with suction curettage and balloon tamponade. m J Obstet GynecoIo210(6):581.e1, 2014

Gala RB: Ectopic pregnancy. In Hofman BL, Schorge JO, Bradshaw KO, et al:

Williams Gynecology, 3rd ed. New York, McGraw-Hill Education, 2016

Gao L, Huang Z, Zhang X, et al: Reproductive outcomes following cesarean scar pregnancy-a case series and review of the literature. Eur J Obstet Gynecol Reprod Bioi 200: 1 02, 2016

Ginsburg ES, Frates MC, Rein MS, et al: Early diagnosis and treatment of cervical pregnancy in an in vitro fertilization program. Fertil Steril 61 :966, 1994

Glezerman M, Press F, Carpman M: Culdocentesis is an obsolete diagnostic tool in suspected ectopic pregnancy. Arch Gynecol Obstet 252:5, 1992 Godin PA, Bassil S, Donnez J: An ectopic pregnancy developing in a previous caesarian section scar. Fertil Sterilo67:398, 1997

Goswami 0, Agrawal N, Arora V: Twin tubal pregnancy: a large unruptured ectopic pregnancy. J Obstet Gynaecol Res 41(1o1):o182,o20o15

Greene ON, Grenache OG, Education Committee of the Academy of Clinical Laboratory Physicians and Scientist: Pathology consultation on human chorionic gonadotropin testing for pregnancy assessment. m J Clin Pathol 144(6):830,o2015

Hajenius PJ, Engelsbel S, Mol BW, et al: Randomized trial of systemic methotrexate versus laparoscopicosalpingostomy in tubal pregnancy. Lancet 350:774,o1997

Hajenius PJ, Mol BWJ, Ankum WM, et al: Clearance curves of serum human chorionic gonadotropin for the diagnosis of persistent trophoblast. Hum Reprod 10:683, 1995

Hammoud AO, Hammoud I, Bujold E, et al: The role of sonographic endometrial patterns and endometrial thickness in the diferential diagnosis of ectopic pregnancy. m J Obstet GynecoIo192:1o370, 2005

Hassan S, Arora R, Bhatia K: Primary ovarian pregnancy: case report and review of literature. BMJ Case Rep Nov 21, 20o12

Hill LM, Kislak S, Martin JG: Transvaginal sonographic detection of the pseudogestational sac associated with ectopic pregnancy. Obstet Gynecol 75(6):986, 1990

Hirakawa M, Tajima T, Yoshimitsu K, et al: Uterine artery embolization along with the administration of methotrexate for cervical ectopic pregnancy: technical and clinical outcomes. AJRAmJ RoentgenoIo192(6):1601, 2009

Hofman BL, Corton MM: Surgeries for benign gynecologic conditions. In Hofman BL, Schorge JO, Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGraw-Hill Education, 20o16

Hoover RN, Hyer M, Pfeifer M, et al: Adverse health outcomes in women exposed in utero to diethylstilbestrol. N Engl J Med 365 (14): 1304, 2011

Huang Q, Zhang M, Zhai RY: he use of contrast-enhanced magnetic resonance imaging to diagnose cesarean scar pregnancies. Int J Gynaecol Obstet 127(2):144,o2014

Hung TH, Jeng CJ, Yang yc, et al: Treatment of cervical pregnancy with methotrexate. Int J Gynaecol Obstet 53:243, 1996

Hyland A, Piazza KM, Hovey KM, et al: Associations of lifetime active and passive smoking with spontaneous abortion, stillbirth and tubal ectopic pregnancy: a cross-sectional analysis of historical data from the Women's Health Initiative. Tob Control 24(4):328, 2015

Jansen RP, Elliott PM: Angular intrauterine pregnancy. Obstet Gynecol 58(2):167,o1981

Jeng ], Ko ML, Shen J: Transvaginal ultrasound-guided treatment of cervical pregnancy. Obstet Gynecol 109: 1 076, 2007

Jermy K, homas J, 000 A, et al: The conservative management of interstitial pregnancy. BJOG 111:1283,o2004

J ung SE, Byun JY, Lee JM, et al: Characteristic MR findings of cervical pregnancy. J Magn Reson Imaging 13(6):918, 2001

Jurkovic 0, Knez J, Appiah A, et al: Surgical treatment of Cesarean scar ectopic pregnancy: eicacy and safery of ultrasound-guided suction curettage. Ultrasound Obstet GynecoIo47(4):51, 2016 Kayatas S, Demirci 0, Kumru P, et al: Predictive factors for failure of salpingostomy in ectopic pregnancy. J Obstet Gynaecol Res 40(2):453, 2014 Kim MJ, Bae JY, Seong WJ, et al: Sonographic diagnosis of a viable abdominal pregnancy with planned delivery after fetal lung maturation. J Clin Ultrasound 41(9):563, 2013 Kirk E, Condous G, Van Calster B, et al: A validation of the most commonly used protocol to predict the success of single-dose methotrexate in the treatment of ectopic pregnancy. Hum Reprod 22(3):858, 2007

Kooi S, Kock HC: A review of the literature on nonsurgical treatment in tubal pregnancy. Obstet Gynecol Surv 47:739, 1992

Krag Moeller LB, Moeller C, homsen SG, et al: Success and spontaneous pregnancy rates following systemic methotrexate versus laparoscopic surgery for tubal pregnancies: a randomized trial. Acta Obstet Gynecol Scand 88(12):1331,o2009

Kung FT, Chang SY, Tsai yc, et al: Subsequent reproduction and obstetric outcome after methotrexate treatment of cevical pregnancy: a review of original literature and international collaborative follow-up. Hum Reprod 12:591, 1997

Lau S, Tulandi T: Conservative medical and surgical management of interstitial ectopic pregnancy. Fertil Steril 72:207, 1999

Li JB, Kong LZ, Fan L, et al: Transvaginal surgical management of cesarean scar pregnancy: analysis of 49 cases from one tertiary care center. Eur J Obstet Gynecol Reprod Bioi 182: 102, 2014a

Li Y, Yang Y, He QZ, et al: Frozen section of uterine curetting in excluding the possibiliry of ectopic pregnancy-a clinicopathologic study of 715 cases. Clin Exp Obstet GynecoIo41(4):419, 2014b

Liang C, Li X, Zhao B, et al: Demonstration of the route of embryo migration in retroperitoneal ectopic pregnancy using contrast-enhanced computed tomography. J Obstet Gynaecol Res 40(3):849,o2014

Lipscomb GH, Bran 0, McCord ML, et al: Analysis of three hundred fifteen ectopic pregnancies treated with single-dose methotrexate. Am J Obstet Gynecol 178:o1o354, 1998

Lipscomb GH, Givens VM, Meyer NL, et al: Comparison of multidose and single-dose methotrexate protocols for the treatment of ectopic pregnancy. m J Obstet GynecoIo192:1844, 2005

Lipscomb GH, McCord ML, Stovall TG, et al: Predictors of success of methotrexate treatment in women with tubal ectopic pregnancies. N Engl J Med 341:1974, 1999a

Lipscomb GH, Puckett KJ, Bran 0, et al: Management of separation pain after single-dose methotrexate therapy for ectopic pregnancy. Obstet Gynecol 93:590, 1999b

Lopez HB, Micheelsen U, Berendtsen H, et al: Ectopic pregnancy and its associated endometrial changes. Gynecol Obstet Invest 38(2):104, 1994

LundorfP, Thorburn J, Hahlin M, et al: Laparoscopic surgery in ectopic pregnancy. A randomized trial versus laparotomy. Acta Obstet Gynecol Scand 70(4-5):343, 1991

Maheux-Lacroix S, Li F, Bujold E, et al: Cesarean scar pregnancies: a systematic review of treatment options. J Minim Invasive Gynecol 24(6):915, 2017 Marcellin L, Menard S, Lamau MC, et al: Conservative management of an advanced abdominal pregnancy at 22 weeks. AJP Rep 4(1):55, 2014

Martin IN Jr, McCaul JF IV: Emergent management of abdominal pregnancy. Clin Obstet Gynecol 33:438, 1990

Martin IN Jr, Sessums JK, Martin RW, et al: Abdominal pregnancy: current concepts of management. Obstet Gynecol 71:549, 1988

Mavrelos 0, Nicks H, Jamil A, et al: Eicacy and safety of a clinical protocol for expectant management of selected women diagnosed with a tubal ectopic pregnancy. Ultrasound Obstet Gynecol 42(1): 1 02, 2013

Melcer Y, Maymon R, Vaknin Z, et al: Primary ovarian ectopic pregnancy: still a medical challenge. J Reprod Med 61(1-2):58,o2016

Melcer Y, Smorgick N, Vaknin Z, et al: Primary ovarian pregnancy: 43 years experience in a single institute and still a medical challenge. Isr Med Assoc J 17(11):687,2015

Memtsa M, Jami! A, Sebire N, et al: Rarity revisited: diagnosis and management of intramural ectopic pregnancy. Ultrasound Obstet Gynecol 42(3):359,o2013 Menon S, Colins J, Barnhart KT: Establishing a human chorionic gonadotropin cutof to guide methotrexate treatment of ectopic pregnancy: a systematic review. Ferti! Steri! 87(3):481, 2007 Mittal SK, Singh N, VermaoAK, et al: Fetal MRI in the pre-operative diagnosis and assessment of secondary abdominal pregnancy: a rare sequela of a previous caesarean section. Diagn Interv RadioIo18(5):496, 2012 Moawad NS, Mahajan ST, Moniz MH, et al: Current diagnosis and treatment of interstitial pregnancy. AmJ Obstet GynecoIo202(1):15, 2010 Mol BWJ, Lijmer JG, Ankum WM, et al: he accuracy of single serum progesterone measurement in the diagnosis of ectopic pregnancy: a meta-analysis. Hum Reprod 13:3220, 1998 Mol F, Strandell A, Jurkovic 0, et al: The ESEP study: salpingostomy versus salpingectomy for tubal ectopic pregnancy; the impact on future ferti!ity: a randomized controlled trial. BMC Womens Health 8:11, 2008 Mol F, van Mello NM, Strandell A, et al: Salpingotomy versus salpingectomy in women with tubal pregnancy (ESEP study): an open-label, multicentre, randomized controlled trial. Lancet 383(9927): 1483, 2014 Moschos E, Sreenarasimhaiah S, Twickler OM: First-trimester diagnosis of cesarean scar ectopic pregnancy. J Clin Ultrasound 36(8):504, 2008a Moschos E, Twickler OM: Endometrial thickness predicts intrauterine pregnancy in patients with pregnancy of unknown location. Ultrasound Obstet Gynecol 32(7):929, 2008b Murji A, Garbedian K, Thomas J, et al: Conservative management of cervical ectopic pregnancy. J Obstet Gynaecol Can 37(11):1016, 2015 Murphy A, Nager CW, Wujek JJ, et al: Operative laparoscopy versus laparotomy for the management of ectopic pregnancy: a prospective trial. Ferti! Steril 57(6):1180, 1992 Nadim B, Infante F, Lu e, et al: he morphological ultrasound types known as 'blob' and 'bagel' signs should be reclassiied from probable to deinite ectopic pregnancy. Ultrasound Obstet Gynecol February 13, 2017 [Epub ahead of print] Nieuwkerk PT, Hajenius PJ, Ankum WM, et al: Systemic methotrexate therapy versus laparoscopic salpingostomy in patients with tubal pregnancy. Part 1. Impact on patients' health-related quality oflife. Fertil Steril 70:511, 1998

Nowak-Markwitz E, Michalak M, Olejnik M, et al: Cutof value of human chorionic gonadotropin in relation to the number of methotrexate cycles in the successful treatment of ectopic pregnancy. Fertil Steril 92(4): 1203, 2009 Nurmohamed L, Moretti ME, Schechter T, et al: Outcome following highdose methotrexate in pregnancies misdiagnosed as ectopic. Am J Obstet GynecoI205(6):533.e1,o2011

Nyberg DA, Hughes MP, Mack A, et al: Extrauterine findings of ectopic pregnancy of transvaginal US: importance of echogenic fluid. Radiology 178:823, 1991 Nyberg DA, Mack A, Laing Fe, et al: Distinguishing normal from abnormal gestational sac growth in early pregnancy. J Ultrasound Med 6(1):23, 1987

Osborn DA, Williams TR, Craig BM: Cesarean scar pregnancy: sonographic and magnetic resonance imaging indings, complications, and treatment. J Ultrasound Med 31(9):1449, 2012

Parker A 3rd, Yano M, Tai A W, et al: MR imaging indings of ectopic pregnancy: a pictorial review. Radiographics 32(5):1445,o2012

Perkins M, Boulet SL, Kissin OM, et al: Risk of ectopic pregnancy associated with assisted reproductive technology in the United States, 2001-2011. Obstet Gynecol 125(1):7,o2015

Perkins SL, Al-Ramahi M, Claman P: Comparison of serum progesterone as an indicator of pregnancy nonviability in spontaneously pregnant emergency room and infertility clinic patient populations. Fertil Steri! 73:499, 2000

Pisarska MD, Carson SA, Buster JE: Ectopic pregnancy. Lancet 351: 1115, 1998 Pouly JL, Mahnes H, Mage G, et al: Conservative laparoscopic treatment of 321 ectopic pregnancies. Ferti! Steril 46: 1 093, 1986

Rabischong B, Larrain 0, Pouly JL, et al: Predicting success of laparoscopic salpingostomy for ectopic pregnancy. Obstet Gynecol 116(3):701,2010 Rahman MS, Al-Suleiman SA, Rahman J, et al: Advanced abdominal preg nancy-observations in 10 cases. Obstet Gynecol 59:366, 1982

Reece A, Petrie RH, Sirmans MF, et al: Combined intrauterine and extra uterine gestations: a review. Am J Obstet Gynecol 146(3):32, 1983

Ries A, Singson P, Bidus M, et al: Use of the endometrial Pipelle in the diagnosis of early abnormal gestations. Fertil Steril 74(3):593, 2000

Roberts RV, Dickinson JE, Leung Y, et al: Advanced abdominal pregnancy: still an occurrence in modern medicine. Aust N Z J Obstet Gynaecol 45(6):518,o2005

Rodgerson JD, Heegaard WG, Plummer 0, et al: Emergency department right upper quadrant ultrasound is associated with a reduced time to diagnosis and treatment of ruptured ectopic pregnancies. Acad Emerg Med 8(4):331, 2001

Rose JS: Ultrasound in abdominal trauma. Emerg Med Clin North Am 22(3):581,o2004

Roras A, Haberman S, Levgur M: Cesarean scar ectopic pregnancies. Obstet Gynecolo107:1373,o2006

Rudra S, Gupta S, Taneja BK, et al: Full term broad ligament pregnancy through a Cesarean scar. Obstet Gynecol Sci 56(6):404, 2013

Sagiv R, Debby A, Sadan 0, et al: Laparoscopic surgery for extrauterine pregnancy in hemodynamically unstable patients. J Am Assoc Gynecol Laparosc 8(4):529,o2001

Scutiero G, Di Gioia P, Spada A, et al: Primary ovarian pregnancy and its management. JSLS 16(3):492,o2012

Seeber BE, Sammel MD, Guo W, et al: Application of redeined human chorionic gonadotropin curves for the diagnosis of women at risk for ectopic pregnancy. Ferti! Steril 86(2):454, 2006

Seifer DB: Persistent ectopic pregnancy: an argument for heightened vigilance and patient compliance. Ferti! Steril 68 :402, 1997

Seifer DB, Gutmann IN, Grant WD, et al: Comparison of persistent ectopic pregnancy after laparoscopic salpingostomy versus salpingostomy at laparotomy for ectopic pregnancy. Obstet Gynecol 81 (3):378, 1993

Shaunik A, Kulp J, Appleby DH, et al: Utility of dilation and curettage in the diagnosis of pregnancy of unknown location. Am J Obstet Gynecol 204(2):130.e131,2011

Sherer OM, Gorelick e, Dalloul M, et al: hree-dimensional sonographic indings of a cervical pregnancy. J Ultrasound Med 27(1): 155,o2008

Silva C, Sammel MD, Zhou L, et al: Human chorionic gonadotropin proile for women with ectopic pregnancy. Obstet Gynecol 107:605,o2006

Song MJ, Moon MH, Kim JA, et al: Serial transvaginal sonographic indings of cervical ectopic pregnancy treated with high-dose methotrexate. J Ultrasound Med 28:55, 2009

Sowter MC, Farquhar CM, Petrie KJ, et al: A randomized trial comparing single dose systemic methotrexate and laparoscopic surgery for the treatment ofunruptured tubal pregnancy. BJOG 108(2):192,o2001

Spandorfer SO, Sawin SW, Benjamin I, et al: Postoperative day 1 serum human chorionic gonadotropin level as a predictor of persistent ectopic pregnancy after conservative surgical management. Ferti! Steril 68:430, 1997

Spiegelberg 0: Zur Casuistic der Ovarialschwangerschaft. Arch Gynaekol 13:73, 1878

Stevens CA: Malformations and deformations in abdominal pregnancy. Am J MedoGeneto47:1189,o1993

Stika CS: Methotrexate: the pharmacology behind medical treatment for ectopic pregnancy. Clin Obstet Gynecol 55(2):433, 2012

Stovall TG, Ling FW, Carson SA, et al: Serum progesterone and uterine curettage in diferential diagnosis of ectopic pregnancy. Ferti! Steri!o57:456, 1992 Stovall TG, Ling FW, Cope BJ, et al: Preventing ruptured ectopic pregnancy with a single serum progesterone. Am J Obstet Gynecol 160: 1425, 1989 Stovall TG, Ling FW, Gray A, et al: Methotrexate treatment of unruptured ectopic pregnancy: a report of 100 cases. Obstet Gynecol 77(5):749, 1991

Stulberg DB, Cain LR, Dahlquist I, et al: Ecropic pregnancy rates and racial disparities in the Medicaid population, 2004-2008. Ferti! Steril 102(6):1671, 2014

Svirsky R, Rozovski U, Vaknin Z, et al: The safety of conception occurring shortly after methotrexate treatment of an ectopic pregnancy. Reprod Toxicol 27(1):85, 2009

Tanaka Y, Mimura K, Kanagawa T, et al: hree-dimensional sonography in the diferential diagnosis of interstitial, angular, and intrauterine pregnancies in a septate uterus. J Ultrasound Med 33(11):2031, 2014 hompson M, Kho K: Minimally invasive surgery. In Hofman BL, Schorge JO, Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGraw-Hill Education, 2016

Timor-Tritsch IE, Cali G, Monteagudo A, et al: Foley balloon catheter to prevent or manage bleeding during treatment for cervical and cesarean scar pregnancy. Ultrasound Obstet Gynecol 46(1): 118, 2015a

Timor-Tritsch IE, Khatib N, Monteagudo A, et al: Cesarean scar pregnancies: experience of 60 cases. J Ultrasound Med 34(4):601, 2015b

Timor-Tritsch IE, Monteagudo A, Cali G, et al: Cesarean scar pregnancy and early placenta accreta share common histology. Ultrasound Obstet Gynecol 43(4):383,o2014a

Timor-Tritsch IE, Monteagudo A, Cali G, et al: Cesarean scar pregnancy is a precursor of morbidly adherent placenta. Ultrasound Obstet Gynecol 44(3):346,o2014b

Timor-Tritsch IE, Monteagudo A, Cali G, et al: Easy sonographic diferential diagnosis between intrauterine pregnancy and cesarean delivery scar pregnancy in the early irst trimester. Am J Obstet GynecoI215(2):225.e1, 2016

Timor-Tritsch IE, Monteagudo A, Matera C, et al: Sonographic evolution of cornual pregnancies treated without surgery. Obstet Gynecol 79(6):1044, 1992

Tsakos E, Tsagias N, Dafopoulos K: Suggested method for the management of heterotopic cervical pregnancy leading to term delivery of the intrauterine pregnancy: case report and literature review. J Minim Invasive Gynecol 22(5):896,o2015

Tulandi T, A1-Jaroudi 0: Interstitial pregnancy: results generated from the Society of Reproductive Surgeons. Obstet Gynecol 103:47, 2004

Tulandi T, Guralnick M: Treatment of tubal ectopic pregnancy by salpingotomy with or without tubal suturing and salpingectomy. Ferti! Steri! 55:53, 1991

Ugur M, Turan C, Vicdan K, et al: Chronic ectopic pregnancy: a clinical analysis of 62 cases. Aust N Z J Obstet Gynaecol 36(2): 186, 1996

Ushakov FB, Elchalal U, Aceman PJ, et al: Cervical pregnancy: past and future.

Obstet Gynecol Surv 52:45, 1997

Uyar I, Yucel OU, Gezer C, et al: Efect of single-dose methotrexate on ovarian reserve in women with ectopic pregnancy. Fertil Sterilo100(5):1310, 2013 Valenzano M, Nicoletti L, Odicino F, et al: Five-year follow-up of placental involution after abdominal pregnancy. J Clin Ultrasound 31 (1):39, 2003 van Mello NM, Mol F, Verhoeve HR, et al: Methotrexate or expectant management in women with an ectopic pregnancy or pregnancy of unknown location and low serum hCG concentrations? A randomized comparison. Hum Reprod 28(1):60,o2013

Verhaegen J, Gallos 10, van Mello NM, et al: Accuracy of single progesterone test to predict early pregnancy outcome in women with pain or bleeding: meta-analysis of cohort studies. B\1] 345:e6077, 2012

Verma U, English 0, Brookfield K: Conservative management of nontubal ectopic pregnancies. Fertil Steril 96(6): 1391,o2011

Verma U, Goharkhay N: Conservative management of cervical ectopic pregnancy. Fertil Steril 91(3):671, 2009

Vermesh M, Graczykowski JW, Sauer MV: Reevaluation of the role of culdocentesis in the management of ectopic pregnancy. Am J Obstet Gynecol 162:41o1, 1990

Vermesh M, Silva PO, Rosen GF, et al: Management of unruptured ectopic gestation by linear salpingostomy: a prospective, randomized clinical trial of laparoscopy versus laparotomy. Obstet Gynecol 73(3 Pt 1):400, 1989

Vermesh M, Silva PO, Sauer MV, et al: Persistent tubal ectopic gestation: patterns of circulating beta-human chorionic gonadotropin and progesterone and management options. Fertil Steri! 50:584, 1988

Wang G, Liu X, Bi F, et al: Evaluation of the eicacy of laparoscopic resection for the management of exogenous cesarean scar pregnancy. Ferri! Steril 101(5):1501,o2014

Wang Q, Peng HL, He L, et al: Reproductive outcomes after previous cesarean scar pregnancy: Follow up of 189 women. Taiwan J Obstet Gynecol 54(5):551,o2015

Wang Y, Xu B, Dai S, et al: An eicient conservative treatment modality for cervical pregnancy: angiographic uterine artery embolization followed by immediate curettage. Am J Obstet Gynecol 204(1):31.e1, 2011

Watrowski R, Lange A, Mackel J: Primary omental pregnancy with secondary implantation into posterior cul-de-sac: laparoscopic treatment using hemostatic matrix. J Minim Invasive Gynecol 22(3):501, 2015

Westrom L, Joesoef R, Reynolds G, et al: Pelvic inflammatory disease and fertility: a cohort study of 1,844 women with Iaparoscopically veriied disease and 657 control women with normalolaparoscopic results. Sex Transm Dis 19(4):185,o1992

Worley KC, Hnat MD, Cunningham FG: Advanced extrauterine pregnancy: diagnostic and therapeutic challenges. Am J Obstet Gynecol 198:297e1, 2008

WU PJ, Han CM, Wang C], et al: Early detection and minimally invasive management of intramural pregnancy. J Minim Invasive GynecoI20(1): 123, 2013

Xiaolin Z, Ling L, Chengxin Y, et al: Transcatheter intraarterial methotrexate infusion combined with selective uterine artery embolization as a treatment option for cervical pregnancy. J Vase Interv RadioI21(6):836, 2010

Yang Q, Piao S, Wang G, et al: Hysteroscopic surgery of ectopic pregnancy in the cesarean section scar. J Minim Invasive Gynecol 16(4):432,o2009

Zakaria MA, Abdallah ME, Shavell VI, et al: Conservative management of cervical ectopic pregnancy: utility of uterine artery embolization. Ferti! Steril 95(3):872,o201o1

Zeck W, Kelters I, Winter R, et al: Lessons learned from four advanced abdominal pregnancies at an East African Health Center. J Perin at Med 35(4):278, 2007

Zee J, Sammel MD, Chung K, et al: Ectopic pregnancy prediction in women with a pregnancy of unknown location: data beyond 48 h are necessary. Hum Reprod 29(3):441, 2014

Zhang B, Jiang ZB, Huang MS, et l: Uterine artery embolization combined with methotrexate in the treatment of cesarean scar pregnancy: results of a case series and review of the literature. J Vase Interv RadioI23(12): 1582,2012

Zhu Q, Li C, Zhao WH, et al: Risk factors and clinical features of ovarian pregnancy: a case-control study. BMJ Open 4(12):e006447, 2014

Zhuang Y, Huang L: Uterine artery embolization compared with methotrexate for the management of pregnancy implanted within a cesarean scar. Am J Obstet GynecoIo201(2):152.e1, 2009

Zuo X, Shen A, Chen M: Successful management of unruptured interstitial pregnancy in 17 consecutive cases by using laparoscopic surgery. Aust N Z J Obstet Gynaecol 52(4):387,o2012

HYDATIDIFORM MOLE-MOLAR PREGNANCY . . . 388

PATHOGENESIS ..e....e....e. .. .. ...e...e...e.... 389

DIAGNOSIS......e.... ..e....e....e............ 391 ......e....e...e....e...e.. .. ...e.. 392

GESTATIONAL TROPHOBLASTIC NEOPLASIA ..e... .. 393

DIAGNOSIS, STAGING, AND PROGNOSTIC SCORING ... 393

HISTOLOGICAL CLASSIFICATION ..........e....e...e.394

TREATMENTe. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395

SUBSEQUENT PREGNANCY ....................... 396 . .. the terminal extremities of the chorionic vili are converted into transparent vesicles with clear, viscid contents. These vay in size from minute bodies a ew milimetres in diameter to cystic structures the size of hazel-nuts, and hang in clusters from the vilous stems, to which they are connected by thin pedicles, giving to the external suace of the chorion a grape-like appearance.

-J. Whitridge Williams (1903)

Gestational trophoblastic disease (GTD) is the term used to encompass a group of tumors typiied by abnormal trophoblast proliferation. Trophoblast produces human chorionic gonadotropin (hCG), thus the measurement of this peptide hormone in serum is essential for GTD diagnosis, management, and surveillance. GTD histologically is divided into hydatidiorm moles, which are characterized by the presence of villi, and into nonmolar trophoblastic malignant neoplasms, which lack villi.

Hydatidiform moles are excessively edematous immature placentas (Benirschke, 2012). These include the benign complete hydatidorm mole and partial hydatidiorm mole and the malignant invasive mole. Invasive mole is deemed malignant due to its marked penetration into and destruction of the myometrium and its ability to metastasize.

Nonmolar trophoblastic neoplasms include choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. hese three are diferentiated by the type of trophoblast they contain.

The malignant forms of gestational trophoblastic disease are termed gestational trophoblastic neoplasia (GTN). hese include invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. Other terms applied to GTN are malignant gestational trophoblastic disease and persistent gestational trophoblastic disease. hese malignancies develop weeks or years following any type of pregnancy, but frequently follow a hydatidiform mole.

Each of the GTN malignancy types is histologically distinct and varies in its propensity to invade and metastasize. However, histological confirmation is typically not available. Instead, measurement of serum hCG levels combined with clinical indingsrather than a histological specimen-is used to diagnose and treat this malignancy. Accordingly, GTN is often identified and efectively treated as a group.

In the past, these metastatic tumors had a prohibitively high mortality rate. However, with chemotherapy, most tumors currently are highly curable. Early-stage GTN is typically cured with single-agent chemotherapy, whereas laterstage disease usually responds to combination chemotherapy (Ngan,i2015).

The classic histological findings of molar pregnancy include trophoblast proliferation and villi with stromal edema (Fig. 20-1).

FIGURE 20-1 Complete hydatidiform mole. A. Gross specimen with characteristic vesicles of variable size. (Used with permission from Dr. Brian Levenson.) B. Low-magnification photomicrograph shows generalized edema and cistern formation (black asterisks) within avascular villi. Haphazard trophoblastic hyperplasia is marked by a yellow asterisk on the right. (Used with permission from Dr. Erika Fong.)

The degree of histological changes, karyotypic diferences, and the absence or presence of embryonic elements are used to clas siy them as either complete orpartial moles. hese two also vary and postevacuation GTN. Of the two, GTN more frequently follows complete hydatidiform mole.

A complete mole has abnormal chorionic villi that grossly appear as a mass of clear vesicles. These vary in size and often hang in clusters from thin pedicles. In contrast, a partial molar pregnancy has focal and less advanced hydatidiform changes and contains some fetal tissue. Both forms of moles usually fill the uterine cavity, but they rarely may be tubal or other forms of ectopic pregnancy (Hassadia, 2012; Sebire, 2005).

An ethnic predisposition is seen with hydatidiform mole, which has increased prevalence in Asians, Hispanics, and American Indians (Drake, 2006; Lee, 2011; Smith, 2006). he incidence in the United States and Europe has been relatively constant at 1 to 2 per 1000 deliveries (Eysbollts, 2016; Lee, 2011).

The strongest risk factors are age and a prior hydatidiform mole. Women at both extremes of reproductive age are most vulnerable. Speciically, adolescents and women aged 36 to 40 years have a twofold risk, but those older than 40 have an almost tenfold risk (ltman, 2008; Sebire, 2002a). With a prior complete mole, the risk of another mole is 0.9 percent, and with a previous partial mole, the rate is 0.3 percent. Mter two prior complete moles, approximately 20 percent of women have a third mole (Eagles, 2015).

Molar pregnancies typically arise from chromosomally abnormal fertilizations Figure 20-2. Complete moles most often have a diploid chromosomal composition (Table

These usually are 46,X and result from androgenesis, meaning both sets of chromosomes are paternal in origin. The chromosomes of the ovum are either absent or inactivated. The ovum is fertilized by a haploid sperm, which then duplicates its own chromosomes after meiosis. Less commonly, the chromosomal pattern may be 46,Y or 46,X and due to fertilization by two sperm, that is, dispermic ertilization or dispermy (Lawler, 1991; Lipata, 2010).

23,Y

FIGURE 20-2 Typical pathogenesis of complete and partial moles.

A. A 46,XX complete mole may be formed if a 23,x-bearing haploid sperm penetrates a 23,X-containing haploid egg whose genes have been "inactivated." Paternal chromosomes then duplicate to create a 46,XX diploid complement solely of paternal origin.

B. A partial mole may be formed if two sperm-either 23,X-or 23,Y-bearing-both fertilize (dispermy) a 23,X-containing haploid egg whose genes have not been inactivated. The resulting fertilized egg is triploid with two chromosome sets being donated by the father. This paternal contribution is termed diandry ..

aTypical karyotypes.

bThese include anemia, hyperthyroidism, hyperemesis gravidarum, preeclampsia, and infection. GTN = gestational trophoblastic neoplasia; hCG = human chorionic gonadotropin.

Partial moles usually have a triploid karyotype-69 ,XX, 69,Y-or much less commonly, 69,YY. These are each composed of two paternal haploid sets of chromosomes contributed by dispermy and one maternal haploid set (see Fig. 20-2B). Less frequently, a similar haploid egg may be fertilized by an unreduced diploid 46,Y sperm. These triploid zygotes result in some embryonic development, however, it ultimately is a lethal fetal condition a oergensen, 2014; Lakovschek, 2011). Fetuses that reach advanced ages have severe growth restriction, multiple congenital anomalies, or both.

Rarely, in some twin pregnancies, one chromosomally normal fetus is paired with a complete diploid molar pregnancy. Importantly, these cases must be distinguished from a single partial molar pregnancy with its associated abnormal fetus. Amniocentesis and fetal karyotyping aid confirmation.

Several unique pregnancy problems complicate such twin pregnancies. And, many women may choose to terminate the gestation, if diagnosed early. In those with continuing pregnancy, survival of the normal fetus varies and depends on associated comorbidity from the molar component. The most worrisome are preeclampsia or hemorrhage, which frequently necessitate preterm delivery. Wee and Jauniaux (2005) reviewed outcomes in 174 women, of whom 82 chose termination. Of the remaining 92 pregnancies, 42 percent either miscarried or had a perinatal death; approximately 60 percent delivered preterm; and only 40 percent delivered at term.

Another concern for those continuing their pregnancy is the risk for developing subsequent GTN. However, most data indicate no significant diference between women who continue or terminate their pregnancy (Massardier, 2009; Sebire, 2002b).

Postdelivery surveillance is conducted as for any molar pregnancy (p. 393).

The presentation of women with a molar pregnancy has changed remarkably over the past several decades because prenatal care is sought much earlier and because sonography is virtually universal. Typically, 1 to 2 months of amenorrhea precede the diagnosis. For example, in 194 women with a complete mole, evacuation was completed at a median gestational age of 9 weeks and at 12 weeks for 172 patients with a partial mole (Sun, 2015b). As a result, most molar pregnancies are detected before complications ensue (Kerkmeijer, 2009; Mangili, 2008).

As gestation advances, symptoms tend to be more pronounced with complete compared with partial moles (Niemann, 2007). Untreated molar pregnancies will almost always cause uterine bleeding that varies from spotting to profuse hemorrhage. Bleeding may presage spontaneous molar abortion, but more often, it follows an intermittent course for weeks to months. In more advanced moles with considerable concealed uterine hemorrhage, moderate iron-deiciency anemia develops. Nausea and vomiting may be signiicant. Of physical findings, many women have uterine growth that is more rapid than expected, and the enlarged uterus is comparatively softer. Fetal heart motion is absent with complete moles. he ovaries can be fuller and cystic from multiple theca-lutein cysts (Fig. 20-3). These are more common with a complete mole and likely result from ovarian overstimulation by excessive hCG levels. Because theca-lutein cysts regress following pregnancy evacuation, expectant management is preferred. Occasionally a larger cyst may undergo torsion, infarction, and hemorrhage. However,

FIGURE 20-3 Sonographic image of an ovary with theca-lutein cysts in a woman with a hydatidiform mole.

oophorectomy is not performed unless extensive infarction persists after untwisting.

The thyrotropin-like efects of hCG frequently cause serum free thyroxine (T4) levels to be elevated and thyroid-stimulating hormone (TSH) levels to be decreased. Despite this, clinically apparent thyrotoxicosis is unusual and in our experience can be mimicked by bleeding and sepsis from infected products. Moreover, the serum free T4ilevels rapidly normalize after uterine evacuation. Despite this, cases of presumed "thyroid storm" have been reported (Koinas, 2015).

Severe preeclampsia and eclampsia are relatively common with advanced molar pregnancies. However, these are seldom seen today because of early diagnosis and evacuation. An exception is the case of a normal fetus coexisting with a complete mole, described earlier. In continuing twin gestations, severe preeclampsia frequently mandates preterm delivery.

prompts pregnancy testing and sonography. Some women will present with spontaneous passage of molar tissue.

With a complete molar pregnancy, serum �-hCG levels are commonly elevated above those expected for gestational age. With more advanced moles, values in the millions are not unusual. Importantly, these high values can lead to erroneous false-negative urine pregnancy test results. Termed a "hook efect," excessive �-hCG hormone levels oversaturate the assay's targeting antibody and create a falsely low reading (Cormano, 2016). In these cases, serum �-hCG determinations with or without sample dilution will clariy the conundrum. With a partial mole, �-hCG levels may also be significantly elevated, but more commonly concentrations fall into ranges expected for gestational age.

Although this is the mainstay of trophoblastic disease diagnosis, not all cases are confirmed initially. Sonographically, a com plete mole appears as an echogenic uterine mass with numerous anechoic cystic spaces but without a fetus or amnionic sac. The appearance is often described as a "snowstorm" (Fig. 20-4). A partial mole has features that include a thickened, multicystic placenta along with a fetus or at least fetal tissue. However, in early pregnancy, these sonographic characteristics are seen in fewer than half of hydatidiform moles. In the largest series of more than 1000 patients with molar pregnancy, the reported sensitivity and speciicity of sonography were 44 and 74 percent, respectively (Fowler, 2006). he most common mimics are incomplete or missed abortion. Occasionally, molar pregnancy may be confused for a multifetal pregnancy or a uterine leiomyoma with cystic degeneration.

FIGURE 20-4 Sonograms of hydatidiform moles. A. Sagittal view of a uterus with a complete hydatidiform mole. The characteristic "snowstorm" appearance is due to an echogenic uterine mass, marked by calipers, that has numerous anechoic cystic spaces. Notably, a fetus and amnionic sac are absent. B. In this image of a partial hydatidiform mole, the fetus is seen above a multicystic placenta. (Used with permission from Dr. Elysia Moschos.)

Surveillance for subsequent neoplasia following molar pregnancy is crucial. Thus, moles must be distinguished from other types of pregnancy failure that have hydropic placental degeneration, which can mimic molar villous changes. Some distinguishing histological characteristics are shown in Table 20-1.

In pregnancies before 10 weeks, classic molar changes may not be apparent because villi may not be enlarged and molar stroma may not yet be edematous and avascular. Histopathologic evaluation can be enhanced by immunohistochemical staining for pS7 expression and by molecular genotyping (Banet, 2014). pS7IP2 is a nuclear protein whose gene is paternally imprinted and maternally expressed. his means that the gene product is produced only in tissues containing a maternal allele. Because complete moles contain only paternal genes, the pS7IP2 protein is absent in complete moles, and tissues do not pick up this stain (Merchant, 200S). In contrast, this nuclear protein is strongly expressed in normal placentas, in spontaneous pregnancy losses with hydropic degeneration, and in partial hydatidiform moles (Castrillon, 2001). Accordingly, immunostaining for pS7IP2 is an efective means to isolate complete mole from the diagnostic list. For distinction of a partial mole from a non molar hydropic abortus, both of which express pS7, molecular genotyping can be used. Molecular genotyping determines the parental source of alleles. Thereby, it can distinguish among a diploid diandric genome (complete mole), a triploid diandric-monogynic genome (partial mole), or biparental diploidy (nonmolar abortus).

Maternal deaths from molar pregnancies are rare because of early diagnosis, timely evacuation, and vigilant postevacuation surveillance for GTN. Preoperative evaluation attempts to identiy known potential complications such as preeclampsia, hyperthyroidism, anemia, electrolyte depletions from hyperemesis, and metastatic disease (Table 20-2) (Lurain, 2010). Most recommend chest radiography, whereas computed tomography (CT) and magnetic resonance (MR) imaging are not routinely done unless a chest radiograph shows lung lesions or unless other extrauterine disease is suspected.

Regardless of uterine size, molar evacuation by suction curettage is usually the preferred treatment. Preoperative cervical dilatation with an osmotic dilator is recommended if the cervix is minimally dilated. Intraoperative bleeding can be greater with molar pregnancy than with a comparably sized uterus containing nonmolar products. hus with large moles, adequate anesthesia, suicient intravenous access, and blood-banking support is imperative. he cervix is mechanically dilated to preferably allow insertion of a larger suction curette. Depending on uterine size, a 10-to 14-mm diameter is typical. As evacuation is begun, oxytocin is infused to limit bleeding. Intraoperative sonography is often recommended to help ensure complete uterine cavity emptying. When the myometrium has contracted, a thorough but gentle curettage with a sharp large-loop

TABLE 20-2. Some Considerations for Management of Hydatidiform Mole

Hemogram; serum 3-hCG, creatinine, electrolyte, and hepatic aminotransferase levels

TSH, free T4 levels

Oxytocin (Pitocin): 20 units in 1000 mL Ringer lactate for continuous infusion One or more other uterotonic agents may be added as needed:

Methylergonovine (Methergine): 0.2 mg = 1 mL = 1 ampule 1M every 2 hr prn

Carboprost tromethamine (PGF20) (Hemabate)k 250 .Lg = 1 mL = 1 ampule 1M every 15-90 min prn

Misoprostol (PGE1) (Cytotec): 200 mg tablets for rectal administration, 800-1000 mg once Karman cannula-size 10 or 14 mm Consider sonography machine

Serum hCG levels: within 48 hours of evacuation, weekly until undetectable, then monthly for 6 months alntrauterine devices are not suitable during surveillance.

hCG = human chorionic gonadotropin; 1M = intramuscular; PG = prostaglandin; T4 = thyroxine; TSH = thyroid-stimulating hormone.

Sims curette is performed. If bleeding continues despite uterine evacuation and oxytocin infusion, other uterotonic agents are given (see Table 20-2). In rare cases, pelvic arterial emboliza tion or hysterectomy may be necessary (Tse, 2007). Profuse management are discussed in Chapter 41 (p. 755).

Some volume of trophoblast is deported into the pelvic venous system during molar evacuation (Hankins, 1987). With large moles, the amount of tissue may be suicient to produce clinically apparent respiratory insuiciency, pulmonary edema, or even embolism. In our earlier experiences with substantial moles, these and their chest radiographic manifestations clear rapidly without specific treatment. However, fatalities have been described (Delmis, 2000). Because of deportation, there is concern that trophoblastic tissue will thrive within the lung parenchyma to cause persistent disease or even overt malignancy. Fortunately, no evidence suggests that this is a major problem.

Following curettage, anti-D immunoglobulin (Rhogam) is given to Rh D-negative women because fetal tissues with a partial mole may include red cells with D-antigen (Chap. 15, p. 305). Those with suspected complete mole are similarly treated because a deinitive diagnosis of complete versus partial mole may not be conirmed until histologicl evaluation of the evacuated products.

Following evacuation, the long-term prognosis for women with a hydatidiform mole is not improved with prophylactic chemotherapy. Moreover, chemotherapy toxicity-including death-may be significant, and thus it is not recommended routinely (Gueye, 2014; Wang, 2017).

Methods other than suction curettage can be considered for select cases. Hysterectomy with ovarian preservation may be preferable for women with complete moles who have inished childbearing. Of women aged 40 to 49 years, 30 to 50 percent will subsequently develop GTN, and hysterectomy markedly reduces this likelihood (Bandy, 1984; Elias, 2010, 2012). Theca-lutein cysts seen at the time of hysterectomy do not require removal, and they spontaneously regress following molar termination. Labor induction or hysterotomy is seldom used for molar evacuation in the United States. Both will likely increase blood loss and theoretically may increase the incidence of persistent trophoblastic disease (American College of Obstetricians and Gynecologists, 2016; Tidy, 2000).

Close biochemical surveillance for persistent gestational neoplasia follows each hydatidiform mole evacuation. This monitoring is by serial measurement of serum 3-hCG to detect persistent or renewed trophoblastic proliferation. s a glycoprotein, hCG shows structural heterogeneity and exists in diferent isoforms. Thus for surveillance, an hCG assay that can detect all forms of hCG should be used (Harvey, 2010; Ngan, 2015). hese are different from those used for routine pregnancy testing (de Medeiros, 2009). he initial 3-hCG level is obtained within 48 hours ater evacuation. This serves as the baseline, which is compared with 3-hCG quantiication done thereater every 1 to 2 weeks until levels progressively decline to become undetectable.

he median time for such resolution is 7 weeks for partial moles and 9 weeks for complete moles. Once 3-hCG is undetectable, this is confirmed with monthly determinations for another 6 months (Lurain, 2010; Sebire, 2007). Concur rently, reliable contraception is imperative to avoid confusion caused by rising 3-hCG levels from a new pregnancy. Most recommend combination hormonal contraception, injectable depot medroxyprogesterone acetate, or progestin implant (Dantas, 2017). he latter two are particularly useful if poor patient compliance is anticipated. Intrauterine devices are not used until 3-hCG levels are undetectable because of the risk of uterine perforation if there is an invasive mole. lthough not recommended, if a woman conceives during surveillance, live birth rates and risk for congenital anomalies appear to mirror the general population (Tuncer, 1999a,b). Mter these 6 months, monitoring is discontinued and pregnancy allowed.

Importantly, during 3-hCG level surveillance, either increasing or persistently plateaued levels mandate evaluation for trophoblastic neoplasia. If the woman has not become pregnant, then these levels signiY increasing trophoblastic proliferation that is most likely malignant. Several factors predispose a patient to trophoblastic neoplasia following molar evacuation. Most important, complete moles have a 15 to 20 percent incidence of malignant sequelae, compared with 1 to 5 percent following partial moles. Surprisingly, with much earlier recognition and evacuation of molar pregnancies, the risk for neoplasia has not been lowered (Schorge, 2000; Sun, 2015a). Other risk factors are older maternal age, 3-hCG levelsi> 100,000 mIU/mL, uterine size that is large for gestational age, theca-lutein cysts >6 cm, and slow decline in 3-hCG levels (Berkowitz, 2009; Kang, 2012; Wolfberg, 2005).

This group includes invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. These tumors almost always develop with or after some form of recognized pregnancy. Half follow hydatidiform mole, a fourth follow miscarriage or tubal pregnancy, and another fourth develop after a preterm or term pregnancy (Goldstein, 2012). Although these four tumor types are histologically distinct, they are usually diagnosed solely by persistently elevated serum 3-hCG levels because tissue is infrequently available for study. Criteria to diagnose postmolar GTN are shown in Table 20-3.

hese placental tumors are characterized clinically by their aggressive invasion into the myometrium and propensity to metastasize. he most common inding with GTN is irregular bleeding associated with uterine subinvolution. The bleeding may be continuous or intermittent, with sudden and sometimes massive hemorrhage. Myometrial perforation from trophoblastic growth may cause intraperitoneal hemorrhage. In some women, lower genital tract metastases are evident, whereas in others only distant metastases are found with no trace of uterine tumor.

• Diagnosis, Staging, and Prognostic Scoring

Consideration for the possibility of GTN is the most important factor in its recognition. Unusually persistent bleeding ater any type of pregnancy should prompt measurement of serum 3-hCG

TABLE 20-3. Criteria for Diagnosis of Gestational Trophoblastic Neoplasia 1.

Plateau of serum �-hCG level (± 10 percent) for four measurements during a period of 3 weeks or longer-days 1, 7, 14,s21 2.

Rise of serum �-hCG levels> 10 percent during three weekly consecutive measurements or longer, during a period of 2 weeks or more-days '1, 7, 14 3.

4.

levels and consideration for diagnostic curettage if levels are elevated. Uterine size is assessed along with careful examination for lower genital tract metastases, which usually appear as bluish vascular masses (Cagayan, 2010). Tissue diagnosis is unnecessary, thus biopsy is not required and may cause significant bleeding.

Once the diagnosis is veriied, in addition to a baseline serum J-hCG level and hemogram, a search for local disease and metastases includes tests of liver and renal function, transvaginal sonography, chest CT scan or radiograph, and brain and abdominopelvic CT scan or MR imaging. Less commonly, positron-emission tomographic (PET) scanning and cerebrospinal luid J-hCG level determination are used to identiy metastases (Lurain, 2011).

GTN is staged clinically using the system of the International Federation of Gynecology and Obstetrics (FIGO) (2009). his includes a modiication of the World Health Organization (WHO) (1983) prognostic index score, with which scores of 0 to 4 are given for each of the categories shown in Table 20-4. Women with WHO scores of 0 to 6 are considered to have low-risk disease, whereas those with a score :::7 are considered in the high-risk group.

Again, it is stressed that the diagnosis of trophoblastic neoplasias is usually made by persistently elevated serum J-hCG levels without conirmation by tissue study. Clinical staging is assigned without regard to histological indings, even if available. Still, there are distinct histological types, described next.

These are the most common trophoblastic neoplasms that follow hydatidiform moles, and almost all invasive moles arise from partial or complete moles. Previously known as chorioadenoma destruens, invasive mole is characterized by extensive tissue invasion by trophoblast and whole villi. There is penetration deep into the myometrium, sometimes with involvement of the peritoneum, adjacent parametrium, or vaginal vault. Although locally aggressive, invasive moles are less prone to metastasize.

his is the most common type of trophoblastic neoplasm to follow a term pregnancy or a miscarriage, and only a third of

TABLE 20-4. International Federation of Gynecology and Obstetrics (FIGO) Staging and Diagnostic Scoring System for Gestational Trophoblastic Neoplasia

Age (years) <40 :::40 Antecedent pregnancy Mole Abortion Term <103 largest tumor size (including uterus) <3 cm 3-4 cm :::5 cm Site of metastases Spleen, kidney GI Liver, brain

Number of metastases

Previous failed chemotherapy drugs :::2 aAdapted by FIGO. blow risk = WHO score of 0 to 6; high risk = WHO score ofs:::7.

J-hCG = beta human chorionic gonadotropin; GI = gastrointestinal; GTN = gestational trophoblastic neoplasia.

Adapted with permission from FIGO Committee on Gynecologic Oncology: Current FIGO staging for cancer of the vagina, fallopian tube, ovary, and gestational trophoblastic neoplasia, Int J Gynaecol Obstet 2009 Apr;l 05(1 )j3-4.

4-6 7-12 >12 103 to 104 104 to 105 :::105

FIGURE 20-5 Metastatic choriocarcinoma. A. Chest radiograph demonstrates widespread metastatic lesions. B. Autopsy specimen with multiple hemorrhagic hepatic metastases. (Used with permission from Dr. Michael Conner.) cases follow a molar gestation (Soper, 2006). Choriocarcinoma is composed of cells reminiscent of early cytotrophoblast and syncytiotrophoblast, however, it contains no villi. his rapidly growing tumor invades both myometrium and blood vessels to create hemorrhage and necrosis. Myometrial tumor may spread outward and become visible on the uterine surface as dark, irregular nodules. Metastases often develop early and are generally blood-borne (Fig. 20-5). The most common sites are the lungs and vagina, but tumor may travel to the vulva, kidneys, liver, brain, ovaries, and bowel. Bleeding can complicated these metastases (Fatema, 2016; Wei, 2016; Zhang, 2017). Choriocarcinomas are commonly accompanied by ovarian theca-lutein cysts.

This rare tumor arises from intermediate trophoblasts at the placental site. hese tumors have associated serum �-hCG levels that may be only modestly elevated. However, they produce variant forms of hCG, and identiication of a high proportion of free �-hCG is considered diagnostic. Treatment of placental site trophoblastic tumor by hysterectomy is preferred because these locally invasive tumors are usually resistant to chemotherapy (Baergen, 2006). For higher-risk stage I and for later stages, adjuvant multidrug chemotherapy is also given (Schmid, 2009).

This rare tumor develops from chorionic-type intermediate trophoblast. he uterus is the main site of involvement, and bleeding and low hCG levels are typical findings (Scott, 2012). Primary treatment is hysterectomy because this tumor is relatively resistant to chemotherapy. Metastatic disease is common, and combination chemotherapy is employed (Davis, 2015) .

Women with GTN are best managed by oncologists, and some (Kohorn, 2014). The prognosis is excellent with rare excep tions, and patients are routinely cured even in the presence of widespread disease. Chemotherapy alone is usually the primary treatment. Although controversial, some also consider a sec ond uterine evacuation to be an adjuvant therapeutic option in some GTN cases to avoid or minimize chemotherapy (Pezeshki, 2004; van Trommel, 2005). In other cases, suction curettage may infrequently be needed to resolve bleeding or remove a sub stantial amount of retained molar tissue. In speciic cases, hys terectomy may be primary or adjuvant treatment (Clark, 2010).

Single-agent chemotherapy protocols are usually suicient for nonmetastatic or low-risk metastatic neoplasia (Lawrie, 2016). In their review of 108 women with low-risk disease, Abrao and colleagues (2008) reported that monotherapy protocols with either methotrexate or actinomycin D were equally efective compared with a regimen containing both. In general, methotrexate is less toxic than actinomycin D (Chan, 2006; Secki, 2010). Regimens are repeated until serum �-hCG levels are undetectable.

Combination chemotherapy is given for high-risk disease, and reported cure rates approximate 90 percent (Lurain, 2010). Several regimens have been used with success. One is EMA-CO, which includes �toposide, methotrexate, gctinomycin D, �yclophosphamide, and

Oncovin (vincristine). In selected cases, adjuvant surgical and radiotherapy may also be employed (Hanna, 2010). Frequent causes of death include hemorrhage from metastatic sites, respiratory failure, sepsis, and multiorgan failure due to widespread chemoresistant disease (Lybol, 2012; Neubauer, 2015).

With either low-or high-risk disease, once serum �-hCG levels are undetectable, serosurveillance is continued for 1 year. During this time, efective contraception is crucial to avoid any teratogenic efects of chemotherapy to the fetus and to mitigate conusion from rising �-hCG levels caused by superimposed pregnany (Secki, 2010; Williams, 2014). For those who conceive despite this within the surveillance year following treatment, pregnancy may continue since most will have a favorable outcome (Tse, 2012; Woolas, 1998). Importantly, this group is advised of the low but important risk of delayed diagnosis if tumor recurs during the pregnancy (Blagden, 2002; Tuncer, 1999b).

A small number of women during surveillance, despite no evidence of metastases, will be found to have very low �-hCG levels that plateau. This phenomenon is called quiescent hCG and presumably is caused by dormant trophoblast. Close observation without therapy is recommended, but 20 percent will eventually have recurrent active and progressive trophoblastic neoplasia (Ngu, 2014).

Women with prior hydatidiform mole generally do not have impaired fertility, and their pregnancy outcomes are usually normal Qoneborg, 2014; Matsui, 2011; Sebire, 2003). One concern is the 2-percent risk for developing trophoblastic disease in a subsequent pregnancy, which was described earlier. Sonographic evaluation is recommended in early pregnancy, and subsequently if indicated.

Women who have successfully completed GTN chemotherapy are advised to delay pregnancy for 12 months. Fertility and pregnancy outcomes are typically normal, and congenital anomaly rates are not increased (Berkowitz, 2000; Tse, 2012). One exception is an unexplained higher stillbirth rate of 1.5 percent compared with a background rate of 0.8 percent (Vargas, 2014).

After hydatidiform mole or GTN treatment, in subsequent pregnancy, the placenta or products of conception are sent for pathological evaluation at delivery. A serum 3-hCG level is measured 6 weeks postpartum (Lurain, 2010).

Abrao A, de Andrade ]M, Tiezzi DG, et al: Treatment for low-risk gestational trophoblastic disease: comparison of single-agent methotrexate, dactinomycin and combination regimens. Gynecol Oncol 108:149,o2008

Altman AD, Bently B, Murray S, et al: Maternal age-related rate of gestational trophoblastic disease. Obstet Gynecol 11o2:244, 2008

American College of Obstetricians and Gynecologists: Diagnosis and treatment of gestational trophoblastic disease. Practice Bulletin No. 53, June 2004, Reairmed 2016

Baergen N, Rutgers ]L, Young RH, et al: Placental site trophoblastic tumor: a study of 55 cases and review of the literature emphasizing factors of prognostic significance. Gynecol Oncol 100:511, 2006

Bandy LC, Clarke-Pearson DL, Hammond CB: Malignant potential of gestational trophoblastic disease at the extreme ages of reproductive life. Obstet Gynecol 64(3):395, 1984

Banet N, DeScipio C, Murphy M, et al: Characteristics of hydatidiform moles: analysis of a prospective series with p57 immunohistochemistry and molecular genotyping. Mod PathoIo27(2):238, 2014

Benirschke K, Burton G], Baergen N (eds): Molar pregnancies. In Pathology of the Human Placenta, 6th ed. New York, Springer, 2012, p 687 Berkowitz RS, Goldstein DP: Current management of gestational trophoblastic diseases. Gynecol Oncol 112(3):654, 2009

Berkowitz RS, Tuncer ZS, Bernstein MR: Management of gestational trophoblastic diseases: subsequent pregnancy experience. Semin Oncol 27(6):678, 2000

Blagden SP, Foskett A, Fisher A, et al: he efect of early pregnancy following chemotherapy on disease relapse and foetal outcome in women treated for gestational trophoblastic tumours. Bro] Cancer 86(1):26,o2002

Cagayan MS: Vaginal metastases complicating gestational trophoblastic neoplasia.o] Reprod Med 55(5-6):229, 2010

Castrillon DH, Sun 0, Weremowicz S, et al: Discrimination of complete hydatidiform mole from its mimics by immunohistochemistry of the paternally imprinted gene product p57KIP2. Am] Surg PathoI25(10):1225, 2001

Chan KK, Huang Y, Tam F, et al: Single-dose methotrexate regimen in the treatment of low-risk gestational trophoblastic neoplasia. Am ] Obstet GynecoIo195:1282,o2006

Clark RM, Nevadunsky NS, Ghosh S, et al: The evolving role of hysterectomy in gestational trophoblastic neoplasia at the New England Trophoblastic Disease Center.o] Reprod Med 55(5-6):194, 2010

Cormano ], Mackay G, Holschneider C: Gestational trophoblastic disease diagnosis delayed by the hook efect. Obstet GynecoIo126(4):811, 2015

Dantas PRS, Maesd. I, Filho ]R, et al: Does hormonal contraception during molar pregnancy follow-up influence the risk and clinical aggressiveness of gestational trophoblastic neoplasia after controlling for risk factors? Gynecol Oncol September 16, 2017 [Epub ahead of print]

Davis MR, Howitt BE, Quade B], et al: Epithelioid trophoblastic tumor: a single institution case series at the New England Trophoblastic Disease Center. Gynecol Oncol 137(3):456,o20o15

Delmis ], Pfeifer 0, Ivanisecvic M, et al: Sudden death from trophoblastic embolism in pregnancy. Euro] Obstet Gynecol Reprod Bioi 92:225, 2000 de Medeiros SF, Norman RJ: Human chorionic gonadotrophin protein core and sugar branches heterogeneity: basic and clinical insights. Hum Reprod Update 15(1):69,o2009

Drake D, Rao GG, McIntire DO, et al: Gestational trophoblastic disease among Hispanic women: a 21-year hospital-based study. Gynecol Oncol 103:81,o2006

Eagles N, Sebire N], Short 0, et al: Risk of recurrent molar pregnancies following complete and partial hydatidiform moles. Hum Reprod 30(9):2055, 20o15

Elias M, Goldstein DP, Berkowitz RS: Complete hydatidiform mole in women older than age 50.] Reprod Med 55(5-6):208, 2010

Elias KM, Shoni M, Bernstein M, et al: Complete hydatidiform mole in women aged 40 to 49 years.o] Reprod Med 57(5-6):254, 2012

Eysbouts K, Bulten ], Ottevanger PB, et al: Trends in incidence for gestational trophoblastic disease over the last 20 years in a population-based study. Gynecol Oncol 140(1):70,o2016

Fatema N, Arora NV, l Abri FM, et al: Pancreatic and hepatic metastasis of an undiagnosed choriocarcinoma: an exceptional cause ofhaemoperitoneum in young women-report of a rare case. Case Rep Oncol 9(3):633,o2016

FIGO Committee on Gynecologic Oncology: Current FIGO staging for cancer of the vagina, fallopian tube, ovary, and gestational trophoblastic neoplasia. Int] Gynaecol Obstet 105:3,2009

Fowler 0], Lindsay I, Seck! M], et al: Routine pre-evacuation ultrasound diagnosis of hydatidiform mole: experience of more than 1000 cases from a regional referral center. Ultrasound Obstet Gynecol 27(1):56, 2006

Goldstein DP, Berkowitz RS: Current management of gestational trophoblastic neoplasia. Hematol Oncol Clin North Am 26(1):111,o2012

Gueye M, Kane-Gueye SM, Ndiaye-Gueye MD, et al: Gestational trophoblastic neoplasia after achieving a nondetectable serum human chorionic gonadotrophin level. B]OG 121(11):1415,o2014

Hankins GO, Wendel GO, Snyder R, et al: Trophoblastic embolization during molar evacuation: central hemodynamic observations. Obstet Gynecol 63:368, 1987

Hanna RK, Soper ]T: The role of surgery and radiation therapy in the management of gestational trophoblastic disease. Oncologist 15(6):593,o2010

Harvey A, Mitchell HD, Stenman UH, et al: Diferences in total human chorionic gonadotropin immunoassay analytical specificiry and ability to measure human chorionic gonadotropin in gestational trophoblastic disease and germ cell tumors.o] Reprod Med 55(7-8):28, 2010

Hassadia A, Kew FM, Tidy]A, et al: Ectopic gestational trophoblastic disease: a case series review.o] Reprod Med 57(7-8):297, 20o12 ]oergensen MW, Niemann I, Rasmussen A,et al: Triploid pregnancies: genetic and clinical features of 158 cases. Am] Obstet GynecoIo211(4):370.e1, 2014 ]oneborg U, Eloranta S, Johansson L, et al: Hydatidiform mole and subsequent pregnancy outcome: a population-based cohort study. Am ] Obstet GynecoIo211(6):681.e1,o2014 Kang WD, Choi HS, Kim SM: Prediction of persistent gestational trophoblastic neoplasia: the role of hCG level and ratio in 2 weeks after evacuation of complete mole. Gynecol OncoIo124(2):250, 2012 Kerkmeijer LG, Massuger LF, Ten Kate-Booij M], et al: Earlier diagnosis and serum human chorionic gonadotropin regression in complete hydatidiform moles. Obstet Gynecol 113:326,o2009

Kofinas ]0, Kruczek A, Sample ], et al: Thyroid storm-induced multi-organ failure in the setting of gestational trophoblastic disease.o] Emerg Med 48(1): 35,o2015

Kohorn EI: Worldwide survey of the results of treating gestational trophoblastic disease.o] Reprod Med 59(3-4):145, 2014

Lakovschek Ie, Streubel B, Ulm B: Natural outcome of trisomy 13, trisomy 18, and triploidy ater prenatal diagnosis. Am] Med Genet A 155A(11):262, 2011 Lawler SO, Fisher A, Dent J: A prospective genetic study of complete and partial hydatidiform moles. Am ] Obstet Gynecol 164: 1270, 1991

Lawrie TA, Alazzam M, Tidyo], et al: First-line chemotherapy in low-risk gestational trophoblastic neoplasia. Cochrane Database Syst Rev 6:CD007102, 2016

Lee C, Smith HO, Kim S]: Epidemiology. In Hancock BW, Seck! M], Berkowitz RS, et al (eds): Gestational trophoblastic disease, 3rd ed. London, International Society for the Study of Trophoblastic Disease, 20o11o, p 57. Available at: http://www.isstd.org/index.html. Accessed April 23, 2016

Upata F, Parkash V, Talmor M, et al: Precise DNA genotyping diagnosis of hydatidiform mole. Obstet GynecoIo115(4):784, 2010

Lurain JR: Gestational trophoblastic disease I: epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole. Am J Obstet Gynecol 203(6):531, 20o10

Lurain JR: Gestational trophoblastic disease II: classification and management of gestational trophoblastic neoplasia. Am J Obstet Gynecol 204(1):11, 2011

Lybol C, Centen DW, homas CM, et al: Fatal cases of gestational trophoblastic neoplasia over four decades in the Netherlands: a retrospective cohort study. BJOG 119(12):1465,o2012

Mangili G, Garavaglia E, Cavoretto P, et al: Clinical presentation of hydatidiform mole in northern Italy: has it changed in the last 20 years? Am J Obstet GynecoIo198(3):302.e1,o2008

Massardier J, Golfner F, Journet D, et al: Twin pregnancy with complete hydatidiform mole and coexistent fetus obstetrical and oncological outcomes in a series of 14 cases. Eur J Obstet Gynecol Reprod BioI 143:84,2009

Matsui H, Iitsuka Y, Suzuka K, et al: Subsequent pregnancy outcome in patients with spontaneous resolution of HCG after evacuation of hydatidiform mole: comparison between complete and partial mole. Hum Reprod 16(6):1274,o2011

Merchant SH, Amin MB, Viswanatha DS, et al: p57KIP2 immunohistochemistry in early molar pregnancies: emphasis on its complementary role in the diferential diagnosis of hydropic abortuses. Hum Pathol 36: 180, 2005

Neubauer NL, Strohl E, Schink Jc, et al: Fatal gestational trophoblastic neoplasia: an analysis of treatment failures at the Brewer Trophoblastic Disease Center from 1979-2012 compared to 1962-1978. GynecoloOncol 138(2):339,o2015

Ngan HY, Seck! MJ, Berkowitz RS, et al: Update on the diagnosis and management of gestational trophoblastic disease. Int J Gynaecol Obstet 131 Suppl 2:S123,o2015

Ngu SF, Chan KK: Management of chemoresistant and quiescent gestational trophoblastic disease. Curr Obstet Gynecol Rep 3:84, 2014

Niemann I, Petersen LK, Hansen ES, et al: Diferences in current clinical features of diploid and triploid hydatidiform mole. BJOG 114:1273,2007

Pezeshki M, Hancock BW, Silcocks P: he role of repeat uterine evacuation in the management of persistent gestational trophoblastic disease. Gynecol Oncol 95(3):423, 2004

Schmid P, Nagai Y, Agawal R: Prognostic markers and long-term outcome of placental-site trophoblastic tumours: a retrospective obsevational study. Lancet 374(9683):48, 2009 Schorge JO, Goldstein DP, Bernstein MR, et al: Recent advances in gestational trophoblastic disease. J Reprod Med 45:692, 2000 Scott EM, Smith L, Desouki MM, et al: Epithelioid trophoblastic tumor: a case report and review of the literature. Case Rep Obstet Gynecol 2012: 862472, 20o12

Sebire NJ, Fisher A, Foskett M, et al: Risk of recurrent hydatidiform mole and subsequent pregnancy outcome following complete or partial hydatidiform molar pregnancy. BJOG 110(1):22,2003

Sebire N], Foskett M, Fisher A, et al: Risk of partial and complete hydatidiform molar pregnancy in relation to maternal age. BJOG 109:99, 2002a

Sebire NJ, Foskett M, Parainas FJ, et al: Outcome of twin pregnancies with complete hydatidiform mole and healthy co-twin. Lancet 359:2165, 2002b

Sebire NJ, Foskett M, Short D, et al: Shortened duration of human chorionic gonadotrophin surveillance following complete or partial hydatidiform mole: evidence for revised protocol of a UK regional trophoblastic disease unit. BJOG 114(6): 60,o2007

Sebire NJ, Lindsay I, Fisher A: Overdiagnosis of complete and partial hydatidiform mole in tubal ectopic pregnancies. Int J Gynecol Pathol 24(3):260, 2005

Seck! MJ, Sebire NJ, Berkowitz RS: Gestational trophoblastic disease. Lancet 376(9742):717,o2010

Smith HO, Wiggins C, Verschraegen CF, et al: Changing trends in gestational trophoblastic disease. J Reprod Med 51 :777, 2006

Soper JT: Gestational trophoblastic disease. Obstet Gynecol 108: 176, 2006

Sun SY, Melamed A, Goldstein DP, et al: Changing presentation of complete hydatidiform mole at the New England Trophoblastic Disease Center over the past three decades: does early diagnosis alter risk for gestational trophoblastic neoplasia? Gynecol Oncol 138(1):46,o2015

Tidy JA, Gillespie M, Bright N, et al: Gestational trophoblastic disease: a study of mode of evacuation and subsequent need for treatment with chemotherapy. Gynecol Oncol 78 pp. 309,o2000

Tse Y, Chan KK, Tam F: 20-year experience of managing profuse bleeding in gestational trophoblastic disease. J Reprod Med (5):397, 200

Tse Y, Ngan HY: Gestational trophoblastic disease. Best Pract Res Clin Obstet GynaecoIo26(3):357, 2012

Tuncer ZS, Bernstein MR, Goldstein DP, et al: Outcome of pregnancies occurring before completion of human chorionic gonadotropin follow-up in patients with persistent gestational trophoblastic tumor. Gynecol Oncol 73(3):345, 1999a

Tuncer ZS, Bernstein MR, Goldstein DP, et al: Outcome of pregnancies occurring within 1 year of hydatidiform mole. Obstet Gynecol 94(4):588, 1999b van Trommel NE, Massuger LF, Verheijen H, et al: he curative efect of a second curettage in persistent trophoblastic disease: a retrospective cohort survey. Gynecol Oncol 99:6, 2005

Vargas R, Barroilhet LM, Esselen K, et al: Subsequent pregnancy outcomes after complete and partial molar pregnancy, recurrent molar pregnancy, and gestational trophoblastic neoplasia: an update from the New England Trophoblastic Disease Center. J Reprod Med 59(5-6):188, 2014

Wang Q, Fu J, Hu L, et al: Prophylactic chemotherapy for hydatidiform moleto prevent gestational trophoblastic neoplasia. Cochrane Database Syst Rev 9:CD007289, 2017

Wee L, Jauniaux E: Prenatal diagnosis and management of twin pregnancies complicated by a co-existing molar pregnancy. Prenat Diagn 25(9):772, 2005

Wei H, Zhang T, Uu B, et al: Choriocarcinoma of unknown origin with multiple organ metastasis and cerebral hemorrhage: a case report and literature review. Oncol Lett 11(6):3749,2016

Williams ], Short D, Dayal L, et al: Efect of early pregnancy following chemotherapy on disease relapse and fetal outcome in women treated for gestational trophoblastic neoplasia. J Reprod Med 59(5-6):248-54, 2014

Wolfberg AJ, Berkowitz RS, Goldstein DP: Postevacuation hCG levels and risk of gestational trophoblastic neoplasia in women with complete molar pregnancy. Obstet Gynecol 106(3):548,o2005

Woolas RP, Bower M, Newlands ES, et al: Influence of chemotherapy for gestational trophoblastic disease on subsequent pregnancy outcome. BJOG 105: 1032, 1998

World Health Organization Scientific Group: Gestational trophoblastic disease.

WHO Tech Rep Ser 692:1,o1983

Zhang W, Uu B, Wu J, et al: Hemoptysis as primary manifestation in three women with choriocarcinoma with pulmonary metastasis: a case series. J Med Case Rep 11(1):110,o201

Physiology of Labor

MATERNAL AND FETAL COMPARTMENTS .......... 400

SEX STEROID HORMONE ROLE . . ................ 401

PROSTAGLANDINS ROLE .......e..e......e..e. . ... 402

PHASE 1: UTERINE QUIESCENCE AND CERVICAL

SOFTENING ................... .......... ... 403

PHASE 2: PREPARATION FOR LABOR ............... 408

PHASE 3: .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411

UTEROTONINS IN PARTURITION PHASE 3 ........... 416

PHASE 4: THE PUERPERIUM ... .................. 417

From time immemorial inquiring minds have sought an explanation or the act that labour usualy ensues about 280 days after the appearance of the last menstrual perio, but thus ar no satiactory universal cause has been discovered.

-J. Whitridge Williams (1903)

The importance of labor physiology was highlighted in the irst edition of Wiliams Obstetrics, in which an entire section was devoted to the topic. Given the science at that time, those nine chapters were concerned with the mechanics of labor and delivery. However, the current understanding of labor includes a wide spectrum of preparedness even before the first regular contractions.

Labor is the last few hours of human pregnancy. It is characterized by forceful and painful uterine contractions that efect cervical dilation and cause the fetus to descend through the birth canal. Extensive preparations take place in both the uterus and cervix long before this. During the irst 36 to 38 weeks of normal gestation, the myometrium is in a preparatory yet unresponsive state. Concurrently, the cervix begins an early stage of remodeling yet maintains structural integrity. Following this prolonged uterine quiescence, a transitional phase follows during which myometrial unresponsiveness is suspended and the cervix undergoes ripening, efacement, and loss of structural cohesion.

The physiological processes that regulate parturition-the bringing forth of young-and the onset of labor continue to be deined. Three general contemporaneous theories describe labor initiation. Viewed simplistically, the irst is the functional loss of prenancy maintenance actors. he second focuses on synthesis of actors that induce parturition. The third suggests that the mature fetus is the source of the initial signal or parturition commencement. Current research supports a model that draws from all three themes. However, labor onset clearly represents the culmination of a series of biochemical changes in the uterus and cervix. hese result from endocrine and paracrine signals emanating from both mother and fetus. Their relative contributions vary between species, and it is these diferences that complicate elucidation of the exact factors that regulate human parturition. When parturition is abnormal, then preterm-labor, dystocia, or postterm pregnancy may result. Of these, preterm labor remains the major contributor to neonatal mortality and morbidity.

The myometrial layer of the uterus is composed of bundles of smooth muscle cells surrounded by connective tissue. In contrast to skeletal or cardiac muscle, the smooth muscle cell is not terminally diferentiated and therefore is readily adaptable to environmental changes. Varied stimuli such as mechanical stretch, inlammation, and endocrine and paracrine signals can modulate

Physiology of Labor 401

FIGURE 21-1 The amnion synthesizes prostaglandins, and late in pregnancy, synthesis is augmented by increased phospholipase A2 and prostaglandin H synthase, type 2 (PGHS-2) activity. During pregnancy, the transport of prostaglandins from the amnion to maternal tissues is limited by expression of the inactivating enzymes, prostaglandin dehydrogenase (PGDH), in the chorion. During labor, PGDH levels decline, and amnion-derived prostaglandins can influence membrane rupture and uterine contractility. The role of decidual activation in parturition is unclear but may involve local progesterone metabolism and higher prostaglandin receptor concentrations, thus enhancing uterine prostaglandin actions and cytokine production. (Redrawn from Smith R: Parturition. N Engl J Med. 2007 Jan 18;356(3):271-283.) the transition of the smooth muscle cell among phenotypes that provide cell growth, proliferation, secretion, and contractility.

In addition to this phenotypic plasticity, several smooth muscle qualities confer advantages for uterine contraction eiciency and fetal delivery. First, the degree of smooth muscle cell shortening with contractions may be one order of magnitude greater than that attained in striated muscle cells. Second, forces can be exerted in smooth muscle cells in multiple directions. his difers from the contraction force generated by skeletal muscle, which is always aligned with the axis of the muscle fibers. hird, smooth muscle is not organized in the same manner as skeletal muscle. In myometrium, the thick and thin ilaments are found in long, random bundles throughout the cells. his plexiform arrangement aids greater shortening and force-generating capacity. Last, greater multidirectional force generation in the uterine fundus compared with that of the lower uterine segment permits versatility in expulsive force directionality.

Lining the thick muscular uterine walls, the endometrium is transformed by pregnancy hormones and is then termed decidua. Composed of stromal cells and maternal immune cells, the decidua serves to maintain the pregnancy via unique immuno regulatory functions that suppress inlammatory signals during gestation. However, at the end of pregnancy, decidual activation ensues. With this, the decidua transitions to induce inflammatory signals and withdraw active immunosuppression, which contribute to parturition initiation.

During pregnancy, the cervix has multiple functions that include: (1) maintenance of barrier function to protect the reproductive tract from infection, (2) maintenance of cervical competence despite greater gravitational forces as the fetus grows, and (3) orchestration of extracellular matrix changes that allow progressively greater tissue compliance.

In nonpregnant women, the cervix is closed and firm, and its consistency is similar to nasal cartilage. By the end of pregnancy, the cervix is easily distensible, and its consistency is similar to the lips of the oral cavity. Observations in threedimensional sonography and magnetic resonance imaging show increases in the cross-sectional area of the cervical canal and in the cervical stroma from early to late pregnancy (House, 2009; Lang, 2010). Concurrent with expansion of the stroma, the cervical epithelia proliferate and exert a pregnancy-specific immunoprotection.

In addition to providing the exchange of nutrients and waste between mother and fetus, the placenta is a key source of steroid hormones, growth factors, and other mediators that maintain pregnancy and potentially aid the transition to parturition. The fetal membranes-amnion and chorion and adjacent decidua-make up an important tissue shell around the fetus that serves as a physiological, immunological, and metabolic shield to protect against untimely parturition initiation.

he amnion provides virtually all of the fetal membranes' tensile strength to resist membrane tearing and rupture (Chap. 5, p. 95). This avascular tissue is highly resistant to penetration by leukocytes, microorganisms, and neoplastic cells (Fig. 21-1). It also constitutes a selective filter to prevent fetal particulatebound lung and skin secretions from reaching the maternal compartment. In this manner, maternal tissues are protected from amnionic fluid constituents that could prematurely accelerate decidual or myometrial activation or could promote adverse events such as amnionic luid embolism.

The chorion is a primarily protective tissue layer and provides immunological acceptance. It is also enriched with enzymes that inactivate uterotonins, which are agents that stimulate contractions. Inactivating enzymes include prostaglandin dehydrogenase, oxytocinase, and enkephalinase (Cheung, 1990; Germain, 1994).

In many species, the role of sex steroid hormones is clear-estrogen promotes and progesterone inhibits the events leading to parturition. nd, the removal of progesterone, that is, progesterone withdrawa, directly precedes progression of parturition. In addition, providing progesterone to some species will delay parturition via a decline in myometrial activity and continued cervical competency (Challis, 1994). In humans, however, it seems most likely that both estrogen and progesterone are components of a broader molecular system that maintains uterine quiescence.

Plasma levels of estrogen and progesterone in normal pregnancy are enormous and in great excess of the ainity constants for their receptors. For this reason, it is diicult to comprehend how relatively subtle changes in the ratio of their concentrations could modulate physiological processes during pregnancy. The teleological evidence, however, for an increased progesteroneto-estrogen ratio in the maintenance of pregnancy and a decline in this ratio for parturition is overwhelming. In all species studied, including humans, administration of the progesteronereceptor antagonists miepristone (RU-48) or onapristone will promote some or all key features of parturition. These include cervical ripening, greater cervical distensibility, and augmented uterine sensitivity to uterotonins (Bygdeman, 1994; Chwalisz, 1994b; Wolf, 1993).

The exact role of estrogen in regulation of human uterine quiescence and cervical competency is less well understood. hat said, estrogen can advance progesterone responsiveness and, in doing so, promote uterine quiescence. At the end of pregnancy, estrogen aids processes that mediate uterine activation and cervical ripening.

Both progesterone and estrogen bind to nuclear receptors that regulate gene transcription in a cell-and context-speciic pattern. Two nuclear receptors for estrogen are estrogen receptor a (ERa) and estrogen receptor 3 (ER3). Nuclear receptor isoforms of the progesterone receptor (PR-A and PR-B) are encoded by difering transcripts from a single gene (Patel, 2015).

Prostaglandins are lipid molecules with varied hormone-like actions. In parturition, they playia prominent role in myometrial contractility, relaxation, and inlammation. Prostaglandins interact with a family of eight diferent G-protein-coupled receptors (p. 406), several of which are expressed in myometrium and cervix (Konopka, 2015; Myatt, 2004).

The major synthetic pathways involved in prostaglandin biosynthesis are shown in Figure 21-2. Prostaglandins are produced using plasma membrane-derived arachidonic acid, which usually is released by the action of phospholipase A2 or C. Arachidonic acid can then act as substrate for both type 1 and 2 prostaglandin H synthase (PGHS-l and -2), which are also called cyclooxygenase-l and -2 (COX-l and -2). Both PGHS isoforms convert arachidonic acid to the unstable prostaglandin G2 and then to prostaglandin H2. hese enzymes are the target of many nonsteroidal antiinlammatory drugs (NSAIDs). Indeed, the tocolytic actions of speciic NSAIDs, as discussed in Chapter 42 (p. 826), were considered promising until they were shown to have adverse fetal efects (Loudon, 2003; Olson, 2003, 2007).

Through prostaglandin isomerases, prostaglandin H2 is converted to active prostaglandins. These include prostaglandins E2 (PGEJ, F2x (PGF2x), and 12 (PGI2). Isomerase expression is tissue-speciic and thereby controls the relative production of various prostaglandins. Another important control point for prostaglandin activity is its metabolism, which most often is

Phospholipase C with through the action of 15-hydroxyprostaglandin dehydrogenase (PGDH). Expression of this enzyme is up regulated during pregnancy in the uterus and cervix, which provides the important ability to rapidly inactivate prostaglandins (Giannoulias, 2002; Kishore, 2014). Thus, myometrial responses to prostaglandins stem from a balance between prostaglandin synthesis versus metabolism, from the relative expression of various prostaglandin receptors, or from a switch in receptor-signaling pathways (Kandola, 2014; Lyall, 2002; Olson, 2007; Smith, 2001). It is entirely possible that prostanoids contribute to myometrial relaxation at one stage of pregnancy and to myometrial contractions after parturition initiation (Myatt, 2004).

In addition to the myometrium, the amnion synthesizes several bioactive pep tides and prostaglandins that cause myometrial relaxation or contraction (see Fig. 21-1). Late in pregnancy, amnionic prostaglandin biosynthesis is increased, and phospholipase A2 and PGHS-2 show greater activity Oohnson, 2002). Accordingly, many hypothesize that prostaglandins regulate events leading to parturition. The amnion is likely the major source for amnionic fluid prostaglandins, and their role in the activation of cascades that promote membrane rupture is clear. he influence of amnion-derived prostaglandins on uterine quiescence and activation, however, is less delineated. his is because prostaglandin transport from the amnion through the chorion to access maternal tissues is limited by expression of PGDH.

Physiology of Labor 403

Importantly, the phases of parturition should not be confused with the clinical stages of labor, that is, the first, second, and third stages-which make up phase 3 of parturition (Fig. 2i1-4).

arturitionContractile 1unresponsiveness, Uterine of labor cervical softening Phase 3 Stimulation Processes Uterine Phase4 Involution Parturient Uterine preparedness contraction, involution, for labo, cervical dilation, cervical repai, tion, a remarkably efective period of expUlsion (three myometrial quiescence is imposed. This stages of labor)

Initiation of maintenance of cervical structural integ parturition Onset of labor

FIGURE 21-3 The phases of parturition.

PHASE 1: UTERINE QUIESCENCE AND CERVICAL SOFTENING

As shown in Figure 21-3, parturition can be arbitrarily divided into four overlapping phases that correspond to the major physiological transitions of the myometrium and cervix during pregnancy (Casey, 1993, 1997; Challis, 2000; Word, 2007). These phases of parturition include: (1) a prelude to it, (2) the preparation for it, (3) the process itself, and (4) recovery.

Stages of Labor : Phase of of pregnancy and is characterized by

Delivery of uterine smooth muscle tranquility with rity (Fig. 21-5). All manner of molecular systems-neural, endocrine, paracrine, and autocrine-are likely called to implement and coordinate a state of relative uterine unresponsiveness. Moreover, a complementary "fail-safe" system that protects the uterus against agents that could perturb the tranquility of phase 1 also must be in place.

During phase 1, the myometrial cells undergo a phenotypic modification to a noncontractile state, and uterine muscle is rendered unresponsive to natural stimuli. Concurrently, the uterus must initiate extensive changes in its size and vascularity to accommodate fetal growth and prepare for uterine :-6

FIGURE 21-4 Composite of the average dilation curve for labor in nulliparous women. The curve is based on analysis of data derived from a large, nearly consecutive series of women. The first stage is divided into a relatively flat latent phase and a rapidly progressive active phase. In the active phase, there are three identifiable parts: an acceleration phase, a linear phase of maximum slope, and a deceleration phase. (Redrawm from Friedman EA: Labor: Clinical Evaluation and Management, 2nd ed. New York, Appleton-Century-Crofts, 1978.) contractions. he myometrial unre sponsiveness of phase 1 continues until near the end of pregnancy. That said, tractions are felt during the quiescent phase, but they do not normally cause cervical dilation. hese contractions are common toward the end of preg nancy, especially in multiparas, and are referred to as Braxton Hicks contractions oralse labor (Chap. 4, p. 50).

The quiescence of phase 1 likely stems from: (1) actions of estrogen and progesterone via intracellular receptors, myometrial-cell plasma membrane receptor-mediated increases in cyclic adenosine monophosphate (cMIP), generation of cyclic guanosine monophosphate (cGMP), and (4) other systems, including modiication of myometrial-cell ion channels.

The balance between myometrial relaxation and contraction is controlled by steroid-and peptide-hormone transcriptional regulation of key genes and their protein products. Quiescence is achieved in part by: (1) diminished intracellular crosstalk and reduced intracellular Ca2+ ([Ca2+J levels; (2) ionchannel regulation of cell membrane • Myometrium is major site of action • Cervix is major site • Both are sites of action

Phase 1 Phase 2 Phase 3 Uterine stretch Gap junction receptors Fetal signals (SPA, PAF, CRH) Fetal membrane Prostaglandins Cortisol? Phase 4

FIGURE 21-5 The key factors thought to regulate the phases of human parturition. CRH = corticotropin-releasing hormone; hCG i.):D o:sD)

CRH?

potential; (3) activation of the uterine endoplasmic reticulum stress-unfolded protein response; and (4) uterotonin degradation. In contrast, contractility results from: (1) enhanced interactions between the actin and myosin proteins; (2) heightened excitability of individual myometrial cells; and (3) promotion of intracellular crosstalk that allows synchronous contractions to develop.

Actin and myosin proteins are essential to muscle contraction. For this, actin must be converted from a globular to a ilamentous form. Indeed, a potential mechanism for maintenance of relaxation is the promotion ofactin into a globular form rather than into ibrils, which are required for contraction (Fig. 21-6). Moreover, actin must be attached to the cytoskeleton at focal points in the cell membrane to allow tension to develop.

Actin must partner with myosin, which is composed of multiple light and heavy chains. The coupling of myosin and actin activates adenosine triphosphatase (ATPase), hydrolyzes adenosine triphosphate, and generates force. This interaction is brought about by enzymatic phosphorylation of the 20-kDa light chain of myosin (Stull, 1998). his is catalyzed by the enzyme myosin light-chain kinase, which is activated by calcium. Calcium binds to calmodulin, a calcium-binding regulatory protein, which in turn binds to and activates myosin lightchain kinase.

hus, logically, uterine relaxation ordinarily is promoted by conditions that lower concentrations of (Ca2+)i. In contrast, prostaglandin dehydrogenase; SPA surfactant protein A.

agents that prompt contraction act on myometrial cells to augment (Ca2+)i levels. Or, they allow an inlux of extracellular calcium through ligand-or voltage-regulated calcium channels (see Fig. 21-6). Voltage-gated ion channels open, additional calcium ions move into the cell, and cellular depolarization follows. For example, prostaglandin F2ex and oxytocin bind their respective receptors during labor to open ligand-activated calcium channels. Activation of these receptors also releases calcium from the sarcoplasmic reticulum to lower electronegativity within the cell. Additionally, greater localization of nonselective cation channels on the cell membrane promotes Ca2+ entry (Ying, 2015). The rise in (Ca2+)i levels is often transient. But, contractions can be prolonged by inhibition of myosin phosphatase, an enzyme which dephosphorylates myosin (Woodcock, 2004).

Regulation of Membrane Potentials

As just noted, myocyte excitability is regulated in part by changes in the electrochemical potential gradient across the plasma membrane. Before labor, myocytes maintain a relatively high interior electronegativity. Maintenance of a hyperpolarized membrane potential attenuates smooth muscle cell excitation and is regulated by ion channels.

Consistent with the importance of myometrial quiescence, numerous potassium channels control membrane potential. One key regulator is the large-conductance voltage-and Ca2+activated K channel (BKeJ (Perez, 1993). In normal physiology, the myometrial BKca channel plays dual and opposing

CRH, �2-sympathomimetics, 8 Oxytocin, thrombin,

Physiology of Labor 405

FIGURE 21 -6 Uterine myocyte relaxation and contraction. A. Uterine relaxation is maintained by factors that increase myocyte cyclic adenosine monophosphate (cAMP) levels. This activates protein kinase A (PKA) to promote phosphodiesterase activity with dephosphorylation of myosin light-chain kinase (MLCK). Other processes serve to maintain actin in a globular form and thus to prevent the fibril formation necessary for contractions. B. Uterine contractions result from reversal of these sequences. Actin now assumes a fibrillar form, and calcium enters the cell to combine with calmodulin to form complexes. These complexes activate MLCK to bring about phosphorylation of the myosin light chains. This generates ATPase activityto cause sliding of myosin over the actin fibrils, which is a uterine contraction. AC = + calcium; DAG = diacylglycerol; Gs and GQ = G-receptor proteins; IP3 = inositol triphosphate; LC20 = light chain 20; PIP3 = phosphatidylinositol 3,4,5-triphosphate;PLC = phospholipase C; R-PKA inactive protein kinase. (Redrawn from Smith R: Parturition. N Engl J Med. 2007 Jan 18;356(3):271-283.) roles to maintain a balance between uterine quiescence and contractility. The Bca channel is abundantly expressed in the myometrium. For most of pregnancy, opening the BKca channel allows potassium to leave the cell to maintain interior electronegativity, thus preventing voltage-gated Ca2+ inlux and contraction. Enhancing Bca channel opening results in myometrial relaxation, whereas inhibition ofthe Bca channel augments myometrial contractility. he ability of Bca channel to regulate calcium dynamics and ultimately uterine contractility from early to late gestation may result from temporal changes in expression ofthe Bca channel and/or Bca interacting partners (Wakle-Prabagaran, 2016).

Cellular signals that control myometrial contraction and relaxation can be efectively transferred between cells through intercellular junctional channels. Communication is established between myocytes by gap junctions, which aid the passage of electrical or ionic coupling currents as well as metabolite coupling. The transmembrane channels that make up the gap junctions consist of two protein "hemi-channels" (Saez, 2005). These connexons are each composed of six connexin subunit proteins (Fig. 21-7). Of these, connexin-43 is expressed in myometrium, and concentrations rise near labor onset. Pairs of connexons establish a conduit between coupled cells for the exchange of small molecules that can be nutrients, waste, metabolites, second messengers, or ions. Optimal numbers and types ofgap junctions are believed to be important for electrical myometrial synchrony.

Progesterone maintains uterine quiescence in part by mechanisms that lower expression of various key proteins needed for contractility. hese contraction-associated proteins (CAPs) include the oxytocin receptor, prostaglandin F receptor, and connexin-43. At the end of pregnancy, increased stretch along with greater estrogen dominance raises CAP levels. Integration ofdiverse regulatory pathways culminates in released inhibition ofconnexin-43 and oxytocin receptor levels to promote greater uterine contractility (Nadeem, 2016; Renthal, 2010; Williams, 2012b).

As another potential mechanism, progesterone maintains uterine quiescence through support of myometrial caspase 3, which is an anticontractile agent Qeyasuria, 2009). his protein degrades both actin and the speciic gap junction protein, connexin-43 (Kyathanahalli, 2015).

called connexins. Six connexins form a hemichannel (connexon), nel. Connexons and gap junction channels can be formed from one or more connexin proteins. The composition of the gap junc tion channel is important for these channels' selectivity with regard to passage of molecules and communication between cells.

In mice, myometrial caspase 3 activation is regulated by a pregnancy-induced endoplasmic reticulum stress response (ERSR). As background, the endoplasmic reticulum aids protein folding and transport. Functional irregularities cause misfolded proteins to accumulate and trigger the ERSR. he ERSR and its unolded-protein response (UPR) are cellular mechanisms that work to maintain homeostasis in the face of stimuli, such as stretch and inlammation. Prolonged ERSR promotes caspase 3 activation to preserve quiescence despite these stimuli.

Various cell surface receptors directly regulate myocyte contractility. Discussions thus far have described ion channel-linked receptors that regulate intracellular Ca2+ and membrane potential. In addition, numerous G-protein-coupled receptors appear to be modified during the phases of parturition. Several of these are present in myometrium and associated with Gos-mediated activation of adenylyl cyclase to yield higher cAMP levels. These receptors together with appropriate ligands may act with sex steroid hormones to maintain uterine quiescence (Price, 2000; Sanborn, 1998). Examples are the LH receptor and corticotropin-releasing hormone receptor 1 (CRHR1), both described in this section (Fig. 21-8). Other G-protein-coupled myometrial receptors, instead, are associated with G-protein-mediated activation of phospholipase C, which remember releases arachidonic acid. Ligands for the G-protein-coupled receptors include numerous neuropeptides, hormones, and autacoids. Many of these are available to the myometrium during pregnancy in high concentration via endocrine or autocrine mechanisms.

3-Adrenoreceptors are prototypical examples of cAMP signaling causing myometrium relaxation. 3-Adrenergic receptors mediate Gs-stimulated increases in adenylyl cyclase, elevated

FIGURE 21-8 G-protein-coupled receptor signal transduction pathways. A. Receptors coupled to heterotrimeric guanosine-triphosphate (GTP)-binding proteins (G proteins) are integral transmembrane proteins tl13t transduce extracellular signals to the cell interior. G-protein-coupled receptors exhibit a common structural motif consisting of seven membrane-spanning regions. B. Receptor occupation promotes interaction between the receptor and the G protein on the interior surface of the membrane. This induces an exchange of guanosine diphosphate (GOP) for GTP on the G protein Q subunit and dissociation of the Q subunit from the 31 heterodimer. Depending on its isoform, the GTP-Q subunit complex mediates intracellular signaling either indirectly by acting on effector molecules such as adenylyl cyclase (AC) or phospholipase C (PLC), or directly by regulating ion channel or kinase function. cAMP cyclic adenosine monophosphate; DAG diacylglycerol; IP3 inositol triphosphate.

levels of cAMP, and myometrial cell relaxation. The rate-lim iting factor is likely the number of receptors expressed and the level of adenylyl cyclase expression. Agents binding to these receptors have been used for tocolysis of preterm labor and include ritodrine and terbutaline (Chap. 42, p. 826).

LH and hCG hormones share the same receptor, and this smooth muscle and blood vessels (Ziecik, 1992). Levels of myometrial LH-hCG receptors during pregnancy are greater before than during labor. Chorionic gonadotropin acts to acti vate adenylyl cyclase by way of a plasma membrane receptor

G's-linked system. This lessens contraction frequency and force and lowers the number of tissue-speciic myometrial cell gap junctions (Ambrus, 1994; Eta, 1994). hus, high circulating levels of hCG may be one mechanism of uterine quiescence.

In the mouse, variations in FSH-receptor density also regulate myometrial contractile activity (Stilley, 2016).

four G-protein-coupled receptors. Speciically, prostaglandin

E receptors 1 through 4 (EP ,-EP 4) are expressed in the myo metrium during pregnancy and with labor onset (Astle, 2005;

Leonhardt, 2003). EP2 and EP4 act through G's to raise cAMP levels and maintain myometrial cell quiescence but switch to a G'q/1i1 calcium-activating pathway during labor (Kandola, 2014). EP] and EP3 receptors act through G'q and G'i to aug ment intracellular Ca2+ and contractility.

he peptide hormone relaxin binds to the G-protein-coupled receptor named reaxin amiy peptide receptor 1 (FP 1). Binding activates adenylyl cyclase in uterine smooth muscle cells. Adenylyl cyclase in turn prevents increased intracellular Ca2+ and thus promotes uterine quiescence (Downing, 1993; Meera, 1995). There are two separate human relaxin genes, designated HI and H2. Of these, HI is primarily expressed in the decidua, trophoblast, and prostate, whereas H2 is primarily expressed in the corpus luteum. Relaxin in plasma of pregnant women is believed to originate exclusively from corpus luteum secretion. Plasma levels peak at approximately 1 ng/mL between 8 and 12 weeks' gestation. Thereater, they decline to lower levels that persist until term.

Corticotropin-releasing hormone (CRH) is synthesized in the placenta and hypothalamus. Discussed on page 410, CRH plasma levels rise dramatically during the inal 6 to 8 weeks of normal pregnancy and are implicated in mechanisms that control the timing of human parturition (Smith, 2007; Wadhwa, 1998). CRH appears to promote myometrial quiescence during most of pregnancy but then aids myometrial contractions with parturition onset. Studies suggest that these opposing actions are achieved by diferential actions of CRH via its receptor CRHR1. In nonlaboring myometrium at term, the interaction of CRH with its CRHR1 receptor activates the Gs-adenylate cyclasecAMP signaling pathway. his results in inhibition of inositol triphosphate (IP3) and stabilization of (Ca2+)j levels (You, 2012). However, in term laboring myometrium, (Ca2+)j concentrations are augmented by CRH activation of G proteins Gq and Gi and prompts stimulation ofIP3 production and greater contractility.

As just described, cAvIP is an important mediator of myometrial relaxation. However, activation of guanylyl cyclase raises

Physiology of Labor 407 intracellular cyclic guanosine monophosphate (cGMP) levels. This also promotes smooth muscle relaxation (Word, 1993). Intracellular cGMP levels are increased in the pregnant myometrium and can be stimulated by atrial natriuretic peptide (ANP) , brain natriuretic peptide (BNP) receptors, and nitric oxide (Telfer, 2001). All of these factors and their receptors are expressed in the pregnant uterus.

In addition to pregnancy-induced compounds that promote myometrial cell refractoriness, the activity of enzymes that degrade or inactivate endogenously produced uterotonins are strikingly increased in phase 1. Some of these degrading enzymes and their respective targets include PGDH and prostaglandins; enkephalinase and endothelins; oxytocinase and oxytocin; diamine oxidase and histamine; catechol O-methyltransferase and catecholamines; angiotensinases and angiotensin-II; and platelet-activating factor (P AF) and P AF acetylhydrolase. Levels of several of these enzymes decrease late in gestation (Germain, 1994).

To ensure uterine quiescence, the synthesis in the decidua of prostaglandins, in particular PGF2', is markedly suppressed.

Suppression of prostaglandin production here persists through out most of pregnancy, and suppression withdrawal is a prereq uisite for parturition (Norwitz, 2015).

Phase 1 of parturition also promotes an environment of immune tolerance to protect the fetus. Namely, decidual stromal cells proactively ensure that fetal antigens do not elicit a maternal immune response. his stems from a reduced capacity to attract T cells. This limited ability derives in part from epigenetic silencing of T cell-attracting inlammatory chemokine genes (Erlebacher, 2013; Nancy, 2012; PrabhuDas, 2015).

The initial stage of cervical remodeling-termed soteningbegins in phase 1 of parturition. It is characterized by greater tissue compliance, yet the cervix remains irm and unyielding. Hegar (1895) irst described palpable softening of the lower uterine segment at 4 to 6 weeks' gestation, and this sign was once used to diagnose pregnancy. Clinically, the maintenance of cervical anatomical and structural integrity is essential for pregnancy to continue to term. Preterm cervical dilation, structural insuiciency, or both may forecast delivery.

Cervical softening results from increased vascularity, cellular hypertrophy and hyperplasia, and slow, progressive compositional and structural changes in the extracellular matrix (Mahendroo, 2012; Myers, 2015; Word, 2007). Key to matrix changes, collagen, which is the main structural protein in the cervix, undergoes conformational changes that alter tissue stifness and flexibility (Zhang, 2012). Speciically, collagen processing and the number or type of stable covalent cross-links between collagen triple helices is altered. Mature cross-links between newly synthesized collagen monomers are reduced due to diminished expression and activity of the cross-link-forming enzymes beginning in early pregnancy (Akins, 2011; Drewes, 2007; Yoshida, 2014). hese enzymes are lysyl hydroxylase and lysyl oxidase. Together, these early pregnancy changes contribute to greater tissue compliance.

Clinical evidence for the importance of matrix changes to cervical sotening is supported by in vivo mechanical evaluation of the cervix (Badir, 2013; Parra-Saavedra, 2011). he prevalence of cervical insuiciency is also higher in those with inherited defects in the synthesis or assembly of collagen or elastic ibers (Anum, 2009; Hermanns-Le, 2005; Rahman, 2003; Wang, 2006). Examples are Ehlers-Danlos and Marfan syndromes, discussed in Chapter 59 (p. 1151). Concurrent with matrix remodeling in the sotening period, genes involved in cervical dilation and parturition are actively repressed (Hari Kishore, 2012).

PHASE 2: PREPARATION FOR LABOR

To prepare for labor, the myometrial tranquility of phase 1 of parturition must be suspended-so-called uterine awakening or activation. This phase 2 of parturition is a progression of uterine changes during the last few weeks of pregnancy. Importantly, shifting events associated with phase 2 can cause either preterm or delayed labor.

Key factors in uterine activation are depicted in Figure 21-5. In species that exhibit progesterone withdrawal, parturition progression to labor can be blocked by administering progesterone to the mother. Whether progesterone administration in the absence of classic progesterone withdrawal in pregnant women can delay the timely onset of parturition or prevent preterm labor continues to be investigated. he possibility that progesterone-containing injections or vaginal suppositories may prevent preterm labor has been studied in several randomized trials conducted during the past 15 years. hese are discussed in Chapter 42 (p. 816), and their use in preventing recurrent preterm birth continues to be debated (Norman, 2016).

Classic progesterone withdrawal resulting from decreased secretion does not occur in human parturition. However, a mechanism for progesterone inactivation, whereby the myometrium and cervix become refractory to progesterone's inhibitory actions, is supported by studies using progesterone-receptor antagonists. Mifepristone is a classic steroid antagonist, acting at the level of the progesterone receptor. Although less efective in inducing abortion or labor in women later in pregnancy, mifepristone appears to have some efect on cervical ripening and on increasing myometrial sensitivity to uterotonins (Berkane, 2005; Chwalisz, 1994a).

The diverse mechanisms by which functional progesterone withdrawal or antagonism is achieved is an active area of research. These include: (1) changes in the relative expression of the nuclear progesterone-receptor isoforms, PR-A, PR-B, and PR-C; (2) diferential interaction of PR-A and PB-B with enhancers and inhibitors of gene expression; (3) alterations in PR activity through changes in the expression of coactivators or corepressors that directly influence receptor function; (4) local inactivation of progesterone by steroid-metabolizing enzymes or synthesis of a natural antagonist; and (5) microRNA regulation of progesterone-metabolizing enzymes and transcription factors that modulate uterine quiescence (Condon, 2003; Mahendroo, 1999; Mesiano, 2002; Nadeem, 2016; Renthal, 2010; Williams, 2012a). Taken together, these observations support the concept that multiple pathways exist for a functional progesterone withdrawal.

Phase 2 myometrial changes prepare it for labor contractions. his results from a shit in the expression of key proteins that control uterine quiescence to an expression of contraction-associated proteins, described earlier (p. 405) (Renthal, 2015). Of these CAPs, myometrial oxytocin receptors and gap junction proteins, such as connexin-43, markedly rise in number. These CAPs increase uterine irritability and responsiveness to uterotonins.

Another critical change in phase 2 is formation of the lower uterine segment from the isthmus. With this development, the fetal head often descends to or even through the pelvic inletso-called lightening. he abdomen commonly undergoes a shape change, sometimes described by women as "the baby dropped." It is also likely that the lower segment myometrium is unique from that in the upper uterine segment, resulting in distinct roles for each near term and during labor. This is supported by human studies that demonstrate diferential expression of prostaglandin receptors and CAPs within the upper-and lower-segment myometrial regions (Astle, 2005; Blanks, 2003; Sparey, 1999). Near term, elevated expression of the HoA13 gene in the lower myometrial segment compared with the upper segment also induces CAP expression and regionalized contractility of the lower segment (Li, 2016).

Because of its long-standing application for labor induction, it seemed logical that oxytocin must playia central role in spontaneous human labor. Myometrial oxytocin receptor levels do rise during phase 2 of parturition, and the level of oxytocin receptor mRNA in human myometrium at term is greater than that found in preterm myometrium (Wathes, 1999). However, it is unclear whether oxytocin plays a role in the early phases of uterine activation or whether its sole function is in the expulsive phase of labor. Most studies of regulation of myometrial oxytocin receptor synthesis have been performed in rodents. Disruption of the oxytocin receptor gene in the mouse does not afect parturition. This suggests that, at least in this species, multiple systems likely ensure that parturition occurs.

Progesterone and estradiol appear to be the primary regulators of oxytocin receptor expression. Estradiol treatment in vivo or in myometrial explants raises myometrial oxytocin receptor concentrations. This action, however, is prevented by simultaneous treatment with progesterone (Fuchs, 1983). Progesterone also may act within the myometrial cell to enhance oxytocin receptor degradation and inhibit oxytocin activation of its receptor at the cell surface (Bogacki, 2002). hese data indicate that one of the mechanisms whereby progesterone maintains uterine quiescence is through inhibition of a myometrial oxytocin response.

Physiology of Labor 409

Before contractions begin, the cervix must undergo extensive remodeling. his eventually leads to the cervix yielding and dilating from forceful uterine contractions. Cervical modiications during phase 2 principally involve connective tissue changes-termed cervical ripening. The transition from the softening to the ripening phase begins weeks or days before labor. During this transformation, the cervical matrix changes its total amounts of gycosaminogycans, which are large linear polysaccharides, and proteogycans, which are proteins bound to these glycosaminoglycans.

Many of the processes that aid cervical remodeling are controlled by the same hormones regulating uterine function. That said, the molecular events of each are varied because of diferences in cellular composition and physiological requirements. For example, the hormone relaxin regulates myometrial quiescence. It also regulates cervical ripening, but through cell proliferation and modulation of extracellular matrix components (Park, 2005; Soh, 2012). The uterine corpus is predominantly smooth muscle. In contrast, the cervix has a high ratio of ibroblasts to smooth muscle cells, and extracellular matrix contributes significantly to overall tissue mass. Recent studies in the nonpregnant human cervix report a spatial gradient of smooth muscle cells. Specifically, smooth muscle cells make up approximately 50 percent of stromal cells at the internal os but only 10 percent at the external os (Vink, 2016).

Collagen. The cervix is an extracellular-matrix-rich tissue. Constituents of the matrix include type I, III, and IV collagen, matricellular proteins, glycosaminoglycans, proteoglycans, and elastic ibers. Of these, collagen is largely responsible for the structural disposition of the cervix. During collagen assembly, multiple collagen triple-helical molecules are cross-linked to one another by the actions of lysyl oxidase to form ibrils. In addition, ibril size, packing, and organization determine the strength and mechanical properties of the cervix. These properties are regulated in part by collagen-binding proteoglycans such as decorin or biglycan, as well as matricellular proteins such as thrombospondin 2 (Fig. 21-9).

Higher turnover of collagen during pregnancy likely allows the gradual replacement of mature cross-linked collagen ibrils with poorly cross-linked ibrils, which yield greater collagen disorganization. his increased turnover, rather than loss of collagen to achieve cervical remodeling, is supported by mouse and human studies that document no changes in collagen content between nonpregnant states and term pregnancy (Akins, 201i1; Myers, 2008; Read, 2007; Yoshida, 2014). In further support, polymorphisms or mutations in genes required for collagen assembly are associated with an elevated incidence of cervical insuiciency (Anum, 2009; Rahman, 2003; Warren, 2007).

Glycosaminoglycans and Proteoglycans. Hyaluronan is a high-molecular-weight polysaccharide that functions alone, whereas most other glycosaminoglycans (GAGs) complex with proteins to form proteoglycans. Hyaluronan is a hydrophilic, space-illing molecule, and thus greater hyaluronan production during cervical ripening is thought to increase viscoelasticity, hydration, and matrix disorganization. Hyaluronan synthesis is carried out by hyaluronan synthase isoenzymes, and expression of these enzymes is elevated in the cervix during ripening (kgul, 2012; Straach, 2005).

Although not well deined, changes in proteoglycan composition are also suggested to accompany cervical ripening. At least three small leucinerich proteoglycans are expressed in the cervix-decorin, biglycan, and ibromodulin (Westergren-Thorsson, 1998). In other connective tissues, decorin interacts with collagen to regulate the packing, order, and strength of collagen fibrils (see Fig. 21-9) (Ameye, 2002). In addition to the cervix, these proteoglycans are expressed in the fetal membranes and uterus.

Inflammatory Changes. In phase 2, resident immune cells are localized to the cervical stroma, although a functional role for these cells in this phase of remodeling has been challenged. Microarray studies comparing gene to allow a gradual increase in mechanical compliance of the cervix, A collagen fiber is made up of many fibrils, Fibril size and packing are regulated in part by small proteoglycans such as ,,obefore and after cervical ripening decorln and by the denSity of collagen cross-links, In phase 1, fibril size is uniform and fibrils are veil organizedoalthough a decline in cross-link density aids softening, During cervical ripening show little rise in proinflammatory ,: ,o,

In phase 2, fibril size IS less uniform, and spacing between collagen fibrils and fibers is greater gene expression. In contrast, proinand disorganized, flammatory and immunosuppressive gene expression in the cervix after delivery increases markedly compared with that during cervical ripening (Bollapragada, 2009; Hassan, 2006, 2009). Further, detailed studies in mice provide evidence that leukocyte migration but not activation takes place before labor. Once labor is underway, activation of neutrophils, pro inflammatory M 1 macrophages, and tissue repair M2 macrophages in the cervix is augmented. This suggests a role for inlammatory cells in postpartum cervical remodeling and repair (Mahendroo, 2012).

Induction of Cervical Ripening

No therapies prevent premature cervical ripening. In contrast, treatment to promote cervical ripening for labor induction includes direct application of prostaglandins PGE2 and PGF2'. Prostaglandins likely modiy extracellular matrix structure to aid ripening. Although the role of prostaglandins in the normal physiology of cervical ripening remains unclear, this property is useful clinically to assist labor induction (Chap. 26, p. 505).

In some nonhuman species, the cascades of events that allow cervical ripening are induced by dropping serum progesterone concentrations. And in humans, administration of progesterone antagonists causes cervical ripening.

In addition to matrix changes, during pregnancy, endocervical epithelial cells proliferate such that endocervical glands account for a signiicant percentage of cervical mass. he endocervical canal is lined with mucus-secreting columnar and stratified squamous epithelia. These cells form both a mucosal barrier and a tight junctional barrier that protect against microbial invasion (Akgul, 2014; Blaskewicz, 2011; Timmons, 2007). The mucosal epithelium recognizes and deters pathogen invasion via expression of toll-like receptors that identiy pathogens and via antimicrobial pep tides and protease inhibitors. In addition, these epithelia express signals to underlying immune cells when a pathogenic challenge exceeds their protective capacity (Wira, 2005).

• Fetal Contributions to Parturition

It is intriguing to envision that the mature human fetus provides the signal to initiate parturition, and evidence for fetal signaling is mounting (Mendelson, 2017). The fetus may give signals through blood-borne agents that act on the placenta or through secretion into the amnionic luid.

Fetal growth is an important component in uterine activation in phase 2 of parturition. With uterine activation, stretch is required for induction of specific CAPs. Namely, stretch increases expression of connexin-43 and oxytocin receptors. Levels of gastrin-releasing peptide, a stimulatory agonist for smooth muscle, are also augmented by stretch in the myometrium (Tattersall, 2012).

Clinical clues for a role of stretch come from the observa preterm labor than singleton ones. And, preterm labor is also signiicantly more common in pregnancies complicated by hydramnios. Although the mechanisms causing preterm birth in these two examples are debated, a role for uterine stretch must be considered.

Cell signaling systems that are inluenced by stretch to regulate the myometrial cell continue to be defined. his processmechanotransduction-may include activation of cell-surface receptors or ion channels, transmission of signals through extracellular matrix, or release of autocrine molecules that act directly on myometrium (Shynlova, 2007; Young, 2011).

The ability of the fetus to provide endocrine signals that initiate parturition has been demonstrated in several species. However, evidence suggests that it is not regulated in the same manner in humans. hat said, the human fetal hypothalamic-pituitaryadrenal-placental axis is considered a critical component of normal parturition. Moreover, premature activation of this axis is considered to prompt many cases of pre term labor (Challis, 2000, 2001). As in the sheep, steroid products of the human fetal adrenal gland are believed to have efects on the placenta and membranes that eventually transform the myometrium from a quiescent to a contractile state. A key component in the human may be the unique ability of the placenta to produce large amounts ofCRH 21-10).

A CRH hormone that is identical to maternal and fetal hypothalamic CRH is synthesized by the placenta in relatively large amounts (Grino, 1987; Saijonmaa, 1988). However, unlike hypothalamic CRH, which is under glucocorticoid negative feedback, cortisol instead stimulates placental CRH production. This ability makes it possible to create a feed-forward endocrine cascade that does not end until delivery.

Maternal plasma CRH levels are low in the first trimester and rise from midgestation to term. In the last 12 weeks, CRH plasma levels rise exponentially, peak during labor, and then fall precipitously after delivery (Frim, 1988; Sasaki, 1987). Amnionic luid CRH concentrations similarly increase in late gestation. CRH is the only trophic hormone-releasing

FIGURE 21-10 The placental-fetal adrenal endocrine cascade.

In late gestation, placental corticotropin-releasing hormone (CRH) stimulates fetal adrenal production of dehydroepiandrosterone sul fate (DHEA-S) and cortisol. The latter stimulates production of placental CRH, which leads to a feed-forward cascade that enhances adrenal steroid hormone production. ACTH = adrenocorticotropic hormone.

factor to have a speciic serum binding protein. During most of pregnancy, CRH-binding protein (CRH-BP) binds most maternal circulating CRH, and this inactivates it (Lowry, 1993). During later pregnancy, however, CRH-BP levels in both maternal plasma and amnionic luid decline, leading to markedly greater levels of bioavailable CRH (Perkins, 1995;

Petraglia, 1997).

In pregnancies in which the fetus can be considered "stressed" from various complications, concentrations of CRH in fetal plasma, amnionic luid, and maternal plasma are greater than those seen in normal gestation (Berkowitz, 1996; McGrath, 2002). he placenta is the likely source of this elevated CRH concentration. For example, placental CRH content is four fold higher in placentas from women with preeclampsia than in those from normal pregnancies (Perkins, 1995).

Placental CRH is thought to play several roles in parturition regulation. It may enhance fetal cortisol production to provide positive feedback so that the placenta produces more CRH. Late in pregnancy-phase 2 or 3 of parturition-modiication in the CRH receptor favors a switch from cAMP formation to increased myometrial cell calcium levels via protein kinase C activation (You, 2012). Oxytocin acts to attenuate CRHstimulated accumulation of cAMP in myometrial tissue. CRH acts to augment myometrial contractile force in response to PGF2: (Benedetto, 1994). Finally, CRH stimulates fetal adrenal Cwsteroid synthesis, thereby increasing substrate for placental aromatization.

Some have proposed that the rising CRH level at the end of gestation relects a etal-placental clock (McLean, 1995). CRH concentrations vary greatly among women, and the rate of rise in maternal CRH levels is a more accurate predictor of pregnancy outcome than is a single measurement (Leung, 2001; McGrath, 2002). In this regard, the placenta and fetus, through endocrinological events, inluence the timing of parturition at the end of normal gestation.

Surfactant protein A (SP-A) produced by the fetal lung is required for lung maturation. SP-A is expressed by the human amnion and decidua, is present in the amnionic luid, and prompts signaling pathways in human myometrial cells (Garcia-Verdugo, 2008; Lee, 2010; Snegovskikh, 2011). he exact mechanisms by which SP-A activates myometrial contractility in women, however, remain to be clarified. One mode may be its efects on prostaglandins. Namely, SP-A selectively inhibits prostaglandin F2: in the term decidua, but SP-A levels drop in the amnionic luid at term (Chaiworapongsa, 2008). In addition to SP-A, the fetal lung makes the uterotonic agent platelet-activating factor (Frenkel, 1996; T oyoshima, 1995). This factor and SP-A playia role in fetal-maternal signaling for parturition (Gao, 2015).

Toward the end of pregnancy, fetal membranes undergo physiological aging termed cellular senescence (Menon, 2016). In human fetal membranes and animal models, stretch and oxidative stress induce senescent fetal membrane to manifest a form of sterile inflammation termed senescent-associated secretory

Physiology of Labor 41s1 phenotype (SASP). This in turn propagates inlammatory signals that further weaken the fetal membrane and activate signals in the decidua and myometrium to initiate parturition. hus, as the functional necessity of fetal membranes declines at term, they are able to promote signals that contribute to parturition initiation.

Some evidence shows that pregnancies with markedly diminished estrogen production may be associated with prolonged gestation. These "natural experiments" include women with inherited placental sulfatase deiciency and fetal anencephaly with adrenal hypoplasia. The broad range of gestational length seen with these disorders, however, calls into question the exact role of estrogen in human parturition initiation.

Other fetal abnormalities that prevent or severely reduce the entry of fetal urine or lung secretions into amnionic fluid do not prolong human pregnancy. Examples are renal agenesis and pulmonary hypoplasia, respectively. Thus, a fetal signal through the paracrine arm of the fetal-maternal communication system does not appear to be mandated for parturition initiation.

Some brain anomalies of the fetal calf, fetal lamb, and sometimes the human fetus delay the normal timing of parturition. More than a century ago, Rea (1898) observed an association between fetal anencephaly and prolonged human gestation. Malpas (1933) extended these observations and described a pregnancy with an anencephalic fetus that was prolonged to 374 days-53 weeks. He concluded that the association between anencephaly and prolonged gestation was attributable to anomalous fetal brain-pituitary-adrenal function. Indeed, the adrenal glands of the anencephalic fetus are very small and, at term, may be only 5 to 10 percent as large as those of a normal fetus. This is caused by developmental failure of the fetal zone that normally accounts for most of fetal adrenal mass and production of Cwsteroid hormones (Chap. 5, p. 104). Such pregnancies are associated with delayed labor and suggest that the fetal adrenal glands are important for the timely onset of parturition.

PHASE 3: LABOR

This phase is synonymous with active labor, which is customarily divided into three stages. These compose the commonly used labor graph shown in Figure 21-4. he irst stage begins when spaced uterine contractions of suicient frequency, intensity, and duration are attained to bring about cervical thinning, termed facement. Several uterotonins may be important to the success of this stage of active labor (see Fig. 21-5). These have been shown to stimulate smooth muscle contraction through G-protein coupling. This labor stage ends when the cervix is fully dilated-about 10 cm-to allow passage of the term-sized fetus. The irst stage of labor, therefore, is the stage of cervical eacement and dilation. The second stage begins when cervical dilation is complete and ends with delivery. Thus, the second stage of labor is the stage of etal expulsion. Last, the third stage begins immediately after delivery of the fetus and ends with the delivery of the placenta. Thus, the third stage of labor is the stage of placental separation and expulsion.

Body Anat.eI.O. Hist.eI.O. Active segmentI II E.O. � Pathological retraction ring (Sandi) Obliterated 1.0. Active segmentIII Passive segment PREGNANT UTERUS AT TERM UTERUS IN LABOR NORMAL EARLY FIRST STAGE UTERUS IN LABOR NORMAL SECOND STAGE UTERUS IN LABOR ABNORMAL SECOND STAGE -DYSTOCIA FIGURE 21-11 Sequence ofdevelopment ofthe segments and rings in the uterus at term and in labor. Note comparison between the uterus of a nonpregnant woman, the uterus at term, and the uterus during labor. The passive lower uterine segment is derived from the isthmus, and the physiological retraction ring develops at the junction ofthe upper and lower uterine segments. The pathological retraction ring develops from the physiological ring. Anat. 1.0. = anatomical internal os; E.O. = external os; Hist. 1.0. = histological internal os;

Ph.R.R. physiological retraction ring.

• First Stage: Clinical Onset of Labor

In some women, forceful uterine contractions that efect delivery begin suddenly. In others, labor initiation is heralded by spontaneous release of a small amount of blood-tinged mucus from the vagina. his extrusion of the mucus plug that had previously illed the cervical canal during pregnancy is referred to as "show" or "bloody show." Its passage indicates that labor is already in progress or likely will ensue in hours to days.

Unique among physiological muscular contractions, those of uterine smooth muscle during labor are painful. Several possible causes have been suggested: (1) hypoxia of the contracted myometrium-such as that with angina pectoris; (2) compression of nerve ganglia in the cervix and lower uterus by contracted interlocking muscle bundles; (3) cervical stretching during dilation; and (4) stretching ofthe peritoneum overlying the fundus.

Of these, compression of nerve ganglia in the cervix and lower uterine segment by the contracting myometrium is an especially attractive hypothesis. Paracervical infiltration with local anesthetic usually produces appreciable pain relief with contractions (Chap. 25, p. 490). Uterine contractions are involuntary and, for the most part, independent of extrauterine control. Neural blockade from epidural analgesia does not diminish their frequency or intensity. In other examples, myometrial contractions in paraplegic women and in women after bilateral lumbar sympathectomy are normal but painless.

Mechanical stretching of the cervix enhances uterine activity in several species, including humans. his phenomenon is the Ferguson relex (Ferguson, 1941). Its exact mechanism is unclear, and release of oxytocin has been suggested but not proven. Manipulation of the cervix and "stripping" the fetal membranes is associated with a rise in blood levels of prostaglandin F2. metabolites.

The interval between contractions narrows gradually from approximately 10 minutes at the onset of irst-stage labor to as little as 1 minute or less in the second stage. Periods ofrelaxation between contractions, however, are essential for fetal welfare. Unremitting contractions compromise uteroplacental blood flow suiciently to cause fetal hypoxemia. In active-phase labor, the duration ofeach contraction ranges from 30 to 90 seconds and averages 1 minute. Contraction intensity varies appreciably during normal labor. Speciically, amnionic fluid pressures generated by contractions during spontaneous labor average 40 mm Hg, but vary from 20 to 60 mm Hg (Chap. 24, p. 479).

Distinct Lower and Upper Uterine Segments. During active labor, the anatomical uterine divisions that were initiated in phase 2 ofparturition become increasingly evident (Figs. 21-11 and 21-12). By abdominal palpation, even before membrane rupture, the two segments can sometimes be diferentiated. he upper segment is firm during contractions, whereas the lower segment is softer, distended, and more passive. This mechanism is imperative because if the entire myometrium, including the lower uterine segment and cervix, were to contract simultaneously and with equal intensity, the net expulsive force would markedly decline. hus, the upper segment contracts, retracts, and expels the fetus. In response to these contractions, the segment -Passive segment--0evel of internal cervical os Cervix Level of external cervical os Vagina

FIGURE 21-12 The uterus at the time ofvaginal delivery. The active upper segment retracts around the presenting part as the fetus descends through the birth canal. In the passive lower segment, there is considerably less myometrial tone.

form a greatly expanded, thinned-out tube through which the fetus can pass.

he myometrium of the upper segment does not relax to its original length after contractions. Instead, it becomes relatively fixed at a shorter length. The upper active uterine segment con tracts down on its diminishing contents, but myometrial ten sion remains constant. he net efect is to take up slack, thus maintaining the advantage gained in expulsion of the fetus.

Concurrently, the uterine musculature is kept in irm contact with the uterine contents. As the consequence of retraction, left of. hus, the upper part of the uterine cavity becomes slightly smaller with each successive contraction. Because of the successive shortening of the muscular fibers, the upper active second-stage labor (see Fig. 21-11). This process continues and immediately after delivery.

Clinically, it is important to understand that the phenomenon of upper segment retraction is contingent on a decrease in the volume of its contents. For this to happen, particularly early in labor when the entire uterus is virtually a closed sac with only minimal cervical dilation, the musculature of the lower segment must stretch. This permits a greater portion of the uterine contents to occupy the lower segment. The upper segment retracts only to the extent that the lower segment distends and the cervix dilates.

Relaxation of the lower uterine segment mirrors the same gradual progression of retraction. Recall that after each contraction of the upper segment, the muscles do not return to their previous length, but tension remains essentially the same. By comparison, in the lower segment, successive lengthening of the fibers with labor is accompanied by thinning, normally to only a few millimeters in the thinnest part. s a result of the lower segment thinning and concomitant upper segment thickening, a boundary between the two is marked by a ridge on the inner uterine surface-the physiological retraction ring. When the thinning of the lower uterine segment is extreme, as in obstructed labor, the ring is prominent and forms a pathological retraction ring. This abnormal condition is also known as the Bandl ring, which is discussed further in Chapter 23 (p. 455).

Changes in Uterine Shape. Each contraction gradually elongates the ovoid uterine shape and thereby narrows the horizontal diameter. This change in shape has important efects on the labor process. First, there is greater etal xis pressure, that is, the smaller horizontal diameter serves to straighten the fetal vertebral column. This presses the upper pole of the fetus firmly against the fundus, whereas the lower pole is thrust farther downward. The lengthening of the ovoid shape has been estimated at 5 to 10 cm. Second, with lengthening of the uterus, the longitudinal muscle ibers are drawn taut. As a result, the lower segment and cervix are the only parts of the uterus that are flexible, and these are pulled upward and around the lower pole of the fetus.

After the cervix is dilated fully, the most important force in fetal expulsion is produced by maternal intraabdominal pressure.

Physiology of Labor 413

Contraction of the abdominal muscles simultaneously with forced respiratory eforts with the glottis closed is referred to as pushing. The force is similar to that with defecation, but the intensity usually is much greater. The importance of intraabdominal pressure is shown by the prolonged descent during labor in paraplegic women and in those with a dense epidural block. And, although increased intraabdominal pressure is necessary to complete second-stage labor, pushing accomplishes little in the first stage. It exhausts the mother, and its associated elevated intrauterine pressures may be harmful to the fetus.

s the result of contraction forces, two fundamental changesefacement and dilation-occur in the ripened cervix. For an average-sized fetal head to pass through the cervix, its canal must dilate to a diameter of approximately 10 cm. At this time, the cervix is said to be completely or ully dilated. Although there may be no fetal descent during cervical efacement, most commonly the presenting fetal part descends somewhat as the cervix dilates.

Cervical facement is "obliteration" or "taking up" of the cervix. It is manifest clinically by shortening of the cervical canal from a length of approximately 3 cm to a mere circular oriice with almost paper-thin edges. The muscular fibers at the level of the internal cervical os are pulled upward, or "taken up," into the lower uterine segment. The condition of the external os remains temporarily unchanged (Fig. 2i1-13).

FIGURE 21-13 Schematic showing effacement and dilation.

A. Before labor, the primigravid cervix is long and undilated in contrast to that of the mUltipara, which has dilation of the internal and external os. B. As efacement begins, the multiparous cervix shows dilation and funneling of the internal os. This is less apparent in the primigravid cervix. C. As complete efacement is achieved in the primigravid cervix, dilation is minimal. The reverse is true in the multipara.

Efacement may be compared to a funneling process in which the whole length of a narrow cylinder is converted into a very obtuse, flaring funnel with a small distal circular opening. Because of growing myometrial activity during uterine preparedness for labor, appreciable efacement of a softened cervix sometimes is accomplished before active labor begins. Efacement causes expulsion of the mucous plug as the cervical canal is shortened.

Because the lower segment and cervix have less resistance during a contraction, a centrifugal pull is exerted on the cervix and creates cervical dilation (Fig. 21-14). As uterine contractions cause pressure on the membranes, the hydrostatic action of the amnionic sac in turn dilates the cervical canal like a wedge. The process of cervical efacement and dilation causes formation of the orebag of amnionic luid. This is the leading portion of fluid and amnionic sac located in front of the presenting part. In the absence of intact membranes, the pressure of the presenting fetal part against the cervix and lower uterine segment is similarly efective. Early rupture of the membranes does not retard cervical dilation so long as the presenting fetal part is positioned to exert pressure against the cervix and lower segment.

Referring back to Figure 21-4, recall that cervical dilation is divided into latent and active phases. The active phase is subdivided further into the acceleration phase, the phase of maximum slope, and the deceleration phase (Friedman, 1978). The duration of the latent phase is more variable and sensitive to extraneous factors. For example, sedation may prolong the latent phase, and myometrial stimulation shortens it. The latent phase duration has little bearing on the subsequent course of labor, whereas the characteristics of the accelerated phase are usually predictive of labor outcome. The first stage ends when cervical dilation is complete.

• Second Stage: Fetal Descent

In many nulliparas, engagement of the head is accomplished before labor begins. hat said, the head may not descend further until late in labor. In the descent pattern of normal labor, a typical hyperbolic curve is formed when the station of the fetal head is plotted as a function of labor duration. Station describes descent of the fetal biparietal diameter in relation to a line drawn between maternal ischial spines (Chap. 22, p. 436). Active descent usually takes place after dilation has progressed for some time (Fig. 21-15). During second-stage labor, the speed of descent is maximal and is maintained until the presenting part reaches the perineal floor (Friedman, 1978). In nulliparas, the presenting part typically descends slowly and steadily. In multiparas, however, particularly those of high parity, descent may be rapid.

he birth canal is supported and functionally closed by the pelvic loor (Chap. 2, p. 21). The most important component of the loor is the levator ani muscle and the ibromuscular connective tissue that covers its upper and lower surfaces. he biomechanical properties of these structures and of the vaginal wall

A B c Internal cervical as External cervical os \ Internal cervical os cervical os cervical os External cervical os FIGURE 21-14 Hydrostatic action of membranes in effecting cervical effacement and dilation, With labor progression, note the changing relations of the internal and external os in (A), (B), and(C), Although not shown in this diagram, with membrane rupture, the presenting part, applied to the cervix and the forming lower uterine segment, acts Similarly,

Physiology of Labor 415 its diminishing contents. Normally, by the time the newborn is completely deliv ered, the uterine cavity is nearly obliter ated. he organ consists of an almost solid mass of muscle, several centimeters thick, above the thinner lower segment. he uterine fundus now lies just below the level of the umbilicus .

in the area of the placental implantation 5.�2 c0 site (Fig. 21-16). For the placenta to accommodate itself to this reduced area, it thickens, but because of limited placen tal elasticity, it is forced to buckle. The resulting tension pulls the weakest layer decidua spongiosa-from that site. Thus, FIGURE 21-15 Labor course divided on the basis of expected evolution of the dilatation placental separation follows the disproand descent curves into three functional divisions. The preparatory division includes the portion created between the relatively latent and acceleration phases. The dilatational division is the phase of maximum slope of unchanged placental size and the reduced dilatation. The pelvic division encompasses both the deceleration phase and the second implantation site size.

stage, which is concurrent with the phase of maximum slope of fetal descent. (Redrawm

Cleavage of the placenta is aided from Friedman EA: Labor: Clinical Evaluation and Management, 2nd ed. New York, greatly by the loose structure of the

Appleton-Century-Crofts, 1978.) spongy decidua. As detachment proceeds, a hematoma forms between the separating change markedly during parturition. These result from altered placenta and the adjacent decidua, which remains attached to extracellular matrix structure or composition (Alperin, 2015; the myometrium. The hematoma is usually the result rather Rahn, 2008; Lowder, 2007).

The levator ani muscle closes the lower end of the pelvic cavity as a diaphragm. Thereby, a concave upper and a convex lower surface are presented. The posterior and lateral portions of the pelvic Boor, which are not spanned by the levator ani muscle, are occupied bilaterally by the piriformis and coccygeus muscles.

The levator ani muscle varies in thickness from 3 to 5 mm, although its margins encircling the rectum and vagina are somewhat thicker. During pregnancy, the levator ani usually undergoes hypertrophy, forming a thick band that extends backward from the pubis and encircles the vagina about 2 cm above the plane of the hymen. On contraction, the levator ani draws both the rectum and the vagina forward and upward in the direction of the symphysis pubis and thereby acts to close the vagina.

In the first stage of labor, the membranes, when intact, and the fetal presenting part serve to dilate the upper vagina. he most marked change consists of stretching levator ani muscle fibers. This is accompanied by thinning of the central portion of the perineum, which becomes transformed from a wedgeshaped, 5-cm-thick tissue mass to a thin, almost transparent membranous structure less than 1 cm thick. hen the perineum is distended maximally, the anus becomes markedly dilated and presents an opening that varies from 2 to 3 cm in diameter and through which the anterior wall of the rectum bulges .

• Third Stage: Delivery of Placenta and Membranes

This stage begins immediately after fetal delivery and involves separation and expulsion of the placenta and membranes. As

FIGURE 21-16 Diminution in size of the placental site after birth of the newborn. A. Spatial relations before birth. B. Placental spatial relations after birth.

the neonate is born, the uterus spontaneously contracts around than the cause of the separation, because in some cases bleeding is negligible.

FIGURE 21-17 Postpartum, membranes are thrown up into folds as the uterine cavity decreases in size. (Used with permission from Dr. Kelley S. Carrick.)

The great decline in uterine cavity surface area simultaneously throws the fetal membranes-the amniochorion and the parietal decidua-into innumerable folds (Fig. 21-17). Membranes usually remain in situ until placental separation is nearly completed. These are then peeled of the uterine wall, partly by further contraction of the myometrium and partly by traction that is exerted by the separated placenta as it descends during expulsion.

After the placenta has detached, it can be expelled by increased abdominal pressure. Completion of the third stage is also accomplished by alternately compressing and elevating the fundus, while exerting minimal traction on the umbilical cord. The retroplacental hematoma either follows the placenta or is found within the inverted sac formed by the membranes. In this process, known as the Schultze mechanism of placental expulsion, blood from the placental site pours into the membrane sac and does not escape externally until after extrusion of the placenta. In the other form of placental extrusion, known as the Duncan mechanism, the placenta separates irst at the periphery and blood collects between the membranes and the uterine wall and escapes from the vagina. In this circumstance, the placenta descends sideways, and its maternal surface appears irst.

Late in pregnancy, during phase 2 of parturition, the number of myometrial oxytocin receptors grows appreciably (Fuchs, 1982; Kimura, 1996). his increase coincides with a greater uterine contractile responsiveness to oxytocin. Prolonged gestation is associated with a delay in the rise of these receptor levels (Fuchs, 1984).

Oxytocin-literally, quick birt-was the irst uterotonin to be implicated in parturition initiation. his nanopeptide is synthesized in the magnocellular neurons of the supraoptic and paraventricular neurons. The prohormone is transported with its carrier protein, neurophysin, along the axons to the neural lobe of the posterior pituitary gland in membrane-bound vesicles for storage and later release. The prohormone is converted enzymatically to oxytocin during transport (Gainer, 1988; Leake, 1990).

In addition to its efectiveness in pharmacologically inducing labor at term, oxytocin is a potent uterotonin and occurs naturally in humans. Subsequent observations provide additional support for this theory: (1) the number of oxytocin receptors strikingly rises in myometrial and decidual tissues near the end of gestation; (2) oxytocin acts on decidual tissue to promote prostaglandin release; and (3) oxytocin is synthesized directly in decidual and extraembryonic fetal tissues and in the placenta (Chibbar, 1993; Zingg, 1995).

Although little evidence suggests a role for oxytocin in phase 2 of parturition, abundant data support its important role during second-stage labor and in the puerperium-phase 4 of parturition. Speciically, maternal serum oxytocin levels are elevated: (1) during second-stage labor, which is the end of phase 3 of parturition; (2) in the early puerperium; and (3) during breastfeeding (Nissen, 1995). Immediately after delivery of the fetus, placenta, and membranes, which completes parturition phase 3, irm and persistent uterine contractions are essential to prevent postpartum hemorrhage. Oxytocin likely causes persistent contractions.

Although their role in phase 2 of parturition in uncomplicated pregnancies is less well defined, a critical role for prostaglandins in phase 3 of parturition is clear (MacDonald, 1993). First, levels of prostaglandins-or their metabolites-in amnionic luid, maternal plasma, and maternal urine are increased during labor. Second, receptors for PGE2 and PGF2x are expressed in the uterus and cervix. Thus, if these tissues are exposed to prostaglandins, they will respond. Third, treatment of pregnant women with prostaglandins, by any of several administration routes, causes abortion or labor at all gestational ages. Moreover, administration of prostaglandin H synthase type 2 (PGHS-2) inhibitors to pregnant women will delay spontaneous labor onset and sometimes arrest preterm labor (Loudon, 2003). Last, prostaglandin treatment of myometrial tissue in vitro sometimes causes contraction, dependent on the prostanoid tested and the physiological status of the tissue treated.

During labor, prostaglandin production within the myometrium and decidua is an eicient mechanism of activating contractions. For example, prostaglandin synthesis is high and unchanging in the decidua during phase 2 and 3 of parturition. Moreover, the receptor level for PGF2x is augmented in the decidua at term, and this increase most likely is the regulatory step in prostaglandin action in the uterus.

he fetal membranes and placenta also produce prostaglandins. Primarily PGE2, but also PGF2x, are detected in amnionic fluid at all gestational ages. As the fetus grows, prostaglandin levels in the amnionic fluid rise gradually. heir greatest

FIGURE 21-18 Sagittal view of the exposed forebag and attached decidual fragments after cervical dilation during labor. (Redrawn from MacDonald PC, Casey ML: Preterm birth. Sci Am 3:42, 1996.) elevation in concentration within amnionic luid, however, is demonstrable after labor begins. hese higher levels likely result as the cervix dilates and exposes decidual tissue (Fig. 21-18). hese higher levels in the forebag, compared with those in the upper compartment, are believed to follow an inflammatory response that signals the events leading to active labor. Together, the rise in cytokine and prostaglandin concentrations further degrade the extracellular matrix, thus weakening fetal membranes.

The endothelins are a family of 21-amino-acid pep tides that powerfully induce myometrial contraction (Word, 1990). The endothelin A receptor is preferentially expressed in smooth muscle, and when activated, it efects a rise in intracellular calcium. Endothelin-1 is produced in myometrium of term gestations and is able to induce synthesis of other contractile mediators such as prostaglandins and inflammatory mediators (Momohara, 2004; Sutclife, 2009). The requirement of endothelin-1 in normal parturition physiology remains to be established.

Two G-protein-linked angiotensin II receptors are expressed in the uterus-AT1 and AT2. In nonpregnant women, the AT2 receptor predominates, but the ATI receptor is preferentially expressed in gravidas (Cox, 1993). Angiotensin II binding to the plasma-membrane receptor evokes contraction. During pregnancy, the vascular smooth muscle that expresses the AT2 receptor is refractory to the pressor efects of infused angiotensin II (Chap. 4, p. 63).

Physiology of Labor 41 7

PHASE 4: THE PUERPERIUM

Immediately and for about an hour after delivery, the myometrium remains persistently contracted. This directly compresses large uterine vessels and allows thrombosis of their lumens to prevent hemorrhage. his is typically augmented by endogenous and pharmacological uterotonic agents (Chap. 27, p. 526).

Uterine involution and cervical repair are prompt remodeling processes that restore these organs to the nonpregnant state. hese protect the reproductive tract from invasion by commensal microorganisms and restore endometrial responsiveness to normal hormonal cyclicity.

During the early puerperium, lactogenesis and milk let-down begin in mammary glands (Chap. 36, p. 656). Reinstitution of ovulation signals preparation for the next pregnancy. Ovulation generally occurs within 4 to 6 weeks after birth. However, it is dependent on the duration of breastfeeding and lactationinduced, prolactin-mediated anovulation and amenorrhea.

Akgul Y, Holt R, Mummert M, et al: Dynamic changes in cervical glycosamino glycan composition during normal pregnancy and preterm birth. Endocrinology 153(7):3493,o2012

Akgul Y, Word A, Ensign LM, et al: Hyaluronan in cervical epithelia protects against infection-mediated preterm birth.] Clin Invest 124(12):5481, 20o14

Akins ML, Luby-Phelps K, Bank A, et al: Cervical softening during pregnancy: regulated changes in collagen cross-linking and composition of matricellular proteins in the mouse. Bioi Reprod 84(5): 1 053, 2011

Alperin M, Lawley OM, Esparza MC, et al: Pregnancy-induced adaptations in the intrinsic structure of rat pelvic loor muscles. Am ] Obstet Gynecol 213(2):191 e191, 2015

Ambrus G, Rao CV: Novel regulation of pregnant human myometrial smooth muscle cell gap junctions by human chorionic gonadotropin. Endocrinology 135(6):2772, 1994

Ameye L, Young MF: Mice deficient in small leucine-rich proteoglycans: novel in vivo models for osteoporosis, osteoarthritis, Ehlers-Danlos syndrome, muscular dystrophy, and corneal diseases. Glycobiology 12(9): 107R, 2002

Anum EA, Hill LD, Pandya A, et al: Connective tissue and related disorders and preterm birth: clues to genes contributing to prematurity. Placenta 30(3):207, 2009

Astle S, Thornton S, Slater OM: Identiication and localization of prostaglandin E2 receptors in upper and lower segment human myometrium during pregnancy. Mol Hum Reprod 11 (4):279,o2005

Badir S, Bajka M, Mazza E: A novel procedure for the mechanical characterization of the uterine cervix during pregnancy. ] Mech Behav Biomed Mater 27:143,o2013

Benedetto C, Petraglia F, Marozio L, et al: Corticotropin-releasing hormone increases prostaglandin F2 alpha activity on human myometrium in vitro. Amo] Obstet GynecoIo171(1):126, 1994

Berkane N, Verstraete L, Uzan S, et al: Use of mifepristone to ripen the cevix and induce labor in term pregnancies. Am] Obstet Gynecol 192: 114, 2005

Berkowitz GS, Lapinski RH, Lockwood q, et al: Corticotropin-releasing factor and its binding protein: maternal serum levels in term and preterm deliveries. Am] Obstet GynecoIo174(5):1477, 1996

Blanks ANI, Vatish M, Allen M], et al: Paracrine oxytocin and estradiol demonstrate a spatial increase in human intrauterine tissues with labor. ] Clin Endocrinol Metab 88(7):3392, 2003

B1askewicz CD, Pudney ], Anderson 0]: Structure and function of intercellular junctions in human cevical and vaginal mucosal epithelia. Bioi Reprod 85(1):97,o2011

Bogacki M, Silvia ], Rekawiecki R, et al: Direct inhibitory efect of progesterone on oxytocin-induced secretion of prostaglandin F(2a1pha) from bovine endometrial tissue. BioI Reprod 67(1): 184, 2002

Bollapragada S, Youssef R, Jordan F, et al: Term labor is associated with a core inlammatory response in human fetal membranes, myometrium, and cervix. Am] Obstet GynecoI200(1):104.e1, 2009

Bygdeman M, Swahn ML, Gemzell-Danielsson K, et al: The use of progesterone antagonists in combination with prostaglandin for termination of pregnancy. Hum Reprod 9 Suppl 1):121, 1994

Casey ML, MacDonald PC: Human parturition: Distinction between the initiation of parturition and the onset of labor. In Ducsay CA (ed): Seminars in Reproductive Endocrinology. New York, Thieme, 1993

Casey ML, MacDonald PC: he endocrinology of human parturition. Ann N Y Acad Sci 828:273, 199

Chaiworapongsa T, Hong JS, Hull WM, et al: The concentration of surfactant protein-A in amniotic luid decreases in spontaneous human parturition at term. J Matern Fetal Neonatal Med 21 (9):652,o2008

Challis JR, Lye SJ: Parturition. In Knobil E, Neill JD (eds): The Physiology of Reproduction, 2nd ed, Vol II. New York, Raven, 1994

Challis JR, lv/".:thews SG, Gibb W, et al: Endocrine and paracrine regulation of birth at term and preterm. Endocr Rev 21(5):514,o2000

Challis JR, Smith SK: Fetal endocrine signals and preterm labor. BioI Neonate 79(3-4):163,o2001

Cheung PY, Walton Jc, Tai HH, et al: Immunocytochemical distribution and localization of 15-hydroxyprostaglandin dehydrogenase in human fetal membranes, decidua, and placenta. Am J Obstet Gynecol 163: 1445, 1990

Chibbar R, Miller FD, Mitchell BF: Synthesis of oxytocin in amnion, chorion, and decidua may inluence the timing of human parturition. J Clin Invest 91(1):185,o1993

Chwalisz K: The use of progesterone antagonists for cervical ripening and as an adjunct to labour and delivery. Hum Reprod 9 Suppl 1): 131, 1994a Chwalisz K, Garield RE: Antiprogestins in the induction of labor. Ann N Y Acad Sci 734:387, 1994b

Condon Jc, Jeyasuria P, Faust JM, et al: A decline in the levels of progesterone receptor coactivators in the pregnant uterus at term may antagonize progesterone receptor function and contribute to the initiation of parturition. Proc Nat! Acad Sci USA 100(16):9518,o2003

Cox BE, Ipson MA, Shaul PW, et al: Myometrial angiotensin II receptor subtypes change during ovine pregnancy. J Clin Invest 92(5):2240, 1993 Downing SJ, Hollingsworth M: Action of relaxin on uterine contractions-a review. J Reprod Fertil 99(2):275, 1993

Drewes PG, Yanagisawa H, Starcher B, et al: Pelvic organ prolapse in ibulin-5 knockout mice: pregnancy-induced changes in elastic iber homeostasis in mouse vagina. Am J Pathol 170:578, 2007

Erlebacher A: Mechanisms ofT cell tolerance towards the allogeneic fetus. Nat Rev Immunol 13(1):23,o2013

Eta E, Ambrus G, Rao CV: Direct regulation of human myometrial contractions by human chorionic gonadotropin. J C1in Endocrinol Metab 79(6):1582,o1994 Ferguson JK: A study of the motility of the intact uterus at term. Surg Gynecol 3, 1941 Frenkel A, Muguruma K, Johnston JM: The biochemical role of plateletactivating factor in reproduction. Prog Lipid Res 35(2):155, 1996 Friedman A: Labor: Clinical Evaluation and Management, 2nd ed. New York, Appleton-Century-Crofts, 1978 Frim OM, Emanuel RL, Robinson BG, et al: Characterization and gestational regulation of corricotropin-releasing hormone messenger RNA in human placenta. J Clin Invest 82(1):287, 1988 Fuchs AR, Fuchs F, Husslein P, et al: Oxytocin receptors and human parturition: a dual role for o:ytocin in the initiation of labor. Science 21o5(4538):1o396,o1982 Fuchs AR, Fuchs F, Husslein P, et al: Oxytocin receptors in the human uterus during pregnancy and parturition. Am J Obstet Gynecol 150(6):734, 1984

Fuchs AR, Periyasamy S, Alexandrova M, et al: Correlation between oxytocin receptor concentration and responsiveness to oxytocin in pregnant rat myometrium: efects of ovarian steroids. Endocrinology 42, 1983 Gainer H, Alstein M, Whitnall MH, et al: The biosynthesis and secretion of oxytocin and vasopressin. In Knobil E, Neill J (eds): he Physiology of Reproduction, Vol II. New York, Raven, 1988 Garcia-Verdugo I, Tanin Z, Dallot E, et al: Surfactant protein A signaling pathways in human uterine smooth muscle cells. BioI Reprod 79(2):348, 2008 Gao L, Rabbitt EH, Condon JC, et al: Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition. J C1in Invest 125( ):2808,o2015 Germain M, Smith J, Casey ML, et al: Human fetal membrane contribution to the prevention of parturition: uterotonin degradation. J Clin Endocrinol Metab 78(2):463, 1994 Giannoulias 0, Patel FA, Holloway AC, et al: Diferential changes in 15-hydroxyprostagland in dehydrogenase and prostaglandin H synthase (types I and II) in human pregnant myometrium. J Clin Endocrinol Metab 87(3):1345,o2002

Grino M, Chrousos GP, Margioris AN: he corticotropin releasing hormone gene is expressed in human placenta. Biochem Biophys Res Commun 148(3):1208, 1987

Hari Kishore A, Li XH, Word A: Hypoxia and PGE(2) regulate MiTF-CX during cervical ripening. Mol Endocrinol 26(12):2031, 2012 Hassan SS, Romero R, Haddad R, et al: The transcriptome of the uterine cer vix before and after spontaneous term parturition. Am J Obstet Gynecol 78,o2006 Hassan SS, Romero R, Tarca AL, et al: The transcriptome of cervical ripening in human pregnancy before the onset oflabor at term: identiication of novel molecular functions involved in this process. J Matern Fetal Neonatal Med 33(12):1183,o2009

Hegar A: Diagnose der frlihesten Schwangerschaftsperiode. Deutsche Medizinische Wochenschrift 21:565, 1895 Hermanns-Le T, Pierard G, Quatresooz P: Ehlers-Danlos-like dermal abnormalities in women with recurrent preterm premature rupture of fetal membranes. Am J Dermatopathol 27(5):407, 2005 House M, Bhadelia A, Myers K, et al: Magnetic resonance imaging of threedimensional cervical anatomy in the second and third trimester. Eur J Obstet Gynecol Reprod BioI 144 SuppIo1:S65, 2009

Jeyasuria P, Wetzel J, Bradley M, et al: Progesterone-regulated caspase 3 action in the mouse may playoa role in uterine quiescence during pregnancy through fragmentation of uterine myocyte contractile proteins. BioI Reprod 80(5):928, 2009

Johnson RF, Mitchell CM, Giles WB, et al: The in vivo control of prostaglandin H synthase-2 messenger ribonucleic acid expression in the human amnion at parturition. J Clin Endocrinol Metab 87(6):2816, 2002 Kandola MK, Sykes L, Lee YS, et al: EP2 receptor activates dual G protein signaling pathways that mediate contrasting proinlammatory and relaxatory responses in term pregnant human myome�rium. Endocrinology 155(2):605,o2014

Kimura T, Takemura M, Nomura S, et al: Expression of oxytocin receptor in human pregnant myometrium. Endocrinology 137(2):780, 1996

Kishore AH, Owens 0, Word A: Prostaglandin E2 regulates its own inactivating enzyme, 15-PGDH, by EP2 receptor-mediated cervical cell-speciic mechanisms. J Clin Endocrinol Metab 99(3):1006, 2014

Konopka CK, Glanzner WG, Rigo ML, et al: Responsivity to PGE2 labor induction involves concomitant diferential prostaglandin E receptor gene expression in cervix and myometrium. Genet Mol Res 14(3):10877,o2015

Kyathanahalli C, Organ K, Moreci RS, et al: Uterine endoplasmic reticulum stress-unfolded protein response regulation of gestational length is caspase-3 and -7-dependent. Proc Nat! Acad Sci USA 112(45):14090,o2015

Lang CT, lams JD, Tangchitnob E, et al: A method to visualize 3-dimensional anatomic changes in the cervix during pregnancy: a preliminary observational study. J Ultrasound Med 29(2):255, 2010

Leake RD: Oxytocin in the initiation oflabor. In Carsten ME, Miller JD (eds):

Uterine Function. Molecular and Cellular Aspects. New York, Plenum, 1990

Lee DC, Romero R, Kim CJ, et al: Surfactant protein-A as an anti-inlammatory component in the amnion: implications for human pregnancy. J Immunol 184(11):6479,o2010

Leonhardt A, Glaser A, Wegmann M, et al: Expression of prostanoid receptors in human lower segment pregnant myometrium. Prostaglandins Leukot Essent Fatty Acids 69(5):30 ,o2003

Leung TN, Chung TK, Madsen G, et al: Rate of rise in maternal plasma corticotrophin-releasing hormone and its relation to gestational length. BJOG 108(5):527,o2001

Li H, Yu Y, Shi Y, et al: HoxA13 stimulates myometrial cells to secrete IL-1 beta and enhance the expression of contraction-associated proteins. Endocrinology (5):2129,o2016

Loudon JA, Groom v!, Bennett PR: Prostaglandin inhibitors in preterm labour. Best Pract Res Clin Obstet GynaecoIo17(5):731, 2003

Lowder JL, Debes \1, Moon OK, et al: Biomechanical adaptations of the rat vagina and supporrive tissues in pregnancy to accommodate delivery. Obstet Gynecol 109(1):136,o200

Lowry PJ: Corricotropin-releasing factor and its binding protein in human plasma. Ciba Found Symp 172: 108, 1993

Lyall F, Lye S, Teoh T, et al: Expression of Gsalpha, connexin-43, connexin-26, and EPl, 3, and 4 receptors in myometrium of prelabor singleton versus multiple gestations and the efects of mechanical stretch and steroids on Gsalpha. J Soc Gynecol Investig 9(5):299, 2002

MacDonald Pc, Casey ML: Preterm birth. Sci Am 3:42, 1996

MacDonald Pc, Casey vlL: he accumulation of prostaglandins (PG) in amniotic luid is an afterefect of labor and not indicative of a role for PGE2 or PGF2 alpha in the initiation of human parturition. J Clin Endocrinol Metab 76(5): 1332, 1993

Mahendroo M: Cervical remodeling in term and preterm birth: insights from an animal model. Reproduction 143(4):429,o2012

Mahendroo MS, Porter A, Russell DW, et al: The parturition defect in steroid 5alpha-reductase type 1 knockout mice is due to impaired cervical ripening. Mol EndocrinoIo13(6):981, 1999

Malpas P: Postmaturity and malformations of the foetus. BJOG 40(6): 1046,o1933

McGrath S, McLean M, Smith D, et al: Maternal plasma corticotropin-releasing hormone trajectories vary depending on the cause of preterm delivery. Am J Obstet Gynecol 186(2):257,o2002

McLean M, Bisits A, Davies J, et al: A placental clock controlling the length of human pregnancy. Nat Med 1(5): 460, 1995

Meera P, Anwer K, Monga M, et al: Relaxin stimulates myometrial calciumactivated potassium channel activity via protein kinase A. Am J Physiol 269(2 Pt 1):C312, 1995

Mendelson CR, Montalbano AP, Gao L: Fetal-to-maternal signaling in the timing of birth. J Steroid Biochem Mol Bioi 170: 19, 2017

Menon R, Bonney EA, Condon J, et al: Novel concepts on pregnancy clocks and alarms: redundancy and synergy in human parturition. Hum Reprod Update 22(5):535, 2016

Mesiano S, Chan EC, Fitter JT, et al: Progesterone withdrawal and estrogen activation in human parturition are coordinated by progesterone receptor A expression in the myometrium. J Clin Endocrinol Metab 8 (6):2924, 2002

Momohara Y, Sakamoto S, Obayashi S, et al: Roles of endogenous nitric oxide synthase inhibitors and endothelin-1 for regulating myometrial contractions during gestation in the rat. Mol Hum Reprod 10(7):505,o2004

Myatt L, Lye SJ: Expression, localization and function of prostaglandin receptors in myometrium. Prostaglandins Leukot Essent Fatty Acids 70(2):137, 2004 Myers M, Feltovich H, Mazza E, et al: he mechanical role of the cervix in pregnancy. J Biomech 48 (9): 151o1, 20o15 dyers KM, Paskaleva AP, House M, et al: Mechanical and biochemical properties of human cervical tissue. Acta Biomater 4(1):104,o2008

Nadeem L, Shynlova 0, Matysiak-Zablocki E, et al: Molecular evidence of functional progesterone withdrawal in human myometrium. Nat Commun 7:11565,o2016

Nancy P, Tagliani E, Tay CS, et al: Chemokine gene silencing in decidual stromal cells limits T cell access to the maternal-fetal interface. Science 336(6086):1317,o2012

Nissen E, Lilja G, Widstrom AM, et al: Elevation of oxytocin levels early post partum in women. Acta Obstet Gynecol Scand 74(7):530, 1995

Norman JE, Marlow N, Messow CM, et al: Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial. he Lancet 38 (10033):2106,o2016

Norwitz ER, Bonney EA, Snegovskikh V, et al: Molecular regulation of parturition: the role of the decidual clock. Cold Spring Harb Perspect �'led 5(11):1,o2015

Olson DM, Ammann C: Role of the prostaglandins in labour and prostaglandin receptor inhibitors in the prevention of preterm labour. Front Biosci 12:1329,o200

Olson DM, Zaragoza DB, Shallow Me, et al: Myometrial activation and preterm labour: evidence supporting a role for the prostaglandin F receptor-a review. Placenta 24 Suppl A:S47, 2003

Park JI, Chang CL, Hsu SY: New Insights into biological roles of relaxin and relaxin-related peptides. Rev Endocr Metab Disord 6(4):291, 2005

Parra-Saavedra M, Gomez L, Barrero A, et al: Prediction of preterm birth using the cervical consistency index. Ultrasound Obstet Gynecol 38(1):44, 2011 Patel B, Elguero S, Thakore S, et al: Role of nuclear progesterone receptor isoforms in uterine pathophysiology. Hum Reprod Update 21(2):155,o2015

Perez GJ, Toro L, Erulkar SD, et al: Characterization of large-conductance, calcium-activated potassium channels from human myometrium. Am J Obstet Gynecol 168(2):652, 1993 , Wolfe CD, Eben F, et al: Corticotrophin-releasing hormone-binding protein in human fetal plasma. J Endocrinol 146(3):395, 1995

Petraglia F, Florio P, Simoncini T, et al: Cord plasma corticotropin-releasing factor-binding protein (CRF-BP) in term and preterm labour. Placenta 18(2-3):115, 1997

PrabhuDas M, Bonney E, Caron K, et al: Immune mechanisms at the maternalfetal interface: perspectives and challenges. Nat Immunol 16(4):328,o2015 Price SA, Pochun I, Phaneuf S, et al: Adenylyl cyclase isoforms in pregnant and non-pregnant human myometrium. J Endocrinol 164(1):21,o2000

Rahman J, Rahman FZ, Rahman W, et al: Obstetric and gynecologic complications in women with Marfan syndrome. J Reprod Med 48(9): 23, 2003

Rahn DD, Ruf MD, Brown SA, et al: Biomechanical properties of the vaginal wall: efect of pregnancy, elastic iber deiciency, and pelvic organ prolapse. Am J Obstet Gynecol 198(5):590 e591, 2008

Rea C: Prolonged gestation, acrania monstrosity and apparent placenta previa in one obstetrical case. JAMA 30(20): 1166, 1898

Read CP, Word A, Ruscheinsky MA, et al: Cervical remodeling during pregnancy and parturition: molecular characterization of the softening phase in mice. Reproduction 134(2):32 ,2007

Physiology of Labor 419

Renthal NE, Chen Ce, Williams KC, et al: miR-200 family and targets, ZEB 1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor. Proc Nat! Acad Sci USA 10 (48):20828,o2010

Renthal NE, Williams KC, \!ontalbano AP, et al: Molecular regulation of parturition: a myometrial perspective. Cold Spring Harb Perspect Med 5(1o1):1,o2015

Saez Je, Retamal A, Basilio D, et al: Connexin-based gap junction hemichannels: gating mechanisms. Biochim Biophys Acta 1711 (2):215, 2005

Saijonmaa 0, Laatikainen T, Wahlstrom T: Corticotrophin-releasing factor in human placenta: localization, concentration and release in vitro. Placenta 9(4):373, 1988

Sanborn BM, Yue e, Wang W, et al: G protein signalling pathways in myometrium: afecting the balance berween contraction and relaxation. Rev Reprod 3(3):196,o1998

Sasaki A, Shinkawa 0, Margioris AN, et al: Immunoreactive corticotropinreleasing hormone in human plasma during pregnancy, labor, and delivery. J Clin Endocrinol Metab 64(2):224, 1987

Shynlova 0, Williams SJ, Draper H, et al: Uterine stretch regulates temporal and spatial expression of ibronectin protein and its alpha 5 integrin receptor in myometrium of unilaterally pregnant rats. Bioi Reprod 77(5):880, 200

Smith GC, Wu X, Nathanielsz PW: Efects of gestational age and labor on expression of prostanoid receptor genes in baboon uterus. Bioi Reprod 64(4): 1131,o2001

Smith R: Parturition. N Engl J Med 356(3):271, 2007

Snegovskikh V, Bhandari V, Wright JR, et al: Surfactant protein-A (SP

A) selectively inhibits prostaglandin F2alpha (PGF2alpha) production in term decidua: implications for the onset of labor. J Clin Endocrinol Metab 96(4):E624,o2011

Soh YM, Tiwari A, Mahendroo M, et al: Relaxin regulates hyaluronan synthesis and aquaporins in the cervix of late pregnant mice. Endocrinology 153(12):6054,o2012

Sparey C, Robson SC, Bailey J, et al: The diferential expression of myometrial connexin-43, cyclooxygenase-1 and -2, and Gs alpha proteins in the upper and lower segments of the human uterus during pregnancy and labor. J Clin Endocrinol Metab 84(5): 1705, 1999

Stilley JA, Guan R, Santillan DA, et al: Diferential regulation of human and mouse myometrial contractile activity by FSH as a function ofFSH receptor density. Bioi Reprod 95(2):36, 2016

Straach KJ, Shelton JM, Richardson JA, et al: Regulation ofhyaluronan expression during cervical ripening. Glycobiology 15(1o):55, 2005

Stull JT, Lin PJ, Krueger JK, et al: J. Myosin light chain kinase: functional domains and structural motifs. Acta Physiol Scand 164(4):471, 1998

Sutclife M, Clarke DL, Bradbury DA, et al: Transcriptional regulation of monocyte chemotactic protein-1 release by endothelin-1 in human airway smooth muscle cells involves NF-kappaB and AP-1. Br J Pharmacol 15 (3):436,o2009

Tattersall M, Cordeaux Y, Charnock-Jones OS, et al: Expression of gastrinreleasing peptide is increased by prolonged stretch of human myometrium, and antagonists of its receptor inhibit contractility. J Physiol 590(9):2081, 20o12

Telfer ]F, Itoh H, Thomson AJ, et al: Activity and expression of soluble and particulate guanylate cyclases in myometrium from nonpregnant and pregnant women: down-regulation of soluble guanylate cyclase at term. J Clin Endocrinol Metab 86(12):5934, 2001

Timmons Be, Mahendroo M: Processes regulating cervical ripening difer from cervical dilation and postpartum repair: insights from gene expression studies. Reprod Sci 14(8 Suppl):53, 2007

Toyoshima K, Narahara H, Furukawa M, et al: Platelet-activating factor. Role in fetal lung development and relationship to normal and premature labor. Clin Perinatolo22(2):263, 1995 ink JY, Qin S, Brock CO, et al: A new paradigm for the role of smooth muscle cells in the human cervix. Am J Obstet Gynecol 215(4):478.el, 2016

Wadhwa PD, Porto M, Garite T], et al: Maternal corticotropin-releasing hormone levels in the early third trimester predict length of gestation in human pregnancy. Am] Obstet GynecoIo179(4):1079, 1998

Wakle-Prabagaran M, Lorca A, vla X, et al: BKCa channel regulates calcium oscillations induced by alpha-2-macroglobulin in human myometrial smooth muscle cells. Proc Nat! Acad Sci USA 113(16):E2335, 2016

Wang H, Parry S, Macones G, et al: A functional SNP in the promoter of the SERPINH 1 gene increases risk of preterm premature rupture of membranes in African Americans. Proc Nat! Acad Sci USoA 103(36):1o3463,o2006

Warren ]E, Silver M, Dalton ], et al: Collagen 1Alphal and transforming growth factor-beta polymorphisms in women with cervical insuiciency.

Obstet Gynecol 110(3):619,o2007

Wathes DC, Borwick Se, Timmons PM, er al: Oxyrocin receptor expression in human term and preterm gestational tissues prior to and following the onset of labour. ] EndocrinoIo161(l):143, 1999

Westergren-horsson G, Norman M, Bjornsson 5, et al: Diferential expressions of mRNA for proteoglycans, collagens and transforming growth factor-beta in the human cervix during pregnancy and involution. Biochim Biophys Acta 1406(2):203, 1998

Williams KC, Renthal NE, Condon JC, et al: MicroNA-200a serves a key role in the decline of progesterone receptor function leading to term and preterm labor. Proc Natl Acad Sci USA 109(19):7529, 2012a

Williams KC, Renthal NE, Gerard D, et al: he microRNA (miR)-199a/214 cluster mediates opposing efects of progesterone and estrogen on uterine contractility during pregnancy and labor. Mol Endocrinolo26(11):1857, 2012b

Wira CR, Grant-Tschudy KS, Crane-Godreau A: Epithelial cells in the female reproductive tract: a central role as sentinels of immune protection. Am J Reprod Immunol 53(2):65, 2005

WolfJP, SimonJ, ItskovitzJ, et al: Progesterone antagonist RU 486 accommodates but does not induce labour and delivery in primates. Hum Reprod 8:759, 1993

Woodcock NA, Taylor CW, Thornton 5: Efect of an oxytocin receptor antagonist and rho kinase inhibitor on the [Ca++li sensitivity of human myometrium. Am J Obstet Gynecol 190:222,o2004

Word A, Kamm E, Stull JT, et al: Endothelin increases cytoplasmic calcium and myosin phosphorylation in human myometrium. Am J Obstet Gynecol 162(4):1103, 1990

Word A, Li XH, Hnat M, et al: Dynamics of cervical remodeling during pregnancy and parturition: mechanisms and current concepts. Semin Reprod Med 25(1):69, 2007

Word A, Stull JT, Casey ML, et al: Contractile elements and myosin light chain phosphorylation in myometrial tissue from nonpregnant and pregnant women. J Clin Invest 92(1):29, 1993

Ying L, Becard M, Lyell D, et al: The transient receptor potential vanilloid 4 channel modulates uterine tone during pregnancy. Sci Transl Med 7(319):319ra204,o2015

Yoshida K, Jiang H, Kim M, et al: Quantitative evaluation of collagen crosslinks and corresponding tensile mechanical properties in mouse cervical tissue during normal pregnancy. PLoS One 9(11):el12391, 2014

You X, Gao L, Liu J, et al: CRH activation of diferent signaling pathways results in diferential calcium signaling in human pregnant myometrium before and during labor. J Clin Endocrinol Metab 97(10):E1851, 20o12

Young RC, Goloman G: Mechanotransduction in rat myometrium: coordination of contractions of electrically and chemically isolated tissues. Reprod Sci 18(1):64,2011 Zhang Y, Akins tvlL, Murari K, et al: A compact fiber-optic SHG scanning endomicroscope and its application to visualize cervical remodeling during pregnancy. Proc Nat! Acad Sci USA 109(32):12878, 2012 Ziecik AJ, Derecka-Reszka K, Rzucidlo SJ: Extragonadal gonadotropin receptors, their distribution and function. J Physiol Pharmacol 43(4 Suppl 1):33, 1992 Zingg HH, Rozen F, Chu K, et al: Oxytocin and oxytocin receptor gene expression in the uterus. Recent Prog Horm Res 50:255, 1995

MECHANISMS OF LABOR .e.........e..e.........e... 421

FETAL POSITION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423

OCCIPUT ANTERIOR PRESENTATION ..e.......e..... 427

NORMAL LABOR CHARACTERISTICS . . . . . . . . . . . . . . . 431 ......................... 432

SECOND STAGE OF LABOR ..e...e.......e.....e..e..e. 434

MANAGEMENT OF NORMAL LABOR ...... ........ 434

MANAGEMENT OF FIRST-STAGE LABOR ...e.....e...e. 436

MANAGEMENT OF SECOND-STAGE LABOR ... ..e..e. 438

LABOR MANAGEMENT PROTOCOLS . . . . . .. . . . . . . . . 438

It olows that some process of adaptation or accommodation of suitable portions or the head to the various pelvic planes is necessary to insure the completion of childbirth.

his is brought about by certain movement of the presenting part, which belong to what is termed the mechanism of labour.

-J. Whitridge Williams (1903)

Labor is the process that leads to childbirth. It begins with the onset of regular uterine contractions and ends with delivery of the newborn and expulsion of the placenta. Pregnancy and birth are physiological processes, and thus, labor and delivery should be considered normal for most women.

Many adaptive changes are required for pregnancy and for labor and delivery. According to Nygaard (2015), vaginal delivery is a traumatic event. To assess this in part, Staer-] ensen and colleagues (2015) obtained transperineal sonographic measurements of the pelvic loor muscles at 21 weeks' and 37 weeks' gestation, and again at 6 weeks, 6 months, and 12 months postpartum. In 300 nulliparas, they measured bladder neck mobility and the area within the urogenital hiatus during Valsalva. This hiatus is the U-shaped opening in the pelvic loor muscles through which the urethra, vagina, and rectum pass (Chap. 2, p. 19). In this study, the levator hiatus area was signiicantly larger at 37 weeks' gestation and at 6 weeks postpartum compared with earlier pregnancy. hen, by 6 months postpartum, the hiatus had improved and narrowed to return to an area comparable to that at 21 weeks' gestation. However, no further improvement was noted by 12 months postpartum. Of note, hiatal area enlargement was only seen in those who delivered vaginally.

These indings demonstrate antepartum changes in pelvic loor structure that may relect adaptations needed to permit vaginal delivery (Nygaard, 2015). Additional pelvic loor changes are discussed in Chapter 4 (p. 52), and the contributions of pregnancy and delivery to later pelvic organ prolapse and incontinence are described in Chapter 30 (p. 568).

At the onset of labor, the position of the fetus with respect to the birth canal is critical to the route of delivery and thus should be determined in early labor. Important relationships include fetal lie, presentation, attitude, and position.

TABLE 22-1 . Fetal Presentation in 68,097 Singleton Pregnancies at Parkland Hospital

Cephalic 96.8 Breech 2.7 1s:36

Transverse lie 0.3 1 :335

Compound 0.1 1:1000

Face 0.05 1 :2000 Brow 0.01 1 :10,000

Fetal lie describes the relationship of the fetal long axis to that of the mother. In more than 99 percent of labors at term, the fetal lie is longitudinal. A transverse lie is less frequent, and predisposing factors include multiparity, placenta previa, hydramnios, and uterine anomalies (Chap. 23, p. 452). Occasionally, the fetal and maternal axes may cross at a 45-degree angle, forming an oblique lie. his is unstable and becomes longitudinal or transverse during labor.

The presenting part is the portion of the fetal body that is either foremost within the birth canal or in closest proximity to it. It typically can be felt through the cervix during vaginal examination. Accordingly, in longitudinal lies, the presenting part is either the fetal head or the breech, creating cephalic and breech presentations, respectively. When the fetus lies with the long axis transversely, the shoulder is the presenting part. Table 22-1 describes the incidences of these various presentations.

These presentations are classified according to the relationship between the head and body of the fetus (Fig. 22-1). Ordinarily, the head is lexed sharply so that the chin contacts the thorx. The occipital fontanel is the presenting part, and this presentation is referred to as a vertex or occiput presentation. Much less often, the fetal neck may be sharply extended so that the occiput and back come into contact, and the face is foremost in the birth canal-oce presentation. The fetal head may assume a position between these extremes. When the neck is only partly lexed, the anterior (large) fontanel may present-sincput presentation. When the neck is only partially extended, the brow may emerge-brow presentation. These latter two are usually transient. As labor progresses, sinciput and brow presentations almost always convert into vertex or face presentations by neck lexion or extension, respectively. Failure to do so can lead to dystocia, discussed in Chapter 23 (p. 452).

FIGURE 22-1 Longitudinal lie. Cephalic presentation. Differences in attitude of the fetal body in (A) vertex, (B) sinciput, (C) brow, and (0) face presentations. Note changes in fetal attitude in relation to fetal vertex as the fetal head becomes less flexed.

The term fetus usually presents with the vertex, most logically because the uterus is piriform or pear shaped. Although the fetal head at term is slightly larger than the breech, the entire podalic pole of the fetus-that is, the breech and extremities-is bulkier and more mobile than the cephalic pole. The cephalic pole is composed of the fetal head only. Until approximately 32 weeks, the amnionic cavity is large compared with the fetal mass, and the fetus is not crowded by the uterine walls. Subsequently, however, the ratio of amnionic luid volume declines relative to the growing fetal mass. As a result, the uterine walls are apposed more closely to the fetal parts. The fetus orients its polarity to make use of the roomier fundus for its bulkier and more mobile podalic pole. The high incidence of breech presentation in hydrocephalic fetuses is in accord with this theory, as the larger fetal cephalic pole requires more room than its podalic pole.

The incidence of breech presentation drops with gestational age and approximates 3 percent at term. When the fetus presents breech, the three general configurations arerank, complete, and ootling presentations, described in Chapter 28 (p. 539). Breech presentation may result from circumstances that prevent normal version from taking place. One example is a septum that protrudes into the uterine cavity (Chap. 3, p. 45). Variances of fetal attitude, particularly extension of the vertebral column as seen in frank breeches, also may prevent the fetus from turning. If the placenta is implanted in the lower uterine segment, it may distort normal intrauterine anatomy and result in a breech presentation.

In the later months of pregnancy, the fetus assumes a characteristic posture described as attitude or habitus (see Fig. 22-1). As a rule, the fetus forms an ovoid mass that corresponds roughly to the shape of the uterine cavity. The fetus becomes folded upon itself to create a convex back. The head is sharply lexed; the chin is almost in contact with the chest; the thighs are lexed over the abdomen; and the legs are bent at the knees. In all cephalic presentations, the arms usually lie across the thorax or parallel to the sides. The umbilical cord ills the space between the

FIGURE 22-2 Longitudinal lie. Vertex presentation. A. Left occiput anterior (LOA). B. Left occiput posterior (LOP).

extremities. his characteristic posture results from the mode of fetal growth and its accommodation to the uterine cavity.

Abnormal exceptions to this attitude occur as the fetal head becomes progressively more extended from the vertex to the face presentation. This results in a progressive change in fetal attitude from a convex (flexed) to a concave (extended) contour of the vertebral column.

Position refers to the relationship of an arbitrarily chosen portion of the fetal presenting part to the right or left side of the birth canal. Accordingly, with each presentation, there may be two positions-right or left. he fetal occiput, chin (mentum), and sacrum are the determining points in vertex, face, and breech presentations, respectively (hgs. 22 2 to

Because the presenting part may be in either the left or right position, there are left and right occipital (LO and RO), left and right mental (LM and RM), and left and right sacral (LS and RS) designations.

Further, the relationship of a given portion of the presenting part to the anterior (A), transverse (T), or posterior (P) portion of the maternal pelvis is considered. As shown in Figures 22-2 to 22-6, there are six varieties of each of the three presentations. Thus, in an occiput presentation, the presentation, position, and variety may be abbreviated in clockwise fashion as:

Approximately two thirds of all vertex presentations are in the let occiput position, and one third in the right.

In shoulder presentations, the acromion (scapula) is the portion of the fetus arbitrarily chosen for orientation with the maternal pelvis. One example of the terminology sometimes employed for this purpose is illustrated in Figure 22-7. The acromion or back of the fetus may be directed either posteriorly or anteriorly and superiorly or inferiorly. Because it is impossible to diferentiate exactly the several varieties of shoulder presentation by clinical examination and because such speciic diferentiation serves no practical purpose, it is customary

FIGURE 22-3 Longitudinal lie. Vertex presentation. A. Right occiput posterior (RaP). B. Right occiput transverse (Ran.

to refer to all transverse lies simply as shoulder presentations. Another term used is transverse lie, with back up or back down, which is clinically important when deciding incision type for cesarean delivery (Chap. 23, p. 453) .

Several methods can be used to diagnose fetal presentation and position. Abdominal examination can be conducted systematically employing the four maneuvers described by Leopold in 1894 and shown in Figure 22-8. he mother lies supine and comfortably positioned with her abdomen bared. hese maneuvers may be diicult if not impossible to perform and interpret if the patient is obese, if amnionic luid volume is excessive, or if the placenta is anteriorly implanted.

he irst maneuver assesses the uterine fundus. It permits identification of fetal lie and determination of which fetal pole-that is, cephalic or podalic-occupies the fundus. he breech gives the sensation of a large, nodular mass, whereas the head feels hard and round and is more mobile.

he second maneuver is accomplished as the palms are placed on either side of the maternal abdomen, and gentle but deep pressure is exerted. On one side, a hard, resistant structure is felt-the back. On the other, numerous small, irregular, mobile parts are felt-the fetal extremities. By noting whether anterior (ROA). orientation can be determined.

FIGURE 22-4 Longitudinal lie. Vertex presentation. Right occiput the back is directed anteriorly, transversely, or posteriorly, fetal

FIGURE 22-5 Longitudinal lie. Face presentation. Left and right mentum anterior and right mentum posterior positions.

FIGURE 22-6 Longitudinal lie. Breech presentation. Left sacrum FIGURE 22-7 Transverse lie. Right acromiodorsoposterior (RADP). The posterior (LSP). shoulder of the fetus is to the mother's right, and the back is posterior.

and colleagues (1993), experienced clinicians have accurately identified fetal malpresentation using Leopold maneuvers with a high sensitivity-88 percent, speciicity-94 percent, positive-predictive value-74 percent, and negative-predictivevalue-97 percent. With experience, it is possible to estimate the size of the fetus with these maneuvers (Field, 1995). However, and especially with an obese woman, estimates by palpation and actual birth weights often correlate poorly (Fox, 2009; Goetzinger, 2014; Noumi, 2005).

Before labor, the diagnosis of fetal presentation and position by vaginal examination is often inconclusive because the presenting part must be palpated through a closed cervix and lower uterine segment. With the onset of labor and after cervical dila tion, vertex presentations and their positions are recognized by palpation of the various fetal sutures and fontanels. Face and breech presentations are identiied by palpation of facial features or the fetal sacrum and perineum, respectively. During this vaginal examination, it is advis able to pursue a deinite routine, comprising four movements. First, the examiner inserts two fingers into the vagina and the presenting part is found. Diferentiation of vertex, FIGURE 22-8 Leopold maneuvers (A-D) performed in fetus with a longitudinal lie in the left face, and breech is then accomocciput anterior position (LOA).

The third maneuver aids confirmation of fetal presentation. The thumb and ingers of one hand grasp the lower portion of the maternal abdomen just above the symphysis pubis. If the presenting part is not engaged, a movable mass will be felt, usually the head. The diferentiation between head and breech is made as in the first maneuver.

The fourth maneuver helps determine the degree of descent. he examiner faces the mother's feet, and the ingertips of both hands are positioned on either side of the presenting part. They exert inward pressure and then slide caudad along the axis of the pelvic inlet. In many instances, when the head has descended into the pelvis, the anterior shoulder or the space created by the neck may be diferentiated readily from the hard head.

Abdominal palpation can be performed throughout the latter months of pregnancy and during and between the contractions of labor. At least in the past, according to Lydon-Rochelle plished readily. Second, if the vertex is presenting, the fingers are directed posteriorly and then swept forward over the fetal head toward the maternal symphysis (Fig. 22-9). During this movement, the fingers necessarily cross the sagittal suture, and its linear course is delineated. Next, the positions of the two fontanels, found at either end of the sagittal suture, are ascertained. For this, fingers are passed to the most anterior extension of the sagittal suture, and the fontanel encountered there is examined and identiied. hen, the fingers pass along the suture to the other end of the head until the other fontanel is felt and diferentiated (Fig.

10). Last, the station, or extent to which the presenting part has descended into the pelvis, can also be established at this time (p. 436). Using these maneuvers, the various sutures and fontanels are determined (Fig. 29-1, p. 554).

identification, especially in obese women or in women with muscular

FIGURE 22-9 Locating the sagittal suture by vaginal examination.

abdominal walls. Compared with digital examinations, sonography for fetal head position determination during secondstage labor is more accurate (Ramphul, 2014; Wiafe, 2016).

In most cases, the vertex enters the pelvis with the sagittal suture lying in the transverse pelvic diameter. The fetus enters the pelvis in the let occiput transverse (LO) position more commonly than right occiput transverse (RO) position (Caldwell, 1934). In occput anterior positions-LOA or ROA-either the head enters the pelvis with the occiput rotated 45 degrees anteriorly from the transverse position, or this rotation occurs subsequently. The mechanism oflabor in all these presentations is usually similar.

The positional changes of the presenting part required to navigate the pelvic canal constitute the mechanisms of labor. The cardinal movements of labor are engagement, descent, lexion, internal rotation, extension, external rotation, and expulsion

During labor, these movements not only are sequential but also show great temporal overlap. For example, as part of engagement, there is both flexion and descent of the head. It is impossible for the movements to be completed unless the presenting part descends simultaneously. Concomitantly, uterine contractions efect important modifications in fetal attitude, or habitus, especially ater the head has descended into the pelvis. These changes consist principally of fetal straightening, with loss of dorsal convexity and closer application of the extremities to the body. As a result, the fetal ovoid is transformed into a cylinder, with the smallest possible cross section typically passing through the birth canal.

FIGURE 22-10 Differentiating the fontanels by vaginal examination.

he mechanism by which the biparietal diameter-the greatest transverse diameter in an occiput presentation-passes through the pelvic inlet is designated engagement. he fetal head may engage during the last few weeks of pregnancy or not until after labor commencement. In many multiparas and some nulliparas, the fetal head is freely movable above the pelvic inlet at labor onset. In this circumstance, the head is sometimes referred to as "floating." A normal-sized head usually does not engage with its sagittal suture directed anteroposteriorly. Instead, as discussed, the fetal head usually enters the pelvic inlet either transversely or obliquely. Segel and coworkers (2012) analyzed labor in 5341 nulliparous women and found that fetal head engagement before labor onset did not afect vaginal delivery rates in either spontaneous or induced labor.

The fetal head tends to accommodate to the transverse axis of the pelvic inlet, whereas the sagittal suture, while remaining parallel to that axis, may not lie exactly midway between the symphysis and the sacral promontory. The sagittal suture frequently is deflected either posteriorly toward the promontory or anteriorly toward the symphysis (Fig. 22-12). Such lateral delection to a more anterior or posterior position in the pelvis is called asynclitism. If the sagittal suture approaches the sacral promontory, more of the anterior parietal bone presents itself to the examining fingers, and the condition is called anterior asynclitism. If, however, the sagittal suture lies close to the symphysis, more of the posterior parietal bone will present, and the condition is called posterior asynclitism. With extreme posterior asynclitism, the posterior ear may be easily palpated.

Moderate degrees of asynclitism are the rule in normal labor.

However, if severe, the condition is a common reason for cepha lopelvic disproportion even with an otherwise normal-sized pelvis. Successive fetal head shiting from posterior to anterior asynclitism aids descent.

This movement is the first reqUISIte for birth of the newborn. In nulliparas, engagement may take place before the onset oflabor, and further descent may not follow until the onset of the second stage. In multiparas, descent usually begins with engagement. Descent is brought about by one or more of four forces: (1) pressure of the amnionic fluid, (2) direct pressure of the fundus upon the breech with contractions, (3) bearing-down eforts of maternal abdominal muscles, and (4) extension and straightening of the fetal body.

1.Head floating, before engagement 5.Complete extension 2.Engagement, descent, flexion 6.Restitution (external rotation) 3.Further descent, internal rotation 7.Delivery of anterior shoulder

FIGURE 22-11 Cardinal movements of labor and delivery from a left occiput anterior position.

4.Complete rotation, beginning extension 8.Delivery of posterior shoulder

Anterior asynclitism Normal synclitism Posterior asynclitism '\ '\, ,/�>,I '.-Occipito-Sagittal � frontal plane -_.. Anterior parietal suture Pelvic inlet plane Posterior parietal

FIGURE 22-12 Synclitism and asynclitism.

As soon as the descending head meets resistance, whether from the cervix, pelvic walls, or pelvic loor, it normally lexes. With this movement, the chin is brought into more intimate contact with the fetal thorax, and the appreciably shorter suboccipitobregmatic diameter is substituted for the longer occipitofrontal diameter (Fig. 22-13).

his movement turns the occiput gradually away from the transverse axis. Usually the occiput rotates anteriorly toward the symphysis pubis, but less commonly, it may rotate posteriorly

FIGURE 22-13 Lever action produces flexion of the head. Conversion from occipitofrontal (left) to suboccipitobregmatic (right) diameter typically reduces the anteroposterior diameter from nearly 12 to 9.5 cm.

toward the hollow of the sacrum (Figs. 22-14 and 22-15).

Internal rotation is essential for completion of labor, except when the fetus is unusually small.

Calkins (1939) studied more than 5000 women in labor to ascertain the time of internal rotation. He concluded that in approximately two thirds, internal rotation is completed by the time the head reaches the pelvic loor; in about another fourth, internal rotation is completed shortly after the head reaches the pelvic loor; and in the remaining 5 percent, rotation does not take place. When the head fails to turn until reaching the pelvic floor, it typically rotates during the next one or two contrac tions in multiparas. In nulliparas, rotation usually occurs dur ing the next three to ive contractions.

Ater internal rotation, the sharply flexed head reaches the vulva and undergoes extension. If the sharply flexed head, on reaching the pelvic floor, did not extend but was driven farther downward, it would impinge on the posterior portion of the perineum and would eventually be forced through the perineal tissues. When the head presses on the pelvic floor, however, two forces come into play. he irst force, exerted by the uterus, acts more posteriorly, and the second, supplied by the resistant pelvic floor and the symphysis, acts more anteriorly. he resultant vector is in the direction of the vulvar opening, thereby causing head extension. his brings the base of the occiput into direct contact with the inferior margin of the symphysis pubis (see Fig. 22-14).

With progressive distention of the perineum and vaginal opening, an increasingly large portion of the occiput gradually appears. The head is born as the occiput, bregma, forehead, nose, mouth, and inally the chin pass successively over the anterior margin of the perineum. Immediately after its delivery, the head drops downward so that the chin lies over the maternal anus.

he delivered head next undergoes restitution (see Fig. 22-11). If the occiput was originally directed toward the left, it rotates

FIGURE 22-14 Mechanism of labor for the left occiput transverse position, lateral view. A. Engagement with posterior asynclitism at the pelvic brim. During descent, the sagittal suture is then deflected toward the sacrum. B. This leads to anterior asynclitism. C. Internal rotation and descent. D. Further internal rotation and descent with extension of the neck.

FIGURE 22-15 Mechanism of labor for right occiput posterior position showing anterior rotation.

toward the left ischial tuberosity. If it was originally directed toward the right, the occiput rotates to the right. Restitution of the head to the oblique position is followed by external rotation completion to again reach a transverse position. This movement corresponds to rotation of the fetal body and serves to bring its bisacromial diameter into relation with the anteroposterior diameter of the pelvic outlet. hus, one shoulder is anterior behind the symphysis and the other is posterior. his movement apparently is brought about by the same pelvic factors that produced internal rotation of the head.

lmost immediately after external rotation, the anterior shoulder appears under the symphysis pubis, and the perineum soon becomes distended by the posterior shoulder. After delivery of the shoulders, the rest of the body quickly passes. When the anterior shoulder is tightly wedged beneath the symphysis, then shoulder dystocia is diagnosed, which is described in Chapter 27 (p. 520).

In approximately 20 percent of labors, the fetus enters the pelvis in an occiput posterior (OP) position (Caldwell, 1934). The right occiput posterior (RaP) is slightly more common than the left (LOP). It appears likely from radiographic evidence that posterior positions are more often associated with a narrow forepelvis. They also are more commonly seen in association wi th anterior placentation (Gardberg, 1994a).

In most occiput posterior presentations, the mechanism of labor is identical to that observed in the transverse and anterior varieties, except that the occiput has to internally rotate to the symphysis pubis through 135 degrees, instead of 90 and 45 degrees, respectively (see Fig. 22-15).

Efective contractions, adequate head lexion, and average fetal size together permit most posteriorly positioned occiputs to rotate promptly as soon as they reach the pelvic loor, and labor is not lengthened appreciably. In perhaps 5 to 10 percent of cases, however, rotation may be incomplete or may not take place at all, especially if the fetus is large (Gardberg, 1994b). Poor contractions, faulty head lexion, or epidural analgesia, which diminishes abdominal muscular pushing and relaxes pelvic floor muscles, may predispose to incomplete rotation. If rotation is incomplete, transverse arrest may result. If no rotation toward the symphysis takes place, the occiput may remain in the direct occiput posterior position, a condition known as persistent occiput posterior. Both can lead to dystocia and cesar ean delivery. Techniques to manually rotate from OP to OA positions are illustrated in Chapter 29 (p. 560).

In vertex presentations, labor forces alter fetal head shape. In prolonged labors before complete cervical dilation, the portion of the fetal scalp immediately over the cervical os becomes edematous. his swelling is known as the caput succedaneum (rig. 22-16). It usually attains a.thickness of only a few millimeters, but in prolonged labors it may be suiciently extensive

FIGURE 22-16 Considerable molding of the head and caput succedaneum formation in a recently delivered newborn.

to prevent diferentiation of the various sutures and fontanels. More commonly, the caput is formed when the head is in the lower portion of the birth canal and frequently only after the resistance of a rigid vaginal outlet is encountered. Because it develops over the most dependent area of the head, one may deduce the original fetal head position by noting the location of the caput succedaneum.

Molding refers to changes in the bony fetal head shape as a result of external compressive forces (see Fig. 22-16). Possibly related to Braxton Hicks contractions, some molding develops before labor. Most studies indicate that there is seldom overlapping of the parietal bones. A "locking" mechanism at the coronal and lambdoidal sutures actually prevents such overlapping (Carlan, 1991). Molding results in a shortened suboccipitobregmatic diameter and a lengthened mentovertical diameter. These changes are of greatest importance in women with contracted pelves or asynclitic presentations. In these circumstances, the degree to which the head is capable of molding may make the diference between spontaneous vaginal delivery and an operative delivery. Some older literature cited severe head molding as a cause for possible cerebral trauma. Because of the multitude of associated factors, for example, prolonged labor with fetal sepsis and acidosis, it is impossible to link molding to any alleged fetal or neonatal neurological sequelae. .10st cases of molding resolve within the week following delivery, although persistent cases have been described (Graham, 2006). Diferentiation of molding, caput succedaneum, and cephalohematoma is discussed in Chapter 33 (p. 628).

The greatest impediment to understanding normal labor is recognizing its start. he strict deinition oflabor is: uterine contractions that bring about demonstrable facement and dilation of the cervix. This does not easily aid the clinician in determining when labor has actually begun, because this diagnosis is conirmed only retrospectively. Several methods may be used to mark its start. One defines onset as the clock time when painful contractions become regular. Unfortunately, uterine activity that causes discomfort, but that does not represent true labor, may develop

FIGURE22-17 Average labor curves for women with singleton term pregnancies presenting in spontaneous labor with vaginal delivery for nulliparas from 1959-1966 compared with those from 2002-2008.

(Redrawn from Laughon SK, Branch W, Beaver J, et al: Changes in labor patterns over 50 years. Am J Obstet Gynecol 206:419.e1.9, 2012.) at any time during pregnancy. False labor often stops spontaneously, or it may proceed rapidly into efective contractions.

A second method deines the onset of labor as beginning at the time of admission to the labor unit. In the United States, admission for labor is frequently based on the extent of cervical dilation accompanied by painful contractions. If a woman has intact membranes, then a cervical dilation of3 to 4 cm or greater is presumed to be a reasonably reliable threshold for the diagnosis of labor. In this case, labor onset commences with the time of admission. his presumptive method obviates many of the uncertainties in diagnosing labor during earlier stages of cervical dilation. Laughon and associates (2012) compared the duration of spontaneous labor at term in nulliparas delivered in the United States between 1959 and 1966 to that of those delivered from 2002 to 2008. As shown in Fiure 22-17, during those 50 years, the length oflabor increased by approximately 2 hours.

• First Stage of Labor

For labor, Friedman (1954) described a characteristic sigmoid pattern by graphing cervical dilationagainst time. his graphical approach, which was based on statistical observations, changed labor management. Friedman developed the concept of three functional labor divisions to describe the physiological objectives ofeach division (Fig. 22-18). First, during the preparatoy division, although the cervix dilates little, its connective tissue components change considerably (Chap. 21, p. 413). Sedation and conduction analgesia are capable of arresting this labor division. he dilationaldivision, duringwhich dilation proceeds at its most rapid rate, is unafected by sedation. Last, the pelvic division commences with the deceleration phase of cervical dilation. The classic labor mechanisms that involve the cardinal fetal movements of the cephalic presentation take place principally during this pelvic division. In actual practice, however, the onset of the pelvic division is seldom clearly identiiable.

As shown in Figure 22-18, the pattern of cervical dilation during the preparatory and dilational divisions of normal labor is a sigmoid curve. Two phases of cervical dilation are deined. he latent phase corresponds to the preparatory division, and 0i::'a� ofdilatation and descent curves into: (1) a preparatory division, including latent and acceleration phases; (2) a dilatational division, occupying the phase of maximum slope; and (3) a pelvic division, encompassing both deceleration phase and second stage concurrent with the phase of maximum slope of descent. (Redrawn from Friedman EA: Labor: Clinical Evaluation and Management, 2nd ed. New York, Appleton-Century-Crofts, 1978.) the activephase to the dilational division. Friedman further subdivided the active phase into the acceleration phase, thephase of mximum slope, and the deceleration phase (Fig. 22-19).

he onset of latent labor, as deined by Friedman (1972), is the pointatwhich the motherperceives regularcontractions. helatent phase for most women ends once dilation of3 to 5 cm is achieved. his threshold may be clinically useul, for it deines dilation limits beyond which active labor can be expected. More recently, a Consensus Committee of the American College of Obstetricians and ::0'a� 0 1)':D

FIGURE 22-19 Composite ofthe average dilatation curve for nulliparous labor. The first stage is divided into a relatively flat latent phase and a rapidly progressive active phase. In the active phase, there are three identifiable component parts that include an acceleration phase, a phase ofmaximum slope, and a deceleration phase. (Redrawn from Friedman EA: Labor: Clinical Evaluation and Management, 2nd ed. New York, Appleton-Century-Crofts, 1978.) -Hendricks, Brenner & Kraus Ledger

Univ. of Michigan -Rodesch et al. Temple Univ.

FIGURE 22-20 Progress of labor in primigravid women from the time of admission. When the starting point on the abscissa begins with admission to the hospital, a latent phase is not observed.

Gynecologists and Society for Maternal-Fetal Medicine (2016c) has redefined active labor to begin at 6 cm. A uller discussion of these labor changes is found in Chapter 23 (p. 445).

his concept of a latent phase has great signiicance in understanding normal human labor, because labor is considerably longer when a latent phase is included. To better illustrate this, labor was diagnosed beginning with their admission, rather than with the onset of regular contractions. When labor is deined similarly, individual labor curves are remarkably comparable.

Aprolonged latent phase was defined by Friedman and Sachtleben (1963) as one exceeding 20 hours in the nullipara and 14 hours in the multipara. hese times corresponded to the 95th percentiles. Factors that afected latent phase duration include excessive sedation or epidural analgesia; unfavorable cervical condition, that is, thick, unefaced, or undilated; and false labor. Of women who had been administered heavy sedation, 85 percent eventually entered active labor. In another 10 percent, uterine contractions ceased, suggesting that they had false labor. The remaining 5 percent experienced persistence of an abnormal latent phase and required oxytocin stimulation. Amniotomy was discouraged because of the 10-percent incidence of false labor. Sokol and associates (1977) reported a 3-to 4-percent incidence of prolonged latent phase, regardless of parity. Friedman (1972) reported that latent phase prolongation did not adversely inluence fetal or maternal morbidity or mortality rates. However, Chelmow and coworkers (1993) disputed the long-held belief that prolongation of the latent phase is benign.

The progress of labor in nulliparas has particular significance because these curves all reveal a rapid change in the slope of cervical dilation rates between 3 and 5 cm (see Fig. 22-20).

Thus, cervical dilation of3 to 6 cm or more, in the presence of uterine contractions, can be taken to reliaby represent the threshold or active labor. Similarly, these curves provide useful guideposts for labor management.

Turning again to Friedman (1955), the mean duration of active-phase labor in nulliparas was 4.9 hours. But, the standard deviation of 3.4 hours is large, hence, the active phase was reported to have a statistical maximum of 11.7 hours. Indeed, rates of cervical dilation ranged from a minimum of 1.2 up to 6.8 cm/hr. Friedman (1972) also found that multiparas progress somewhat faster in active-phase labor, with a minimum normal rate of 1.5 cm/hr. His analysis of active-phase labor concomitantly describes rates of fetal descent and cervical dilation (see Fig. 22-18). Descent begins in the later stage of active dilation, commencing at 7 to 8 cm in nulliparas and becoming most rapid after 8 cm.

Hendricks and coworkers (1970) challenged Friedman's conclusions about the course of normal human labor. Their principal diferences included: (1) absence of a latent phase, (2) no deceleration phase, (3) brevity ofilabor, and (4) dilation at similar rates for nulliparas and multiparas after 4 cm. They disputed the concept of a latent phase because they observed that the cervix dilated and efaced slowly during the 4 weeks preceding labor. They contended that the latent phase actually progressed over several weeks. hey also reported that labor was relatively rapid. Specifically, the average time from admission to complete dilation was 4.8 hours for nulliparas and 3.2 hours for multiparas.

Others have reassessed the Friedman labor curves. Zhang and associates (2010) studied electronic labor records from 62,415 parturients with spontaneous labor at term and vaginal birth. For nulliparas, the median time to progress from 4 to 5 cm was 1.3 hours, from 5 to 6 cm 0.8 hours, and thereafter, additional centimeters were gained approximately each 0.5 hours. They found that normal labor may take more than 6 hours to progress from 4 to 5 cm and more than 3 hours to progress from 5 to 6 cm dilation. Rates for multiparas were similar from 4 to 6 cm. Then, labor accelerated much faster in multiparas. Data from this study form the foundation for new guidelines regarding cesarean delivery indications for labor arrest put forth in the Obstetric Care Consensus document by the American College of Obstetrics and Gynecology and Society for Maternal-Fetal Medicine (2016c) and described in Chapter 23 (p. 444).

In a study performed at Parkland Hospital, epidural analgesia was found to lengthen the active phase of the Friedman labor curve by 1 hour (lexander, 2002). his increase was the result of a slight but significant decline in the rate of cervical dilation-1.4 cm/hr in women given epidural analgesia compared with 1.6 cm/hr in those without such analgesia. Several other reports also note that maternal obesity lengthens the irst stages oflabor by 30 to 60 minutes (Chin, 2012; Kominiarek, 2011). Finally, Adams and coworkers (2012) found that maternal fear prolonged labor by approximately 45 minutes.

Active-phase abnormalities have been reported to occur in 25 percent of nulliparous and 15 percent of multiparous labors (Sokol, 1977). Friedman (1972) subdivided active-phase problems into protraction and arrest disorders. Abnormal labor patterns, diagnostic criteria, and treatment methods are summarized in Chapter 23 (p. 442).

• Second Stage of Labor his stage begins with complete cervical dilation and ends with fetal delivery. The median duration is approximately 50 minutes for nulliparas and about 20 minutes for multiparas, but it is highly variable (Kilpatrick, 1989). In a woman of higher parity with a previously dilated vagina and perineum, two or three expulsive eforts after full cervical dilation may suice to complete delivery. Conversely, in a woman with a contracted pelvis, with a large fetus, or with impaired expulsive eforts from conduction analgesia or sedation, the second stage may be longer. Higher maternal body mass index does not interfere with second-stage labor length (Carlhall, 2013; Robinson, 2011). Abnormalities of this labor stage are described in Chapter 23 (p. 446).

he normal duration of labor may be clouded by the many clinical variables that afect the conduct of labor in modern obstetrical units. Kilpatrick and Laros (1989) reported that the mean length of irst-and second-stage labor was approximately 9 hours in nulliparas without regional analgesia, and that the 95th percentile upper limit was 18.5 hours. Corresponding times for multiparas were a mean of 6 hours and a 95th percentile maximum of 13.5 hours. These authors defined labor onset as the time when a woman recalled regular, painful contractions every 3 to 5 minutes that led to cervical change.

Spontaneous labor was analyzed in nearly 25,000 women delivered at term at Parkland Hospital in the early 1990s. Almost 80 percent of women were admitted with a cervical dilation of 5 cm or less. Parity-nulliparous versus multiparous-and cervical dilation at admission were significant determinants of the length of spontaneous labor. The median time from admission to spontaneous delivery for all parturients was 3.5 hours, and 95 percent of all women delivered within 10.1 hours. These results suggest that normal human labor is relatively short.

• Summary of Normal Labor

Labor is characterized by brevity and considerable biological variation. Active labor can be reliably diagnosed when cervical dilation is :3 cm in the presence of uterine contractions. Once this cervical dilation threshold is reached, normal progression to delivery can be expected, depending on parity, in the ensuing 4 to 6 hours. Anticipated progress during a 1-to 3-hour second stage is monitored to ensure fetal safety. Finally, most women in spontaneous labor, regardless of parity, if left unaided, will deliver within approximately 10 hours after admission for spontaneous labor. Insuicient uterine activity is a common and correctable cause of abnormal labor progress. Thereore, when the length of otherwise normal labor exceeds the expected norm, interventions other than cesarean delivery-or example, oxytocin administration-must be irst considere.

The ideal management of labor and delivery requires two potentially opposing viewpoints on the part of clinicians. First, birthing should be recognized as a normal physiological process that most women experience without complications. Second, intrapartum complications, often arising quickly and unexpectedly, should be anticipated. Thus, clinicians must simultaneously make every woman and her supporters feel comfortable, yet ensure safety for the mother and newborn if complications suddenly develop. he American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017) have collaborated in the development of Guidelines or Perinatal Care. These provide detailed information on the appropriate content of intrapartum care, including both personnel and facility requirements (Table 22-2).

Labor and delivery outside the hospital is elected by some parturients. This option and its risks and benefits are discussed in Chapter 27 (p. 524).

Congress enacted EMT ALA in 1986 to ensure public access to emergency services regardless of the ability to pay. All Medicare-participating hospitals with emergency services must provide an appropriate screening examination for any pregnant woman experiencing contractions and presenting to the emergency department for evaluation.

The deinition of an emergency condition makes specific reference to a pregnant woman who is having contractions. Labor is defined as "the process of childbirth beginning with the latent phase of labor continuing through delivery of the placenta. A woman experiencing contractions is in true labor unless a physician certifies that after a reasonable time of observation the woman is in false labor." A woman in true labor is considered "unstable" for interhospital transfer purposes until the newborn and placenta are delivered. A stable woman may, however, be transferred at the direction of the patient or by a physician who certifies that the benefits of treatment at another facility outweigh the transfer risks. Physicians and hospitals violating these federal requirements are subject to civil penalties and termination from participation in the Medicare program.

• Identification of Labor

Pregnant women are urged to report early in labor rather than to procrastinate until delivery is imminent for fear that they might be experiencing false labor. Early admittance is especially important if during antepartum care the woman, her fetus, or both are found to have risk factors for intrapartum complica tions.

Although the diferentiation between false and true labor is diicult at times, the diagnosis usually can be clariied by contraction frequency and intensity and by cervical dilation. Pates and associates (2007) studied one commonly used recommendation given to pregnant women. Namely, in the absence of ruptured membranes or bleeding, uterine contractions 5 minutes apart for 1 hour-that is, ::12 contractions in 1 hourmay signiY labor onset. Among 768 women in this study at Parkland Hospital, active labor deined as cervical dilation ::4 cm was diagnosed within 24 hours in three fourths of women with ::12 contractions per hour. Bailit and coworkers (2005) compared labor outcomes of 6121 women who presented in active labor deined as uterine contractions plus cervical dilation ::4 cm with those of 2697 women who presented in the latent phase. Women admitted during latent-phase labor had more active-phase arrest, more frequent need for oxytocin labor stimulation, and higher rates of chorioamnionitis. It was concluded that physician interventions in women presenting in the latent phase may have been the cause of subsequent labor abnormalities.

In those instances when a diagnosis of labor cannot be established with certainty, observation for a longer period is often wise. Women who present to Parkland Hospital for labor 24°/7 ,. .

symptoms at weeks gestatIon or greater are routmely evaluated in a labor triage unit contiguous to our labor and delivery unit. All women in the triage area are evaluated by nurse practitioners and certiied nurse midwives using written protocols. Women with uncomplicated pregnancies with intact membranes and cervical dilation < 4 cm receive continuous external fetal monitoring for up to 2 hours. Women diagnosed with labor by either cervical change or persistent uterine contractions are admitted. After review by a physician, women without cervical change or with abatement of contractions return home with a diagnosis of false labor. In a recent study, a total of 3949 women with uncomplicated pregnancies between and 416r weeks' gestation were diagnosed with false labor. The mean inteval from hospital discharge to when they again presented was 4.9 days (Nelson, 2017). Within this protocol, hospital discharge with false labor at term was not associated with higher rates of adverse neonatal outcomes or cesarean delivery. he American College of Obstetricians and Gynecologists (2016a) has endorsed hospital-based obstetrical triage units.

Maternal blood pressure, temperature, pulse, and respiratory rate are recorded. Fetal heart rate is evaluated using a portable Doppler device, sonography, or fetoscope. The pregnancy record is promptly reviewed to identiY complications. Problems identiied or anticipated during prenatal care should be displayed prominently in the pregnancy record. Most often, unless there has been bleeding in excess of bloody show, a cervical examination is performed. he gloved index and second ingers are introduced into the vagina while avoiding the anal region.

During prenatal care, the woman is instructed to be aware of luid leakage from the vagina and to report such an event promptly. Rupture of the membranes is signiicant for three reasons. First, if the presenting part is not ixed in the pelvis, the umbilical cord can prolapse and be compressed. Second, labor is likely to begin soon if the pregnancy is at or near term.

hird, if delivery is delayed after membrane rupture, intrauter ine and neonatal infection is more likely as the time interval increases (Herbst, 2007).

During sterile speculum examination, ruptured membranes are diagnosed if amnionic luid pools in the posterior fornix or clear fluid lows from the cevical canal. lthough several diagnostic tests for [he detection of ruptured membranes have been recommended, none is completely reliable. If the diagnosis remains uncertain, another method involves pH determination of vaginal luid. The pH of vaginal secretions normally ranges from 4.5 to 5.5, whereas that of amnionic luid is usually > .0. The use of the indicator nitrazine to identiY ruptured membranes is a simple and fairly reliable method. Test papers are impregnated with the dye, and the color of the reaction between these paper strips and vaginal luids is interpreted by comparison with a standard color chart. A pH above 6.5 is consistent with ruptured membranes. False-positive test results may occur with coexistent blood, semen, or bacterial vaginosis, whereas false-negative tests may result with scant luid.

Other tests to identiY amnionic luid include arborization or ferning of vaginal luid, which suggests amnionic rather than cervical luid. Amnionic luid crystallizes to form a fernlike pattern due to its relative concentrations of sodium chloride, proteins, and carbohydrates. Detection of alpha-fetoprotein in the vaginal vault has been used to identiY amnionic luid (Yamada, 1998). Although rarely required, identiication may also follow injection of indigo carmine into the amnionic sac via abdominal amniocentesis. Last, speciic amnionic luid proteins can be sought using point-of-care assays. These include AmniSure, which binds placental alpha microglobulin-1, and ROM Plus, which detects insulin growth factor binding protein-1 plus alpha-fetoprotein (Doret, 2013; Igbinosa, 2017).

The degree of cervical facement relects the length of the cervical canal compared with that of an unefaced cervix. When the length of the cervix is reduced by one half, it is 50-percent efaced. When the cervix becomes as thin as the adjacent lower uterine segment, it is completely, or 100-percent, efaced.

Cervical dilation is determined by estimating the average diameter of the cervical opening by sweeping the examining inger from the margin of the cevical opening on one side to that on the opposite side. The diameter traversed is estimated in centimeters. The cervix is said to be fully dilated when the diameter measures 10 cm, because the presenting part of a term-size newborn usually can pass through a cervix this widely dilated.

he position of the cervix is determined by the relationship of the cervical os to the fetal head and is categorized as posterior, midposition, or anterior. Along with position, the consistency of the cervix is determined to be soft, irm, or intermediate between these two.

heetal station, that is, the level of the presenting fetal part in the birth canal, is described in relationship to the ischial spines. These spines lie halway between the pelvic inlet and the pelvic outlet. When the lowermost portion of the presenting fetal part is at the level of the spines, it is designated s being at zero (0) station.

In the past, the long axis of the birth canal above and below the ischial spines was arbitrarily divided into thirds by some and into fifths (approximately 1 em) by other groups. In 1989, the American College of Obstetricians and Gynecologists adopted the classiication of station that divides the pelvis above and below the spines into ifths. Each ifth represents 1 em above or below the spines. hus, as the presenting fetal part descends from the inlet toward the ischial spines, the designation is -5, -4, -3, -2, -1i, then 0 station. Below the spines, as the presenting fetal part descends, it passes +1, +2, +3, +4, and +5 stations to delivery. Station + 5 em corresponds to the fetal head being visible at the introitus.

If the leading part of the fetal head is at 0 station or below, most often the fetal head has engaged-thus, the biparietal plane has passed through the pelvic inlet. f the head is unusualy moded or f caput succedaneum ormation is extensive, or both, engagement might not have taken place although the head appears to be at 0 station.

In a study done at five teaching centers in Denver, residents, nurses, and faculty were surveyed to determine what definitions were being used to describe fetal station (Carollo, 2004). Four diferent deinitions were in use. Disturbingly, these investigators found that few caregivers were aware that others were using diferent deinitions of station! Dupuis and associates (2005) tested the reliability of clinical estimations of station using the position of the leading part in centimeters above or below the spines. A birth simulator was used in which station could be precisely measured and compared with the vaginal examination done by clinicians. hey reported that the clinical examiners were incorrect a third of the time.

hese ive characteristics-cervical dilation, efacement, consistency, position, and fetal station-are assessed when tabulating the Bishop score. his score is commonly used to predict labor induction outcome and is discussed in Chapter 26 (p. 505). Taken together, these factors suggest the subjective "favorability" of the cervix for induction success.

When a woman is admitted in labor, most often the hematocrit or hemoglobin concentration is checked. he hematocrit can be measured easily and quickly. At Parkland Hospital, blood is collected in a standard collection tube with anticoagulant. From this, a heparinized capillary tube is filled to spin in a microhematocrit centrifuge in the labor and delivery unit. his provides a hematocrit value within 3 minutes. he initial collection tube is also sent to the hematology laboratory for evaluation if the point-of-care hematocrit is <30 volume percent. Another labeled tube of blood is allowed to clot and sent to the blood bank for blood type and antibody screen, if needed. A final sample is collected for syphilis and human immunodeficiency virus (HIV) serology. In some labor units, a cleancatch voided specimen is examined in all women for protein and glucose. At Parkland Hospital, however, we obtain a urine specimen for protein determination in hypertensive women only (Table 40-1, p. 712).

Women with no prenatal care are considered to be at risk for syphilis, hepatitis B, and HIV, and laboratory screening studies for these, as well as a blood type and antibody screen, are performed (American Academy of Pediatrics and American College of Obstetricians and Gynecologists, 2017). Some states, for example, Texas, require routine testing for syphilis, hepatitis B, and HIV in all women admitted to labor and delivery units, even if these were done during prenatal care.

• Management of First-Stage Labor

As soon as possible after admittance, the remainder of a general examination is completed. Whether a pregnancy is normal can best be determined when all examinations, including record and laboratory review, are completed. A rational plan for monitoring labor can then be established based on the needs of the fetus and the mother. Because labor lengths vary markedly among individuals, precise statements regarding anticipated labor duration are unwise.

In general, pain relief should depend on the needs and desires of the woman. The American College of Obstetricians and Gynecologists (2017) has speciied optimal goals for anesthesia care in obstetrics. his is discussed in detail in Chapter 25. In some units, women can choose to spend part of irststage labor in a large water tub. isks and benefits are described in Chapter 27 (p. 524).

This is discussed in detail in Chapter 24. Briely, the American Academy of Pediatrics and American College of Obstetricians and Gynecologists (2017) recommend that during irst-stage labor, in the absence of any abnormalities, the fetal heart rate should be checked immediately after a contraction at least every 30 minutes and then every 15 minutes during the second stage. If continuous electronic monitoring is used, the tracing is evaluated at least every 30 minutes during the irst stage and at least every 15 minutes during second-stage labor. For women with pregnancies at risk, fetal heart auscultation is performed at least every 15 minutes during irst-stage labor and every 5 minutes during the second stage. Continuous electronic monitoring may be used with evaluation of the tracing every 15 minutes during the first stage of labor, and every 5 minutes during the second stage.

Temperature, pulse, and blood pressure are evaluated at least every 4 hours. If membranes have been ruptured for many hours before labor onset or if there is a borderline temperature elevation, the temperature is checked hourly.

Although uterine contractions are usually assessed with electronic monitoring, they can be quantitatively and qualitatively evaluated manually (Chap. 24, p. 478). With the palm of the hand resting lightly on the uterus, the time of contraction onset is determined. Its intensity is gauged from the degree of irm ness the uterus achieves. At the acme of efective contractions, the finger or thumb cannot readily indent the uterus during a "irm" contraction. he time at which the contraction disap pears is noted next. his sequence is repeated to evaluate the frequency, duration, and intensity of contractions.

During the first stage of labor, the need for subsequent vaginal examinations to monitor cervical change and present ing part position will vary considerably. When the membranes rupture, an examination to exclude cord prolapse is performed expeditiously if the fetal head was not deinitely engaged at the previous examination. he fetal heart rate is also checked immediately and during the next uterine contraction to help detect occult umbilical cord compression. At Parkland Hos pital, periodic pelvic examinations are typically performed at 2-to 3-hour intervals to evaluate labor progress. Evidence implicating the number of vaginal examinations in infection related morbidity is conlicting (Cahill, 2012; Soper, 1989).

Food and liquids with particulate matter should be withheld during active labor and delivery. Gastric emptying time is remarkably prolonged once labor is established and analgesics are administered. As a consequence, ingested food and most medications remain in the stomach and are not absorbed. Instead, they may be vomited and aspirated (Chap. 25, p. 499). According to the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017), oral intake of moderate amounts of clear liquids is reasonable for women with uncomplicated labor. Modest amounts of clear liquids such as water, clear tea, black cofee, carbonated beverages, Popsicles, and pulp-free fruit juices are allowed in uncomplicated laboring women. In those with appreciable risks for aspiration or those with significant risks for cesarean delivery, further restriction may be instituted. For example, for those with planned cesarean delivery, liquids are halted 2 hours before and solids are stopped 6 to 8 hours prior to surgery (American College of Obstetricians and Gynecologists, 2016b).

Although an intravenous (IV) infusion system is often routinely established early in labor, real need for this in the normal pregnant woman is limited, at least until analgesia is administered. However, venous access is advantageous during the immediate puerperium to administer oxytocin prophylactically and at times therapeutically when uterine atony persists. Moreover, with longer labors, the administration of glucose, sodium, and water to the otherwise fasting woman at the rate of 60 to 120 mLlhr prevents dehydration and acidosis. Shrivastava and associates (2009) noted shorter labors in nulliparas delivering vaginally who were provided an intravenous normal saline with dextrose solution compared with those given saline solution only. In another study, 195 women in labor received lactated Ringer or isotonic sodium chloride solution at a rate of either 125 or 250 mLlhr. The mean volume of total IV luid was 2008 mL in the 125 mL/hr group and 2487 mL in the 250 mL/hr group (Garite, 2000). Labor lasted more than 12 hours in signiicantly more of the women given a 125 mLlhr infusion compared with those given 250 mLlhr-26 versus 13 percent, respectively. In yet another study, 31i1 nulliparas with uncomplicated pregnancies in spontaneous labor at term received one of three IV infusions (Edwards, 2014). Group 1 was given 125 mLlhr of lactated Ringer solution with 5 percent dextrose (D5LR), Group 2 received 250 mLihour of the same solution (D5LR), and Group 3 was administered 25 mL/hr of D5LR. Groups 1 and 2 were allowed ice chips, Popsicles, and hard candy, and Group 3 also received Gatorade. Oral intake was limited in Groups 1 and 2 but was ad libitum in Group 3. The authors concluded that any of the regimens studied was safe but none was superior for labor performance.

In bed, the laboring woman may assume the position she finds most comfortable, and often this will be lateral recumbency. Lying supine is typically avoided to avert aortocaval compression and its potential to lower uterine perfusion (Chap. 4, p. 62). However, the normal laboring woman need not be conined to bed early in labor. A comfortable chair may be beneicial psychologically and perhaps physiologically. Others encourage ambulation.

Proponents of walking report that it shortens labor, lowers rates of oxytocin augmentation, diminishes the need for analgesia, and decreases the frequency of operative vaginal delivery (Flynn, 1978; Read, 1981). In their Cochrane review, Lawrence and associates (2013) found that labor in ambulant or upright positions shortened irst-stage labor by about 1 hour and lowered cesarean delivery and epidural analgesia rates. Lupe and Gross (1986) concluded, however, that no conclusive evidence supports assertions that upright maternal posture or ambulation improves labor. hey reported that women preferred to lie on their side or sit in bed. Few chose to walk, fewer to squat, and none wanted the knee-chest position. Parturients tended to assume fetal positions in later labor. Most women enthusiastic about ambulation returned to bed when active labor began (Carlson, 1986; Williams, 1980).

Bloom and colleagues (1998) conducted a randomized trial to study the efects of walking during irst-stage labor. In 1067 women with uncomplicated term pregnancies delivered at Parkland Hospital, these investigators reported that ambulation did not afect labor duration. mbulation did not reduce the need for analgesia, nor was it harmul to the newborn. Because of these observations, we give women without complications the option to select either recumbency or supervised mbulation during labor.

Rupture of Membranes

If the membranes are intact, temptation is great, even during normal labor, to perform amniotomy. The presumed beneits are more rapid labor, earlier detection of meconium-stained amnionic luid, and the opportunity to apply an electrode to the fetus or insert a pressure catheter into the uterine cavity for monitoring. he advantages and disadvantages of amniotomy are discussed in Chapter 26 (p. 511). Importantly, the fetal head must be well applied to the cervix and not be dislodged from the pelvis during the procedure to avoid umbilical cord prolapse.

In cases with prolonged membrane rupture, deined as greater than 18 hours, antimicrobial administration for prevention of group B streptococcal infections is recommended. his is discussed in Chapter 64 (p. 1221). his practice similarly lowers rates of chorioamnionitis and endometritis (Saccone, 2015).

Distention of the bladder can hinder descent of the fetal presenting part and lead to subsequent bladder hypotonia and infection. Periodically during labor, the suprapubic region is inspected and palpated to detect distention. If the bladder is readily seen or palpated above the symphysis, the woman should be encouraged to void. At times, those who may be unable to void on a bedpan may be able to ambulate with assistance to a toilet and successfully void. If the bladder is distended and voiding is not possible, catheterization is indicated. Carley and coworkers (2002) found that 51 of 11,332 vaginal deliveries (1 in 200) were complicated by postpartum urinary retention. Most women resumed normal voiding before discharge from the hospital. Musselwhite and associates (2007) reported retention in 4.7 percent of women who had labor epidural analgesia. Risk factors for retention were primiparity, oxytocin-induced or augmented labor, perineal lacerations, operative vaginal delivery, catheterization during labor, and labor durationi> 10 hours.

• Management of Second-Stage Labor

With full cervical dilation, which signiies the onset of the second stage, a woman typically begins to bear down. With descent of the presenting part, she develops the urge to defecate. Uterine contractions and the accompanying expulsive forces may now last 1 minute and recur at an interval no longer than 90 seconds. As discussed earlier, the median duration of the second stage is 50 minutes in nulliparas and 20 minutes in multiparas, although the interval can vary. Monitoring intervals of the fetal heart rate were discussed on page 436, and interpretation of second-stage electronic fetal heart rate patterns is discussed in Chapter 24 (p. 469).

In most cases, bearing down is reflexive and spontaneous during second-stage labor. Occasionally, a woman may not employ her expulsive forces to good advantage and coaching is desirable. Her legs should be half-flexed so that she can push with them against the mattress. When the next uterine contraction begins, she is instructed to exert downward pressure as though she were straining at stool. A woman is not encouraged to push beyond the completion of each contraction. Instead, she and her fetus are allowed to rest and recover. During this period of actively bearing down, the fetal heart rate auscultated during the contraction is likely to be slow but should recover to normal range before the next expulsive efort. Fetal and obstetrical outcomes appear to be unafected whether pushing is coached or uncoached during second-stage labor (Bloom, 2006; Tuuli, 2012). Bloom and colleagues (2006) studied efects of actively coaching expulsive eforts in women without epidural analgesia. hey reported that although the second stage was slightly shorter in coached women, no other maternal advantages were gained.

Several positions during the second stage have been recommended to augment pushing eforts. Eason and colleagues (2000) reviewed various posltlons and their efect on the incidence of perineal trauma. They found that the supported upright position had no advantages over the recumbent one. Upright positions include sitting, kneeling, squatting, or resting with the back at a 30-degree elevation. In women with regional analgesia, one recent randomized trial found higher vaginal delivery rates in those in a recumbent position compared with an upright one-41 versus 35 percent (The Epidural and Position Trial Collaborative Group, 2017). In women without epidural analgesia, Gupta (2017) in their review compared upright positions with supine or lithotom) positions and their efect on labor. Upright positions ofered a slightly shorter interval to delivery as well as fewer episiotomies and operative vaginal deliveries. However, rates of blood loss > 500 mL and perhaps of second-degree lacerations were increased. Berghella and coworkers (2008) hypothesized that parity, less intense aortocaval compression, improved fetal alignment, and larger pelvic outlet diameters might explain these indings. In an earlier study, a 20-to 30-percent increase in the area of the pelvic outlet was noted with squatting compared with the supine position (Russell, 1969). Finally, Babayer and associates (1998) cautioned that prolonged sitting or squatting during the second stage may cause neuropathy of the common fibular (formerly common peroneal) nerve.

As the head descends through the pelvis, the perineum begins to bulge and the overlying skin becomes stretched. Now the scalp of the fetus may be visible through the vulvar opening. At this time, the woman and her fetus are prepared for delivery, which is described in Chapter 27 (p. 516).

An orderly and systematic approach to labor management results in reproducible beneficial maternal and perinatal outcomes (lthabe, 2008). Several labor management protocols are subsequently presented. These include those from the National Maternity Hospital in Dublin, from the World Health Organization, and from Parkland Hospital.

In Dublin more than 30 years ago, O'Driscoll and associates (1984) pioneered the concept that a disciplined, standardized labor management protocol reduced the number of cesarean deliveries for dystocia. Their overall cesarean delivery rate was 5 percent in the 1970s and 1980s with such management. The approach is now referred to as active management of labor. Two of its components-amniotomy and oxytocinhave been widely used, especially in English-speaking countries outside the United States. With this protocol, labor is diagnosed when painful contractions are accompanied by complete cervical efacement, bloody "show," or ruptured membranes. Women with such indings are committed to delivery within 12 hours. Pelvic examination is performed each hour for the next 3 hours, and thereafter at 2-hour intervals. When dilation has not increased by at least 1 cm/hr, amniotomy is performed. Progress is again assessed at 2 hours, and high-dose oxytocin infusion, described in Chapter 26 (p. 509), is started unless dilation of at least 1 cm/hr is attained. Women are constantly attended by midwives. If membranes rupture before admission, oxytocin is begun for no progress at the I-hour mark.

such active management with their "traditional" approach to cago. hey randomly assigned 705 nulliparas with uncompli cated pregnancies in spontaneous labor at term. he cesarean delivery rate was significantly lower with active versus tradi tional management-10.5 versus 14.1 percent, respectively.

Subsequent studies did not show this. Wei and associates tion in cesarean delivery rates when active management of labor was compared with standard care. Frigoletto and coworkers (1995) reported another randomized trial with 1934 nullipa rous women at Brigham and Women's Hospital in Boston.

ened labor, it did not afect the cesarean delivery rate. hese observations have since been reported by others (Brown, 2013).

A partograph was designed by the World Health Organization (WHO) for use in developing countries (Dujardin, 1992). According to Orji (2008), the partograph is similar for nulliparas and multiparas. Labor is divided into a latent phase, which should last no longer than 8 hours, and an active phase. The active phase starts at 3 cm dilation, and progress should be no slower than 1 cm/hr. A 4-hour wait is recommended before intervention when the active phase is slow. Labor is graphed, and analysis includes use of alert and action lines. Lavender and colleagues (2006) randomized 3000 nulliparous women to labor interventions at 2 hours versus 4 hours as recommended by WH O. Their cesarean delivery rate was unafected, and they concluded that interventions such as amniotomy and oxytocin were needlessly increased using the 2-hour time interval. From their Cochrane Database review, Lavender and associates (2013) do not recommend use of the partograph for standard labor management.

At Parkland Hospital, women are admitted if active labor is diagnosed or if ruptured membranes are conirmed. Labor is defined as cervical dilation of 3 to 4 cm or more in the presence of uterine contractions. Management guidelines direct that a pelvic examination be performed approximately every 2 hours. Inefective labor is suspected when the cervix does not dilate within approximately 2 hours of admission. Amniotomy is then performed, and labor progress determined at the next 2-hour evaluation. In women whose labors do not progress, an intrauterine pressure catheter is placed to assess uterine function. Hypotonic contractions and no cervical dilation after an additional 2 to 3 hours result in stimulation of labor using the high-dose oxytocin regimen described in Chapter 26 (p. 509). The goal is uterine activity of 200 to 250 Montevideo units for 2 to 4 hours before dystocia can be diagnosed. If hypotonic contractions are strongly suspected, internal monitors may be placed with amniotomy and again cervical change and contraction pattern are assessed in 2 hours. Conirmation of deicient Montevideo units at that time may prompt oxytocin augmentation for maternal or fetal indications.

Dilation rates of 1 to 2 cm/hr are accepted as evidence of progress after satisfactory uterine activity has been established with oxytocin. This can require up to 8 hours or more before cesarean delivery is performed for dystocia. The cumulative time required to efect this stepwise management approach permits many women to establish efective labor. This management protocol has been evaluated in more than 20,000 women with uncomplicated pregnancies. Importantly, these labor interventions and the relatively infrequent use of cesarean delivery did not jeopardize the fetus-newborn.

Adams SS, Eberhard-Gran M, Eskild A: Fear of childbirth and duration of labour: a study of 2206 women with intended vaginal delivery. BJOG 119(10):1238,r2012

Alexander JM, Sharma SK, Mcintire DD, et al: Epidural analgesia lengthens the Friedman active phase of labor. Obstet Gynecol 100:46,r2002

Althabe F, Buekens P, Bergel E, et al: A behavioral intervention to improve obstetrical care. N Engl J Med 358:1929, 2008

American Academy of Pediatrics and the American College of Obstetricians and Gynecologists: Guidelines for Perinatal Care, 8th ed. Elk Grove Village, AAP, 2017

American College of Obstetricians and Gynecologists: Obstetric forceps. Committee Opinion 71, August 1989 American College of Obstetricians and Gynecologists: Hospital-based triage of obstetric patients. Committee Opinion No. 667, July 2016a

American College of Obstetricians and Gynecologists: Oral intake during labor. Committee Opinion No. 441, September 2009, Reairmed 2016b American College of Obstetricians and Gynecologists: Obstetric analgesia and anesthesia. Committee Opinion No. 177, April 2017

American College of Obstetricians and Gynecologists, Society for MaternalFetal Medicine: Safe prevention of the primaty cesarean delivery. Obstetric Care Consensus No. I, March 2014, Reairmed 2016c

Babayer M, Bodack MP, Creatura C: Common peroneal neuropathy secondary to squatting during childbirth. Obstet Gynecol 91 :830, 1998

Bailit JL, Dierker L, Blanchard MH, et al: Outcomes of women presenting in active versus latent phase of spontaneous labor. Obstet Gynecol 105:77, 2005

Berghella V, Baxter JK, Chauhan SP: Evidence-based labor and delivery management. Am J Obstet Gynecol 199:445,2008

Bloom SL, Casey BM, Schafer JI, et al: A randomized trial of coached versus uncoached maternal pushing during the second stage of labor. Am J Obstet Gyneco1r194:10,r2006

Bloom SL, Mcintire DO, Kelly MA, et al: Lack of efect of walking on labor and delivery. N Engl J Med 339:76, 1998

Brown He, Paranjothy S, Dowswell T, et al: Package of care for active management in labour for reducing caesarean section rates in low-risk women. Cochrane Database Syst Rev 9:CD004907, 2013

Cahill AG, DuY CR, Odibo AO, et al: Number of cervical examinations and risk of intrapartum maternal fever. Obstet Gynecol 119(6): 1096, 2012 Caldwell WE, Moloy HC, D'Esopo DA: A roentgenologic study of the mecha nism of engagement of the fetal head. Am J Obstet Gynecol 28:824, 1934 Calkins LA: he etiology of occiput presentations. Am J Obstet Gynecol 37:618, 1939

Carlan 5J, Wyble L, Lense J, et al: Fetal head molding: diagnosis by ultrasound and a review of the literature. J Perinatal 11r: 1 05, 1991

Carley ME, Carley JM, Vasdev G, et al: Factors that are associated with clinically overt postpartum urinary retention after vaginal delivery. Am J Obstet Gynecol 187:430,r2002

Carlhall S, Kallen K, Blomberg M: Maternal body mass index and duration of labor. Eur J Obstet Gynecol Reprod Bioi 171 (1):49, 2013

Carlson JM, Diehl JA, Murray MS, et al: Maternal position during parturition in normal labor. Obstet Gynecol 68:443, 1986

Carollo Te, Reuter JM, Galan HL, et al: Defining fetal station. Am J Obstet Gyneco1r191:1793,r2004 Chelmow D, Kilpatrick SJ, Laros RK J r: Maternal and neonatal outcomes after prolonged latent phase. Obstet Gynecol 81 :486, 1993

Chin JR, Henry E, Holmgren CM, et al: Maternal obesity and contraction strength in the first stage ofrlabor. m J Obstet :129.e1,r2012

Doret M, Cartier R, Miribel J, et al: Premature preterm rupture of the membrane diagnosis in early pregnancy: PAMG-l and IGFBP-l detection in amniotic fluid with biochemical tests. Clin Biochem 46(18): 1816, 2013

Dujardin B, De Schampheleire I, Sene H, et al: Value of the alert and action lines on the partogram. Lancet 339: 1336, 1992

Dupuis 0, Silveira R, Zentner A, et al: Birth simulator: Reliability of transvaginal assessment of fetal head station as defined by the American College of Obstetricians and Gynecologists classification. Am J Obstet Gynecol 192:868, 2005

Eason E, Labrecque M, Wells G, et al: Preventing perineal trauma during childbirth: a systematic review. Obstet Gynecol 95:464, 2000

Edwards K, Reed CA, Villano KS, et l: Efect of hydration on spontaneous labor outcomes in nulliparous pregnant women: a multicenter randomized controlled trial comparing three methods. Am] PerinatoI31(6):455, 2014

Field NT, Piper ]M, Langer 0: he efect of maternal obesity on the accuracy offetal weight estimation. Obstet Gynecol 86(1): 1 02, 1995

Flynn vl, Kelly], Hollins G, et al: Ambulation in labour. BM] 2:591, 1978

Fox NS, Bhavsar V, Saltzman DH, et al: Influence of maternal body mass index on the clinical estimation of fetal weight in term pregnancies. Obstet Gynecol 113(3):641,o2009

Friedman E: The graphic analysis of labor. Am ] Obstet Gynecol 68: 1568, 1954

Friedman A: An objective approach to the diagnosis and management of abnormal labor. Bull N Y Acad Med 48:842, 1972

Friedman A: Labor: Clinical Evaluation and Management, 2nd ed. New York, Appleton-Century-Crofts, 1978

Friedman A: Primigravid labor: a graphicostatistical analysis. Obstet Gynecol 6:567, 1955

Friedman A, Sachtleben MR: Amniotomy and the course of labor. Obstet GynecoIo22:755, 1963 Frigoletto FD ]r, Lieberman E, Lang]M, et al: A clinical trial of active management of labor. N Englo] Med 333:745, 1995

Gardberg M, Tuppurainen M: Anterior placental location predisposes for occiput posterior presentation near term. Acta Obstet Gynecol Scand 73: 151, 1994a Gardberg M, Tuppurainen M: Persistent occiput posterior presentation-a clinical problem. Acta Obstet Gynecol Scand 73:45, 1994b

Garite T], Weekso], Peters-Phair K, et al: A randomized controlled trial of the efect of increased intravenous hydration on the course of labor in nulliparous women. Am] Obstet GynecoIo183:1544, 2000

Goetzinger R, Odibo AO, Shanks L, et al: Clinical accuracy of estimated fetal weight in term pregnancies in a teaching hospital. ] Matern Fetal Neonatal Med 27(1):89,o2014

Graham]M ]r, Kumar A: Diagnosis and management of extensive vertex birth molding. Clin Pediatr (Phila) 45(7):672, 2006

Gupta ]K, Sood A, Hofmeyr G], et al: Position in the second stage of labour for women without epidural anaesthesia. Cochrane Database Syst Rev 5:CD002006, 2017

Hendricks CH, Brenner WE: Cardiovascular efects of oxytocic drugs used postpartum. Am] Obstet GynecoIo108:751, 1970

Herbst A, Kallen K: Time between membrane rupture and delivery and septicemia in term neonates. Obstet Gynecol 110:612,o2007

Igbinosa I, Moore FA 3rd, Johnson C, et al: Comparison of rapid immunoassays for rupture offetal membranes. BMC Pregnancy Childbirth 17(1): 128,2017 Kilpatrick S], Laros K ]r: Characteristics of normal labor. Obstet Gynecol 74:85, 1989

Kominiarek MA, Zhang ], VanVeldhuisen P, et al: Contemporary labor patterns: the impact of maternal body mass index. Am ] Obstet Gynecol 205:244.e1,o2011

Laughon SK, Branch W, Beaver ], et al: Changes in labor patterns over 50 years. Am] Obstet GynecoI206:419.e1.9, 2012 Lavender T, lirevic A, Walkinshaw S: Efect of diferent partogram action lines on birth outcomes. Obstet Gynecol 108:295,o2006

Lavender T, Hart A, Smyth M: Efect of partogram use on outcomes for women in spontaneous labour at term. Cochrane Database Syst Rev 7:CD005461,o20o13

Lawrence A, Lewis L, Hofmeyr G], et al: Maternal positions and mobility during irst stage labour. Cochrane Database Syst Rev 10:CD003934, 2013 Leopold]: Conduct of normal births through external examination alone. Arch

GynaekoIo45:337, 1894

L6pez-Zeno ]A, Peaceman M, Adashek ]A, et al: A controlled trial of a program for the active management of labor. N Engl] Med 326:450, 1992 Lupe P], Gross TL: Maternal upright posture and mobility in labor: a review.

Obstet GynecoIo67:727, 1986

Lydon-Rochelle M, Albers L, Gowoda], et al: Accuracy of Leopold maneuvers in screening for malpresentation: a prospective study. Birth 20: 132, 1993

Musselwhite L, Faris P, Moore K, et al: Use of epidural anesthesia and the risk of acute postpartum urinary retention. Amo] Obstet Gynecol 196:472, 2007

Nelson DB, McIntire DO, Leveno K]: False labor at term in singleton pregnancies: Discharge after a standardized assessment and perinatal outcomes. Obstet GynecoIo130(1):139, 2017

Noumi G, Collado-Khoury F, Bombard A, et al: Clinical and sonographic estimation of fetal weight performed in labor by residents. Am ] Obstet GynecoIo192:1407,o2005

Nygaard I: Pelvic loor recovery ater childbirth. Obstet Gynecol 125(3):529, 20o15

O'Driscoll K, Foley M, MacDonald 0: Active management of labor as an alternative to cesarean section for dystocia. Obstet Gynecol 63:485, 1984 Orji E: Evaluating progress of labor in nulliparas and multiparas using the modiied WHO partograph. Into] Gynaecol Obstet 102:249,o2008

Pates ]A, McIntire DO, Leveno K]: Uterine contractions preceding labor.

Obstet Gynecol 110:566, 2007

Ramphul M, Ooi PV, Burke G, et al: Instrumental delivery and ultrasound: a multicentre randomised controlled trial of ultrasound assessment of the fetal head position versus standard care as an approach to prevent morbidity at instrumental delivery. B]OG 121(8):1029,o2014

Read ]A, Miller FC, Paul RH: Randomized trial of ambulation versus oxytocin for labor enhancement: a preliminary report. Am ] Obstet Gynecol 139(6):669, 1981

Robinson BK, Mapp DC, Bloom SL, et al: Increasing maternal body mass index and characteristics of the second stage of labor. Obstet Gynecol 118:1309,o2011

Russell ]G: Moulding of the pelvic outlet. ] Obstet Gynaecol Br Commonw 76:817,o1969

Saccone G, Berghella V: Antibiotic prophylaxis for term or near-term premature rupture of membranes: metaanalysis of randomized trials. Amo] Obstet Gynecol. 2015 May;212(5):627.e1

Segel SY, Carreno CA, Weiner MS, et al: Relationship between fetal station and successful vaginal delivery in nulliparous women. Am ] Perinatol 29:723,o2012

Shrivastava K, Garite T], Jenkins SM, et al: A randomized, double-blinded, controlled trial comparing parenteral normal saline with and without dextrose on the course oflabor in nulliparas. Amo] Obstet Gynecol 200(4):379. el,o2009

Sokol R], Stojkov ], Chik L, et al: Normal and abnormal labor progress: 1. A quantitative assessment and survey of the literature. ] Reprod Med 18:47, 1977

Soper DE, Mayhall CG, Dalton HP: Risk factors for imraamniotic infection: a prospective epidemiologic study. Am] Obstet GynecoIo161(3):562, 1989

Staer-]ensen ], Siafarikas F, Hilde G, et al: Postpartum recovery of levator hiatus and bladder neck mobility in relation to pregnancy. Obstet Gynecol 125(3):531,o2015

Tuuli MG, Frey A, Odibo AO, et al: Immediate compared with delayed pushing in the second stage oflabor. Obstet Gynecol 120:660, 2012

Wei S, Wo BL, Qi HP, et al: Early amniotomy and early oxytocin for prevention of, or therapy for, delay in irst stage spontaneous labour compared with routine care. Cochrane Database Syst Rev 8:CD006794, 2013

Wiafe YA, Whitehead B, Venables H, et al: he efectiveness of intrapartum ultrasonography in assessing cervical dilatation, head station and position: a systematic review and meta-analysis. Ultrasound 24(4) :222, 2016

Williams M, hon MH, Studd ]W: A study of the beneits and acceptability of ambulation in spontaneous labor. B]OG 87: 122, 1980

Yamada H, Kishida T, Negishi H, et al: Silent premature rupture of membranes, detected and monitored serially by an AFP kit. ] Obstet Gynaecol Res 24:103, 1998

Zhango], Landy H], Branch OW, et al: Contemporary patterns of spontaneous labor with normal neonatal outcomes. Obstet Gynecol 116: 1281, 2010

DYSTOCIA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441

ABNORMALITIES OF THE EXPULSIVE FORCES ........ 442

PREMATURELY RUPTURED MEMBRANES AT TERM ... 447

PRECIPITOUS LABOR AND DELIVERY ............... 448

FETOPELVIC DISPROPORTION . . . . . . . . . . . . . . . . . . . . 448

PELVIC CAPACITY .............................. 448

FACE PRESENTATION . . . . . . . . . . . . . . . . . . . . . . . . . . . 450

BROW PRESENTATION . . . . . . . . . . . . . . . . . . . . . . . . . . 452 TRANSVERSE LIE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452 COMPOUND PRESENTATION ..................... 454 COMPLICATIONS WITH DYSTOCIA. . . . . . . . . . . . . . . . . 454 ... pains become less requent and less intense, although giving rise to quite as much or even more suering than previousy. At the same time, the cervix, which was becoming obliterated and dilated in a satiactory manner, ceases to make urther proress and labour apparenty comes to a stanstill.

-J.

he term dystocia as described by Williams in the irst edition of this text still applies today. It literally means dficult labor and is characterized by abnormally slow labor progress. Similar to the factors described by Williams, dystocia arises from three distinct abnormality categories. First, uterine contractions may be insuiciently strong or inappropriately coordinated to eface and dilate the cevix-uterine dyunction. lso, voluntary maternal muscle efort during second-stage labor may be inadequate. Second, fetal abnormalities of presentation, position, or anatomy may slow progress. Last, structural changes can contract the maternal bony pelvis. Or, soft tissue abnormalities of the reproductive tract may form an obstacle to fetal descent. More simply, these alterations can be mechanistically simplified into three categories that include abnormalities of the powers-uterine contractility and maternal expulsive efort; of the passenger-the fetus; and of the passage-the pelvis and lower reproductive tract.

23-1 oten interact singly or in combination to produce dysfunctional labor. Commonly used expressions today such as cephalopelvic disproportion and ailure to progress are used to describe inefective labors. Of these,

TABLE 23-1. Common Clinical Findings in Women with Ineffective Labor

Inadequate cervical dilation or fetal descent:

Fetopelvic disproportion:

Inadequate pelvic capacity Malpresentation or pOSition of the fetus Abnormal fetal anatomy cephalopelvic disproportion is a term that came into use before the 20th century to describe obstructed labor resulting from disparity between the fetal head size and maternal pelvis. But, the term originated at a time when the main indication for cesarean delivery was overt pelvic contracture due to rickets (0lah, 1994). Such absolute disproportion is now rare, and most cases result from malposition of the fetal head within the pelvis (asynclitism) or from inefective uterine contractions. True disproportion is a tenuous diagnosis because many women who undergo cesarean delivery for this reason subsequently deliver even larger newborns vaginally in subsequent pregnancies. A second phrase, ailure to progress in either spontaneous or stimulated labor, has become an increasingly popular description of inefectual labor. his term reflects lack of progressive cervical dilation or lack of fetal descent. Neither of these two terms is specific.

• Mechanisms of Dystocia

At the end of pregnancy, the fetal head encounters a relatively thick lower uterine segment and undilated cervix. With the . onset of labor, the factors influencing progress are uterine contractions, cervical resistance, and the forward pressure exerted by the leading fetal part.

Ater complete cervical dilation, the mechanical relationship between the fetal head size and position and the pelvic capacity, namelyetopelvic proportion, becomes clearer as the fetus attempts to descend. Because of this, abnormalities in fetopelvic proportions become more apparent once the second stage is reached.

Uterine muscle malfunction can result from uterine overdistention, obstructed labor, or both. Thus, infective labor is generaly accepted as a possible warning sign of etopelvic disproportion.

Although artificial separation of labor abnormalities into pure uterine dysfunction andetopelvic disproportion simplifies classification, it is an incomplete characterization because these two abnormalities are closely interlinked. Indeed, the bony pelvis rarely limits vaginal delivery. In the absence of objective means of precisely distinguishing these two causes of labor failure, clinicians must rely on a trial of labor to determine if labor can be successful in efecting vaginal delivery.

Cervical dilation as well as propulsion and expulsion of the fetus are brought about by uterine contractions. During second-stage labor, these contractions are then reinforced by voluntary or involuntary muscular action of the abdominal wall-"pushing." The diagnosis of uterine dysfunction in the latent phase is diicult and sometimes can be made only in retrospect. Women who are not yet in active labor commonly are erroneously treated for this dysfunction.

Beginning in the 1960s, at least three significant advances have aided treatment of uterine dysfunction. First is the realization that undue labor prolongation may contribute to maternal and perinatal morbidity and mortality rates. Second, dilute intravenous infusion of oxytocin is administered to treat certain types of uterine dysfunction. Last, cesarean delivery is selected rather than diicult midforceps delivery when oxytocin fails or its use is inappropriate.

• Types of Uterine Dysfunction

Reynolds and coworkers (1948) emphasized that uterine contractions of normal labor are characterized by a gradient of myometrial activity. These forces are greatest and last longest at the fundus-considered fundal dominance-and they diminish toward the cervix. Caldeyro-Barcia and colleagues (1950) from Montevideo, Uruguay, inserted small balloons into the myometrium at various levels (Chap. 24, p. 478). hey reported that in addition to a gradient of activity, the onset of the contractions difered in the fundus, midzone, and lower uterine segments. Larks (1960) described the stimulus as starting in one cornu and then several milliseconds later in the other. he excitation waves then join and sweep over the fundus and down the uterus. Normal spontaneous contractions often exert pressures approximating 60 mm Hg (Hendricks, 1959). Even so, the Montevideo group ascertained that the lower limit of contraction pressure required to dilate the cervix is 15 mm Hg.

From these observations, two physiological types of uterine dysfunction are defined. In the more common hypotonic uterine dyunction, there is no basal hypertonus, and uterine contractions have a normal gradient pattern (synchronous). However, pressure during a contraction is insuicient to dilate the cervix.

In the second type, hypertonic uterine dysunction or incoordinate uterine dyunction, either basal tone is elevated appreciably or the pressure gradient is distorted. Gradient distortion may result from more forceful contraction of the uterine midsegment than the fundus, from complete asynchrony of the impulses originating in each cornu, or from a combination of these two.

hese just-described types of uterine dysfunction can in turn lead to labor abnormalities (Table 23-2). First, the latent phase may be prolonged, which is defined as exceeding 20 hours in the nullipara and 14 hours in the multipara. In some, uterine contractions cease, suggesting false labor. In the remainder, an abnormally long latent phase persists and is often treated with oxytocin stimulation.

In active labor, disorders are divided into slower-than-normal progress-a protraction disorder-or complete cessation of progress-an arrest disorder. Terms presented in Table 23-2 and their diagnostic criteria more precisely describe abnormal labor. To be diagnosed with either of these, a woman must be in the active phase of labor, which is defined by cervical change.

hese criteria and management of abnormal labor have recently undergone a sea change. In 2014, the American College of Obstetricians and Gynecologists and the Society for vIaternal-Fetal Medicine issued their irst Obstetric Care Consensus titled Sae Prevention of the Primary Cesarean Delivery. It was reairmed in 2016. his consensus statement was a response to concerns that cesarean delivery was overused in the United States. Namely, approximately one in three women who give birth each year undergoes this surgery (Fig. 31-1, p. 592). New recommendations from the Consensus Committee are based on

TABLE 23-2. Abnormal Labor Patterns, Diagnostic Criteria, and Methods of Treatment

Arrest Disorders Prolonged deceleration phase Secondary arrest of dilation Arrest of descent Failure of descent

CPo = cephalopelvic disproportion. Modified from Cohen, 1983.

<l.2scm/hr 1.5 cm/hr Expectant and Cesarean delivery for CPD >2 hr >2 hr Evaluate for cpo: > 1 hr > 1 hr CPO: cesarean

No descent in deceleration No CPD: oxytocin "more recent data used to revise the definition of contemporary normal labor progress" and reflect a signiicant revision of the preexisting understanding of abnormal labor.

Active-Phase Protraction. Of active-phase disorders, protraction disorders are less well described, and the time necessary before diagnosing slow progress is undefined. he Wodd Health Organization (1994) has proposed a labor management partograph in which protraction is defined as < 1 cm/ hr cervical dilation for a minimum of 4 hours. hese criteria were adapted from those of Cohen and Friedman (1983) and shown in Table 23-2. For this disorder, observation for further progress is appropriate treatment. If insuicient Montevideo units are noted, oxytocin augmentation is initiated. According to the Consensus Committee (2016), slow but progressive irststage labor should not be an indication for cesarean delivery.

Active-Phase Arrest. Handa and Laros (1993) diagnosed active-phase arrest, deined as no dilation for 2 hours or more, in 5 percent of term nulliparas. This incidence has not changed since the 1950s (Friedman, 1978). Inadequate uterine contractions, deined as less than 180 Montevideo units, calculated as shown in Figure 23-1, were diagnosed in 80 percent of women with active-phase arrest. Hauth and coworkers (1986, 1991)

FIGURE 23-' Montevideo units are calculated by subtracting the baseline uterine pressure from the peak contraction pressure for each contraction in a 1 O-minute window and adding the pressures generated by each contraction. In the example shown, there were five contractions, producing pressure changes of 52,50,47,44, and 49 mm Hg, respectively. The sum of these five contractions is 242 Montevideo

Final study sample n 62,41e5

FIGURE 23-2 Study cohort for the analysis of spontaneous labor in the Consortium on Safe Labor study. NICU = neonatal intensive care unit. (Data from Zhang, 2010.) reported that when labor is efectively induced or augmented with oxytocin, 90 percent of women achieve 200 to 225 Montevideo units, and 40 percent achieve at least 300 Montevideo units. hese results suggest that certain minimums of uterine activity should be achieved before performing cesarean delivery for dystocia.

Other criteria should also be met. First, the latent phase should be completed, and the cervix is dilated ::4 cm. Also, a uterine contraction pattern of 200 Montevideo units or more in a 10-minute period has been present for 2 or more hours without cervical change. Rouse and associates (1999) challenged the "2-hour rule" on the grounds that a longer time, that is, at least 4 hours, is necessary before concluding that the active phase of labor has failed. We agree. The Consensus Committee (2016) has expanded the criteria, as described next.

Obstetric Care Consensus Committee. There are four recom mendations by the Consensus Committee (2016) applicable to management of the irst-stage labor. The irst admonishes against cesarean delivery in the latent phase of labor. Speciically, a prolonged latent phase is not an indication for cesarean delivery. This guideline is not new and is traceable to the work of Friedman (1954), on which traditional tenets are based.

The second directive, too, is conventional practice. It recommends against cesarean delivery if labor is progressive but slow-aprotraction disorder. This instance is typically managed with observation, assessment of uterine activity, and stimulation of contractions as needed.

A third instruction addresses the cervical dilation threshold that serves to herald active labor. Namely, a cervical dilation of 6 cm-not 4 cm-is now the recommended threshold. Thus, before this threshold, standards for active-phase progress should not be applied.

A fourth stipulation notes that cesarean delivery for activephase arrest "should be reserved for women at or beyond 6 cm of dilation with ruptured membranes who fail to progress despite 4 hours of adequate uterine activity, or at least 6 hours of oxytocin administration with inadequate contractions and no cervical change."

According to the Consensus Committee (2016), the "6-cm rule" stems from labor data from the Consortium on Safe Labor study (Zhang, 2010). This study derived its numbers from a retrospective observational dataset built from abstracted labor and delivery information from 19 hospitals across the United States. Various statistical methods and heavy manipulations of these numbers were used (Cohen, 2015b). As shown in Figure 23-2, a total of 62,415 women were analyzed after excluding all women with cesarean deliveries or asphyxiated newborns. The Consensus Committee (2016) was explicit that "the Consortium on Safe Labor data, rather than the standards proposed by Friedman should inform evidence-based labor management." Described in Chapter 21 (p. 432), the latter are labor curves that have been used since irst proposed by Friedman (1955).

Critics of the Consensus Committee (2016) recommendations note that the Consortium on Safe Labor data were derived from clinical settings with a net cesarean rate of 30 percent. hus, adherence to the new recommendations may fail to achieve desired cesarean rate reductions. Also, the study lacked a focus on neonatal safety, given that all the asphyxiated neonates were excluded. Supporters note that the study of prolonged first-stage labors by Cheng and coworkers (2010) found higher rates of cesarean delivery and chorioamnionitis but not higher rates of neonatal morbidity. However, Harper and associates (2014) analyzed maternal and neonatal adverse outcomes related to first-stage labor lengths. In 5030 women, first-stage labor durations were divided into those <90th percentile or those ::90th percentile, with incremental increases thereafter. These authors concluded that a longer irst-stage labor was associated with maternal and neonatal complications and that these should be balanced against the risks of cesarean delivery. his concern for adverse fetal and maternal efects resulting from the new Consensus Committee guidelines was echoed by Cohen and Friedman (2015a,b).

Spontaneous onset of labor, Singletons, cephalic n = 98,169 Excluded: 23,280 cesarean births Vaginal delivery n = 74,889 women

TABLE 23-3. Comparison of Study Populations Analyzed to Define Normal Labor Curves

Year of data collection Early 1950s 1992-1996 Caudal/epidural analgesia (%) 8 48 Oxytocin augmentation (%) 9 50 aTripler Army Hospital. Data from Friedman, 1955; Zhang, 2002.

TABLE 23-4. Rate of Change at Each Stage of Cervical Dilation

Cervical Dilation Rate of Cervical Dilation 2 0.3 (0.1, 1.8) 3 0.4 (0.1,s1.8) 4 0.6 (0.2, 1 .8) 5 1.2 (0.3, 5.0) 6 1.7 (0.5, 6.3) 7 2.2 (0.7, 7.1) 8 2.4 (0.8, 7.7) 9 2.4 (0.7, 8.3) aMedian (5th and 95th percentiles). Data from Zhang, 2002.

Another caveat notes that the eicacy of these recommendations to achieve their primary goal is limited. In support, one retrospective cohort study of 200 women undergoing induction or augmentation before and 200 ater guideline changes found a cesarean delivery rate drop from 35 to 25 percent (WilsonLeedy, 2016). However, although the study was not powered to assess adverse neonatal outcomes, nonsigniicant but higher rates of umbilical artery gases with pH <7 and base deficit > 12 mmollL were noted in the postguideline group (Marte, 2016). In another evaluation of outcomes before and ater guideline implementation, cesarean delivery rates were unchanged. Overall, there were no associations between length of arrest and maternal or neonatal morbidity, but neonatal respiratory morbidity rates rose in newborns of women with longer periods of arrested dilation (Rosenbloom, 2017). Thus, additional studies are needed to define risks and beneits of the new guidelines.

Background for the 6-cm Rule. Review of selected publications helps explain the Consensus Committee (2016) evolution to a 6-cm rule. First, Zhang and coworkers (2002) compared study populations from one report by Friedman (1955) with one from 1992 to 1996 at TripIer Army Hospital, Hawaii (Table 23-3). The Friedman labor curves relected women in spontaneous labor with infrequent use of neuraxial labor analgesia or �: 6.2 0).;;

Duration of labor (hours)

FIGURE 23-3 Cervical dilation curves. (From Friedman (1955) and Zhang (2002).) oxytocin augmentation. In contrast, in the TripIer cohort, approximately 50 percent of women had neuraxial analgesia or augmentation. The rate of cervical change for the ensuing hour at each cervical dilation between 2 and 9 cm in the T ripIer group is shown in Table 23-4. Progress is slow between 4 and 6 cm but accelerates thereafter. his could reasonably be interpreted as the active phase beginning at 6 cm. Shown in Figure 23-3 are the labor curves for Friedman (1955) compared to the TripIer cohort. These difer in a flattening of the active phase beginning at 3 to 4 cm in the TripIer group. his is consistent with the labor results obtained in the Safe Labor Consortium study (Zhang, 2010). Namely, the 6-cm rule for active labor derives from a slowing of the rate or lattening of the slope of cervical change in irst-stage labor.

N euraxial analgesia delays the active phase of spontaneous labor and flattens the slope. For example, Gambling and associates (1998) compared combined spinal epidural (CSE) labor analgesia against intermittent intravenous (IV) boluses of 50 mg meperidine in 1223 nulliparas in spontaneous labor at term. The active phase of labor was diagnosed when cervical dilation was 4 cm in the presence of regular uterine contractions. s shown in Table 23-5, mean cervical dilation at first pain aAdministered as intermittent intravenous boluses. bMedian value.

CPresented as number (%).

dpresented as mean ± standard deviation. Data from Gambling, 1998.

TABLE 23-6. 9000 Women Undergoing Primary Cesarean Delivery for Dystocia

Percentage of

Women with Noted Median (1st, 3rd 6 cm (5,s8) Augmentation to delivery time 9.3 hr (6, 13)

Data from Alexander, 2003.

relief was 5 cm in both study groups. Oxytocin augmentation rates were signiicantly greater in the CSE group. Also, the first analgesia-to-delivery interval was lengthened (5 versus 4 hours). However, cesarean delivery rates did not difer significantly.

Importantly, the efect of neuraxial analgesia to slow activephase labor should not negatively afect use of neuraxial pain relie. As described in Chapter 25 (p. 495), investigators at Parkland Hospital completed five randomized trials involving a total of 2703 nulliparas in spontaneous labor at term (Sharma, 2004). Various neuraxial techniques were compared with meperidine for pain relief. First-stage labor was significantly lengthened with neuraxial analgesia (8.1 versus 6.6 hours) but cesarean delivery rates for dystocia were unafected (9.i1 versus 8.1 percent).

In sum, neuraxial analgesia slows the active phase of firststage labor. his currently is empirically corrected by augmentation of uterine contractions. Thus, recommendations of the Consensus Committee regarding protraction disorders are correct. Second, the Consensus Committee (2016) suggests that cesarean deliveries for dystocia are being done before 6 cm cervical dilation. However, there is good reason to believe that all of the Committee's first-stage recommendations are actually already empirically in use but are concurrent with an overall cesarean delivery rate in excess of 30 percent. For example, Table 23-6 lists labor characteristics in 9000 women with primary cesarean deliveries for dystocia at 13 university hospitals between 1999 and 2000 (Alexander, 2003). Notably, the median cervical dilation at the time ofcesarean for dystocia was 6 cm. Moreover, Figure 23-4 depicts primary cesarean delivery rates for dystocia at Parkland Hospital between 1988 and 2017. The rate has not changed significantly in 28 years. Thus, Consensus Committee (2016) guidelines may fail to prevent additional cesareans for dystocia. Again, additional studies are needed.

Fetal descent largely follows complete dilation. Moreover, the second stage incorporates many of the cardinal movements necessary for the fetus to negotiate the birth canal (Chap. 22, p. 428). Accordingly, disproportion ofthe fetus and pelvis frequently becomes apparent during second-stage labor.

Similar to irst-stage labor, time boundaries have been supported to limit second-stage duration to minimize adverse maternal and fetal outcomes. he second stage in nulliparas is limited to 2 hours and extended to 3 hours when regional analgesia is used. For multiparas, 1 hour is the limit, extended to 2 hours with regional analgesia.

Cohen (1977) investigated the fetal efects of second-stage labor length at Beth Israel Hospital. He included 4403 term nulliparas in whom electronic fetal heart rate monitoring was performed. he neonatal mortality rate was not increased in women whose second-stage labor exceeded 2 hours. Epidural analgesiawas used commonly, and this likely accounted for the large number of pregnancies with a prolonged second stage. These data inluenced decisions to permit an additional hour for the second stage when regional analgesia is used.

Menticoglou and coworkers (1995a,b) also challenged the prevailing dicta on second-stage duration. Their concern stemmed from grave neonatal injuries associated with forceps rotations to shorten second-stage labor. As a result, they allowed a longer second stage to decrease the operative vaginal delivery rate. Between 1988 and 1992, second-stage labor exceeded 2 hours in a fourth of 6041 nulliparas at term. Labor epidural 4 0)) 3.�i0C)E 20:0E)0). 0

Year of delivery

FIGURE 23-4 Primary caesarean delivery rates for dystocia in lowrisk women at term at Parkland Hospital from 1988 to 2017.

analgesia was used in 55 percent. he length of the second stage, even in those lasting up to 6 hours or more, was not related to neonatal outcome. hese results were attributed to careful use of electronic monitoring and scalp pH measurements. hese investigators concluded that there is no compelling reason to intervene with a possibly diicult forceps or vacuum extraction because a certain number of hours have elapsed. hey observed, however, that after 3 hours in the second stage, delivery by cesarean or other operative method increased progressively. By 5 hours, the prospects for spontaneous delivery in the subse quent hour were only 10 to 15 percent.

Newer guidelines have been promoted by the Consensus Com mittee (2016) for second-stage labor. These recommend allowing a nullipara to push for at least 3 hours and a multipara to push for at least 2 hours before second-stage labor arrest is diagnosed.

One caveat is that maternal and fetal status should be reassuring.

hese authors provide options to these times before cesarean deliv ery is performed. Namely, longer durations may be appropriate as long as progress is documented. Also, a speciic maximal length of undergo operative delivery has not been identiied.

Intuitively, the goal to lower cesarean delivery rates is best balanced with one to ensure neonatal safety. And, it is problematic that no robust data on neonatal outcomes support the safety of allowing prolonged second-stage labor. Data from many evaluations reveal that serious newborn consequences attend second-stage labors longer than 3 hours (Allen, 2009; Bleich, 2012; Laughon, 2014; Leveno, 2016; Rosenbloom, 2017). Other data, when adjusted for labor variables, show no diference in neonatal complications for these longer second stages (Cheng, 2004; Le Ray, 2009; Rouse, 2009). Grobman and colleagues (2016) have argued that the absolute number of such adverse outcomes is small and "overall outcomes remain good." hat said, some of the complications are severe. Thus, to fully ascertain specific efect of these guidelines on morbidity rates, randomized controlled trials are needed.

It is possible that prolonged first-stage labor presages that with the second stage. Nelson and associates (20l3) studied the relationships between the lengths of the irst and second stages of labor in 12,523 nulliparas at term delivered at Parkland Hospital. The second stage signiicantly lengthened concomitantly with increasing irst-stage duration. The 95th percentile was 15.6 and 2.9 hours for the first and second stages, respectively. Women with first stages lasting longer than 15.6 hours (>95th percentile) had a 16-percent rate of second-stage labor lasting 3 hours (95th percentile). his compared with a 4.5-percent rate of prolonged second stages in women with irst-stage labors lasting <95th percentile.

With ull cervical dilation, most women cannot resist the urge to "bear down" or "push" each time the uterus contracts (Chap. 22, p. 438). he combined force created by contractions of the uterus and abdominal musculature propels the fetus downward. At times, force created by abdominal musculature is compromised suiciently to slow or even prevent spontaneous vaginal delivery. Heavy sedation or regional analgesia may reduce the reflex urge to push and may impair the ability to contract abdominal muscles efectively. In other instances, the inherent urge to push is overridden by the intense pain created by bearing down. Two approaches to second-stage pushing in women with epidural analgesia have yielded contradictory results. The irst advocates pushing forcefully with contractions ater complete dilation, regardless of the urge to push. With the second, analgesia inusion is stopped and pushing begins only ater the woman regains the sensory urge to bear down. Fraser and coworkers (2000) found that delayed pushing reduced diicult operative deliveries, whereas Manyonda and associates (1990) reported the opposite. Hansen and colleagues (2002) randomly assigned 252 women with epidural analgesia to one of the two approaches. No adverse maternal or neonatal outcomes were linked to delayed pushing despite signiicantly prolonging second-stage labor. Plunkett and coworkers (2003), in a similar study, confirmed these indings.

Descent of the leading edge of the presenting part to the level of the ischial spines (0 station) is deined as engagement. A higher station at the onset of labor is signiicantly linked with subsequent dystocia (Friedman, 1965, 1976; Handa, 1993). Roshanfekr and associates (1999) analyzed fetal station in 803 nulliparas at term in active labor. At admission, the third with the fetal head at or below 0 station had a 5-percent cesarean delivery rate. This compared with a 14-percent rate for those with higher stations. The prognosis for dystocia, however, was not related to incrementally higher fetal head stations above the pelvic midplane (0 station). Importantly, 86 percent of nulliparous women without fetal head engagement at diagnosis of active labor delivered vaginally. hese observations apply especially for parous women because the head typically descends later in labor.

Various labor factors have been implicated as causes of uterine dysfunction. As described, neuraxial analgesia can slow labor and has been associated with lengthening both first and second stages of labor and slowing the rate of fetal descent.

Chorioamnionitis is associated with prolonged labor, and some clinicians have suggested that this maternal intrapartum infection itself contributes to abnormal uterine activity. Satin and coworkers (1992) studied the efects of chorioamnionitis on oxytocin stimulation in 266 pregnancies. Infection diagnosed late in labor was found to be a marker of cesarean delivery performed for dystocia. Specifically, 40 percent of women developing chorioamnionitis after requiring oxytocin for dysfunctional labor later required cesarean delivery for dystocia. However, this was not a marker in women diagnosed as having chorioamnionitis early in labor. It is likely that uterine infection in this clinical setting is a consequence of dysfunctional, prolonged labor rather than a cause of dystocia.

Membrane rupture at term without spontaneous uterine contractions complicates approximately 8 percent of pregnancies. In the past, labor stimulation was initiated if contractions did not begin ater 6 to 12 hours. Practice-changing research included that of Hannah (1996) and Peleg (1999) and their associates, who enrolled a total of 5042 pregnancies with ruptured membranes in a randomized investigation. hey measured the efects of induction versus expectant management and also compared induction using intravenous oxytocin with that using prostaglandin E2 gel. There were approximately 1200 pregnancies in each of the four study arms. They concluded that labor induction with intravenous oxtocin was preferred management. This was based on signiicantly fewer intrapartum and postpartum infections in women whose labor was induced. There were no significant differences in cesarean delivery rates. Subsequent analysis by Hannah and coworkers (2000) indicated higher rates of adverse outcomes when expectant management at home was compared with in-hospital observation. Mozurkewich and associates (2009) reported lower rates of chorioamnionitis, metritis, and neonatal intensive care unit admissions for women with term ruptured membranes whose labors were induced compared with those managed expectantly. At Parkland Hospital, labor is induced soon ater admission when ruptured membranes are conirmed at term. In those with hypotonic contractions or with advanced cervical dilation, oxytocin is selected to lower potential hyperstimulation risk. In those with an unfavorable cervix and no or few contraction, prostaglandin E1 (misoprostol) is chosen to promote cervical ripening and contractions. he benefit of prophylactic antibiotics in women with ruptured membranes before labor at term is unclear (Passos, 2012). However, in those with membranes ruptured longer than 18 hours, antibiotics are instituted for group B streptococcal infection prophylaxis (Chap. 64, p. 1221).

Labor can be too slow, but it also can be abnormally rapid. Precipitous labor and delivery is extremely rapid labor and delivery. It may result from an abnormally low resistance of the soft parts of the birth canal, from abnormally strong uterine and abdominal contractions, or rarely from the absence of painful sensations and thus a lack of awareness of vigorous labor.

Precipitous labor terminates in expulsion of the fetus in less than 3 hours. Using this deinition, 25,260 live births-3 percent-were complicated by precipitous labor in the United States in 2013 (Martin, 2015). Despite this incidence, little published information describes maternal and perinatal outcomes.

For the mother, precipitous labor and delivery seldom are accompanied by serious maternal complications if the cervix is efaced appreciably and compliant, if the vagina has been stretched previously, and if the perineum is relaxed. Conversely, vigorous uterine contractions combined with a long, irm cervix and a noncompliant birth canal may lead to uterine rupture or extensive lacerations of the cervix, vagina, vulva, or perineum (Sheiner, 2004). It is in these latter circumstances that amnionic-luid embolism most likely develops (Chap. 41, p. 785). Precipitous labor is frequently followed by uterine atony. he uterus that contracts with unusual vigor bore delivery is likey to be hypotonic ater delivey. In one report of 99 term pregnancies, short labors were more common in multiparas who typically had contractions at intervals less than 2 minutes. Precipitous labors have been linked to cocaine abuse and associated with placental abruption, meconium, postpartum hemorrhage, and low Apgar scores (Mahon, 1994).

For the neonate, adverse perinatal outcomes from rapid labor may be increased considerably for several reasons. The tumultuous uterine contractions, often with negligible intervals of relaxation, prevent appropriate uterine blood flow and fetal oxygenation. Resistance of the birth canal may rarely cause intracranial trauma. Acker and coworkers (1988) reported that Erb or Duchenne brachial palsy was associated with such labors in a third of cases. Finally, during an unattended birth, the newborn may fall to the loor and be injured, or it may need resuscitation that is not immediately available.

As treatment, analgesia is unlikely to modiy these unusually forceful contractions to a signiicant degree. The use of tocolytic agents such as magnesium sulfate or terbutaline is unproven in these circumstances. Use of general anesthesia with agents that impair uterine contractibility such as isoflurane is often excessively heroic. Certainly, any oxytocin being administered should be stopped immediately.

Fetopelvic disproportion arises from diminished pelvic capacity, from abnormal fetal size or presentation, or more usually from both. The pelvic inlet, midpelvis, or pelvic outlet may be contracted solely or in combination. Any contraction of the pelvic diameters that diminishes pelvic capacity can create dystocia during labor. Normal pelvic dimensions are additionally discussed and illustrated in Chapter 2 (p. 30).

Using clinical measures, it is important to identiy the shortest anteroposterior diameter through which the fetal head must pass. Before labor, the fetal biparietal diameter averages from 9.5 to as much as 9.8 cm. Therefore, it might prove diicult or even impossible for some fetuses to pass through a pelvic inlet that has an anteroposterior diameter < 10 cm. Mengert (1948) and Kaltreider (1952), employing x-ray pelvimetry, demonstrated that the incidence of diicult deliveries rises when either the anteroposterior diameter of the inlet is < 10 cm or the transverse diameter is < 12 cm. As expected, when both diameters are contracted, dystocia rates are much greater than when only one is contracted. Either of these measures is used to consider a pelvis contracted.

The anteroposterior diameter of the inlet, which is the obstetrical conjugate, is commonly approximated by manually measuring the diagonal conjugate, which is approximately 1.5 cm greater. Ascertainment of these measures is described in Chapter 2 (p. 30). Therefore, inlet contraction usually is defined as a diagonal conjugate < 11.5 cm.

A small woman is likely to have a small pelvis, but she is also likely to have a small neonate. Thoms (1937) studied 362 nulliparas and found that the mean birth weight of their ofspring was significantly lower-280 g-in women with a small pelvis than in those with a medium or large pelvis.

Normally, cervical dilation is aided by hydrostatic action of the unruptured membranes or after their rupture, by direct application of the presenting part against the cervix. In con tracted pelves, however, because the head is arrested in the pelvic inlet, the entire force exerted by the uterus acts directly on the portion of membranes that contact the dilating cervix.

Consequently, early spontaneous rupture of the membranes is more likely.

After membrane rupture, absent pressure by the head against the cervix and lower uterine segment predisposes to less efec tive contractions. Hence, further dilation may proceed very slowly or not at all. Cibils and Hendricks (1965) reported that the mechanical adaptation of the fetal passenger to the bony passage plays an important part in determining the eiciency of contractions. The better the adaptation, the more eicient the contractions. hus, cervical response to labor provides a prog nostic view of labor outcome in women with inlet contraction.

A contracted inlet also plays an important part in the pro duction of abnormal presentations. In nulliparas with normal pelvic capacity, the presenting part at term commonly descends into the pelvic cavity before labor onset. When the inlet is con tracted considerably or there is marked asynclitism, descent usually does not take place until after labor onset, if at all.

Cephalic presentations still predominate, but the head loats freely over the pelvic inlet or rests more laterally in one of the iliac fossae. Accordingly, very slight influences may cause the fetus to assume other presentations. In women with contracted pelves, face and shoulder presentations are encountered three times more frequently, and the cord prolapses four to six times more often.

his inding is more common than inlet contraction. It frequently causes transverse arrest of the fetal head, which potentially can lead to a diicult midforceps operation or to cesarean delivery.

The obstetrical plane of the midpelvis extends from the inferior margin of the symphysis pubis through the ischial spines and touches the sacrum near the junction of the fourth and ifth vertebrae. A transverse line theoretically connecting the ischial spines divides the midpelvis into anterior and posterior portions (Fig. 2-16, p. 30). he former is bounded anteriorly by the lower border of the symphysis pubis and laterally by the ischiopubic rami. The posterior portion is bounded dorsally by the sacrum and laterally by the sacrospinous ligaments, forming the lower limits of the sacrosciatic notch.

Average midpelvis measurements are as follows: transverse, or interischial spinous, 10.5 cm; anteroposterior, from the lower border of the symphysis pubis to the junction of 54-5, 11.5 cm; and posterior sagittal, from the midpoint of the interspinous line to the same point on the sacrum, 5 cm. he deinition of midpelvic contractions has not been established with the same precision possible for inlet contractions. Even so, the midpelvis is likely contracted when the sum of the interspinous and posterior sagittal diameters of the midpelvis-normally, 10.5 plus 5 cm, or 15.5 cm-falls to 13.5 cm or less. his concept was emphasized by Chen and Huang (1982) in evaluating possible midpelvic contraction. Nlidpelvic contraction is suspected whenever the interspinous diameter is < 10 cm. When it mea sures < 8 cm, the midpelvis is contracted.

Although no precise manual method permits measure of midpelvic dimensions, a suggestion of contraction sometimes can be inferred if the spines are prominent, the pelvic sidewalls converge, or the sacrosciatic notch is narrow. Moreover, Eller and Mengert (1947) noted that the relationship between the intertuberous and interspinous diameters of the ischium is suf ficiently constant that narrowing of the interspinous diameter can be anticipated when the intertuberous diameter is narrow.

A normal intertuberous diameter, however, does not always exclude a narrow interspinous diameter.

This inding usually is defined as an interischial tuberous diam eter of 8 cm or less. The pelvic outlet may be roughly likened to two triangles, with the interischial tuberous diameter con stituting the base of both. The sides of the anterior triangle are the pubic rami, and its apex is the inferoposterior surface of the symphysis pubis. The posterior triangle has no bony sides but is limited at its apex by the tip of the last sacral vertebra-not the tip of the coccyx. Diminution of the intertuberous diam eter with consequent narrowing of the anterior triangle must inevitably force the fetal head posteriorly. Floberg and asso almost 1 percent of more than 1400 unselected nulliparas with term pregnancies. A contracted outlet may cause dystocia not tion. Oulet contraction without concomitant midplane contrac tion is rare.

Although the disproportion between the fetal head and the pelvic outlet is not suiciently great to give rise to severe dystocia, it may play an important part in perineal tears. With increased narrowing of the pubic arch, the occiput cannot emerge directly beneath the symphysis pubis but is forced farther down upon the ischiopubic rami. The perineum, consequently, becomes increasingly distended and thus exposed to risk of laceration.

Vallier (2012) reviewed experiences with pelvic fractures and pregnancy. Trauma from automobile collisions was the most common cause. Moreover, they note that fracture pattern, minor malalignment, and retained hardware are not absolute indications for cesarean delivery. In determining suitability for vaginal delivery, fracture healing requires 8 to 12 weeks and thus recent fracture merits cesarean delivery (Amorosa, 2013). A history of pelvic fracture warrants careful review of previous radiographs and possible imaging pelvimetry later in pregnancy.

The techniques for clinical evaluation using digital examination of the bony pelvis during labor are described in detail in Chapter 2 (p. 30). The value of radiological imaging to assess pelvic capacity has also been examined. First, with x-ray pelvimetry alone, the prognosis for successful vaginal delivery in any given pregnancy with cephalic presentation cannot be established (Mengert, 1948). Similarly, one systematic review found insufficient evidence to support the use of x-ray pelvimetry with cephalic presentations (Pattinson, 2017).

Advantages of pelvimetry with computed tomography (CT) compared with those of conventional x-ray pelvimetry include greater accuracy and easier performance. With either method, costs are comparable, and x-ray exposure is small (Chap. 46, p. 906). Depending on the machine and technique employed, fetal doses with CT pelvimetry may range from 250 to 1500 mrad (Moore, 1989).

Advantages of magnetic resonance (MR) pelvimetry include lack of ionizing radiation, accurate measurements, complete fetal imaging, and the potential for evaluating soft tissue dystocia (McCarthy, 1986; Stark, 1985). Zaretsky and colleagues (2005) used l\1R imaging to measure pelvic and fetal head volume to identiy those women at greatest risk of undergoing cesarean delivery for dystocia. Signiicant associations were found between some of the measures and cesarean delivery for dystocia. However, these researchers could not with accuracy predict which individual woman would require cesarean delivery. Others have reported similar indings (Sporri, 1997).

Fetal size alone is seldom a suitable explanation for failed labor. Even with current technology, a fetal size threshold to predict fetopelvic disproportion is still elusive. Most cases of disproportion arise in fetuses whose weight is well within the range of the general obstetrical population. As shown in Figure 23-5, two thirds of neonates who required cesarean delivery after failed forceps delivery weighed <3700 g. hus, other factorsfor example, malposition of the head-obstruct fetal passage through the birth canal. hese include asynclitism, occiput posterior position, and face or brow presentation.

For fetal head size estimation, clinical and radiographical methods to predict fetopelvic disproportion have proved �0 �O >� � x:5•x3 xO

FIGURE 23-5 Birthweight distribution of 362 newborns born by cesarean delivery after a failed forceps attempt at Parkland Hospital from 1989-1•999. Only 12 percent (n 44) of the newborns weighed >4000 g (dark bars).

disappointing. Mueller (1885) and Hillis (1930) described a clinical maneuver to predict disproportion. The fetal brow and the suboccipital region are grasped through the abdominal wall with the fingers, and firm pressure is directed downward in the axis of the inlet. If no disproportion exists, the head readily enters the pelvis, and vaginal delivery can be predicted. Thorp and coworkers (1993) performed a prospective evaluation of this Mueler-Hillis maneuver. They found no relationship between failed descent during the maneuver and subsequent labor dystocia.

Measurements of fetal head diameters using plain radiographical techniques are not used because of parallax distortions. he biparietal diameter and head circumference can be measured sonographically, and investigators have attempted to use this information in the management of dystocia. hurnau and colleagues (1991) used the etal-pelvic index to identiy labor complications. Unfortunately, the sensitivity of such measurements to predict cephalopelvic disproportion is poor (Ferguson, 1998; Korhonen, 2015). We believe that no current method of measurement satisfactorily predicts fetopelvic disproportion based on head size.

With this presentation, the neck is hyperextended so that the occiput is in contact with the fetal back, and the chin (mentum) is presenting (Fig. 23-6). The fetal face may present with the chin (mentum) anteriorly or posteriorly, relative to the maternal symphysis pubis (Chap. 22, p. 425). Although some mentum posterior presentations persist, most convert spontaneously to anterior even in late labor (Duf, 1981). If not, the fetal brow (bregma) is pressed against the maternal symphysis pubis. his position precludes lexion of the fetal head necessary to negotiate the birth canal. hus, a mentum posterior presentation is undeliverable except with a very preterm fetus.

FIGURE 23-6 Face presentation. The occiput is the longer end of the head lever. The chin is directly posterior. Vaginal delivery is impossible unless the chin rotates anteriorly.

450FIGURE 23-7 Mechanism of labor for right mentoposterior position with subsequent rotation of the mentum anteriorly and delivery.

Face presentation is diagnosed by vaginal examination and palpation of facial features. A breech may be mistaken for a face presentation. Namely, the anus may be mistaken for the mouth, and the ischial tuberosities for the malar prominences. Digital diferentiation is described in Chapter 28 (p. 540). Radiographically, demonstration of the hyperextended head with the facial bones at or below the pelvic inlet is characteristic.

Cruikshank and White (1973) reported an incidence of 1 in 600, or 0.17 percent. As shown in Table 22-1 (p. 422), among more than 70,000 singleton newborns delivered at Parkland Hospital, approximately 1 in 2000 had a face presentation at delivery.

Causes of face presentations are numerous and include conditions that favor extension or prevent head lexion. Preterm fetuses, with their smaller head dimensions, can engage before conversion to vertex position (Shafer, 2006). In exceptional instances, marked enlargement of the neck or coils of cord around the neck may cause extension. Bashiri and associates (2008) reported that fetal malformations and hydramnios were risk factors for face or brow presentations. Anencephalic fetuses naturally present by the face.

Extended neck positions develop more frequently when the pelvis is contracted or the fetus is very large. In a series of 141 face presentations studied by Hellman and coworkers (1950), the incidence of inlet contraction was 40 percent. his high incidence of pelvic contraction should be kept in mind when considering management.

High parity is a predisposing factor for face presentation (Fuchs, 1985). In these cases, a pendulous abdomen permits the back of the fetus to sag forward or laterally, often in the same direction in which the occiput points. his promotes extension of the cervical and thoracic spine.

Mechanism of Labor

Face presentations rarely are observed above the pelvic inlet. Instead, the brow generally presents early and is usually converted to present the face after further extension of the neck during descent. he mechanism of labor in these cases consists of the cardinal movements of descent, internal rotation, and flexion, and the accessory movements of extension and external rotation (Fig. 23-7). Descent is brought about by the same factors as in cephalic presentations. Extension results from the relation of the fetal body to the delected head, which is converted into a two-armed lever, the longer arm of which extends from the occipital condyles to the occiput. When resistance is encountered, the occiput must be pushed toward the back of the fetus while the chin descends.

The objective of internal rotation of the face is to bring the chin under the symphysis pubis. Only in this way can the neck traverse the posterior surface of the symphysis pubis. If the chin rotates directly posteriorly, the relatively short neck cannot span the anterior surface of the sacrum, which measures about 12 cm in length. Moreover, the fetal brow (bregma) is pressed against the maternal symphysis pubis. This position precludes lexion necessary to negotiate the birth canal. Hence, as discussed earlier, birth of the head from a mentum posterior position is impossible unless the shoulders enter the pelvis at the same time, an event that is impossible except when the fetus is extremely small or macerated. Internal rotation results from the same factors as in vertex presentations.

After anterior rotation and descent, the chin and mouth appear at the vulva, the undersurface of the chin presses against the symphysis, and the head is delivered by lexion. The nose, eyes, brow (bregma), and occiput then appear in succession over the anterior margin of the perineum. ter birth of the head, the occiput sags backward toward the anus. Next, the chin rotates externally to the side toward which it was originally directed, and the shoulders are born as in cephalic presentations.

Edema may sometimes significantly distort the face. At the same time, the skull undergoes considerable molding, manifested by an increase in length of the occipitomental diameter of the head.

In the absence of a contracted pelvis and with efective labor, successful vaginal delivery usually will follow. Fetal heart rate monitoring is probably better done with external devices to avoid damage to the face and eyes. Because face presentations among term-size fetuses are more common when there is some degree of pelvic inlet contraction, cesarean delivery frequently is indicated. Attempts to convert a face presentation manually into a vertex presentation, manual or forceps rotation of a persistently posterior chin to a mentum anterior position, and internal podalic version and extraction are dangerous and should not be attempted. Low or outlet forceps delivery of a mentum anterior face presentation can be completed and is described in Chapter 29 (p. 562).

This rare presentation is diagnosed when that portion of the fetal head between the orbital ridge and the anterior fontanel presents at the pelvic inlet. As shown in Figure 23-8, the fetal head thus occupies a position midway between full lexion (occiput) and extension (face). Except when the fetal head is small or the pelvis is unusually large, engagement of the fetal head and subsequent delivery cannot take place as long as the brow presentation persists.

The causes of persistent brow presentation are the same as those for face presentation. A brow presentation is commonly unstable and often converts to a face or an occiput presentation (Cruikshank, 1973). The presentation may be recognized by abdominal palpation when both the occiput and chin can be palpated easily, but vaginal examination is usually necessary. The frontal sutures, large anterior fontanel, orbital ridges, eyes, and root of the nose are felt on vaginal examination, but neither the mouth nor the chin is palpable.

FIGURE 23-8 Brow posterior presentation.

With a very small fetus and a large pelvis, labor is generally easy. With a larger fetus, it is usually diicult. his is because engagement is impossible until there is marked molding that shortens the occipitomental diameter or more commonly, until the neck either lexes to an occiput presentation or extends to a face presentation. The considerable molding essential for vaginal delivery of a persistent brow characteristically deforms the head. he caput succedaneum is over the forehead, and it may be so extensive that identiication of the brow by palpation is impossible. In these instances, the forehead is prominent and squared, and the occipitomental diameter is diminished.

In transient brow presentations, the prognosis depends on the ultimate presentation. If the brow persists, prognosis is poor for vaginal delivery unless the fetus is small or the birth canal is large. Principles of management are the same as those for a face presentation.

In this position, the long axis of the fetus is approximately perpendicular to that of the mother. When the long axis forms an acute angle, an oblique lie results. The latter is usually only transitory, because either a longitudinal or transverse lie commonly results when labor supervenes. For this reason, the oblique lie is called an unstable lie in Great Britain.

FIGURE 23-9 Leopold maneuver performed on a woman with a fetal transverse lie, right acromiodorsoanterior position.

In a transverse lie, the shoulder is usually positioned over the pelvic inlet. The head occupies one iliac fossa, and the breech the other. This creates a shoulder presentation in which the side of the mother on which the acromion rests determines the designation of the lie as right or let acromial. And because in either position the back may be directed anteriorly or posteriorly, superiorly or inferiorly, it is customary to distinguish varieties as dorsoanterior and dorsoposterior (Fig. 23-9).

A transverse lie is usually recognized easily, often by inspection alone. The abdomen is unusually wide, whereas the uterine fundus extends to only slightly above the umbilicus. No fetal pole is detected in the fundus, and the ballottable head is found in one iliac fossa and the breech in the other. The position of the back is readily identifiable. When the back is anterior, a hard resistance plane extends across the front of the abdomen. When it is posterior, irregular nodulations representing fetal small parts are felt through the abdominal wall.

On vaginal examination, in the early stages of labor, if the side of the thorax can be reached, it may be recognized by the "gridiron" feel of the ribs. With further dilation, the scapula and the clavicle are distinguished on opposite sides of the thorax. The position of the axilla indicates the side of the mother toward which the shoulder is directed.

(0.3 percent) at both the Mayo Clinic and the University of Iowa Hospital (Cruikshank, 1973; Johnson, 1964). This is remarkably similar to the incidence at Parkland Hospital of approximately 1 in 335 singleton fetuses.

Some of the more common causes of transverse lie include: (1) abdominal wall relaxation from high parity, (2) preterm fetus, (3) placenta previa, (4) abnormal uterine anatomy, (5) hydramnios, and (6) contracted pelvis.

Women with four or more deliveries have a tenfold incidence of transverse lie compared with nulliparas. A relaxed and pendulous abdomen allows the uterus to fall forward, delecting the long axis of the fetus away from the axis of the birth canal and into an oblique or transverse position. Placenta previa and pelvic contraction act similarly. A transverse or oblique lie occasionally develops in labor from an initial longitudinal position.

Mechanism of Labor

Spontaneous delivery of a fully developed newborn is impossible with a persistent transverse lie. After rupture of the membranes, if labor continues, the fetal shoulder is forced into the pelvis, and the corresponding arm frequently prolapses (Fig. 23-10). After some descent, the shoulder is arrested by the margins of the pelvic inlet. As labor continues, the shoulder is impacted irmly in the upper part of the pelvis. he uterus then contracts vigorously in an unsuccessful attempt to overcome the obstacle. With time, a retraction ring rises increasingly higher and becomes more marked. With this neglected transverse lie, the uterus will eventually rupture. Even without this complication, morbidity is increased because of the frequent association

FIGURE 23-10 Neglected shoulder presentation. A thick cular band forming a pathological retraction ring has developed just above the thin lower uterine segment. The force generated during a uterine contraction is directed centripetally at and above the level of the pathological retraction ring. This serves to stretch further and possibly to rupture the thin lower segment below the retraction ring.

with placenta previa, the increased likelihood of cord prolapse, and the necessity for major operative eforts.

If the fetus is small-usually < 800 g-and the pelvis is large, spontaneous delivery is possible despite persistence of the abnormal lie. The fetus is compressed with the head forced against its abdomen. A portion of the thoracic wall below the shoulder thus becomes the most dependent part, appearing at the vulva. he head and thorax then pass through the pelvic cavity at the same time. he fetus, which is doubled upon itself and thus sometimes referred to as condupLicato corpore, is expelled.

Active labor in a woman with a transverse lie is usually an indication for cesarean delivery. Before labor or early in labor, with the membranes intact, attempts at external version are worthwhile in the absence of other complications. If the fetal head can be maneuvered by abdominal manipulation into the pelvis, it should be held there during the next several contractions in an attempt to ix the head in the pelvis.

With cesarean delivery, because neither the feet nor the head of the fetus occupies the lower uterine segment, a low transverse incision into the uterus may lead to diicult fetal extraction. his is especially true of dorsoanterior presentations. herefore, a vertical hysterotomy incision is often indicated .

With this, an extremity prolapses alongside the presenting part, and both present simultaneously in the pelvis (Fig. 23-11). Goplerud and Eastman (1953) identiied a hand or arm prolapsed alongside the head once in every 700 deliveries. Much less common was prolapse of one or both lower extremities alongside a cephalic presentation or a hand alongside a breech. At Parkland Hospital, compound presentations were identiied in only 68 of more than 70,000 singleton fetuses-an incidence of approximately 1 in 1000. Causes of compound presentations are conditions that prevent complete occlusion of the pelvic inlet by the fetal head, including preterm labor.

In most cases, the prolapsed part should be left alone, because most often it will not interfere with labor. If the arm is prolapsed alongside the head, the condition should be observed closely to ascertain whether the arm retracts out of the way with descent of the presenting part. If it fails to retract and if it appears to prevent descent of the head, the prolapsed arm should be pushed gently upward and the head simultaneously downward by fundal pressure.

In general, rates of perinatal mortality and morbidity are increased as a result of concomitant preterm delivery, prolapsed cord, and traumatic obstetrical procedures. Serious injury to the forearm is rare (Kwok, 2015; Tebes, 1999).

Dystocia, especially if labor is prolonged, is associated with a higher incidence of several common obstetrical and neonatal complications. Inection, either intrapartum chorioamnionitis or postpartum pelvic infection, is more common with desultory

FIGURE 23-11 Compound presentation. A. The left hand is lying in front of the vertex. With further labor, the hand and arm may retract from the birth canal, and the head may then descend normally. B. Photograph of a small 34-week fetus with a compound presentation that delivered uneventfully with the hand presenting first. (Used with permission from Dr. Elizabeth Mosier.) and prolonged labors. Pospartum hemorrhage rates from atony are increased with prolonged and augmented labors. Uterine tears with hysterotomy also occur at greater incidence if the fetal head is impacted in the pelvis.

Uterine rupture is another risk. Abnormal thinning of the lower uterine segment creates a serious danger during prolonged labor, particularly in women of high parity and in those with a prior cesarean delivery. When disproportion is so pronounced that there is no engagement or descent, the lower uterine segment becomes increasingly stretched, and rupture may follow. In such cases, the normal contraction ring is usually exaggerated, like that shown in Figure 23-10.

Such pathological retraction rings are localized constrictions of the uterus that develop in association with prolonged obstructed labors. Seldom encountered today, the pathological retraction ring o/Bandl is associated with marked stretching and thinning of the lower uterine segment. In contemporary practice, after birth of a irst twin, a pathological ring may still develop occasionally as an hourglass constriction of the uterus. he band may be seen clearly as a uterine indentation and signifies impending rupture of the lower uterine segment. he ring can sometimes be relaxed and delivery efected with appropriate general anesthesia, but for the second twin (Chap. 45, p. 890).

Fistula ormation may result from dystocia, as the presenting part is irmly wedged into the pelvic inlet. Tissues of the birth canal lying between the leading part and the pelvic wall may be subjected to excessive pressure. Because of impaired circula tion, necrosis can result and become evident several days after delivery as vesicovaginal, vesicocervical, or rectovaginal istulas.

Most often, pressure necrosis follows a very prolonged second stage. Such fistulas are rarely seen today except in undeveloped countries.

recent attention. The pelvic floor is exposed to direct compres sion from the fetal head and to downward pressure from mater nal expulsive eforts. These forces stretch and distend the pelvic floor, resulting in functional and anatomical alterations in the muscles, nerves, and connective tissues. Accumulating evidence suggests that such efects on the pelvic floor during childbirth can afect urinary or anal continence and pelvic support. hese relationships are discussed in Chapter 30 (p. 568).

Lower extremiy nerve injuy in the mother can follow prolonged second-stage labor. Wong and colleagues (2003) reviewed neurological injury involving the lower extremities in association with labor and delivery. The most common mechanism is external compression of the common fibular (formerly common peroneal) nerve. This is usually caused by inappropriate leg positioning in stirrups, especially during prolonged second-stage labor. hese and other injuries are discussed in Chapter 36 (p. 661). Fortunately, symptoms resolve within 6 months of delivery in most women.

Similar to the mother, the incidence of peripartum fetal sepsis rises with longer labors. Caput succedaneum and molding develop commonly and may be impressive (Fig. 22-16, p. 431) (Buchmann, 2008). Mechanical trauma such as nerve injury, fractures, and cephalohematoma are also more frequent and are discussed further in Chapter 33 (p. 627).

Acker DB, Gregory KD, Sachs BP, et al: Risk factors for Erb-Duchenne palsy.

Obstet Gynecol 71:389, 1988 Alexander J: MFMU Cesarean Registry: labor characteristics of women undergo ing cesarean delivery for dystocia. Am J Obstet Gynecol 189(6):5138,2003 Allen VM, Baskett TF, O'Connell CM, et al: Maternal and perinatal outcomes with increasing duration of the second stage oflabor. Obstet Gynecol 113(6):1248,r2009

American College of Obstetricians and Gynecologists, Society for Matenal

Fetal Medicine: Safe prevention of the primary cesarean delivery. Obstetric

Care Consensus No.r1, March 2014, Reairmed 2016

Amorosa LF, Amorosa JH, Wellman OS, et al: Management of pelvic injuries in pregnancy. Orthop Clin North Am 44(3):301,r2013

Bashiri A, Burstein E, Bar-David J, et al: Face and brow presentation: independent risk factors. ] Matern Fetal Neonatal Med 21 (6):357, 2008

Bleich AT, Alexander ]M, McIntire DO, et al: An analysis of second-stage labor beyond 3 hours in nulliparous women. Am] PerinatoI29:717, 2012

Buchmann E], Libhaber E: Sagittal suture overlap in cephalopelvic disproportion: blinded and non-participant assessment. Acta Obstet Gynecol Scand 87(7):731,r2008

Caldeyro-Barcia R, Alvarez H, Reynolds SR: A better understanding of uterine contractility through simultaneous recording with an internal and a seven channel external method. Surg Obstet Gynecol 91:641, 1950

Chen HY, Huang SC: Evaluation of midpelvic contraction. Int Surg 67:516, 1982

Cheng YW, Hopkins LM, Caughey AB: How long is too long: does a prolonged second stage oflabor in nulliparous women afect matenal and neonatal outcomes? Am] Obstet GynecoIr191(3):933, 2004

Cheng YW, Shafer BL, Bryant AS, et al: Length of the irst stage of labor and associated perinatal outcomes in nulliparous women. Obstet Gynecol 116(5):1127,r2010

Cibils LA, Hendricks CH: Normal labor in vertex presentation. Am J Obstet GynecoIr91:385, 1965

Cohen W: InAuence of the duration of second stage labor on perinatal outcome and puerperal morbidity. Obstet Gynecol 49:266, 1977

Cohen W, Friedman EA: Management of Labor. Baltimore, University Park Press, 1983 Cohen WR, Friedman EA: Misguided guidelines for managing labor. Am J Obstet Gynecol 212(6):753.el, 2015a

Cohen WR, Friedman EA: Perils of the new labor management guidelines. Am J Obstet Gynecol 212(4):420, 2015b

Cruikshank DP, White CA: Obstetric malpresentations: twenty years' experience. Am J Obstet Gynecol 116:1097, 1973

Duf P: Diagnosis and management of face presentation. Obstet Gynecol 57:105,r1981

Eller We, Mengert WF: Recognition of mid-pelvic contraction. Am ] Obstet Gynecol 53:252, 1947

Ferguson ]E, Newberry YG, DeAngelis GA, et al: he fetal-pelvic index has minimal utility in predicting fetal-pelvic disproportion. Am J Obstet Gynecol 179: 1186, 1998

Floberg], Belfrage P, Ohlsen H: InAuence of pelvic outlet capacity on labor.

A prospective pelvimetry study of 1,429 unselected primiparas. Acta Obstet Gynecol Scand 66: 121, 1987

Fraser WD, Marcoux 5, Krauss I, et al: Multicenter, randomized, controlled trial of delayed pushing for nulliparous women in the second stage of labor with continuous epidural analgesia. Am J Obstet Gynecol 182: 1165,r2000

Friedman E: The graphic analysis of labor. Am] Obstet Gynecol68: 1568, 1954 Friedman EA: Labor. Clinical Evaluation and Management, 2nd ed. New York, Appleton-Century-Crofts,

Friedman EA: Primigravid labor; a graphicostatistical analysis. Obstet Gynecol 6(6):567, 1955

Friedman EA, Sachtleben MR: Station of the fetal presenting part 11: effect on the course oflabor. Am] Obstet Gynecol 93:530, 1965

Friedman EA, Sachtleben MR: Station of the fetal presenting part IV: arrest of descent in nulliparas. Obstet :129,r1976 Fuchs K, Peretz BA, Marcovici R, et al: The grand multipara-is it a problem?

Int J Gynaecol Obstet 73:321, 1985

Gambling DR, Sharma SK, Ramin SM, et al: A randomized study of combined spinal-epidural analgesia versus intravenous meperidine during labor: impact on cesarean delivery rate. Anesthesiology 89(6): 1336, 1998

Goplerud ], Eastman N]: Compound presentation: survey of 65 cases. Obstet Gynecol 1:59, 1953

Grobman WA, Bailit], Lai Y, et al: Association of the duration of active pushing with obstetric outcomes. Obstet Gynecol 12 (4):667, 2016

Handa VL, Laros RK: Active-phase arrest in labor: predictors of cesarean delivery in a nulliparous population. Obstet Gynecol 81 :758, 1993

Hannah M, Ohlsson A, Farine 0, et al: International Term PROM Trial: a RCT of induction of labor for prelabor rupture of membranes at term. Am J Obstet Gynecol 174:303, 1996

Hannah ME, Hodnett ED, Willan A, et al: Prelabor rupture of the membranes at term: expectant management at home or in hospital? Obstet Gynecol 96:533, 2000

Hansen SL, Clark SL, Foster JC: Active pushing versus passive fetal descent in the second stage of labor: a randomized controlled trial. Obstet Gynecol 99:29,r2002

Harper LM, Caughey AB, Roehl A, et al: Deining an abnormal irst stage of labor based on maternal and neonatal outcomes. m J Obstet Gynecol 210(6):536.el,r2014

Hauth )C, Hankins GO, Gilstrap LC III: Uterine contraction pressures achieved in parturients with active phase arrest. Obstet Gynecol 78:344, 1991

Hauth )C, Hankins GO, Gilstrap LC III, et al: Uterine contraction pressures with oxytocin induction/augmentation. Obstet GynecoI68:305, 1986

Hellman LM, Epperson )W, Connally F: Face and brow presentation: the experience of the Johns Hopkins Hospital, 1896 to 1948. Am ) Obstet Gynecol 59:831, 1950

Hendricks CH, Quilligan E), Tyler AB, et al: Pressure relationships between intervillous space and amniotic fluid in human term pregnancy. Am ) Obstet Gynecol77:1028, 1959

Hillis OS: Diagnosis of contracted pelvis by the impression method. Surg Gynecol Obstet 51:857,o1930

Johnson CE: Transverse presentation of the fetus. )MA 187:642,o1964 Kaltreider OF: Criteria of midplane contraction. Am) Obstet GynecoI63:392, 1952

Korhonen U, Taipale P, Heinonen S: Fetal pelvic index to predict cephalopelvic disproportion-a retrospective clinical cohort study. Acta Obstet Gynecol Scand 94(6):615, 2015

Kwok CS, Judkins CL, Sherratt M: Forearm injury associated with compound presentation and prolonged labour.o) Neonatal Surg 4(3):40,o2015 Larks SO: Electrohysterography. Springfield, Thomas, 1960

Laughon SK, Berghella V, Reddy UM, et a1: Neonatal and maternal outcomes with prolonged second stage oflabor. Obstet Gynecol 124(1):57,2014

Le Ray C, Audibert F, Goinet F, et al: When to stop pushing: efects of duration of second-stage expulsion eforts on maternal and neonatal outcomes in nulliparous women with epidural analgesia. Amo) Obstet Gynecol 201(4):361.e1,o2009

Leveno K), Nelson DB, McIntire DO: Second-stage labor: how long is too long? Am) Obstet Gynecol 214(4):484, 2016

Mahon TR, Chazotte C, Cohen WR: Short labor: characteristics and outcome.

Obstet Gynecol 84:47, 1994

Manyonda IT, Shaw DE, Drife )0: he efect of delayed pushing in the second stage of labor with continuous lumbar epidural analgesia. Acta Obstet Gynecol Scand 69:291, 1990

Marte K, Voutsos L: Reduction in the cesarean delivery rate after obstetric care consensus guideline implementation. Obstet Gynecol 128(6):1445,o2016 Martin )A, Hamilton BE, Osterman M), et al: Births: final data for 2013. Nat!

Vital Stat Rep 64(1):1, 2015

McCarthy S: Magnetic resonance imaging in obstetrics and gynecology. Magn Reson Imaging 4:59, 1986

Mengert F: Estimation of pelvic capaciry.o)1A 138:169, 1948 Menticoglou SM, Manning F, Harman C, et 1: Perinatal outcomes in relation to second-stage duration. Am ) Obstet Gynecol 173:906, 1995a

Menticoglou SM, Perlman M, Manning FA: High cervical spinal cord injury in neonates delivered with forceps: report of 15 cases. Obstet Gynecol 86:589, 1995b

Moore MM, Shearer DR: Fetal dose estimates for CT pelvimetry. Radiology 171:265,o1989

Mozurkewich E, Chilimigras ), Koepke E, et al: Indications for induction of labour: a best-evidence review. B)OG 116(5):626,o2009

Mueller P: About the prognosis for delivery with a narrow pelvis. Arch GynaekoIo27:311, 1885

Nelson DB, McIntire DO, Leveno K): Relationship of the length of the first stage oflabor to the length of the second stage. Obstet GynecoIo122:27, 2013 Olah KS, Neilson ): Failure to progress in the management of labour. B)OG 101:1, 1994

Passos F, Cardose K, Coelho M, et a1: Antibiotic prophylaxis in premature rupture of membranes at term. Obstet GynecoIo120:1045, 2012

Pattinson RC, Cuthbert A, Vannevel V: Pelvimetry for fetal cephalic presentations at or near term for deciding on mode of delivery. Cochrane Database Syst Rev 3:CD000161, 2017

Peleg 0, Hannah ME, Hodnett ED, et 1: Predictors of cesarean delivery after prelabor rupture of membranes at term. Obstet Gynecol 93: 1 03o1, 1999

Plunkett BA, Lin A, Wong CA, et a1: Management of the second stage oflabor in nulliparas with continuous epidural analgesia. Obstet Gynecol 102:109, 2003

Reynolds SR, Heard 00, Bruns P, et 1: A multichannel strain-gauge tocodynamometer: an instrument for studying patterns of uterine contractions in pregnant women. Bull Johns Hopkins Hosp 82:446, 1948

Rosenbloom )1, Stout M), Tuuli MG, et al: New labor management guidelines and changes in cesarean delivery patterns. m)Obstet Gynecol October 14, 2017 [Epub ahead of print]

Roshanfekr 0, Blakemore K), Leeo), et 1: Station at onset of active labor in nulliparous patients and risk of cesarean delivery. Obstet Gynecol 93:329, 1999 Rouse D), Oweno), Hauth ]C: Active-phase labor arrest: oxytocin augmenta tion for at least 4 hours. Obstet Gynecol 93:323, 1999

Rouse D), Weiner S), Bloom SL, et a1: Second-stage labor duration in nulliparous women: relationship to maternal and perinatal outcomes. Am ) Obstet GynecoIo201(4):357.e1,o2009

Satin A), Maberry lC, Leveno ), et al: Chorioamnionitis: a harbinger of dystocia. Obstet Gynecol 79:913, 1992

Shafer BL, Cheng W, Vargas ]E, et a1: Face presentation: predictors and delivery route. Am] Obstet Gynecol 194(5):elO, 2006

Sharma SK, McIntire DO, Wiley), et al: Labor analgesia and cesarean delivery: an individual patient meta-analysis of nulliparous women. Anesthesiology 100(1):142,o2004

Sheiner E, Levy A, Mazor M: Precipitate labor: higher rates of maternal complications. Euro] Obstet Gynecol Reprod BioI 116(1):43, 2004

Sporri S, Hanggi W, Brahetti A, et a1: Pelvimetry by magnetic resonance imaging as a diagnostic tool to evaluate dystocia. Obstet Gynecol 89:902, 1997 Stark DO, McCarthy SM, Filly A, et a1: Pelvimetry by magnetic resonance imaging. Am) RadioIo144:947, 1985

Tebes CC, Mehta P, Calhoun DA, et 1: Congenital ischemic forearm necrosis associated with a compound presentation. ] Matern Fetal Med 8:281, 1999 Thoms H: he obstetrical signiicance of pelvic variations: a study of 450 primiparous women. Bl] 2:210, 1937

Thorpo)M )r, Pahel-Short L, Bowes WAo)r: The Mueller-Hillis maneuver: can it be used to predict dystocia? Obstet Gynecol 82:5o19, 1993

Thurnau GR, Scates DH, Morgan MA: he fetal-pelvic index: a method of identiying fetal-pelvic disproportion in women attempting vaginal birth after previous cesarean delivery. Am) Obstet Gynecol 165:353, 1991

Vallier A, Cureton BA, Schubeck 0: Pregnancy outcomes ater pelvic ring injury.o) Orthop Trauma 26(5):302,o2012

Wilson-Leedy ]G, DiSilvestro A), Repke ]T, et al: Reduction in the cesarean delivery rate after Obstetric Care Consensus guideline implementation. Obstet GynecoIo128(1):145, 2016

Wong CA, Scavone BM, Dugan S, et 1: Incidence of postpartum lumbosacral spine and lower extremiry nerve injuries. Obstet Gynecol 101o:279,o2003 World Health Organization: Partographic management of labour. Lancet 343:1399, 1994

Zaretsky MV, Alexander ]M, McIntire DO, et al: Magnetic resonance imaging pelvimetry and the prediction of labor dystocia. Obstet Gynecol 106:919, 2005

Zhango), Landy H), Branch OW, et al: Contemporary patterns of spontaneous labor with normal neonatal outcomes. Obstet Gynecol 116: 1281, 2010 Zhang], Troendle ]F, Yancey MK: Reassessing the labor curve in nulliparous women. m) Obstet GynecoIo187(4):824, 2002

ELECTRONIC FETAL MONITORING ................. 457

OTHER INTRAPARTUM ASSESSMENT TECHNIQUES ... 470

NONREASSURING FETAL STATUS ................. 472

MECONIUM IN THE AMNIONIC FLUID .............. 474

FETAL HEART RATE PAIERNS AND BRAIN INJURY ... 476

CURRENT RECOMMENDATIONS ................... 478

INTRAPARTUM SURVEILLANCE OF UTERINE ACTIVIY ... 478

To study the orces exerted by labour, a rubber bag was inserted into the uterus which was connected with a manometer. In this way it was ound that the intra-uterine pressure, in the intervals between the contractions, was represented by a column of mercury 20 millimeters high, 5 of which were due to the toniciy of the wals and 15 to its contents. During the pains, however, the mercury rose consideraby, reaching a height of from 80 to 250 milimeters.

-J. Whitridge Williams (1903)

Little is written in the first edition of this textbook concerning monitoring of the fetus during labor. Much later, periodic auscultation of the fetal heartbeat with a fetoscope was adopted. These practices were eclipsed in the late 1960s and early 1970s by the development of electronic fetal monitoring (Hon, 1958). It was hoped that the continuous graph-paper portrayal of the fetal heart rate was potentially diagnostic in assessing pathophysiological events afecting the fetus.

When first introduced, electronic fetal heart rate monitoring was used primarily in complicated pregnancies but gradually became used in most pregnancies. Now, more than 85 percent of all live births in the United States undergo electronic fetal monitoring (Ananth, 2013).

Direct fetal heart measurement is accomplished by attaching a bipolar spiral electrode directly to the fetus (Fig.

The wire electrode penetrates the fetal scalp, and the second pole is a metal wing on the electrode. The electrical fetal cardiac signal-P wave, QRS complex, and T wave-is ampliied and must be applied because air conducts ultrasound waves poorly. he device Mother 50 mm/sec

FIGURE 24-1 Internal electronic fetal monitoring. Schematic representation of a bipolar electrode attached to the fetal scalp for detection of fetal QRS complexes (F). Also shown is the maternal heart and corresponding electrical complex (M) that is detected.

is held in position by an elastic belt.

FIGURE 24-3 The top tracing shows standard fetal monitor tracing of heart rate using a fetal scalp electrode, Spiking ofthe fetal rate in the monitor tracing is due to premature atrial con entiation of fetal cardiac motion from tractions, The second panel displays accompanying contractions, The bottom two tracings repmaternal arterial pulsations (Neilson, resent cardiac electrical complexes detected from fetal scalp and maternal chest wall electrodes, 2008). ECG = electrocardiogram; F = fetus; M = mother; PAC = fetal premature atrial contraction, fed into a cardiotachometer for heart rate calculation. he peak R-wave voltage is the portion of the fetal electrocardiogram (ECG) most reliably detected.

n example of the method of fetal heart rate processing employed when a scalp electrode is used is shown in Figure 24-2. Time (t) in milliseconds between fetal R waves is fed into a cardiotachometer, where a new fetal heart rate is set with the arrival ofeach new R wave. As also shown in Figure 24-2, a premature atrial contraction is computed as a heart rate acceleration because the interval (t2) is shorter than the preceding one (t1). he phenomenon of continuous R-to-R wave fetal heart rate computation is known as beat-to-beat variabiliy.

Electrical cardiac complexes detected by the electrode include those generated by the mother. However, the amplitude of the maternal ECG signal is diminished when recorded through the fetal scalp electrode and is masked by the fetal ECG. Shown in Figure 24-3 are simultaneous recordings of maternal chest wall ECG signals and fetal scalp electrode ECG signals. This fetus is experiencing premature atrial contractions, which cause the cardiotachometer to rapidly and erratically seek new heart rates, resulting in the "spiking" shown in the standard fetal monitor tracing. Importantly, when the fetus is dead, the maternal R waves are still detected by the scalp electrode as the next best signal and are counted by the cardiotachometer (Fig. 24-4).

Although membrane rupture may be avoided, external monitoring does not provide the precision of fetal heart rate measurement aforded by internal monitoring (Nunes, 2014). In some women-for example, those who are obese-external monitoring may be dificult (Brocato, 2017).

With external monitoring, the fetal heart rate is detected through the maternal abdominal wall using the ultrasound Doppler principle. Ultrasound waves undergo a shift in frequency as they are reflected from moving fetal heart valves and from pulsatile blood ejected during systole (Chap. 10, p. 213). he unit consists of a transducer that emits ultrasound and a sensor to detect a shift in frequency of the reflected sound. The transducer is placed on the maternal abdomen at a site where fetal heart action is best detected. A coupling gel

FIGURE 24-2 Schematic representation offetal electrocardiographic signals used to compute continuing beat-to-beat heart rate with scalp electrodes, Time intervals (tIl t21 t3) in milliseconds between successive fetal R waves are used by a cardiotachometer to compute instantaneous fetal heart rate, ECG = electrocardiogram; PAC = premature atrial contraction, contractions.

FIGURE 24-4 Placental abruption. In the upper panel, the fetal scalp electrode first detected the heart rate of the dying fetus. After fetal death, the maternal electrocardiogram complex is detected and recorded. The second panel displays an absence of uterine

Ultrasound Doppler signals are edited electronically before fetal heart rate data are printed onto monitor paper. Relected ultrasound signals from moving fetal heart valves are analyzed through a microprocessor that compares incoming signals with the most recent previous signal. This process, called autocorrelation, is based on the premise that the fetal heart rate has regularity, whereas "noise" is random and without regularity. Several fetal heart motions must be deemed electronically acceptable by the microprocessor before the fetal heart rate is printed. Such electronic editing has greatly improved the tracing quality of the externally recorded fetal heart rate. Other features of current fetal monitors include the capability to monitor twin fetuses, monitor concurrent maternal heart rate, display the fetal ECG, and record maternal pulse oximetry values. Many fetal monitors are capable of interfacing with archival storage systems, which obviates maintaining actual paper tracings.

Technological advances now allow fetal heart rate monitoring from a remote, centralized location. Theoretically, the ability to monitor several patients simultaneously was hoped to improve neonatal outcomes. That said, only one study on centralized fetal monitoring has been reported. Anderson and colleagues (2011) measured the ability of 12 individuals to detect critical signals in fetal heart rate tracings on one, two, or four monitors. The results showed that detection accuracy declined as the number of displays increased.

The interpretation of fetal heart rate patterns can be problematic without deinitions and nomenclature. In one example, Blackwell and colleagues (2011) asked three .1aternal-Fetal Medicine specialists to independently interpret 154 fetal heart rate tracings. Interobserver agreement was poor for the most ominous tracings and moderate for less severe patterns.

The National Institute of Child Health and Human Development (NICHD) Research Planning Workshop (1997) brought together investigators with exper tise in the ield to propose standardized, tion of fetal heart rate patterns during labor. This workshop reconvened in 2008.

he deinitions proposed as a result of this second workshop are used in this chapter and have been adopted by the American

College of Obstetricians and Gynecolo

Importantly, interpretation of electronic fetal heart rate data is based on the visual pattern of the heart rate as portrayed on chart recorder graph paper. Thus, the choice of vertical and horizontal scaling greatly afects the appearance of the fetal heart rate. Scal ing factors recommended by the NICHD

Workshop are 30 beats per minute (beats/ min or bpm) per vertical cm (range, 30 to paper speed. Fetal heart rate variation is falsely displayed at the slower 1 cm/ min paper speed compared with that of the smoother baseline recorded at 3 cm/min. hus, pattern recognition can be con siderably distorted depending on the scaling factors used.

This refers to the modal characteristics that prevail apart from periodic accelerations or decelerations associated with uterine contractions. Descriptive characteristics of baseline fetal heart activity include rate, beat-to-beat variabili, etal arrhythmia, and distinct patterns such as sinusoidal or saltatory fetal heart rates.

With increasing fetal maturation, the heart rate decreases. This continues postnatally such that the average rate is 85 bpm by age 8 years (Tintinalli, 2016). Pillai and James (1990) reported that the baseline fetal heart rate declined an average of 24 bpm between 16 weeks' gestation and term, or approximately 1 bpm per week. his normal gradual slowing of the fetal heart rate is thought to correspond to maturation of parasympathetic (vagal) heart control (Renou, 1969).

The baseline fetal heart rate is the approximate mean rate rounded to increments of 5 bpm during a 10-minute tracing segment. In any 10-minute window, the minimum interpretable baseline duration must be at least 2 minutes. If the baseline fetal heart rate is less than 110 bpm, it is termed bradycardia . If the baseline rate is greater than 160 bpm, it is called tachycardia. The average fetal heart rate is considered the result of tonic balance between accelerator and decelerator influences on pacemaker cells. In this concept, the sympathetic system is the accelerator influence, and the parasympathetic system is the decelerator factor mediated by vagal slowing of heart rate (Dawes, 1985). Heart rate also is under the control of arterial chemoreceptors such that both hypoxia and hypercapnia can modulate rate. More severe and prolonged hypoxia, with a

TABLE 24-' . Electronic Fetal Monitoring Definitions

Baseline • The mean FHR rounded to increments of 5 bpm during a 1 O-min segment, excluding: -Periods of marked FHR variability -Segments of baseline that difer by more than 25 bpm

The baseline must be for a minimum of 2 min in any 1 O-min segment or the baseline for that time period is indeterminate. In this case, one may refer to the prior 1 O-min window for determination of baseline.

Normal FHR baseline: 11s0-1s60 bpm

Tachycardia: FHR baselines is greater than 160 beats per minute

Bradycardia: FHR baseline is less than 11s0 beats per minute

Baseline • Fluctuations in the baseline FHR that are irregular in amplitude and frequency variability • Variability is visually quantified as the amplitude of peak-to-trough in beats per minute -Absent: amplitude range undetectable -Minimal: amplitude range detectable but 5 beats per minutes or fewer -Moderate (normal): amplitude range 6-25 beats per minute -Marked: amplitude range greater than 25 beats per minute

Acceleration • A visually apparent abrupt increase (onset to peak in less than 30 seconds) in the FHR

At 32 weeks of gestation and beyond, an acceleration has a peak of 15 bpm or more above baseline, with a duration of 15 sec or more but less than 2 minutes from onset to return

Before 32 weeks, an acceleration has a peak of 10 bpm or more above baseline, with a duration of 10 seconds or more but less than 2 minutes from onset to return

If an acceleration lasts 10 minutes or longer, it is a baseline change

Early deceleration • Visually apparent usually symmetrical gradual decrease and return of the FHR associated with a

A gradual FHR decrease is defined as from the onset to the FHR nadir of 30 seconds or more

The decrease in FHR is calculated from the onset to the nadir of the deceleration

The nadir of the deceleration occurs at the same time as the peak of the contraction

In most cases the onset, nadir, and recovery of the deceleration are coincident with the beginning, peak, and ending of the contraction, respectively Late deceleration • Visually apparent usually symmetrical gradual decrease and return of the FHR associated with a

A gradual FHR decrease is defined as from the onset to the FHR nadir of 30 seconds or more

The decrease in FHR is calculated from the onset to the nadir of the deceleration

The deceleration is delayed in timing, with the nadir of the deceleration occurring after the peak of the contraction

In most cases the onset, nadir, and recovery of the deceleration occur after the beginning, peak, and ending of the contraction, respectively deceleration • An abrupt FHR decrease is defined as from the onset of the deceleration to the beginning of the

FHR nadir of less than 30 seconds

The decrease in FHR is calculated from the onset to the nadir of the deceleration

The decrease in FHR is 15 beats per minute or greater, lasting 15 seconds or greater, and less than 2 minutes in duration

When variable decelerations are associated with uterine contraction, their onset, depth, and duration commonly vary with successive uterine contractions

Prolonged • Visually apparent decrease in the FHR below the baseline deceleration • Decrease in FHR from the baseline that is 15 per minute or more, and less than 2 minutes in duration • If a deceleration last 10 minutes or longer, it is a baseline change

Sinusoidal pattern • Visually apparent, smooth, sine wave-line undulating pattern in FHR baseline with a cycle frequency of 3-5 per minute which persists for 20 dinutes or more

FHR = fetal heart rate. Data from Macones, 2008.

FIGURE 24-6 Schematic representation of short-term beat-tobeat variability measured by a fetal scalp electrode. t time interval between successive fetal R waves. (Adapted with permission from Klavan M, Laver AT, Boscola MA: Clinical concepts of fetal heart rate monitoring. Waltham, Hewlett-Packard, 1977.)

FIGURE 24-5 Fetal bradycardia measured with a scalp electrode (upper paneD in a pregnancy complicated by placental abruption and subsequent fetal death. Concurrent uterine contractions are shown in the lower panel.

rising blood lactate level and severe metabolic acidemia, induces a prolonged fall in heart rate (hakor, 2009).

Bradycardia. In the third trimester, the normal mean baseline fetal heart rate has generally been accepted to range between 120 and 160 bpm. But, pragmatically, a rate between 100 and 119 bpm, in the absence of other changes, usually is not considered to represent fetal compromise. Such low but potentially normal baseline heart rates also have been attributed to head compression from occiput posterior or transverse positions, particularly during second-stage labor (Young, 1976). Such mild bradycardias were observed in 2 percent of monitored pregnancies and averaged approximately 50 minutes in duration. Freeman and associates (2003) have concluded that bradycardia within the range of 80 to 120 bpm and with good variability is reassuring. Interpretation of rates less than 80 bpm is problematic, and such rates generally are considered nonreassuring.

Some causes of fetal bradycardia include congenital heart block and serious fetal compromise 0aeggi, 2008; Larma, 2007). Figure 24-5 shows bradycardia in a fetus dying from placental abruption. Maternal hypothermia under general anesthesia for repair of a cerebral aneurysm or during maternal cardiopulmonary bypass for open-heart surgery can also cause fetal bradycardia. Sustained fetal bradycardia in the setting of severe pyelonephritis and maternal hypothermia also has been reported (Hankins, 1997). Involved fetuses apparently are not harmed by several hours of such bradycardia.

Tachycardia. Fetal tachycardia is deined as a baseline heart rate greater than 160 bpm. The most common explanation for fetal tachycardia is maternal fever from chorioamnionitis, although fever from any source can produce this. In some cases, fetal tachycardia may precede overt maternal fever (Gilstrap, 1987). Fetal tachycardia caused by maternal infection typically is not associated with fetal compromise unless there are associated periodic heart rate changes or fetal sepsis.

Other causes of fetal tachycardia include fetal compromise, cardiac arrhythmias, and maternal administration of parasympathetic inhibiting (atropine) or sympathomimetic (terbutaline) drugs. Prompt relief of the compromising event, such as correction of maternal hypotension caused by epidural analgesia, can result in fetal recovery. he key feature to distinguish fetal compromise in association with tachycardia seems to be concomitant heart rate decelerations.

Wandering Baseline. This baseline rate is unsteady and "wanders" between 120 and 160 bpm (Freeman, 2003). This rare finding is suggestive of a neurologically abnormal fetus and may occur as a preterminal event. In contrast, changes of the normal baseline are common in labor and do not predict morbidity (Yang, 2017).

Baseline variability is an important index of cardiovascular function and appears to be regulated largely by the autonomic nervous system (Kozuma, 1997). That is, a sympathetic and parasympathetic "push and pull" mediated via the sinoatrial node produces moment-to-moment or beat-to-beat oscillation of the baseline heart rate. Such heart rate change is deined as baseline variability. Variability can be further analyzed over the short term and long term, although these terms have fallen out of use. Short-term variabiliy relects the instantaneous change in fetal heart rate from one beat-or R wave-to the next. This variability is a measure of the time interval between cardiac systoles (Fig. 24-6). Short-term variability can most reliably be determined to be normally present only when electrocardiac cycles are measured directly with a scalp electrode. Long-term variability is used to describe the oscillatory changes during 1 minute and result in the waviness of the baseline (Fig. 24-7).

FIGURE 24-7 Schematic representation of long-term beat-to-beat variability of the fetal heart rate ranging between 125 and 135 bpm. (Adapted with permission from Klavan M, Laver AT, Boscola MA:

Clinical concepts of fetal heart rate monitoring. Waltham, HewlettPackard, 1977.) he normal frequency of such waves is three to ive cycles per minute (Freeman, 2003).

It should be recognized that precise quantitative analysis of both short-and long-term variability presents several frustrating problems due to technical and scaling factors (Parer, 1985). hus, most clinical interpretation is based on visual analysis with subjective judgment of the smoothness or latness of the baseline. According to Freeman and associates (2003), no evidence suggests that the distinction between short-and long-term variability has clinical relevance. Similarly, the NICHD Workshop (1997) did not recommend diferentiating short-and long-term variability because in actual practice they are visually determined as a unit. The workshop panel defined baseline variability as those baseline luctuations of two cycles per minute or greater. They recommended the criteria shown in Figure 24-8 for quantification of variability. Normal beatto-beat variability was accepted to be 6 to 25 bpm.

Increased Variability. Several physiological and pathological processes can afect beat-to-beat variability. Greater variability accompanies fetal breathing and body movements (Dawes, 1981; Van Geijn, 1980). Pillai and James (1990) reported increased baseline variability with advancing gestation. Up to 30 weeks, baseline characteristics were similar during both fetal rest and activity. After 30 weeks, fetal inactivity was associated with diminished baseline variability, but fetal activity enhanced it. Last, the baseline fetal heart rate becomes more physiologically ixed (less variable) as the rate rises. This phenomenon presumably relects less cardiovascular physiological wandering as beat-to-beat intervals shorten with a higher heart rate.

Decreased Variability. A common cause of diminished beatto-beat variability is administration of analgesic drugs during labor (Chap. 25, p. 487). Various central nervous system depressant drugs can cause transient diminished beat-to-beat variability. Included are narcotics, barbiturates, phenothiazines, tranquilizers, and general anesthetics. Corticosteroids also dampen variability (Knaven, 2017). As one specific example, variability regularly diminishes within 5 to 10 minutes following intravenous meperidine administration, and the efects may last up to 60 minutes or longer (Hill, 2003; Petrie, 1993). Butorphanol given intravenously has similar efects (Schucker, 1996). And, chronically administered buprenorphine suppresses fetal heart rate and movement (Jansson, 2017).

Magnesium suate, widely used in the United States for tocolysis or management of hypertensive gravidas, is associated with diminished beat-to-beat variability. In a study of nearly 250 term gestations, magnesium sulfate administration led to decreased variability but without evidence of adverse neonatal efects (Duy, 2012). Others have echoed these findings (Hallak, 1999; Lin, 1988). With magnesium sulfate tocolysis of preterm labor, variability was also diminished in most reviewed studies (Nensi, 2014; Verdurmen, 2017).

Of greatest concern, diminished beat-to-beat variability can be an ominous sign indicating a seriously compromised fetus. Paul and coworkers (1975) reported that loss of variability in combination with decelerations was associated with etal acidemia. Decreased variability was deined as an excursion of the baseline of;5 bpm (see Fig. 24-8). Severe maternal acidemia can also lower fetal beat-to-beat variability, for example, in a mother with diabetic ketoacidosis.

According to Dawes (1985), metabolic acidemia that causes depression of the fetal brainstem or the heart itself creates the loss of variability. hus, diminished beat-to-beat variability, when it relects fetal compromise, likely relects acidemia rather than hypoxia. Indeed, mild degrees of fetal hypoxemia have been reported actually to enhance variability, at least initially (Murotsuki, 1997).

Reduced baseline heart rate variabiliy is the single most reliable sign of etal compromise. Smith and coworkers (1988) performed a computerized analysis of beat-to-beat variability in growth-restricted fetuses before labor. Diminished variability (;4.2 bpm) maintained for 1 hour was diagnostic of developing acidemia and imminent fetal death. In contrast, Samuelof and associates (1994) evaluated variability in 2200 consecutive deliveries and concluded that variability by itself could not be used as the only indicator of fetal well-being. They also warned that good variability should not be interpreted as necessarily reassuring. Blackwell and associates (2011) found that even experts often disagreed as to whether variability was absent or minimal (;5 bpm).

In sum, beat-to-beat variability is afected by fetal physiology, and its meaning difers depending on the clinical setting. Decreased variability in the absence of decelerations is unlikely to reflect fetal hypoxia (Davidson, 1992). A persistently flat fetal heart rate baseline-absent variability-within the normal baseline rate range and without decelerations may relect a previous fetal insult that has resulted in neurological damage (Freeman, 2003).

When fetal cardiac arrhythmias are irst suspected using electronic monitoring, indings can include baseline bradycardia, tachycardia, or most commonly in our experience, abrupt baseline spiking (Fig. 24-9). An arrhythmia can only be documented, practically speaking, when scalp electrodes are used. Some fetal monitors can be adapted to output the scalp electrode signals into an ECG recorder. Because only a single lead is obtained, analysis and interpretation of rhythm and rate disturbances are severely limited.

Southall and associates (1980) studied fetal cardiac rate and rhythm disturbances in 934 normal pregnancies between 30 and 40 weeks. Arrhythmias, episodes of bradycardia < 100 bpm, or tachycardia > 180 bpm were encountered in 3 percent. Most supraventricular arrhythmias are of little signiicance during labor unless there is coexistent fetal heart failure as evidenced by hydrops. Many supraventricular arrhythmias disappear in the immediate neonatal period, although some are associated with structural cardiac defects (Api, 2008). Intermittent baseline bradycardia is frequently due to congenital heart block. Conduction defects, most often complete atrioventricular (A V) block, usually are found in association with maternal connective tissue diseases (Chap. 59, p. 1142). Antepartum evaluation of the fetus with an identiied arrhythmia and potential treatment options are discussed in Chapter 16 (p. 315).

FIGURE 24-8 Grades of baseline fetal heart rate variability shown in the following five panels. 1. Undetectable, absent variability. 2. Minimal variability, ;5 bpm. 3. Moderate (normal) variability, 6 to 25 bpm. 4. Marked variability, >25 bpm. 5. Sinusoidal pattern. This differs from variability in that it has a smooth, sinelike pattern of regular fluctuation and is excluded in the definition of fetal heart rate variability. (Adapted with permission from National Institute of Child Health and Human Development Research Planning Workshop, 1997.)

FIGURE 24-9 Internal fetal monitoring at term demonstrated occasional abrupt beat-to-beat fetal heart rate spiking due to erratic extrasystoles shown in the corresponding fetal electrocardiogram. The normal newborn was delivered spontaneously and had normal cardiac rhythm in the nursery.

Most fetal arrhythmias without comorbid fetal hydrops are inconsequential during labor, but they may hinder interpretation of fetal heart rate tracings. Sonographic evaluation of fetal anatomy and echo cardiography can be useful. Generally, in the absence of fetal hydrops, neonatal outcome is not measurably improved by pregnancy intervention. At Parkland Hospital, intrapartum fetal cardiac arrhythmias, especially those associated with clear amnionic fluid, are typically managed conservatively.

A true sinusoidal pattern such as that shown in panel 5 of Figure 24-8 can be observed with fetal intracranial hemorrhage, with severe fetal asphyxia, and with severe feral anemia. he last may stem from anti-D alloimmunization, fetomaternal hemorrhage, twin-twin transusion syndrome, fetal parvoviral infection, or vasa previa with bleeding. Insigniicant sinusoidal patterns have been reported following administration of meperidine, morphine, alphaprodine, and butorphanol (Angel, 1984; Egley, 1991; Epstein, 1982). Shown in Figure 24-10 is a sinusoidal pattern seen with maternal meperidine administration. An important characteristic of this pattern when due to narcotics is the sine frequency of 6 cycles per minute. A sinusoidal pattern also has been described with chorioamnionitis, fetal distress, and umbilical cord occlusion (lvlurphy, 1991). Young (1980a) and Johnson (1981) with their coworkers concluded that intrapartum sinusoidal fetal heart patterns were not generally associated with fetal compromise. hus, management is usually dictated by the clinical setting. Modanlou and Freeman (1982), based on their extensive review, proposed adoption of a strict definition: 1.

Stable baseline heart rate of 120 to 160 bpm with regular oscillations 2.

Amplitude of 5 to 15 bpm (rarely greater)

FIGURE 24-10 Sinusoidal fetal heart rate pattern associated with maternal intravenous meperidine administration. Sine waves are occurring at a rate of 6 cycles per minute.

3.

Long-term variability frequency of 2 to 5 cycles per minute 4.

5.

Oscillation of the sinusoidal waveform above or below a baseline 6.

Absent accelerations.

Although these criteria were selected to deine a sinusoidal pattern that is most likely ominous, they observed thar the pattern associated with alphaprodine is indistinguishable. Other investigators have proposed a classiication of sinusoidal heart rate patterns into mild-amplitude 5 to 15 bpm, intermediate-16 to 24 bpm, and major-::25 bpm to quantiy fetal risk (Murphy, 1991; Neesham, 1993).

Some have defined intrapartum sine wavelike baseline variation with periods of acceleration as pseudosinusoidal. Murphy and colleagues (1991) reported that pseudosinusoidal patterns were seen in 15 percent of monitored labors. Mild pseudosinusoidal patterns were associated with use of meperidine and epidural analgesia. Intermediate pseudosinusoidal patterns were linked to fetal sucking or transient episodes of fetal hypoxia caused by umbilical cord compression. Egley and associates (1991) reported that 4 percent of fetuses demonstrated sinusoidal patterns transiently during normal labor. hese authors observed patterns persisting for up to 90 minutes in some cases.

The pathophysiology of sinusoidal patterns is unclear, in part due to various deinitions. There seems to be general agreement that antepatum sine wave baseline undulations portend severe fetal anemia. Still, few anti-D alloimmunized fetuses develop this pattern (Nicolaides, 1989). The sinusoidal pattern has been reported to develop or disappear ter fetal transusion (Del Valle, 1992; Lowe, 1984). Ikeda and associates (1999) proposed that the pattern is related to waves of arterial blood pressure, reflecting oscillations in the baroreceptor-chemoreceptor feedback mechanism.

These refer to deviations from baseline that are temporally related to uterine contractions. Acceleration refers to a rise in fetal heart rate above baseline, and deceleration is a drop below the baseline rate. The nomenclature most commonly used in the United States is based on the timing of the deceleration in relation to contractions-thus, eary, late, or variable. he waveform of these decelerations is also significant for pattern recognition.

In early and late decelerations, the slope of fetal heart rate change is gradual, resulting in a curvilinear and uniform or symmetrical waveform. With variable decelerations, the slope of fetal heart rate change is abrupt and erratic, giving the waveform a jag ged appearance. The NICHD Workshop (1997) proposed that decelerations be defined as recurrent if they accompanied �50 percent of contractions in any 20-minute period.

Another system now used less often to describe decelera tions is based on the pathophysiological events considered most likely to underlie the pattern. In this system, early decelera tions are termed head compression, late decelerations are termed uteroplacental insuiciency, and variable decelerations are cord compression patterns.

hese are abrupt heart rate increases above the fetal heart rate baseline and defined by n onset-to-peak rise within 30 seconds (American College of Obstetricians and Gynecologists, 2017a). At 32 weeks' gestation and beyond, an acceleration has a peak � 15 bpm above baseline. Its duration is � 15 sec but <2 minutes from onset to baseline return (see Table 24-1). Before 32 weeks, a peak �10 bpm for 10 seconds to 2 minutes is considered normal. Prolonged acceleration is defined as �2 minutes but < 10 minutes.

According to Freeman and coworkers (2003), accelerations most often occur antepartum, in early labor, and in association with variable decelerations. Proposed mechanisms for intrapartum accelerations include fetal movement, stimulation by uterine contractions, umbilical cord occlusion, fetal stimulation during pelvic examination, scalp blood sampling, and acoustic stimulation. Accelerations are common during labor. These are virtually always reassuring and almost always conirm that the fetus is not acidemic at that time.

As with beat-to-beat variability, accelerations represent intact neurohormonal cardiovascular control mechanisms linked to fetal behavioral states. Krebs and colleagues (1982) analyzed electronic heart rate tracings in nearly 2000 fetuses and found sporadic accelerations during labor in 99.8 percent. Fetal heart rate accelerations during the irst or last 30 minutes during labor, or both, were a favorable sign for fetal well-being. The absence of such accelerations during labor, however, is not necessarily an unfavorable sign unless coincidental with other nonreassuring changes. he chance of acidemia in the fetus that fails to respond to stimulation in the presence of an otherwise nonreassuring pattern approximates 50 percent (Clark, 1984; Smith, 1986).

his physiological response shows a gradual fetal heart rate decline and then return to baseline associated with a contraction (Fig.

Freeman and associates (2003) defined early decelerations as those generally seen in active labor between 4 and 7 cm cervical dilation. In their deinition, the degree of deceleration is generally proportional to the contraction strength and rarely falls below 100 to 110 bpm or 20 to 30 bpm below baseline. Such decelerations are common during active labor and not associated with tachycardia, loss of variability, or other fetal heart rate changes. Importantly, early decelerations are not associated with fetal hypoxia, acidemia, or low Apgar scores.

FIGURE 24-11 Features of early fetal heart rate deceleration. Characteristics include a gradual decline in the heart rate with both onset and recovery coincident with the onset and recovery of the contraction. The nadir of the deceleration is 30 seconds or more after the deceleration onset.

Head compression probably causes vagal nerve activation as a result of dural stimulation, and this mediates the heart rate deceleration (Paul, 1964). Ball and Parer (1992) concluded that fetal head compression is a likely cause not only of the deceleration shown in Figure 24-11 but also of those shown in Figure 24-12, which typically occur during second-stage labor.

FIGURE 24-12 Two diferent fetal heart rate patterns during second-stage labor that are likely both due to head compression (upper pane0. Maternal pushing eforts (lower pane0 correspond to the spikes with uterine contractions. Fetal heart rate deceleration () is consistent with the pattern of head compression shown in Figure 24-1o1. Deceleration (B), however, is "variable" in appearance because of its jagged configuration and may alternatively represent cord occlusion.

FIGURE 24-13 Features of late fetal heart rate deceleration. Characteristics include gradual decline in the heart rate with the contraction nadir, and recovery occurring after the end ofthe contraction. The nadir ofthe deceleration occurs 30 seconds or more after the onset of the deceleration.

Indeed, they observed that head compression is the likely cause of many variable decelerations classically attributed to cord compression.

The fetal heart rate response to uterine contractions can reflect uterine perfusion or placental function. A late deceleration is a smooth, gradual, symmetrical decline in fetal heart rate beginning at or after the contraction peak and returning to baseline only after the contraction has ended. his deceleration reaches its nadir within 30 seconds of its onset. In most cases, the onset, nadir, and recovery of the deceleration occur after the beginning, peak, and ending of the contraction, respectively (Fig. 24-13). The magnitude of late decelerations is seldom more than 30 to 40 bpm below baseline and typically not more than 10 to 20 bpm. Late decelerations usually are not accompanied by accelerations. Myers and associates (1973) studied monkeys in which they compromised uteroplacenral perfusion by lowering maternal aortic blood pressure. The interval or lag from the contraction onset until the late deceleration onset was directly related to basal fetal oxygenation. hey demonstrated that the length of the lag was predictive of the fetal P02 but not fetal pH. he lower the fetal P02 before contractions, the shorter the lag to the onset of late decelerations. his lag relected the time necessary for the fetal P02 to fall below a critical level necessary to stimulate arterial chemoreceptors, which mediated the decelerations.

Murata and coworkers (1982) also showed that a late deceleration was the irst fetal heart rate consequence ofuteroplacental-induced hypoxia. During the course of progressive hypoxia that led to death over 2 to 13 days, monkey fetuses invariably exhibited late decelerations before development of acidemia. Variability of the baseline heart rate disappeared as acidemia developed.

Generally, any process that produces maternal hypotension, excessive uterine activity, or placental dysfunction can induce late decelerations. The two most common sources are hypotension from epidural analgesia and uterine hyperactivity from onset : sece: 1 ...

FIGURE 24-14 Features ofvariable fetal heart rate decelerations. Characteristics include an abrupt decline in the heart rate, and onset that commonly varies with successive contractions. The deceleration measures : 15 bpm for : 15 seconds and has an onset-to-nadir phase of <30 seconds. Total duration is <2 minutes.

oxytocin stimulation. Maternal diseases such as hypertension, diabetes, and collagen vascular disorders can cause chronic placental dysfunction. Placental abruption can produce acute late decelerations.

he most frequent deceleration patterns encountered during labor are variable decelerations attributed to umbilical cord occlusion. In a study of more than 7000 monitor tracings, variable decelerations were identified in 40 percent when labor had progressed to 5 cm dilation and in 83 percent by the end of first-stage labor (Melchior, 1985). A variable deceleration is defined as an abrupt drop in the fetal heart rate beginning with the onset of the contraction and reaching a nadir in less than 30 seconds. he decrease must last between 15 seconds and 2 minutes and must be :::15 bpm in amplitude. The onset of deceleration typically varies with successive contractions (Fig. 24-14).

Hon (1959) tested the efects of umbilical cord compression on fetal heart rate (Fig. 24-15). In experimental animals, complete occlusion of the umbilical cord produces abrupt, jagged-appearing deceleration of the fetal heart rate 24-16). Concomitantly, fetal aortic pressure rises. Itskovitz and colleagues (1983) observed that variable decelerations in fetal lambs occurred only after umbilical blood flow was reduced by at least 50 percent.

Two types ofvariable decelerations are shown in Figure 24-17. The deceleration denoted by "A" is very much like that seen with complete umbilical cord occlusion in experimental animals (see Fig. 24-16). Deceleration "B," however, has a diferent configuration because of the "shoulders" of acceleration before and ater the deceleration component. Lee and coworkers (1975) proposed that this form of variable deceleration was caused by difering degrees of partial cord occlusion. In this physiological scheme, occlusion of only the vein reduces fetal blood return, thereby triggering a baroreceptor-mediated c'Eii. 40

FIGURE 24-15 A. The effects oF 25-second cord compression compared with those of 40 seconds in panel (8). (Redrawn with permission from Hon EH: The fetal heart rate patterns preceding death in utero, Am J Obstet Gynecol. 1959 Jul;78(l ):47-56.) acceleration. With increasing intrauterine pressure and subsequent complete cord occlusion, fetal systemic hypertension develops due to obstruction of umbilical artery flow. This stimulates a baroreceptor-mediated deceleration. Presumably, the aftercoming shoulder of the acceleration represents the same events occurring in reverse (Fig. 24-18).

Ball and Parer (1992) concluded that variable decelerations are mediated vagally and that the vagal response may be due to chemoreceptor or baroreceptor activity or both. Partial or complete cord occlusion produces an increase in afterload (baroreceptor) and a drop in fetal arterial oxygen content (chemoreceptor). These both result in vagal activity leading to deceleration. In fetal monkeys, the baroreceptor relexes appear to operate during the first 15 to 20 seconds of umbilical cord occlusion followed by decline in P02 at approximately 30 seconds, which then serves as a chemoreceptor stimulus (MuellerHeubach, 1982).

Thus, variable decelerations represent fetal heart rate reflexes that relect either blood pressure changes due to interruption of umbilical flow or changes in oxygenation. It is likely that most fetuses have experienced brief but recurrent periods of hypoxia due to umbilical cord compression during gestation. The frequency and inevitability of cord occlusions undoubtedly have provided the fetus with these physiological mechanisms as a means of coping. The great dilemma for the obstetrician in managing variable fetal heart rate decelerations is determining when variable decelerations are pathological. According to the American College of 0bstetricians and Gynecologists (2017 a), recurrent variable decelerations with minimal-to-moderate beat-to-beat variability are indeterminate, whereas those with absent variability are abnorma.

FIGURE 24-16 Total umbilical cord occlusion (arrow) in the sheep fetus is accompanied by an increase in fetal aortic blood pressure. Blood pressure changes in the umbilical vessels are also shown. (Redrawn with permission from Kunzel W: Fetal heat rate alterations in partial and total cord occlusion. In Kunzel W (ed): Fetal Heart Rate Monitoring: Clinical Practice and Pathophysiology. Berlin, Springer, 1985.)

FIGURE 24-17 Varying (variable) fetal heart rate decelerations. Deceleration (8) exhibits "shoulders" of acceleration compared with deceleration (A).

Fetal heart rate Uterine contraction occlusion Complete occlusion IIIIIIIIII I: Partial occlusion Umbilical vein Umbilical artery Fetal systolic BP Umbilical cord FIGURE 24-18 Schematic representation ofthe fetal heart rate efects with partial and complete umbilical cord occlusion. Uterine pressures generated early in a contraction cause cord compres-sion predominantly ofthe thin-walled umbilical vein. The resulting decrease in fetal cardiac output leads to an initial compensatory rise in fetal heart rate. As cord compression intensifies, umbilical arteries are then also compressed. The resulting rise in fetal systolic blood pressure leads to a vagal-mediated fetal heart rate deceleration. As the contraction abates and compression is relieved first on the umbilical arteries, elevated fetal systolic blood pressures drop and the deceleration resolves. A final increase in fetal heart rate is seen as a result of persistent umbilical vein occlusion. With completion of the uterine contraction and cord compression, the fetal heart rate returns to baseline. BP = blood pressure. (Adapted with permission from Lee (V, DiLaretto pc, Lane JM: A study offetal heart rate acceleration patterns, Obstet Gynecol. 1975 Feb;45(2):142-146.) Other fetal heart rate patterns have been associatedwith umbilical cord compression. Saltatoy baseline heart rate (Fig. 24-19) was first linked o umbilical cord complications during labor (Hammacher, 1968). he pattern consists ofrapidlyrecurringcouplets of acceleration and deceleration causing relatively large oscillations of the baseline fetal heart rate. We also observed a relationship between cord occlusion and the saltatory pattern in postterm pregnancies (Leveno, 1984). In the absence of other fetal heart rate finings, these do not signal fetal compromise. Lamba is a pattern involving an acceleration followed by a variable deceleration with no acceleration at the end ofthe deceleration. This pattern typically is seen in early labor and is not ominous (Freeman, 2003). This lambda pattern may result from mild cord compression or stretch. Overshootis a variable deceleration followed by acceleration. The clinical significance ofthis pattern is controversial (Westgate, 2001). Prolonged Deceleration This pattern, which is shown in Figure 24-20, is deined as an isolated deceleration ::15 bpm that lasts ::2 minutes but

FIGURE 24-19 Saltatory baseline fetal heart rate showing rapidly recurring couplets ofacceleration combined with deceleration.

< 10 minutes from onset to return to baseline. Prolonged decelerations are diicult to interpret because they are seen in many diferent clinical situations. Some of the more frequent causes are cervical examination, uterine hyperactivity, cord entanglement, and maternal supine hypotension.

Epidural, spinal, or paracervical analgesia may induce a prolonged deceleration (Eberle, 1998). Hill and associates (2003) observed prolonged deceleration in 1 percent of women given epidural analgesia during labor at Parkland Hospital. Other causes of prolonged deceleration include maternal hypoperfusion or hypoxia from any cause, placental abruption, umbilical

FIGURE 24-20 Prolonged fetal heart rate deceleration due to uterine hyperactivity. Approximately 3 minutes of the tracing are shown, but the fetal heart rate returned to normal after uterine hypertonus resolved. Vaginal delivery later ensued.

Loss of variability pH 6.9

FIGURE 24-21 Cord-compression fetal heart rate decelerations in second-stage labor associated with tachycardia and loss of variability. The umbilical cord arterial pH was 6.9.

cord knots or prolapse, maternal seizures including eclampsia and epilepsy, application of a fetal scalp electrode, impending birth, or maternal Valsalva maneuver. In one example, Ambia and colleagues (2017) described prolonged decelerations lasting 2 to 10 minutes following an eclamptic seizure.

he placenta is efective in resuscitating the fetus if the original insult does not recur immediately. Occasionally, such self-limited prolonged decelerations are followed by loss of beat-to-beat variability, baseline tachycardia, and even a period of late decelerations, all of which resolve as the fetus recovers. Freeman and colleagues (2003) emphasize that the fetus may die during prolonged decelerations. hus, management of prolonged decelerations can be extremely tenuous. Management of isolated prolonged decelerations is based on bedside clinical judgment, which inevitably will sometimes be imperfect given the unpredictability of these decelerations.

Decelerations are virtually ubiquitous during the second stage of labor. In one study, only 1.4 percent of more than 7000 deliveries lacked decelerations during second-stage labor (Melchior, 1985). Both cord and fetal head compressions have been implicated as causes of decelerations and baseline bradycardia in this stage. Profound, prolonged fetal heart rate deceleration in the 10 minutes preceding vaginal delivery has been described (Boehm, 1975). And, similar prolonged second-stage decelerations were associated with a stillbirth and neonatal death (Herbert, 1981). hese experiences attest to the unpredictability of the fetal heart rate during second-stage labor.

Spong and associates (1998) analyzed the characteristics of second-stage variable fetal heart rate decelerations in 250 deliveries. hey found that as the total number of decelerations <70 bpm increased, the 5-minute Apgar score decreased. Of other patterns in second-stage labor, Picquard and coworkers (1988) reported that loss of beat-to-beat variability and baseline fetal heart rate < 90 bpm predicted fetal acidemia. Krebs and associates (1981) also found that persistent or progressive baseline bradycardia or baseline tachycardia was associated with lower Apgar scores. Gull and colleagues (1996) observed that abrupt fetal heart rate deceleration to < 100 bpm associated with loss of beat-to-beat variability for 4 minutes or longer was predictive of fetal acidemia. Thus, abnormal baseline heart rate-either bradycardia or tachycardia, absent beat-tobeat variability, or both-in the presence of deep second-stage decelerations is associated with a greater risk for fetal compromise (Fig.

With this approach, women with low-risk pregnancies are monitored for a short time on admission for labor. In one study, 3752 low-risk women in spontaneous labor at admission were randomly assigned either to auscultation of the fetal heart or to 20 minutes of electronic fetal monitoring (Mires, 2001). Use of admission electronic fetal monitoring did not improve neonatal outcome. Moreover, its use resulted in a greater number of interventions, including operative delivery. A similar study echoed these neonatal outcomes (Impey, 2003). More than half of the women enrolled in these studies eventually required continuous monitoring. A review by Devane and associates (2017) found that admission fetal monitoring programs for low-risk pregnancy are associated with a higher risk for cesarean delivery. Somewhat related, with the increasing rate of scheduled cesarean deliveries in the United States, clinicians and hospitals must decide whether fetal monitoring is required before the procedure in low-risk women.

Fetal heart rate pattern interpretations are subjective. hus, the potential for computer assistance to enhance the precision of identiying abnormal patterns appeared promising. he INFANT Collaborative Group (2017) studied whether the addition of computer-based decision-support software for interpretation of fetal heart rate patterns lowered the number of poor neonatal outcomes. In this trial, 23,515 women were randomized to computer-assisted interpretation compared with 23,055 women in a conventional clinical interpretation arm. Perinatal outcomes such as intrapartum stillbirth, early neonatal death, and neonatal encephalopathy were not improved by computer assistance. Cesarean delivery rates were similar in both groups. Moreover, a 2-year follow-up of a subset of the surviving children showed no diferences in their neurological development.

According to the American College of Obstetricians and Gynecologists (2017a), measurements of the pH in capillary scalp blood may help identiy the fetus in serious distress. However, this group also emphasizes that neither normal nor abnormal scalp pH results are predictive of neonatal outcome. Notably, the procedure is now used uncommonly and is not available at most hospitals in the United States.

With sampling, an illuminated endoscope is inserted through the dilated cervix after membrane rupture and is pressed irmly against the fetal scalp (Fig. 24-22). The skin is wiped clean with a cotton swab and coated with a silicone gel, which allows fetal blood to accumulate s discrete globules. An incision is made through the fetal scalp to a depth of 2 mm with a special blade on a long handle. As a drop of blood forms on the surface, it is immediately collected into a heparinized glass capillary tube . The pH of the blood is measured promptly.

FIGURE 24-22 The technique of fetal scalp sampling using an amnioscope. The end of the endoscope is displaced from the fetal vertex approximately 2 cm to show the disposable blade against the fetal scalp before incision.

The pH of fetal capillary scalp blood is usually lower than that of umbilical venous blood and approaches that of umbilical arterial blood. In one algorithm, if the pH is :7.25, labor is observed, and if between 7.20 and 7.25, the pH measurement is repeated within 30 minutes (Zalar, 1979). If the pH is <7.20, another scalp blood sample is collected immediately, and the mother is taken to an operating room and prepared for surgery. Delivery is performed promptly if the low pH is conirmed. Otherwise, labor is allowed to continue, and scalp blood samples are repeated periodically.

he only beneits reported for scalp blood pH testing are fewer cesarean deliveries for fetal distress (Young, 1980b). However, Goodwin and coworkers (1994) showed a decrease in the scalp pH sampling rate from approximately 1.8 percent in the mid-1980s to 0.03 percent by 1992. This drop in sampling rate was not associated with a higher cesarean delivery rate for fetal distress. They concluded that scalp blood pH sampling was unnecessary.

Kruger and colleagues (1999) have advocated the use of fetal scalp blood lactate concentration as an adjunct to pH. WibergItzel and associates (2008) randomly assigned 1496 fetuses to scalp blood pH analysis and 1496 to scalp blood lactate analysis. They found either to be equivalent in predicting fetal acidemia. The advantage of lactate measurement was that a smaller amount of blood was needed, which led to a lower procedural failure rate compared with scalp blood sampling for pH.

Clark and coworkers (1984) have suggested that fetal scalp stimulation is an alternative to scalp blood sampling. his proposal was based on the observation that heart rate acceleration in response to pinching the fetal scalp with an Allis clamp just before obtaining blood was invariably associated with a normal pH. Conversely, failure to provoke acceleration was not uniformly predictive of fetal acidemia. Later, Elimian and associates (1997) reported that of 58 cases in which the fetal heart rate accelerated > 10 bpm after 15 seconds of gentle digital stroking of the scalp, 100 percent had a scalp blood pH of > 7.20. Without an acceleration, however, only 30 percent had a scalp blood pH > 7.20. Following a prospective cohort study, Tahir Mahmood and coworkers (2017) concluded that fetal scalp stimulation was a reliable alternative to scalp blood pH determination.

Fetal heart rate acceleration in response to vibroacoustic stimulation has been recommended as a substitute for fetal scalp blood sampling (Edersheim, 1987). The technique uses an electronic artificial larynx placed approximately 1 cm from or directly onto the maternal abdomen (Chap. 17, p. 337). Response to vibroacoustic stimulation is considered normal if a fetal heart rate acceleration of at least 15 bpm for at least 15 seconds occurs within 15 seconds after the stimulation and with prolonged fetal movements (Sherer, 1994).

0 0 80 40 o ,, 15 1111111111111111111111-1-"."." ".".".".'." 45 60 75

FIGURE 24-23 Frequency distribution of umbilical artery oxygen saturation values in 1281 vigorous newborn infants. Dotted line indicates normal distribution. (Redrawn with permission from Arikan GM, Scholz HS, Petru E, et al: Cord blood oxygen saturation in vigorous infants at birth: what is normal? BJOG. 2000 Aug;l07(8):987-994.)

Lin and colleagues (2001) prospectively studied vibroacoustic stimulation in 113 women in labor with either moderateto-severe variable or late fetal heart rate decelerations. hey concluded that this technique is an efective predictor of fetal acidosis in the setting ofvariable decelerations. The predictability for fetal acidosis, however, is limited in the setting of late decelerations. Other investigators have reported that vibroacoustic stimulation in second-stage labor did not predict neonatal outcome or enhance labor management (Anyaegbunam, 1994).

Skupski and coworkers (2002) performed a metaanalysis of reports on intrapartum fetal stimulation tests published between 1966 and 2000. Four types of fetal stimulation were analyzed and included fetal scalp puncture for blood pH testing, llis clamp pinching of the fetal scalp, vibroacoustic stimulation, and digital strokingofthe fetal scalp. Results were similar for all four methods. These investigators concluded that intrapartum stimulation tests were useful to exclude fetal acidemia. They cautioned, however, that these tests are "less than perfect."

Using technology similar to that of adult pulse oximetry, this instrumentation allows assessment offetal oxyhemoglobin saturation once membranes are ruptured. A unique padlike sensor is inserted through the cervix and positioned against the fetal face. he transcervical device reliably registers fetal oxygen saturation in 70 to 95 percent ofwomen throughout 50 to 88 percent of their labors (Yam, 2000). Using fetal pulse oximetry, the lower limit for normal fetal oxygen saturation is generally considered to be 30 percent (Gorenberg, 2003; Stiller, 2002). However, when measured in umbilical arterial blood, fetal oxygen saturation normally varies greatly, as shown in Figure 24-23. Bloom u:

J:Jr� and associates (1999) reported that brief, transient fetal oxygen saturations <30 percent were common during labor because such values were observed in 53 percent offetuses with normal outcomes. When persistent for 2 minutes or longer, however, saturation values <30 percent were associated with a greater risk of potential fetal compromise.

women with term pregnancies and in whom predeined abnor mal fetal heart rate patterns developed. Patients received either continuous fetal pulse oximetry. he use of fetal pulse oxim etrysigniicantlyreduced the cesarean delivery rate for nonreas suring fetal status from 10.2 to 4.5 percent. Alternatively, the cesarean delivery rate for dystocia rose significantly from 9 to 19 percent when pulse oximetry was used. No neonatal ben eits or adverse efects were associated with fetal pulse oximetry.

Based on these observations, the Food and Drug Administra tion approved marketing of the Nellcor N-400 Fetal Oxygen

Monitoring System.

Since then, three other randomized trials have compared fetal pulse oximetry with standard care. In all three trials, neo natal outcomes were similar between the two study arms. East and coworkers (2006) reported that the addition of oximetry fetal heart rate pattern. However, Bloom (2006) and lauser (2005), each with their colleagues, found no diference in cesar ean delivery rates between the two study groups. Because of these indings, in 2005, the manufacturer discontinued sale of the fetal oximeter system in the United States.

As fetal hypoxia worsens, the fetal ECG changes. Namely, the mature fetus exposed to hypoxemia develops an elevated ST segment and a progressive rise in the T-wave height that can be expressed as a T:QRS ratio (Fig. 24-24). Increasing T:QRS ratios are thought to relect the fetal cardiac ability to adapt to hypoxia and appear before neurological damage. Further worsening of hypoxia then leads to progressively negative ST-segment delection that takes on a biphasic form (Fig. 24-25). It is reasonable to consider that ST-segment abnormalities might occur late in the course of fetal compromise. Indeed, it has been hypothesized that ST-segment changes relect myocardial tissue hypoxia.

Because of these indings, several investigators have assessed the value of analyzing these parameters as an adjunct to conventional fetal monitoring. The technique requires internal fetal heart monitoring and special equipment to process the fetal ECG. In 2005, the manufacturer-Neoventa Medicalreceived Food and Drug Administration approval for their ST analysis program named the STAN system.

Several studies have evaluated ST-segment changes with fetal monitoring. In one randomized trial of 2400 pregnancies, neonatal outcomes were not improved compared with those in which conventional fetal monitoring alone was used (Westgate, 1993). However, the cesarean delivery rate for fetal distress declined in those with ST-segment analysis. Amer-Wahlin and colleagues (2001, 2007) found that the addition ofST-segment analysis to conventional fetal monitoring significantly lowered cesarean delivery rates for fetal distress and reduced metabolic acidemia in umbilical artery blood.

A Normal ST• Aerobic metabolism B Generation ofT:QRS ratios• Positive energy balance raw-ECG Average of 30 ECG complexes IncreasedT-wave amplitude• Hypoxia/anaerobic metabolism• Adrenaline surge R T ratio

FIGURE 24-24 A. ST segment changes in normal and hypoxic conditions. B. Generation ofT:QRS ratios. (Redrawn with permission from Devoe L: ECG analysis: the next generation in electronic fetal monitoring? Contemporary Ob/Gyn, September 15,o2006.)

Subsequently, Doria and associates (2007) introduced STAN as a clinical practice and reported no changes in the incidence of operative delivery or neonatal encephalopathy. And, one metaanalysis of ive randomized trials comprising 15,352 patients found that ST-segment analysis did not lower rates of cesarean delivery or fetal metabolic acidemia at birth (Becker, 2012).

Last, in a trial by the NICHD, 5532 women were randomly assigned to an ST-segment analysis arm (the open group) and 5576 to standard intrapartum management (the masked group). he primary outcome was a composite of one or more of seven events associated with fetal compromise (Belfort, 2015). In the open group, clinical practice was directed to some degree by predetermined ST-segment analysis guidelines. hese stipulated that intervention should be withheld, that is, expectant management adopted, for at least 60 minutes despite the presence of minimal variability; variable decelerations lasting �60 seconds or dropping to �60 bpm; recurrent late decelerations; or prolonged decelerations lasting >2 minutes, so long as no ST-eventwas present. hese guidelines did not pertain to the standard usual management group. Notably, in the open group, 55 women were delivered when STAN guidelines indicated that labor should continue. his composed 20 percent ofthe total 287 cesarean deliveries performed for fetal distress in this group. Clearly, the attending physicians abandoned the open group protocol that stipulated nonintervention. They likely perceived the fetal heart rate patterns to reflect those formerly accepted in their usual practice as nonreassuring.

FIGURE 24-25 Biphasic ST-segment waveform with progressive fetal hypoxia. (Adapted with permission from Devoe L: ECG analysis: the next generation in electronic fetal monitoring? Contemporary Ob/Gyn, September 15,o2006.)

The results of this trial showed that STAN had no efect on neonatal outcome or cesarean delivery rates (Belfort, 2015). In their review, Neilson and colleagues (2015) reached similar conclusions. hese results have essentially eliminated use ofSTsegment analysis in the United States, but this technology is still used in Europe.

Doppler interrogation of the umbilical artery has been studied as another potential adjunct to conventional fetal monitoring. Further described in Chapter 10 (p. 213), abnormal Doppler waveforms may signiy pathological umbilical-placental vessel resistance. From their review, Farrell and associates (1999) concluded that this technique, used intrapartum, was a poor predictor of adverse perinatal outcomes.

The termetal distress is too broad and vague to be applied with any precision to clinical situations (American College ofObstetricians and Gynecologists, 2014). Uncertainty regarding the diagnosis based on interpretation of fetal heart rate patterns has given rise to descriptions such as reassuring or nonreassuring. he term "reassuring" suggests a restoration of confidence in the health of the fetus by a particular pattern. In contrast, a "nonreassuring" designation suggests inability to remove doubt. hese patterns during labor are dynamic, and they can rapidly change from reassuring to nonreassuring and vice versa.

These assessments are subjective clinicaljudgments that are inevitaby subject to impeection and must be reconized as such.

The diiculty in assigning a nonreassuring label to fetal heart rate patterns stems in part from the fact that these patterns are more a reflection of fetal physiology than of pathology. Physiological control of heart rate includes various interconnected mechanisms that depend on blood flow and oxygenation. Moreover, the activity of these control mechanisms is inluenced by the preexisting state of fetal oxygenation, for example, as seen with chronic placental insuiciency. Importantly, the fetus is tethered by an umbilical cord, whereby blood flow is constantly in jeopardy. Moreover, normal labor is a process of increasing acidemia (Rogers, 1998). hus, normal labor is a process of repeated fetal hypoxic events that can infrequently lead to signiicant acidemia.

Identiication of "fetal distress" based on fetal heart rate patterns is imprecise and controversial. Experts in interpretation of these patterns often disagree with each other. Ayres-de-Campos and colleagues (1999) investigated interobserver agreement of fetal heart rate pattern interpretation and found that agreement-or conversely, disagreement-was related to whether the pattern was normal, suspicious, or pathological. Speciically, experts agreed on 62 percent of normal patterns, 42 percent of suspicious patterns, and only 25 percent of pathological patterns. Keith and coworkers (1995) asked each of 17 experts to review 50 tracings on two occasions, at least 1 month apart. Approximately 20 percent changed their own interpretations, and approximately 25 percent did not agree with the interpretations of their colleagues.

To develop standardized and unambiguous deinitions of fetal heart rate (FHR) tracings, the NICHD (1997) held a succession of workshops in 1995 and 1996 and published recommendations for interpreting these patterns. As previously shown in Table 24-1, a second workshop was convened to reevaluate these recommendations and clariy terminology (Macones, 2008). A major result was the recommendation of a three-tier system for classification of FHR patterns (1 able 24-2). The American College of Obstetricians and Gynecologists (2017b) has recommended use of this tiered system.

A few studies have assessed this three-tiered system. J ackson and coworkers (201i1) studied 48,444 women in labor and found that category I (normal FHR) patterns were observed during labor in 99.5 percent of tracings. Category II (indeterminate FHR) patterns were found in 84.i1 percent of tracings, and category III (abnormal FHR) patterns were seen in 0.1 percent (54 women). Most-84 percent of women-had a mix of categories during labor. Cahill and colleagues (2012) retrospectively correlated the incidence of umbilical cord acidemia (pH :;7.10) with fetal heart rate characteristics during the 30 minutes preceding delivery. None of the three categories demonstrated a significant association with cord blood acidemia. The American College of Obstetricians and Gynecologists and the American Academy of Pediatrics (2014) concluded that a category I or II tracing with a 5-minute Apgar scorei> 7 or with normal arterial blood acid-base values was not consistent with an acute hypoxic-ischemic event.

TABLE 24-2. Three-Tier Fetal Heart Rate Interpretation System

Include all of the following: • Baseline rate: 110-160 bpm

Baseline FHR variability: moderate

Early decelerations: present or absent

Accelerations: present or absent

Include all FHR tracings not categorized as Category I or III.

of those encountered in clinical care. Examples include any of the following:

Absence of induced accelerations after fetal stimulation Periodic or episodic decelerations

Prolonged deceleration :2 min but < 1 0 min

Variable decelerations with other characteristics, such as slow return to baseline, "overshoots,"

Include either: • Absent baseline FHR variability and any of the following: bpm = beats per minute; FHR = fetal heart rate. Reproduced with permission from Macones GAl Hankins GO, Spong CY, et al: The 2008 National Institute of Child Health and Human Development workshop report on electronic fetal monitoring: update on definitions, interpretation, and research guidelines, Obstet Gynecol. 2008 Sep;1s12(3))661-666.

Sholapurkar (2012) challenged the validity of the threetier system because most abnormal fetal heart rate patterns fall into the indeterminate category II. It was further suggested that this resulted from most fetal heart rate decelerations being inappropriately classiied as variable decelerations due to cord compression. A group of 19 experts led by Clark (2013) observed that more than 80 percent of fetuses have FHR patterns in tier II. hey proposed a management algorithm for these fetuses, however, their hypothetical algorithm was not clinically tested.

Parer and King (2010) compared this situation in the United States with that of other countries in which a consensus on classiication and management has been reached by several professional societies. Some of these include the Royal College of Obstetricians and Gynaecologists, the Society of Obstetricians and Gynaecologists of Canada, the Royal Australian and New Zealand College of Obstetricians and Gynaecologists, and the Japan Society of Obstetrics and Gynecology. These authors further comment that the NICHD three-tier system is inadequate because category II-an indeterminate FHR pattern-contains a vast heterogenous mixture of patterns that prevents development of a management strategy.

Parer and Ikeda (2007) had previously proposed a colorcoded ive-tier system for both FHR interpretation and management. Two subsequent reports have compared the five-and three-tier systems. Bannerman and associates (2011) found that the two systems were similar in fetal heart rate interpretations for tracings that were either very normal or very abnormal. Coletta and coworkers (2012) found that the ive-tier system had better sensitivity than the three-tier system. Elliott and colleagues (2010) used computerization to measure the performance of a ive-tier classiication system but failed to successfully analyze and categorize 2472 fetal heart recordings.

It is apparent that, after 50 years of continuous electronic fetal heart rate monitoring use, there is not a consensus on interpretation and management recommendations for FHR patterns (Parer, 2011).

• Meconium in the Amnionic Fluid

Obstetricians have long realized that meconium during labor is problematic in the prediction of fetal distress or asphxia. Indeed, although 12 to 22 percent oflabors are complicated by meconium, only a few are linked to neonatal mortality. In an investigation from Parkland Hospital, meconium was found to be a "low-risk" obstetrical hazard because the perinatal mortality rate attributable to meconium was only 1 death per 1000 live births (Nathan, 1994).

Three theories regarding fetal passage of meconium may explain, in part, the tenuous connection between its detection and neonatal mortality. First, fetuses may pass meconium in response to hypoxia, and meconium therefore signals fetal compromise (Walker, 1953). Second, in utero passage of meconium may represent normal gastrointestinal tract maturation under neural control (Mathews, 1979). A inal theory posits that meconium passage follows vagal stimulation from common but transient umbilical cord entrapment with resultant increased bowel peristalsis (Hon, 1961).

Ramin and associates (1996) studied almost 8000 pregnancies with meconium-stained amnionic fluid delivered at Parkland Hospital. Meconium aspiration syndrome was signiicantly associated with fetal acidemia at birth. Other signiicant correlates of aspiration included cesarean delivery, forceps to expedite delivery, intrapartum heart rate abnormalities, depressed Apgar scores, and need for assisted ventilation at delivery. Analysis of the type of fetal acidemia based on umbilical blood gases suggested that the fetal compromise associated with meconium aspiration syndrome was an acute event. his is because most acidemic fetuses had abnormally increased PC02 values rather than a pure metabolic acidemia.

Dawes and coworkers (1972) observed that such hypercarbia in fetal lambs induces gasping and resultant increased amnionic fluid inhalation. Jovanovic and Nguyen (1989) observed that meconium gasped into the fetal lungs caused aspiration syndrome only in asphyxiated animals.

Ramin and colleagues (1996) hypothesized that the pathophysiology of meconium aspiration syndrome includes, but is not limited to, fetal hypercarbia, which stimulates fetal respiration leading to aspiration of meconium into the alveoli. Lung parenchymal injury is secondary to acidemia-induced alveolar cell damage. In this pathophysiological scenario, meconium in amnionic fluid is a fetal environmental hazard rather than a marker of preexistent compromise. This proposed pathophysiological sequence is not all-inclusive, because it does not account for approximately half of the cases of meconium aspiration syndrome in which the fetus is not acidemic at birth.

Thus, it was concluded that the high incidence of meconium observed in the amnionic fluid during labor often represents fetal passage of gastrointestinal contents in conjunction with normal physiological processes. lthough normal, such meconium becomes an environmental hazard when fetal acidemia supervenes. Importantly, such acidemia occurs acutely, and therefore meconium aspiration is unpredictable and likely unpreventable. Moreover, Greenwood and colleagues (2003) showed that clear amnionic fluid was also a poor predictor. In a prospective study of 8394 women with clear amnionic fluid, they found that clear fluid was an unreliable sign of fetal wellbeing.

Growing evidence indicates that many newborns with meconium aspiration syndrome have suffered chronic hypoxia before birth (Ghidini, 2001). Blackwell and associates (2001) found that 60 percent of neonates diagnosed with meconium aspiration syndrome had umbilical artery blood pH ::7.20, implying that the syndrome was unrelated to the neonatal condition at delivery. Similarly, markers of chronic hypoxia, such as elevated fetal erythropoietin levels and increased nucleated red blood cell counts in newborns, suggest that chronic hypoxia is involved in many meconium aspiration syndrome cases (Dollberg, 2001; Jazayeri, 2000).

In the recent past, routine obstetrical management of a newborn with meconium-stained amnionic fluid included intrapartum suctioning of the oropharynx and nasopharynx. In 2005, management guidelines were signiicantly modiied. Now, the American College of Obstetricians and Gynecologists (2017c) recommends that newborns with meconium-stained amnionic fluid, regardless of their vigor, should no longer routinely receive intrapartum suctioning. Suctioning is reserved for those with airway obstruction. hey also recommend that an appropriately credentialed team with full resuscitation skills be available (Chap. 32, p. 607).

TABLE 24-3. Some Resuscitative Measures for Category II or Category III Tracings

Tachysystole with category II or III tracing Discontinue oxytocin or prostaglandins; tocolytics: terbutaline, magnesium sulfate

Recurrent variable decelerations Reposition mother; amnioinfusion; with cord prolapse, manually elevate Prolonged decelerations or bradycardia the presenting part while preparing for immediate delivery aSimultaneous evaluation of the suspected cause(s) is also an important step in management of abnormal FHR tracings.

The combination of multiple interventions Simultaneously may be appropriate and potentially more effective than doing them individually or serially.

FHR = fetal heart rate.

Principal management options for variant fetal heart rate patterns consist of correcting any fetal insult, if possible. Suggestions are listed in Table 24-3. he woman is moved to a lateral position, and supplemental oxygen is provided by mask. Correcting maternal hypotension caused by regional analgesia and discontinuing oxytocin both serve to improve uteroplacental perfusion. Vaginal examination excludes a prolapsed cord or impending delivery. Simpson and James (2005) assessed the beneits of three maneuvers in 52 women with fetal oxygen saturation sensors already in place. They used intravenous hydration-500 to 1000 mL of lactated Ringer solution given over 20 minutes; lateral versus supine positioning; and administration of supplemental oxygen at lOiLl min using a nonrebreathing mask. Each of these maneuvers signiicantly raised fetal oxygen saturation levels.

Terbutaline sulfate given to relax the uterus can be a temporizing maneuver in the management of nonreassuring fetal heart rate patterns during labor. A single 250-�g intravenous or subcutaneous injection is used to inhibit uterine contractions and thereby improve fetal oxygenation. Cook and Spinnato (1994) described their 10-year experiences with terbutaline tocolysis in 368 pregnancies. Such resuscitation improved fetal scalp blood pH values, although all fetuses underwent cesarean delivery. hese investigators concluded that although the studies were small and rarely randomized, most reported favorable results with terbutaline tocolysis for nonreassuring patterns. Small intravenous doses of nitroglycerin-60 to 180 �g-also have been reported to be beneicial (Mercier, 1997). Bullens and associates (2015) concluded in their review that tocolysis was beneicial. Still, the American College of Obstetricians and Gynecologists (20i1i7b) cites that evidence is insuicient to recommend tocolysis for nonreassuring fetal heart rate patterns.

Such therapy improved the heart rate pattern in half of the women studied. Later, .Miyazaki and Nevarez (1985) randomly assigned 96 nulliparas in labor with cord compression patterns and found that those who were treated with amnioinfusion required cesarean delivery for fetal distress less often. Based on many of these early reports, transvaginal amnioinfusion has been extended into three clinical areas (Dad, 2016). hese include: (1) treatment of variable or prolonged decelerations; (2) prophylaxis for women with oligohydramnios, as with prolonged ruptured membranes; and (3) attempts to dilute or wash out thick meconium (Chap. 33, p. 620).

Many diferent amnioinusion protocols have been reported, but most provide a 500-to 800-mL bolus of warmed normal saline followed by a continuous inusion of approximately 3 mLimin (Owen, 1990; Pressman, 1996). In another study, Rinehart and colleagues (2000) gave either a 500-mL bolus of normal saline at room temperature alone or a similar bolus plus a continuous inusion at 3 mLimin. heir study included 65 women with variable decelerations, and the investigators found neither method to be superior. Wenstrom and associates (1995) surveyed use of mnioinusion in teaching hospitals in the United States. The procedure was used in 96 percent of the 186 centers surveyed, and it was estimated that 3 to 4 percent of llwomen delivered at these centers received such inusion. Potential complications of mnioinusion are summarized in Table 24-4.

TABLE 24-4. Complications Associated with Amnioinfusion from a Survey of 186 Obstetrical Units

Data from Wenstrom, 1995.

able or prolonged decelerations attributed to cord entrapment.

For variable decelerations, Hofmeyr and Lawrie (2012) reviewed the efects of amnioinfusion in the management of fetal heart rate patterns associated with umbilical cord compression. They concluded that amnioinfusion appeared to be useful in reducing the occurrence of variable decelerations, improving neonatal outcome, and lowering cesarean delivery rates. The American College of Obstetricians and Gynecologists (2016) has concluded that amnioinfusion is a reasonable approach in the treatment of repetitive variable decelerations regardless of meconium status.

For oligohydramnios, amnioinfusion has been used prophylactically to avoid intrapartum fetal heart rate patterns from cord occlusion. Nageotte and coworkers (1991) found that this resulted in signiicantly fewer and less severe variable decelerations in labor. However, the cesarean delivery rate or condition of term newborn was not improved. In a randomized investigation, Macri and colleagues (1992) studied prophylactic amnioinfusion in 170 term and postterm pregnancies complicated by both thick meconium and oligohydramnios. Amnioinfusion significantly reduced meconium aspiration syndrome rates and cesarean delivery rates for fetal distress. In contrast, Ogundipe and associates (1994) randomly assigned 116 term pregnancies with an amnionic luid index < 5 cm to receive prophylactic amnioinfusion or standard obstetrical care. Overall cesarean delivery rates, delivery rates for fetal distress, or umbilical cord acid-base studies did not difer significantly between groups.

For meconium-stained amnionic luid, Pierce and associates (2000) reviewed 13 prospective trials of intrapartum amnioinfusion for 1924 women with meconium-stained fluid. In the amnioinfusion group, newborns were signiicantly less likely to have meconium below the vocal cords, and meconium aspiration syndrome rates were lower. he cesarean delivery rate was also reduced in the amnioinfusion group. Similar results were reported by Rathore and coworkers (2002).

In contrast, several investigators were not supportive of amnioinfusion for meconium staining. For example, Usta and associates (1995) reported that amnioinfusion was not feasible in half of women with moderate or thick meconium who were randomized to this treatment. These investigators were unable to demonstrate improved neonatal outcomes with this treatment. Spong and coworkers (1994) also concluded that although prophylactic amnioinfusion did dilute meconium, it did not improve perinatal outcome. Last, Fraser and colleagues (2005) randomized amnioinfusion in 1998 women with thick meconium-stained amnionic fluid in labor and found no beneits. Hofmeyr and associates (2014) reported mixed results from their review. Because of these indings, the American College of Obstetricians and Gynecologists (2016) does not recommend amnioinfusion to dilute meconium-stained amnionic fluid.

Studies that have attempted to correlate fetal heart rate patterns with brain injury primarily have examined infants identiied in medicolegal actions. Phelan and Ahn (1994) reported that among 48 fetuses later found to be neurologically impaired, a persistent nonreactive fetal heart rate tracing was already present at the time of admission in 70 percent. They concluded that fetal neurological injury occurred predominately before arrival to the hospital. When they looked retrospectively at heart rate patterns in 209 brain-injured newborns, they concluded that there was not a single unique pattern associated with fetal neurological injury (Ahn, 1996). Graham and associates (2006) reviewed the world literature published between 1966 and 2006 on the efect of fetal heart rate monitoring to prevent perinatal brain injury and found no beneit.

Fetal heart rate patterns necessary for perinatal brain damage have been studied in experimental animals. .1yers (1972) described the efects of complete and partial asphyxia in rhesus monkeys. Complete asphyxia was produced by total occlusion of umbilical blood low that led to prolonged deceleration (Fig. 24-26). Fetal arterial pH did not drop to 7.0 until approximately 8 minutes after complete cessation of oxygenation and umbilical low. At least 10 minutes of such prolonged deceleration was required before there was evidence of brain damage in surviving fetuses.

Myers (1972) also produced partial asphyxia in rhesus monkeys by impeding maternal aortic blood flow. This resulted in ...A �EEI0). /0 5 1005 10 Asphyxia (min) 0.

.Cordclamp010 120 20 40 0)0 ..

:JQ) .0

FIGURE 24-26 Prolonged deceleration in a rhesus monkey shown with blood pressure and biochemical changes during total occlusion of umbilical cord blood flow. (Data from Myers, 1972.) analgesia was used in 55 percent. The length of the second stage, even in those lasting up to 6 hours or more, was not related to neonatal outcome. These results were attributed to careful use of electronic monitoring and scalp pH measurements. These investigators concluded that there is no compelling reason to intervene with a possibly diicult forceps or vacuum extraction because a certain number of hours have elapsed. They observed, however, that after 3 hours in the second stage, delivery by cesarean or other operative method increased progressively. By 5 hours, the prospects for spontaneous delivery in the subse quent hour were only 10 to 15 percent.

Newer guidelines have been promoted by the Consensus Com mittee (2016) for second-stage labor. These recommend allowing a nullipara to push for at least 3 hours and a multipara to push for at least 2 hours before second-stage labor arrest is diagnosed.

One caveat is that maternal and fetal status should be reassuring.

These authors provide options to these times before cesarean deliv ery is performed. Namely, longer durations may be appropriate as long as progress is documented. Also, a specific maximal length of undergo operative delivery has not been identiied.

Intuitively, the goal to lower cesarean delivery rates is best balanced with one to ensure neonatal safety. And, it is problematic that no robust data on neonatal outcomes support the safety of allowing prolonged second-stage labor. Data from many evaluations reveal that serious newborn consequences attend second-stage labors longer than 3 hours (Allen, 2009; Bleich, 2012; Laughon, 2014; Leveno, 2016; Rosenbloom, 2017). Other data, when adjusted for labor variables, show no diference in neonatal complications for these longer second stages (Cheng, 2004; Le Ray, 2009; Rouse, 2009). Grobman and colleagues (2016) have argued that the absolute number of such adverse outcomes is small and "overall outcomes remain good." That said, some of the complications are severe. Thus, to fully ascertain specific efect of these guidelines on morbidity rates, randomized controlled trials are needed.

It is possible that prolonged first-stage labor presages that with the second stage. Nelson and associates (2013) studied the relationships between the lengths of the irst and second stages of labor in 12,523 nulliparas at term delivered at Parkland Hospital. The second stage signiicantly lengthened concomitantly with increasing irst-stage duration. The 95th percentile was 15.6 and 2.9 hours for the first and second stages, respectively. Women with irst stages lasting longer than 15.6 hours (>95th percetile) had a 16-percent rate of second-stage labor lasting 3 hours (95th percentile). his compared with a 4.5-percent rate of prolonged second stages in women with irst-stage labors lasting <95th percentile.

With full cervical dilation, most women cannot resist the urge to "bear down" or "push" each time the uterus contracts (Chap. 22, p. 438). The combined force created by contractions of the uterus and abdominal musculature propels the fetus downward. At times, force created by abdominal musculature is compromised suiciently to slow or even prevent spontaneous vaginal delivery. Heavy sedation or regional analgesia may reduce the reflex urge to push and may impair the ability to contract abdominal muscles efectively. In other instances, the inherent urge to push is overridden by the intense pain created by bearing down. Two approaches to second-stage pushing in women with epidural analgesia have yielded contradictory results. The irst advocates pushing forcefully with contractions after complete dilation, regardless of the urge to push. With the second, analgesia inusion is stopped and pushing begins only ater the woman regains the sensory urge to bear down. Fraser and coworkers (2000) found that delayed pushing reduced diicult operative deliveries, whereas Manyonda and associates (1990) reported the opposite. Hansen and colleagues (2002) randomly assigned 252 women with epidural analgesia to one of the two approaches. No adverse maternal or neonatal outcomes were linked to delayed pushing despite signiicantly prolonging second-stage labor. Plunkett and coworkers (2003), in a similar study, confirmed these indings.

Descent of the leading edge of the presenting part to the level of the ischial spines (0 station) is deined as engagement. A higher station at the onset of labor is signiicantly linked with subsequent dystocia (Friedman, 1965, 1976; Handa, 1993). Roshanfekr and associates (1999) analyzed fetal station in 803 nulliparas at term in active labor. At admission, the third with the fetal head at or below 0 station had a 5-percent cesarean delivery rate. This compared with a 14-percent rate for those with higher stations. The prognosis for dystocia, however, was not related to incrementally higher fetal head stations above the pelvic midplane (0 station). Importantly, 86 percent of nulliparous women without fetal head engagement at diagnosis of active labor delivered vaginally. These observations apply especially for parous women because the head typically descends later in labor.

Various labor factors have been implicated as causes of uterine dysfunction. As described, neuraxial analgesia can slow labor and has been associated with lengthening both first and second stages of labor and slowing the rate of fetal descent.

Chorioamnionitis is associated with prolonged labor, and some clinicians have suggested that this maternal intrapartum infection itself contributes to abnormal uterine activity. Satin and coworkers (I992) studied the efects of chorioamnionitis on oxytocin stimulation in 266 pregnancies. Infection diagnosed late in labor was found to be a marker of cesarean delivery performed for dystocia. Speciically, 40 percent of women developing chorioamnionitis after requiring oxytocin for dysfunctional labor later required cesarean delivery for dystocia. However, this was not a marker in women diagnosed as having chorioamnionitis early in labor. It is likely that uterine infection in this clinical setting is a consequence of dysfunctional, prolonged labor rather than a cause of dystocia.

Membrane rupture at term without spontaneous uterine contractions complicates approximately 8 percent of pregnancies. In the past, labor stimulation was initiated if contractions did not begin ater 6 to 12 hours. Practice-changing research included that of Hannah (1996) and Peleg (1999) and their associates, who enrolled a total of 5042 pregnancies with ruptured membranes in a randomized investigation. They measured the efects of induction versus expectant management and also compared induction using intravenous oxytocin with that using prostaglandin E2 gel. There were approximately 1200 pregnancies in each of the four study arms. They concluded that labor induction with intravenous oxytocin was preferred management. This was based on signiicantly fewer intrapartum and postpartum infections in women whose labor was induced. There were no signiicant differences in cesarean delivery rates. Subsequent analysis by Hannah and coworkers (2000) indicated higher rates of adverse outcomes when expectant management at home was compared with in-hospital observation. Mozurkewich and associates (2009) reported lower rates of chorioamnionitis, metritis, and neonatal intensive care unit admissions for women with term ruptured membranes whose labors were induced compared with those managed expectantly. At Parkland Hospital, labor is induced soon ater admission when ruptured membranes are confirmed at term. In those with hypotonic contractions or with advanced cervical dilation, oxytocin is selected to lower potential hyperstimulation risk. In those with an unfavorable cervix and no or few contraction, prostaglandin E\ (misoprostol) is chosen to promote cervical ripening and contractions. he beneit of prophylactic antibiotics in women with ruptured membranes before labor at term is unclear (Passos, 2012). However, in those with membranes ruptured longer than 18 hours, antibiotics are instituted for group B streptococcal infection prophylaxis (Chap. 64, p. 1221).

Labor can be too slow, but it also can be abnormally rapid. Precipitous labor and delivey is extremely rapid labor and delivery. It may result from an abnormally low resistance of the soft parts of the birth canal, from abnormally strong uterine and abdominal contractions, or rarely from the absence of painful sensations and thus a lack of awareness of vigorous labor.

Precipitous labor terminates in expulsion of the fetus in less than 3 hours. Using this definition, 25,260 live births-3 percent-were complicated by precipitous labor in the United States in 2013 (Martin, 2015). Despite this incidence, little published information describes maternal and perinatal outcomes.

For the mother, precipitous labor and delivery seldom are accompanied by serious maternal complications if the cervix is efaced appreciably and compliant, if the vagina has been stretched previously, and if the perineum is relxed. Conversely, vigorous uterine contractions combined with a long, firm cervix and a noncompliant birth canal may lead to uterine rupture or extensive lacerations of the cervix, vagina, vulva, or perineum (Sheiner, 2004). It is in these latter circumstances that amnionic-luid embolism most likely develops (Chap. 41, p. 785). Precipitous labor is frequently followed by uterine atony. The uterus that contracts with unusual vigor bore delivery is likey to be hypotonic ater delivey. In one report of 99 term pregnancies, short labors were more common in multiparas who typically had contractions at intervals less than 2 minutes. Precipitous labors have been linked to cocaine abuse and associated with placental abruption, meconium, postpartum hemorrhage, and low Apgar scores (Mahon, 1994).

For the neonate, adverse perinatal outcomes from rapid labor may be increased considerably for several reasons. he tumultuous uterine contractions, often with negligible intervals of relaxation, prevent appropriate uterine blood low and fetal oxygenation. Resistance of the birth canal may rarely cause intracranial trauma. Acker and coworkers (1988) reported that Erb or Duchenne brachial palsy was associated with such labors in a third of cases. Finally, during an unattended birth, the newborn may fall to the floor and be injured, or it may need resuscitation that is not immediately available.

As treatment, analgesia is unlikely to modiy these unusually forceful contractions to a significant degree. he use of tocolytic agents such as magnesium sulfate or terbutaline is unproven in these circumstances. Use of general anesthesia with agents that impair uterine contractibility such as isoflurane is often excessively heroic. Certainly, any oxytocin being administered should be stopped immediately.

Fetopelvic disproportion arises from diminished pelvic capacity, from abnormal fetal size or presentation, or more usually from both. he pelvic inlet, midpelvis, or pelvic outlet may be contracted solely or in combination. ny contraction of the pelvic diameters that diminishes pelvic capacity can create dystocia during labor. Normal pelvic dimensions are additionally discussed and illustrated in Chapter 2 (p. 30).

Using clinical measures, it is important to identiy the shortest anteroposterior diameter through which the fetal head must pass. Before labor, the fetal biparietal diameter averages from 9.5 to as much as 9.8 cm. Therefore, it might prove diicult or even impossible for some fetuses to pass through a pelvic inlet that has an anteroposterior diameter <10 cm. Mengert (1948) and Kaltreider (1952), employing x-ray pelvimetry, demonstrated that the incidence of diicult deliveries rises when either the anteroposterior diameter of the inlet is < 10 cm or the transverse diameter is < 12 cm. As expected, when both diameters are contracted, dystocia rates are much greater than when only one is contracted. Either of these measures is used to consider a pelvis contracted.

he anteroposterior diameter of the inlet, which is the obstetrical conjugate, is commonly approximated by manually measuring the diagonal conjugate, which is approximately 1.5 cm greater. Ascertainment of these measures is described in Chapter 2 (p. 30). herefore, inlet contraction usually is defined as a diagonal conjugate < 11.5 cm.

A small woman is likely to have a small pelvis, but she is also likely to have a small neonate. homs (1937) studied 362 nulliparas and found that the mean birthweight of their ofspring was significantly lower-280 g-in women with a small pelvis than in those with a medium or large pelvis.

as the rise in this pressure above a resting pressure baseline. hese investigators also introduced the concept of Montevideo units to deine uterine activity (Chap. 23, p. 443). With this deinition, uterine performance is the product of contraction intensity in mm Hg multiplied by the number of contractions in a 10-minute span. For example, three contractions in 10 minutes, each of 50 mm Hg intensity, would equal 150 Montevideo units.

During the irst 30 weeks of pregnancy, uterine activity is comparatively quiescent. Contractions are seldom greater than 20 mm Hg, and these have been equated with those irst described by John Braxton Hicks. Uterine activity increases gradually after 30 weeks, and it is noteworthy that these Braxton Hicks contractions also increase in intensity and frequency. Uterine activity is further enhanced during the last weeks of pregnancy. During this phase, the cervix ripens (Chap. 21, p. 409).

According to Caldeyro-Barcia and Poseiro (1960), clinical labor usually commences when uterine activity reaches values between 80 and 120 Montevideo units. his translates into approximately three contractions of 40 mm Hg every 10 minutes. Importantly, no clear-cut division marks labor onset, which is a gradual and progressive transition.

In irst-stage labor, uterine contractions progressively grow in intensity from approximately 25 mm Hg at labor commencement to 50 mm Hg at its end. At the same time, the frequency advances from three to ive contractions per 10 minutes, and uterine baseline tone rises from 8 to 12 mm Hg. Uterine activity is further enhanced during second-stage labor, aided by maternal pushing. Indeed, contraction intensity of 80 to 100 mm Hg is typical, and the uterus contracts as frequently as ive to six times each 10 minutes. Hauth and coworkers (1986) quantiied uterine contraction pressures in 109 women at term who received oxytocin for labor induction or augmentation. Most of these women achieved 200 to 225 Montevideo units, and 40 percent had up to 300 units to efect delivery. The authors suggested that these levels of uterine activity should be sought before consideration of cesarean delivery for presumed dystocia (Chap. 23, p. 443).

Interestingly, the duration of uterine contractions-60 to 80 seconds-does not lengthen appreciably from early active labor through the second stage (Bakker, 2007; Pontonnier, 1975). Presumably, this duration constancy serves fetal respiratory gas exchange. During a uterine contraction, as the intrauterine pressure exceeds that of the intervillous space, respiratory gas exchange is halted. This leads to functional fetal "breath holding," which has a 60-to 80-second limit that remains relatively constant.

readily be depressed by the inger. At greater intensities, the uterine wall then becomes so hard that it resists easy depression. Uterine contractions usually are not associated with pain until their strength exceeds 15 mm Hg. Presumably, this is the minimum pressure required to distend the lower uterine segment and cervix. It follows that Braxton Hicks contractions exceeding 15 mm Hg may be perceived as uncomfortable because distention of the uterus, cervix, and birth canal is generally thought to produce discomfort.

Hendricks (1968) observed that "the clinician makes great demands upon the uterus." The uterus is expected to remain well relaxed during pregnancy, to contract efectively but intermittently during labor, and then to remain in a state of almost constant contraction for several hours postpartum. Figure 24-28 demonstrates an example of normal uterine activity during labor. Uterine activity progressively and gradually rises from early through late labor. Interestingly, uterine contractions after birth are identical to those resulting in delivery of the newborn. Logically, the uterus that performs poorly before delivery is also prone to atony and puerperal hemorrhage.

J.A. 5-26-60

Intrauterine pressure (mm Hg) Delivery 2:54 PM.

8:45 A.M.

10:20 A.M.

1:10ePM. 2:30 PM.

3:30 PM.

5:20 P.M.

Caldeyro-Barcia and Poseiro (1960) also observed empirically that uterine contractions are clinically palpable only after their intensity exceeds 10 mm Hg. Moreover, until the intensity of contractions reaches 40 mm Hg, the uterine wall can

FIGURE 24-28 Intrauterine pressure recorded through a single catheter.

A. Prelabor. B. Early labor. C. Active labor. D. Late labor. E. Spontaneous activity Y2 hour postpartum. F. Spontaneous activity 2Y2 hours postpartum. (Redrawn from Hendricks (H: Uterine contractility changes in the early puerperium, (lin Obstet Gynecol. 1968 Mar;11 (1 ):125-144.) , I of the --contraction

Amnionic pressure[1 0 Tonus -.A

FIGURE 24-29 Schematic representation of the normal contractile wave of labor. Large uterus on the let shows the four points at which intramyometrial pressure was recorded with microballoons. Four corresponding pressure tracings are shown in relation to each other by shading on the small uteri at top. (Adapted with permission from (aldeyro-Barcia R, Poseiro JJ: Physiology ofthe uterine contraction. (lin Obstet Gynecol 1960 3:386.) • Origin and Propagation of Contractions

The normal contractile wave of labor originates near the uterine end of one of the fallopian tubes. hus, these areas act as "pacemakers" (Fig. 24-29). he right pacemaker usually predominates over the left and starts most contractile waves. Contractions spread from the pacemaker area throughout the uterus at 2 em/sec, and the whole organ is depolarized within 15 seconds. his depolarization wave propagates downward toward the cervix. Intensity is greatest in the fundus, and it diminishes in the lower uterus. his phenomenon is thought to relect the reduced myometrial thickness from the fundus to the cervix. Presumably, this descending pressure gradient serves to direct fetal descent toward the cervix and to eface the cer vix. Importantly, all parts of the uterus are synchronized and reach their peak pressure almost simultaneously, giving rise to the curvilinear waveform shown in Figure 24-29. Young and Zhang (2004) have shown that the initiation of each contraction is triggered by a tissue-level bioelectrical event.

The pacemaker theory also serves to explain the varying intensity of adjacent coupled contractions shown in panels A and B of Figure 24-28. Such coupling was termed incoordination by Caldeyro-Barcia and Poseiro (1960). A contractile wave begins in one cornual-region pacemaker but does not synchronously depolarize the entire uterus. As a result, another contraction begins in the contralateral pacemaker and produces the second contractile wave ofthe couplet. hese small contractions alternating with larger ones appear to be typical of early labor. Indeed, labor may progress with such uterine activity, albeit at a slower pace. hese authors also observed that labor would progress slowly ifregular contractions were hypotonicthat is, contractions with intensity <25 mm Hg or frequency <2 per 10 minutes.

Terms for the description and quantiication of uterine contractions have been recommended by the American College of Obstetricians and Gynecologists (2017b). Normal uterine activiy is defined as five or fewer contractions in 10 minutes, averaged during a 30-minute span. Tachysystole is more than ive contractions in 10 minutes, averaged over 30 minutes. Tachysystole can be applied to spontaneous or induced labor. he term hyperstimulation was abandoned.

Stewart and associates (2012) prospectively studied uterine tachysystole in 584 women undergoing labor induction with misoprostol at Parkland Hospital. A higher rate of adverse neonatal outcomes was not associated with an increasing number of contractions per 10 minutes or per 30 minutes. Counts of six or more contractions in 10 minutes, however, were significantly associated with fetal heart rate decelerations.

Electrodes for fetal heart rate evaluation and catheters for uterine contraction measurement are both associated with infrequent but potentially serious complications. Rarely, an intrauterine pressure catheter during placement may lacerate a fetal vessel in the placenta. Also with insertion, placental and possibly uterine perforation can cause hemorrhage, abruption, serious morbidity, and spurious recordings that have resulted in inappropriate management. Severe cord compression has been described from entanglement with the pressure catheter. Injury to the fetal scalp or breech by a heart rate electrode is rarely severe. However, application at some other site-such as the eye in face presentations-can be serious.

Both the fetus and the mother may be at greater risk of infection from internal monitoring (Faro, 1990). Scalp wounds from the electrode may become infected, and subsequent cranial osteomyelitis has been reported (Brook, 2005; Eggink, 2004; McGregor, 1989). The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017) have recommended that certain maternal infections, including human immunodeficiency virus (HIV), herpes simplex virus, and hepatitis Biand C virus, are relative contraindications to internal fetal monitoring.

Adamsons K, Myers E: Late decelerations and brain tolerance of the fetal monkey to intrapartum asphyxia. Am J Obstet Gyneco1o128:893, 197

Ahn MO, Korst L, Phelan JP: Intrapartum fetal heart rate patterns in 209 brain damaged infants. Am J Obstet GynecoIo174:492, 1996

Alfirevic Z, Devane 0, Gyte GM, et al: Continuous cardiotocography (CTG) as a form of electronic fetal monitoring (EFM) for fetal assessment during labour. Cochrane Database Syst Rev 2:CD006066, 2017

Ambia M1, Yule SS, Wells E: Does fetal bradycardia during eclamptic seizure necessitate cesarean delivery? Unpublished data, 20o17

Amer-Wihlin I, Arulkumaran S, Hagberg H, et al: Fetal electrocardiogram:

ST waveform analysis in intrapartum surveillance. BJOG 114: 1191,2007

Amer-Wahlin 1, Hellsten C, Noren H, et al: Cardiotocography only versus cardiotocography plus ST analysis of fetal electrocardiogram for intrapartum fetal monitoring: a Swedish randomized controlled trial. Lancet 358:534, 200o1

American Academy of Pediatrics and the American College of Obstetricians and Gynecologists: Guidelines for Perinatal Care, 8th ed. Elk Grove Village, AAP, 2017

American College of Obstetricians and Gynecologists: Amnioinfusion does not prevent meconium aspiration syndrome. Committee Opinion No. 346, October 2006, Reairmed 2016

American College of Obstetricians and Gynecologists: Intrapartum fetal heart rate monitoring: nomenclature, interpretation, and general management principles. Practice Bulletin No. 106, July 2009, Reairmed 2017 a

American College of Obstetricians and Gynecologists: Management of intrapartum fetal heart rate tracings. Practice Bulletin No. 116, November 2010, Reairmed 2017b

American College of Obstetricians and Gynecologists: Summary: delivery of a newborn with meconium-stained amniotic fluid. Committee Opinion No. 689, March 2017c

American College of Obstetricians and Gynecologists, American Academy of Pediatrics: Neonatal encephalopathy and neurologic outcome. Washington, ACOG,o2014

Ananth CV, Chauhan SP, Chen HY, et al: Electronic fetal monitoring in the United States. Obstet Gynecol 121(5):927,o2013

Anderson BL, Scerbo MW, Belfore A, et al: Time and number of displays impact critical signal detection in fetal heart rate tracings. Am J Perinatol 28(6):435,o2011

Angel J, Knuppel R, Lake M: Sinusoidal fetal heart rate patterns associated with intravenous butorphanol administration. Am J Obstet Gynecol 149:465, 1984 Anyaegbunam M, Ditchik A, Stoessel R, et al: Vibroacoustic stimulation of the fetus entering the second stage oflabor. Obstet Gynecol 83:963, 1994 Api 0, Carvalho JS: Fetal dysrhythmias. Best Pract Res Clin Obstet Gynaecol 22(1):31, 2008

Arikan GM, Scholz HS, Petru E, et al: Cord blood oxygen saturation in vigorous infants at birth: what is normal? BJOG 107:987,o2000

Ayres-de-Campos 0, Bernardes J, Costa-Pereira A, et al: Inconsistencies in classiication by experts of cardiotocograms and subsequent clinical decision. BJOG 106:1307, 1999

Bakker JJ, Verhoeven CJ, Janssen PF, et al: Outcomes after internal versus external tocodynamometry for monitoring labor. N Engl J Med 362:306, 2010 Bakker PC, Kurver PH, Duik OJ, et al: Elevated uterine activity increases the risk offetal acidosis at birth. Am J Obstet Gynecol 196:313,o2007

Ball RH, Parer JT: he physiologic mechanisms of variable decelerations. Am J Obstet Gynecol 166:1683, 1992

Bannerman CG, Grobman WA, Antoniewicz L: Assessment of the concordance among 2-tier, 3-tier, and 5-tier fetal heart rate classiication systems. Am J Obstet GynecoI205(3):288.e1, 2011

Banta HD, Thacker SB: Electronic fetal monitoring: lessons from a formative case of health technology assessment. Int J Technol Assess Health Care 18:762,o2002

Becker JH, Bax L, Amer-Wahlin I, et al: ST analysis of the fetal electrocardiogram in intrapartum fetal monitoring. Obstet Gynecol 119:145,2012 Belfort A, Saade GR, hom E, et al: A randomized trial of intrapartum fetal

ECG ST-segment analysis. N Engl J Med 373(7):632, 2015

Blackwell Sc, Groman WA, Antoniewicz L, et al: Interobserver and intraobserver reliability of the NICHD 3-tier fetal heart rate interpretation system. Am J Obstet Gynecol 8.e1,2011

Blackwell SC, Moldenhauer J, Hassan 55, et al: Meconium aspiration syndrome in term neonates with normal acid-base status at delivery: is it diferent? Am J Obstet Gynecol 184: 1422, 2001

Bloom SL, Spong CY, hon E, et al: Fetal pulse oximetry and cesarean delivery. N Engl J Med 335:21, 2006

Bloom SL, Swindle RG, McIntire DO, et al: Fetal pulse oximetry: duration of desaturation and intrapartum outcome. Obstet Gynecol 93: 1036, 1999 Boehm FH: Prolonged end stage fetal heart rate deceleration. Obstet Gynecol 45:579, 1975

Brocato B, Lewis 0, Mulekar M, et al: Obesity's impact on intrapartum electronic fetal monitoring. J Matern Fetal Neonatal Med August 30, 2017 [Epub ahead of print]

Brook I: Infected neonatal cephalohematomas caused by anaerobic bacteria. J Perinat Med 33(3):255, 2005

Bullens LM, van Runnard Heimel pJ, van der Hout-van der Jaqt MB, et al: Interventions for intrauterine resuscitation in suspected fetal distress during term labor: a systematic review. Obstet Gynecol Surv 70(8):524, 2015

Cahill AG, Roehl A, Odibo AO, et al: Association and prediction of neonatal acidemia. Am J Obstet Gynecol 207:206.e1, 2012

Caldeyro-Barcia R, Poseiro JJ: Physiology of the uterine contraction. Clin Obstet Gynecol 3:386, 1960

Chen HY, Chauhan SP, Ananth C: Electronic fetal heart monitoring and its relationship to neonatal and infant mortaliry in the United States. Am J Obstet GynecoIo204(6):491.e1, 2011

Clapp JF, Peress NS, Wesley M, et al: Brain damage after intermittent partial cord occlusion in the chronically instrumented fetal lamb. Am J Obstet Gynecol 159:504, 1988

Clark SL, Gimovsky ML, Miller FC: The scalp stimulation test: a clinical alternative to fetal scalp blood sampling. m J Obstet Gyneco1o148:274, 1984

Clark SL, Nageotte MP, Garite TJ, et al: Intrapartum management of category II fetal heart rate tracings: towards standardization of care. Am J Obstet GynecoIo209(2):89,o2013

Coletta J, Murphy E, Rubeo Z, et al: The 5-tier system of assessing fetal heart rate tracings is superior to the 3-tier system in identiying fetal acidemia. Am J Obstet Gynecol 206:226.e1, 2012

Cook VD, Spinnato JA: Terbutaline tocolysis prior to cesarean section for fetal distress. J Matern Fetal Med 3:219, 1994

Dad N, Abushama M, Konje JC, et al: What is the role of amnioinfusion in modern day obstetrics? J Matern Fetal Neonatal Med 29(17):2823,o2016

Davidson SR, Rankin JH, Martin CB Jr, et al: Fetal heart rate variability and behavioral state: analysis by power spectrum. Am J Obstet Gynecol 167:717,o1992

Dawes GS: he control of fetal heart rate and its variability in counts. In Kunzel W (ed): Fetal Heart Rate Monitoring. Berlin, Springer, 1985 Dawes GS, Fox HE, Leduc BM, et al: Respiratory movements and rapid eye movement sleep in the foetal Iamb. J Physiol 220:119, 1972

Dawes GS, Visser GHA, Goodman JDS, et al: Numerical analysis of the human fetal heart rate: modulation by breathing and movement. Am J Obstet Gynecol 140:535, 1981

Del Valle GO, Jofe GM, Izquierdo A, et al: Acute posttraumatic fetal anemia treated with fetal intravascular transfusion. m J Obstet Gynecol 166:127, 1992

Devane 0, Lalor JG, Daly S, et al: Cardiotocography versus intermittent auscultation of fetal heart on admission to labour ward for assessment of fetal wellbeing. Cochrane Database Syst Rev 1 :CD005122, 2017

Devoe L: ECG analysis: the next generation in electronic fetal monitoring?

Contemporary Ob/Gyn, September 15, 2006

Dollberg S, Livny S, Mordecheyev N, et al: Nucleated red blood cells in meconium aspiration syndrome. Obstet Gynecol 97:593, 2001

Doria V, Papageorghiou AT, Gustafsson A, et al: Review of the i rst 1502 cases of ECG-ST waveform analysis during labour in a teaching hospital. BJOG 114: 1202, 2007

DuY CR, Odibo AO, Roehl A, et al: Efect of magnesium sulfate on fetal heart rate patterns in the second stage oflabor. Obstet Gynecol 119(6): 1129, 2012

East CE, Brennecke SP, King JF, et al: le efect of intrapartum fetal pulse oximetry, in the presence of a nonreassuring fetal heart rate pattern, on operative delivery rates: a multicenter, randomized, controlled trial (the FOREMOST trial). Am J Obstet Gynecol 194:606,2006

Eberle RL, Norris MC, Eberle AM, et al: The efect of maternal position on fetal heart rate during epidural or intrathecal labor analgesia. Am J Obstet Gynecol 179: 150, 1998

Edersheim TG, Hutson JM, Druzin ML, et al: Fetal heart rate response to vibratory acoustic stimulation predicts fetal pH in labor. Am J Obstet Gynecol 157:155 ,198

Eggink BH, Richardson q, Rowen JL: Gardnerela vaginalis-infected scalp hematoma associated with electronic fetal monitoring. Pediatr Infect Dis J 23:276, 2004

Egley Cc, Bowes WA, Wagner 0: Sinusoidal fetal heart rate pattern during labor. Am J Perinatol 8:197, 1991

Elimian A, Figueroa R, Tejani N: Intrapartum assessment of fetal well-being: a comparison of scalp stimulation with scalp pH sampling. Obstet Gynecol 89:373, 199

Elliott C, Warrick PA, Graham E, et al: Graded classiication of fetal heart rate tracings: association with neonatal metabolic acidosis and neurologic morbidity. Am J Obstet Gynecol 202(3):258.e1, 2010

Epstein H, Waxman A, Gleicher N, et al: Meperidine induced sinusoidal fetal heart rate pattern and reversal with naloxone. Obstet Gynecol 59:225, 1982 Faro S, Martens MG, Hammill HA, et al: Antibiotic prophylaxis: is there a diference? Am J Obstet Gynecol 162:900, 1990

Farrell T, Chien PFW, Gordon A: Intrapartum umbilical artery Doppler velocimetry as a predictor of adverse perinatal outcome: a systematic review. BJOG 106:783, 1999

Fraser WD, Hofmeyer J, Lede R, et al: Amnioinfusion for the prevention of the meconium aspiration syndrome. N Engl J Med 353:9, 2005

Freeman RK, Garite TH, Nageotte MP: Fetal Heart Rate Monitoring, 3rd ed.

Philadelphia, Lippincott Williams & Wilkins, 2003

Garite TJ, Dildy GA, McNamara H, et al: A multicenter controlled trial of fetal pulse oximetry in the intrapartum management of nonreassuring fetal heart rate patterns. Am J Obstet Gynecol 183:1049,r2000

Ghidini A, Spong CY: Severe meconium aspiration syndrome is not caused by aspiration of meconium. Am J Obstet Gynecol 185:931, 2001

Gilstrap LC III, Hauth Jc, Hankins GO, et al: Second stage fetal heart rate abnormalities and type of neonatal acidemia. Obstet Gynecol 70: 191, 1987 Goodwin TM, Milner-Masterson L, Paul RH: Elimination of fetal scalp blood sampling on a large clinical service. Obstet Gynecol 83:971, 1994

Gorenberg OM, Pattillo C, Hendi P, et al: Fetal pulse oximetry: correlation between oxygen desaturation, duration, and frequency and neonatal outcomes. Am J Obstet Gynecol 189:136,r2003

Graham EM, Petersen SM, Christo OK, et al: Inrrapartum electronic fetal heart rate monitoring and the prevention of perinatal brain injury. Obstet Gynecol 108:656,r2006

Greenwood C, Lalchandani S, MacQuillan K, et al: Meconium passed in labor: how reassuring is clear amniotic Auid? Obstet Gynecol 102:89, 2003 Grimes DA, Peipert JF: Electronic fetal monitoring as a public health screening program. Obstet GynecoIr116:1397, 2010

Gull 1, Jafa AJ, Oren M, et al: Acid accumulation during end-stage bradycardia in term fetuses: how long is too long? BJOG 103:1096, 1996

Gunn AJ: Cerebral hypothermia for prevention of brain injury following perinatal asphyxia. Curr Opin Pediatr 12(2): Ill, 2000

Gunn AJ, Gunn TR, de Haan HH, et al: Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest 99(2):248, 1997

Hallak M, Martinez-Poyer J, Kruger ML, et al: The efect of magnesium sulfate on fetal heart rate parameters: a randomized, placebo-controlled trial. Am J Obstet Gynecol 181: 1122, 1999

Hammacher K, Huter K, Bokelmann J, et al: Foetal heart frequency and perinatal conditions of the fetus and newborn. Gynaecologia 166:349,r1968 Hankins GO, Leicht TL, Van Houk JW: Prolonged fetal bradycardia secondary to maternal hypothermia in response to urosepsis. Am J Perinatol 14:217,r199 Hauth Jc, Hankins GV, Gilstrap LC, et al: Uterine contraction pressures with oxytocin induction/augmentation. Obstet Gynecol 68:305, 1986 Hendricks CH: Uterine contractility changes in the early puerperium. Clin Obstet Gynecolr11(l):125, 1968 Herbert CM, Boehm FH: Prolonged end-stage fetal heart deceleration: a reanalysis. Obstet Gynecol 57:589, 1981 Hill JB, Alexander JM, Sharma SK, et al: A comparison of the efects of epidural and meperidine analgesia during labor on fetal heart rate. Obstet Gynecol 102:333,r2003 Hofmeyr GJ, Lawrie TA: Amnioinfusion for potential or suspected umbilical cord compression in labour. Cochrane Database Syst Rev 1 :CDOOOO 13, 2012 Hofmeyr GJ, Xu H, Eke AC: Amnioinfusion for meconium-stained liquor in labour. Cochrane Database Syst Rev 1 :CDOOOO 14, 2014 Hon EH: he electronic evaluacion of the fetal heart rate. Am J Obstet Gynecol 75:1215, 1958

Hon EH: he fetal heart rate pattens preceding death in utero. Am J Obstet Gynecol 78:47, 1959 Hon EH, Bradfield AM, Hess OW: The electronic evaluation of the fetal heart rate. Am J Obstet Gynecol 82:291, 1961 Ikeda T, Murata Y, Quilligan EJ, et al: Two sinusoidal heart rate patterns in fetal lambs undergoing extracorporeal membrane oxygenation. Am J Obstet Gynecol 180:462, 1999 Impey L, Raymonds M, MacQuillan K, et al: Admission cardiotocography: a randomised controlled trial. Lancet 361:465,r2003 INFANT Collaborative Group: Computerised interpretation of fetal heart rate during labour (INFANT): a randomised controlled trial. Lancet 389(10080):1719,r2017 ItskovitzJ, LaGamma EF, Rudolph AM: Heart rate and blood pressure response to umbilical cord compression in fetal lambs with special reference to the mechanisms of variable deceleration. Am J Obstet Gynecol 147:451, 1983

Jackson M, Holmgren CM, Esplin MS, et al: Frequency of fetal heart rate categories and short-term neonatal outcome. Obstet Gynecol 118:803, 2011

Jaeggi ET, Friedberg MK: Diagnosis and management of fetal bradyarrhythmias. Pacing Clin Electrophysiol 31 Suppl 1 :S50, 2008

Jansson LM, Velez M, McConnell , et al: Maternal buprenorphine treatment and fetal neurobehavioral development. Am J Obstet Gynecol 216(5):529. el,r2017

Jazayeri A, Politz L, Tsibris JC, et al: Fetal erythropoietin levels in pregnancies complicated by meconium passage: does meconium suggest fetal hypoxia? Am J Obstet Gynecol 183: 188, 2000

Johnson TRJr, Compton A, Rotmeusch J, et al: Signiicance of the sinusoidal fetal heart rate pattern. Am J Obstet Gynecol 139:446, 1981

Jovanovic R, Nguyen HT: Experimental meconium aspiration in guinea pigs.

Obstet Gynecol 73:652, 1989

Keith RD, Beckley S, Garibaldi JM, et al: A multicentre comparative study of 17 experts and an intelligent computer system for managing labour using the cardiotocogram. BJOG 102:688, 1995

Klauser CK, Christensen EE, Chauhan SP, et al: Use of fetal pulse oximetry among high-risk women in labor: a randomized clinical trial. nl J Obstet Gynecol 192: 1810, 2005

Klavan M, Laver AT, Boscola MA: Clinical concepts of fetal heart rate monitoring. Waltham, Hewlett-Packard, 1977

Knaven 0, Ganzevoort W, deBoer M, et a1: Fetal heart rate variation after corticosteroids for fetal maturation. Eur J Obstet Gynecol Reprod BioI 216:38, 2017

Kozuma S, Watanabe T, Bennet L, et al: The efect of carotid sinus denervation on fetal heart rate variation in normoxia, hypoxia and post-hypoxia in fetal sleep. BJOG 104:460, 1997

Krebs HB, Petres RE, Dunn LJ: Itrapartum fetal heart rate monitoring. 5.

Fetal heart rate patterns in the second stage of labor. Anl J Obstet Gynecol 140:435, 1981

Krebs HB, Petres E, Dunn LJ, et al: Intrapartum fetal heart rate monitoring, 6.

Prognostic signiicance of accelerations. Am J Obstet Gynecol 142:297, 1982

Kruger K, Hallberg B, Blennow M, et al: Predictive value of fetal scalp blood lactate concentration and pH as markers of neurologic disability. Am J Obstet Gynecol 181: 1072, 1999

Kunzel W: Fetal heart rate alterations in partial and total cord occlusion. In Kunzel W (ed): Fetal Heart Rate Monitoring: Clinical Practice and Pathophysiology. Berlin, Springer, 1985

Larma ]0, Silva AM, Holcroft C], et al: Intrapartum electronic fetal heart rate monitoring and the identification of metabolic acidosis and hypoxicischemic encephalopathy. Am] Obstet Gynecol 197(3):301.el, 2007

Lee CV, DiLaretto PC, Lane ]M: A study of fetal heart rate acceleration patterns. Obstet GynecoIr45:142, 1975

Leveno K], Cunningham FG, Nelson S: Prospective comparison of selective and universal electronic fetal monitoring in 34,995 pregnancies. N Engl ] Med 315:615, 1986

Leveno K], Quirk]G, Cunningham FG, et l: Prolonged pregnancy: observations concerning the causes of fetal distress. Am] Obstet Gynecol 150:465, 1984 Lin CC, Pielet BW, Poon E, et al: Efect of magnesium sulfate on fetal heart rate variability in preeclamptic patients during labor. Am] Perinatol 5(3):208, 1988 Lin Cc, Vassallo B, Mittendorf R: Is intrapartum vibroacoustic stimulation an efective predictor of fetal acidosis? ] Perinat Med 29:506, 2001 Lowe W, Leveno K], Quirk ]G, et al: Sinusoidal fetal heart rate patterns after intrauterine transfusion. Obstet Gynecol 64:215, 1984

Macones GA, Hankins GO, Spong CY, et a1: The 2008 National Institute of Child Health and Human Development workshop report on electronic fetal monitoring: update on deinitions, interpretation, and research guidelines. Obstet Gynecol 112(3):661,r2008

Macri C], Schrimmer DB, LeungA, et al: Prophylactic amnioinfusion improves outcome of pregnancy complicated by thick meconium and oligohydramnios. Amr] Obstet GynecoIr167:1r17, 1992

Martis R, Emilia 0, Nutdiati OS, et al: Intermittent auscultation (A) of fetal heart rate in labour for fetal well-being. Cochrane Database Syst Rev 2:CD008680, 2017

Mathews TG, Warshaw ]B: Relevance of the gestational age distribution of meconium passage in utero. Pediatrics 64:30, 19

McGregor ]A, McFarren T: Neonatal cranial osteomyelitis: a complication of fetal monitoring. Obstet Gynecol 73(2):490, 1989

Melchior], Benard N: Incidence and pattern oHetal heart rate alterations during labor. In Kunzel W (ed): Fetal Heart Rate Monitoring: Clinical Practice and Pathophysiology. Berlin, Springer, 1985

Mercier F], Dounas M, Bouaziz H, et al: Intravenous nitroglycerin to relieve intrapartum fetal distress related to uterine hyperactivity: a prospective observation study. Anesth Analg 84: 11r17, 1997

Mires G, Williams F, Howie P: Randomised controlled trial of cardiotocography versus Doppler auscultation of fetal heart at admission in labour in low risk obstetric population. BM] 322: 1457, 2001 �riyazaki FS, Nevarez F: Saline amnioinfusion for relief of repetitive variable decelerations: a prospective randomized study. Am ] Obstet Gynecol 153:301, 1985

Miyazaki FS, Taylor NA: Saline amnioinfusion for relief of variable or prolonged decelerations. Am ] Obstet Gynecol 146:6 0, 1983

Modanlou H, Freeman RK: Sinusoidal fetal heart rate pattern: its deinition and clinical signiicance. Am] Obstet Gynecol 142: 1 033, 1982

Mueller-Heubach E, Battelli AF: Variable heart rate decelerations and transcutaneous P02 (tc P02) during umbilical cord occlusion in the fetal monkey. Amr] Obstet Gynecol 144:796, 1982

Murata Y, Martin CB, Ikenoue T, et al: Fetal heart rate accelerations and late decelerations during the course of intrauterine death in chronically catheterized rhesus monkeys. Am] Obstet Gynecol 144:218, 1982

Murotsuki ], Bocking AD, Gagnon R: Fetal heart rate pattens in growthrestricted fetal sleep induced by chronic fetal placental embolization. Am J Obstet Gynecol 176:282, 1997

Murphy W, Russell V, Collins A, et al: The prevalence, aetiology and clinical signiicance of pseudo-sinusoidal fetal heart rate pattens in labour. B]OG 98:1093, 1991 \lyers E: Two patterns of perinatal brain damage and their conditions of occurrence. Am J Obstet Gynecol 112:246, 1972

Myers E, Mueller-Heubach E, Adamsons K: Predictability of the state of fetal oxygenation from a quantitative analysis of the components oflate deceleration. Am J Obstet Gynecol 115: 1083, 19

Nageotte MP, Bertucci L, Towers CV, er al: Prophylactic amnioinfusion in pregnancies complicated by oligohydramnios: a prospective study. Obstet Gynecol 77:677, 1991

Nathan L, Leveno K], Carmody T], et al: Meconium: a 1990s perspective on an old obstetric hazard. Obsret Gynecol 83:328, 1994

National Institute of Child Health and Human Development Research Planning Workshop: Electronic feral heart rare monitoring: research guidelines for integration. Am] Obstet Gynecol 177: 1385, 1997

Nedelcur], Klein MA, Aquzzi A, et al: Resuscitative hypothermia protects the neonatal rat brain from hypoxic-ischemic injul". Brain Pathol 10(1):61, 2000

Neesham DE, Umstad MP, Cincotta RB, et al: Pseudo-sinusoidal fetal heart rate pattern and fetal anemia: case report and review. Aust N Z J Obstet Gynaecol 33:386, 1993

Neilson DR ]r, Freeman RK, Mangan S: Signal ambiguity resulting in unexpected outcome with extenal fetal heart rate monitoring. Am J Obstet Gynecol 198:717,r2008

Neilson ]P: Fetal electrocardiogram (ECG) for fetal monitoring during labour. Cochrane Database System Rev 5:CDOOOl16, 2015

Nensi A, De Silva DA, von Dadelszen P, et al: Efect of magnesium sulphate on fetal heart rate parameters: a systematic review. ] Obstet Gynaecol Can 36(12):1055,r2014

Nicolaides KH, Sadovsky G, Cetin E: Fetal heart rate pattens in red blood cell isoimmunized pregnancies. Am] Obstet Gynecol 161 :351, 1989

Nunes I, Ayres-de-Campos 0, Costa-Santos C, et al: Diferences berween extenal and intenal fetal heart rate monitoring during the second stage oflabar: a prospective observational study. J Perinat Med 42(4):493, 2014

Ogundipe OA, Spong CY, Ross MG: Prophylactic amnioinfusion for oligohydramnios: are-evaluation. Obstet Gynecol 84:544, 1994

Owen ], Henson BV, Hauth ]C: A prospective randomized study of saline solution amnioinfusion. Am] Obstet Gynecol 162:1146, 1990

Parer JT: Personalities, politics and territorial tifs: a half century of fetal heart rate monitoring. Am] Obstet Gynecol 204(6):548, 2011

Parer JT, Ikeda T: A framework for standardized management of intrapartum fetal heart rate pattern. Am J Obstet Gynecol 197:26, 2007

Parer ]T, King TL: Fetal heart rate monitoring: the next step? Am J Obstet Gynecol 203(6):520, 2010 Parer W], Parer ]T, Holbrook RH, et al: Validity of mathematical models of quantitating fetal heart rate variability. Am] Obstet Gynecol 153:402, 1985

Paul RH, Snidon AK, Yeh SY: Clinical fetal monitoring. 7. he evaluation and signiicance of intrapartum baseline FHR variability. Am ] Obstet Gynecol 123:206, 19

Paul WM, Quilligan E], MacLachlan T: Cardiovascular phenomena associated with fetal head compression. Am J Obstet Gynecol 90:824, 1964

Petrie RH: Dose/response efects of intravenous meperidine in fetal heart rate variability. ] Matern Fetal Med 2:215, 1993

Phelan ]P, Ahn MO: Perinatal observations in forty-eight neurologically impaired term infants. Amr] Obstet GynecoIr171:424, 1994

Picquard F, Hsiung R, Mattauer M, et al: The validity of fetal heart rate monitoring during the second stage oflabor. Obstet Gynecol 2:746, 1988

Pierce ], Gaudier FL, Sanchez-Ramos L: Intrapartum amnioinfusion for meconium-stained fluid: meta-analysis of prospective clinical trials. Obstet Gynecol 95:1051, 2000

Pillai M, James 0: he development of fetal heart rate pattens during normal pregnancy. Obstet Gynecol 76:812, 1990

Pontonnier G, Puech F, Grandjean H, et al: Some physical and biochemical parameters during normal labour. Fetal and maternal study. BioI Neonate 26:159,r1975

Pressman EK, Blakemore K]: A prospective randomized trial of rwo solutions for intrapartum amnioinfusion: efects on fetal electrolytes, osmolality, and acid-base status. Am] Obstet Gynecol 175:945, 1996

Ramin KD, Leveno K], Kelly MS, et al: Amnionic fluid meconium: a fetal environmental hazard. Obstet Gynecol 87: 181, 1996

Rathore AM, Singh R, Ramji S, et al: Randomised trial of amnioinfusion during labour with meconium stained amniotic luid. B]OG 109: 17, 2002 Renou P, Warwick N, Wood C: Autonomic control of fetal heart rate. Am ]

ObstetrGynecolr105:949,r1969

Resnik R: Electronic fetal monitoring: the debate goes on ... and on ... and on. Obstet Gynecol 121 (5):917, 2013

Rinehart BK, Terrone DA, Barrow ]H, et al: Randomized trial of intermittent or continuous amnioinfusion for variable decelerations. Obstet Gynecol 96:5, 1,r2000

Rocha E, Hammond R, Richardson B: Necrotic cell injury in the preterm and near-term ovine fetal brain after intermittent umbilical cord occlusion. Am J Obstet Gynecol 191:488, 2004

Rogers MS, Mongelli M, Tsang KH, et al: Lipid peroxidation in cord blood at birth: the efect of labour. B]OG 105:739, 1998

Samuelof A, Langer 0, Berkus M, et al: Is fetal heart rate variability a good predictor of fetal outcome? Acta Obstet Gynecol Scand 73:39, 1994 Schucker JL, Sarno AP, Egerman RS, et al: The efect of butorphanol on the fetal heart rate reactivity during labor. Am] Obstet Gynecol 174:491, 1996

Sherer OM: Blunted fetal response to vibroacoustic stimulation associated with matenal intravenous magnesium sulfate therapy. Amr] Perinatol 11r:401, 1994

Sholapurkar SL: he conundrum of vanishing early decelerations in British obstetrics, a step backwards? Detailed appraisal of British and American classiications of fetal heart rate decelerationsBfallacies of emphasis on waveform and putative aetiology.r] Obstet Gynaecol 32(6):505, 2012

Simpson KR, James DC: Eicacy of intrauterine resuscitation techniques in improving fetal oxygen status during labor. Obstet Gynecolr105: 1362,2005 Skupski DW, Rosenberg CR, Eglinton GS: Intrapartum fetal stimulation tests: a meta-analysis. Obstet Gynecol 99: 129, 2002

Smith CV, Nguyen HN, Phelan JP, et al: Intrapartum assessment of fetal wellbeing: a comparison of fetal acoustic stimulation with acid-base determinations. Am J Obstet GynecoIr155:726, 1986

Smith JH, Anand KJ, Cotes PM, et al: Antenatal fetal heart rate variation in relation to the respiratory and metabolic status of the compromised human fetus. BJOG 95:980, 1988

Southall DP, Richards J, Hardwick A, et al: Prospective study of fetal heart rate and rhythm patterns. Arch Dis Child 55:506, 1980

Spong CY, Ogundipe OA, Ross MG: Prophylactic amnioinfusion for meconium-stained amniotic fluid. Am J Obstet Gynecolr1 1:931, 1994

Spong CY, Rasul C, CoHea JV, et al: Characterization and prognostic signiicance of variable decelerations in the second stage of labor. Am J Perinatol 15:369, 1998

Stewart RD, Bleich AT, Lo JY, et al: Deining uterine tachysystole: how much is too muc,? Am J Obstet Gynecol 207:290.el, 2012

Stiller R, von Mering R, Konig V, et al: How well does reflectance pulse oximetry reflect intrapartum fetal acidosis? Am J Obstet Gynecol 186: 1351, 2002

Tahir Mahmood U, O'Gorman C, vfarchocki Z, et al: Fetal scalp stimulation (FSS) versus fetal blood sampling (FBS) for women with abnormal fetal heart rate monitoring in labor: a prospective cohort study. J Matern Fetal Neonatal Med May 19, 2017 [Epub ahead of print]

Thakor AS, Giussani DA: Efects of acute acidemia on the fetal cardiovascular defense to acute hypoxemia. Am J Physiol Regul Integr Comp Physiol 296(1):R90, 2009

Tintinalli JE, Stapczynski JS, Ma OJ, et al: Tintinalli's Emergency Medicine:

A Comprehensive Study Guide, 8th ed. New York, McGraw-Hill, 2016 Tooley JR, Satas S, Porter H, et al: Head cooling with mild systemic hypothermia in anesthetized piglets is neuroprotective. Ann Neurol 53(1):65, 2003 Usta 1M, Mercer BM, Aswad NK, et al: The impact of a policy of amnioinfusion for meconium-stained amniotic fluid. Obstet Gynecol 85:237, 1995

Van Geijn HP, Jongsma HN, deHaan J, et al: Heart rate as an indicator of the behavioral state. Am J Obstet Gynecol 136: 1 061, 1980

Verdurmen l,Hulsenboom AD, van Laar JO, et al: Efect of tocolytic drugs on fetal heart rate variability: a systematic review. J Matern Fetal Neonatal Med 30(20):2387, 2017

Wagner BP, N edelcu J, Vlartin E: Delayed postischemic hypothermia improves long-term behavioral outcome after cerebral hypoxia-ischemia in neonatal rats. Pediatr Res 51 (3):354, 2002

Walker J: Foetal anoxia. J Obstet Gynaecol Br Commonw 61:162, 1953 � enstrom K, Andrews W, Maher JE: Amnioinfusion survey: prevalence protocols and complications. Obstet Gynecol 86:572, 1995

Westgate J, Harris M, Curnow JSH, et al: Plymouth randomized trial of cardiotocogram only versus ST waveform plus cardiotocogram for intrapartum monitoring in 2400 cases. Am J Obstet GynecoIr169:1151, 1993

Westgate JA, Bennet L, De Haan HH, et al: Fetal heart rate overshoot during repeated umbilical cord occlusion in sheep. Obstet Gynecol 97:454, 2001

Wiberg-Itzel E, Lipponer C, Norman M, et al: Determination of pH or lactate in fetal scalp blood in management of intrapartum fetal distress: randomised controlled multicenter trial. BMJ 336: 1284, 2008

Yam J, Chua S, Arulkumaran S: Intrapartum fetal pulse oximetty. Part I: principles and technical issues. Obstet Gynecol Surv 55: 163, 2000

Yang M, Stout MJ, Lopez ]D, et al: Association of fetal heart rate baseline change and neonatal outcomes. Am] PerinatoI34(9):879, 2017

Young BK, Katz M, Wilson SJ: Sinusoidal fetal heart rate, 1. Clinical significance. Am] Obstet GynecoIr136:587, 1980a

Young BK, Weinstein HM: Moderate fetal bradycardia. Am J Obstet Gynecol 126:271, 1976

Young DC, Gray ]H, Luther ER, et al: Fetal scalp blood pH sampling: its value in an active obstetric unit. Am J Obstet GynecoIr136:276, 1980b

Young RC, Zhang P: Functional separation of deep cytoplasmic calcium from subplasmalemmal space calcium in cultured human uterine smooth muscle cells. Cell Calcium 36(1):11, 2004

Zalar RW, Quilligan EJ: The influence of scalp sampling on the cesarean section rate for fetal distress. Am J Obstet Gynecol 135:239, 1979

GENERAL PRINCIPLES .s..s...........s....s....s..s... 486 ANALGESIA AND SEDATION DURING LABOR ........ 487

REGIONAL ANALGESIA ..........s...s...s..s..s....s.. 488

SPINAL (SUBARACHNOID) BLOCK .....s............ 490

EPIDURAL ANALGESIA .s...s...s.....s.....s......... 492

LOCAL INFILTRATION FOR CESAREAN DELIVERY ....s. 497

GENERAL ANESTHESIA ......s..............s....s.. 498

POSTPARTUM ANALGESIA .s.......s...s....s....s..s.. 500

We are indebted to Sir James .Simpson, the discoverer of chloroorm, or the introduction of anaesthesia into obstetrical practice. He employed ether or this purpose in 184, and replaced it by chloroorm. Every one agrees as to the marked beneits derived from anaesthesia when operative procedures are to be undertaken, but there is stil considerable dference of opinion as to the advisabiliy of its routine employment in normal labour.

-]. Whitridge Williams (1903)

As cited by Williams, anesthetic techniques were a most welcome addition to obstetrics. That said, obstetrical anesthesia presents unique challenges. Labor begins without warning, and anesthesia may be required within minutes of a full meal. Vomiting with potential aspiration of the gastric contents is a constant threat due to delayed gastric emptying during pregnancy. Disorders of pregnancy such as preeclampsia, placental abruption, or sepsis further compound provision of obstetrical anesthesia.

Of all anesthesia-related deaths in the United States from 1995 to 2005,i3.6 percent were in pregnant women (Li, 2009). Creanga and colleagues (2017) analyzed deaths of women during or within 1 year of pregnancy in the United States from 2011 through 2013. Of these deaths, they found that 3 of 2009 (0.2 percent) were attributable to anesthesia complications. As shown in Table 25-1, between 1979 and 2002, anesthesia-related maternal mortality rates decreased nearly 60 percent, and currently approximately ive deaths per million live births are attributed to anesthesia complications.

About two thirds of deaths associated with general anesthesia are caused by intubation failure or induction problems during cesarean delivery. Deaths associated with regional analgesia are caused by high spinal or epidural blocks-26 percent; respiratory failure-19 percent; and drug reaction-19 percent. he improved case-fatality rate for general anesthesia is especially notable considering that such anesthesia is now used for the highest-risk patients and the most hurried emergencies, that is, decision-to-incision intevals < 15 minutes (Bloom, 2005).

25-1 . Case-Fatality Rates and Rate Ratios of Anesthesia-Related Deaths During Cesarean Delivery by Type of Anesthesia in the United States, ,979-2002 aDeaths per million general or regional anesthetics. (I = confidence interval.

Data from Hawkins, 201s1.

The most signiicant factor linked to lower maternal mortality rates is the greater use of regional analgesia (Hawkins, 2011). In-house anesthesia coverage that is available around the clock is certainly another contributing factor. Logically, with increased use of regional analgesia, there are now reports of complications with these techniques. Indeed, compared to pre-1990 data, post-1990 obstetrical anesthesia was associated with more legal claims involving regional analgesia (Davies, 2009). In a recent analysis of 466,442 obstetrical hospital discharges, complications associated with regional analgesia accounted for 81 percent of anesthesia-related adverse events (Guglielminotti, 2015).

For the fetus, recent human studies suggest that single, relatively short exposure to general anesthetic and sedation is unlikely to have negative efects on subsequent behavior or learning. his evidence is presented in Chapter 46 (p. 901). That said, in 2016, the Food and Drug Administration (FDA) warned that repeated or lengthy use of general anesthetic and sedation drugs in pregnant women during their third trimester may afect fetal brain development. Listed drugs include inhalation agents used in general anesthesia as well as lorazepam, ketamine, propofol, and midazolam. Notably, the American College of Obstetricians and Gynecologists (2016a) and the Society for Obstetric Anesthesia and Perinatology (2017) have voiced concerns with this statement and cited the lack of signiicant human data, especially in pregnant women, to underpin this warning.

he American College of Obstetricians and Gynecologists (2017a) recognizes that a woman's request for labor pain relief is suicient medical indication for its provision. Identification of any of the risk factors shown in Table 25-2 should prompt consultation with anesthesia personnel to permit a joint management plan. This plan should include strategies to minimize the need for emergency anesthesia.

Goals for optimizing obstetrical anesthesia services have been established by the American College of Obstetricians and Gynecologists (2017 a) and the American Society of Anesthesiologists (2016) and include:

TABLE 25-2. Maternal Factors That May Prompt Anesthetic Consultation

Obstructive lesions: edema, anatomical abnormalities, trauma Decreased range of motion in opening the mouth or small

Obstetrical complications with a high risk of operative delivery

Matenal medical complications such as cardiopulmon 1.

Availability of a licensed practitioner who is credentiled to administer n appropriate anesthetic whenever necessary and to maintain support of vital unctions in an obstetrical emergency.

2.

Availability of anesthesia personnel to permit the start of a cesarean delivery within 30 minutes of the decision to perform the procedure.

3.

Anesthesia personnel immediately available to perform an emergency cesarean delivery during the active labor of a woman attempting vaginal birth ater cesarean (Chap. 31, p. 597).

4.

Appointment of a qualified anesthesiologist to be responsible for all anesthetics administered.

5.

Availability of a qualified physician with obstetrical privileges to perform operative vaginal or cesarean delivery during administration of anesthesia.

6.

Availability of equipment, facilities, and support personnel equal to that provided in any surgical suite.

7.

Immediate availability of personnel, other than the surgical team, to assume responsibility for resuscitation of a depressed newborn (Chap. 32, p. 606).

To meet these goals, 24-hour, in-house anesthesia coverage is usually necessary. Providing such service in smaller facilities is more challenging-a problem underscored by the fact that approximately a third of all hospitals providing obstetrical care perform fewer than 500 deliveries per year. The financial burden incurred to provide 24/7 obstetrical anesthesia coverage may result in cost deicits (Bell, 2000). Compounding this burden, some third-party payers have denied reimbursement for epidural analgesia in the absence of a specific medical indication-an approach repudiated by the American College of Obstetricians and Gynecologists (2017a).

Regarding obstetricians, they should be proficient in local and pudendal analgesia. These may be administered in appropriately selected circumstances described on page 489.

Hawkins (2010) emphasized that labor pain is a highly individual response to variable stimuli that are uniquely received and interpreted (Fig.

These stimuli are modified by emotional, motivational, cognitive, social, and cultural circumstances. Labor pain caused by uterine contractions and cervical dilation is transmitted through visceral aferent sympathetic nerves entering the spinal cord from Tto through Lt. Later in labor, perineal stretching transmits painful stimuli through the pudendal nerve and sacral nerves S2 through 54' Cortical responses to pain and anxiety during labor are complex and may be inluenced by maternal expectations for childbirth, her age, preparation through education, emotional support, and other factors. Pain perception is heightened by fear and the need to move into various positions. A woman may be motivated to have a certain type of birthing experience, and these opinions will influence her judgment regarding pain management.

Maternal physiological responses to labor pain can influence maternal and fetal well-being and labor progress. For example, hyperventilation may induce hypocarbia. A greater metabolic rate augments oxygen consumption. Increases in cardiac output and vascular resistance may raise maternal blood pressure. Pain, stress, and anxiety trigger release of stress hormones such as

Cortical responses to pain pain, anxle y, age,

FIGURE 25-' Sources of pain during labor and maternal physiological responses. (Reproduced with permission from Hawkins JL: Epidural analgesia for labor and delivery, N Engl J Med. 2010 Apr 22;362(16):1503-1510.) cortisol and �-endorphins. The sympathetic nervous system response to pain leads to a marked elevation in circulating catecholamines that can adversely afect uterine activity and uteroplacental blood low. Efective analgesia attenuates or eliminates these responses.

If uterine contractions and cervical dilatation cause discomfort, pain relief is ofered. If neuraxial analgesia is contraindicated or unavailable or is declined, a narcotic from Table 25-3 plus one of the tranquilizer-antiemetic drugs such as promethazine (Phenergan) is usually appropriate. With a successful program of analgesia and sedation, the mother ideally rests quietly between contractions. In this circumstance, discomfort usually is felt at the acme of an efective uterine contraction.

Meperidine, 50 to 100 mg, with promethazine, 25 mg, may be administered intramuscularly at intervals of 2 to 4 hours. A more rapid efect is achieved by giving meperidine intravenously in doses of 25 to 50 mg every 1 to 2 hours. Whereas analgesia is mximal 30 to 45 minutes after an intramuscular injection, it develops almost immediately following intravenous administration. Meperidine readily crosses the placenta and can have a prolonged half-life in the newborn (American College of Obstetricians and Gynecologists, 20l7a). Its depressant efect in the fetus follows closely behind the peak maternal analgesic efect.

TABLE 25-3. Some Parenteral Analgesic Agents for Labor Pain

Meperidine 25-50 mg (IV) Q 1-2 hr 5 min (IV) �.1A8-20 hr 50-100 mg (1M) Q 2-4 hr 30-45 min (1M) �60 hr Fentanyl 50-100 tg (IV) Q 1 hr 1 min �5 hr Morphine 2--5 mg (IV) Q 4 hr 5 min (IV) �.7 hr

IV = intravenously, 1M = intramuscularly; Q = every.

According to Bricker and Lavender (2002), meperidine is the most common opioid used worldwide for pain relief during labor. In one randomized study at Parkland Hospital, patientcontrolled intravenous analgesia with meperidine was found to be an inexpensive and reasonably efective method for labor analgesia (Sharma, 1997). Women randomized to self-administered analgesia were given a 50-mg meperidine plus 25-mg promethazine dose intravenously as an initial bolus. hereafter, an infusion pump was set to deliver 15 mg of meperidine every 10 minutes as needed until delivery. Neonatal sedation, as measured by the need for naloxone treatment in the delivery room, was identiied in 3 percent of newborns. Both meperidine and its metabolite, normeperidine, are lipophilic and readily cross the placenta. Analgesia with meperidine was associated with lower Apgar scores in comparison to epidural analgesia (Sharma, 2004). Normeperidine is a strong respiratory depressant that has a significantly longer half-life than meperidine and is likely responsible for the fetal side efects of meperidine.

his synthetic opioid receptor agonist-antagonist analgesic, given in 1-to 2-mg intravenous doses, compares favorably with 40 to 60 mg of meperidine. Its major side efects are somnolence, dizziness, and dysphoria. Neonatal respiratory depression is reported to be less than with meperidine. Importantly, the two drugs are not given contiguously because butorphanol antagonizes the narcotic efects of meperidine. Butorphanol has been associated with transient sinusoidal fetal heart rate patterns (Hatjis, 1986).

This is another mixed opioid receptor agonist-antagonist analgesic. It can be given intramuscularly, intravenously, or subcutaneously. he usual dose is 10 to 20 mg, administered every 4 to 6 hours irrespective of the route of administration. Small doses of nalbuphine may also be used to treat pruritus associated with neuraxial opioids.

This short-acting and potent synthetic opioid may be given in doses of 50 to 1 00 �g intravenously every hour. Its main disadvantage is its short duration of action, which requires frequent dosing or use of a patient-controlled intravenous infusion pump.

This is a synthetic opioid with an extremely rapid onset of action. It is hydrolyzed rapidly, resulting in a half-life of 3.5 minutes (Ohashi, 2016). Although it readily crosses the placenta, it is quickly metabolized or redistributed within the fetus (Kan, 1998). Various dosing regimens have been studied, and single boluses appear to mirror the periodic uterine contraction pattern. Infusions, on the other hand, have been reported to cause maternal apnea (Waring, 2007). Due to the aforementioned risks, only trained personnel should administer it, and only under strictly controlled circumstances.

Efficacy and Safety of Parenteral Agents

Hawkins and colleagues (1997) reported that four of 129 maternal anesthetic-related deaths were from parenteral sedation-one from aspiration, two from inadequate ventilation, and one from overdosage. Opioids used during labor may cause newborn respiratory depression. Naloxone is a narcotic antagonist capable of reversing this respiratory depression. It acts by displacing the narcotic from specific receptors in the central nervous system. Withdrawal symptoms may be precipitated in recipients who are physically dependent on narcotics. For this reason, naloxone is contraindicated in a newborn of a narcotic-addicted mother.

Inhaled nitrous oxide has a rapid onset and ofset that provides analgesia during episodic contractions. It can be self-administered as a mixture of 50-percent nitrous oxide and 50-percent oxygen premixed in a single cylinder (Entonox) or using a blender that mixes the two gases from separate tanks (Nitronox). he gases are connected to a breathing circuit through a one-way valve that opens only during inspiration. he use of intermittent nitrous oxide for labor pain is generally regarded s safe for the mother and newborn, but pain control is less efective than epidural analgesia (Barbieri, 2014; Likis, 2014). In many cases, nitrous oxide simply serves to delay more deinitive neuraxial analgesia. For maximal eicacy, nitrous oxide is inhaled 30 seconds prior to the start of a contraction, although this prevents adequate rest for the mother. Nitrous oxide is also associated with nausea and vomiting. The environmental and health risk of its use without proper scavenging remains to be carefully evaluated (King, 2014).

Various nerve blocks have been developed over the years to provide pain relief during labor and/or delivery. These include pudendal, paracervical, and neuraxial blocks such as spinal, epidural, and combined spinal-epidural techniques.

Some of the more commonly used nerve block anesthetics, along with their usual concentrations, doses, and durations of action, are summarized in Table 25-4. he dose of each agent varies widely and is dependent on the particular nerve block and physical status of the woman. he onset, duration, and quality of analgesia can be enhanced by raising the volume and/or concentration. his can be done safely only by incrementally administering small-volume boluses of the agent and by careully monitoring early warning signs of toxicity. Administration of these agents must be followed by appropriate monitoring for adverse reactions. Equipment and personnel to manage these reactions must be immediately available.

Most often, serious toxicity follows inadvertent intravenous injection. Systemic toxicity from local anesthetics typically manifests in the central nervous and cardiovascular systems. For this reason, when epidural analgesia is initiated, dilute epinephrine is sometimes added and given as a test dose. A sudden significant rise in the maternal heart rate or blood pressure immediately after administration suggests intravenous catheter placement. his should halt further injection and should prompt catheter repositioning. Local anesthetic agents are manufactured in more than one concentration and ampule size, which raises the potential for dosing errors.

aWithout epinephrine.

bEsters are hydrolyzed by plasma cholinesterases and amides by hepatic clearance. D&C = dilatation and curettage.

Data from Liu SS, Lin Y: Local anesthetics. In Barash P, Cullen B, Stoeling R, et al (eds): Clinical Anesthesia, 6th ed. Philadelphia, Lippincott Williams & Wilkins, 2009.

Early symptoms are those of stimulation, but as serum levels rise, depression follows. Symptoms may include light-headedness, dizziness, tinnitus, metallic taste, and numbness of the tongue and mouth. Patients may show bizarre behavior, slurred speech, muscle fasciculation and excitation, and ultimately, generalized convulsions, followed by loss of consciousness.

hese manifestations generally develop later than those of cerebral toxicity. Moreover, no symptoms may develop because signs are usually induced by higher serum drug levels. he notable exception is bupivacaine, which is associated with neurotoxicity and cardiotoxicity at virtually idenricalilevels (Mulroy, 2002). Because of its toxicity risk, use of a 0.75-percent solution of bupivacaine for epidural injection has been proscribed by the FDA. Similar to neurotoxicity, cardiovascular toxicity is characterized first by stimulation and then by depression. Accordingly, hypertension and tachycardia are soon followed by hypotension, cardiac arrhythmias, and impaired uteroplacental perfusion.

• Management of Local Anesthetic

Seizures and severe ventricular arrhythmias can follow large doses of local anesthetics that are given inadvertently. Labor and delivery units should be stocked with a 20-percent lipid emulsion solution (Intralipid). It is administered as a rapid intravenous bolus followed by an infusion upon the first sign of local anesthetic systemic toxicity (Neal, 2012). Controlling seizures and securing the airway are essential to prevent aspiration and hypoxemia. Benzodiazepines, such as midazolam or lorazepam, may be used to help control seizures, particularly if lipid emulsions are not available. Magnesium sulfate also controls convulsions (Chap 40, p. 736). Abnormal fetal heart follow and stem from maternal hypoxia. With proper manage ment, including supportive measures, the fetus usually recovers.

herefore, it is best for the fetus and mother to delay delivery until the mother is stabilized.

With proper treatment of local anesthetic systemic toxicity (LAST) with lipid emulsions, vital signs usually return to normal. The woman, however, should be monitored, placed in the lateral decubitus position to avoid aortocaval compression, and provided continued supportive care. Vasopressors can be used to support blood pressure. With cardiac arrest, emergency cesarean delivery is considered if maternal vital signs have not been restored within 5 minutes (Chap, 47, p. 931). As with convulsions, however, the fetus is likely to recover more quickly in utero once maternal cardiac output is reestablished.

Pain with vaginal delivery arises from stimuli from the lower genital tract. These are transmitted primarily through the pudendal nerve, the peripheral branches of which provide sensory innervation to the perineum, anus, vulva, and clitoris. The pudendal nerve passes beneath the sacrospinous ligament just as the ligament attaches to the ischial spine. Sensory nerve fibers of the pudendal nerve are derived from ventral branches of the S2 through S4 nerves.

The pudendal nerve block is a relatively safe and simple method of providing analgesia for spontaneous delivery. As shown in Figure 25-2, a tubular introducer is used to sheathe and guide a 15-cm-long 22-gauge needle into position near the pudendal nerve. The end of the introducer is placed against the vaginal mucosa just beneath the tip of the ischial spine. he in troducer allows 1.0 to 1.5 em of needle to at the injection site. he infection may spread posteriorly to the hip joint, into the gluteal musculature, or into the retropsoas space (Svancarek, 1977).

his block usually provides satisfactory pain relief during irst-stage labor. How ever, because the pudendal nerves are not blocked during paracervical blockade, addi

Ischial spine tional analgesia is required for delivery. For

Pudendal nerve paracervical blockade, usually 5 to 10 mL of lidocaine (1 to 2 percent) or chloroprocaine (3 percent) is injected into the cervix later ally at 3 and 9 o'clock. Because these anes thetics are relatively short acting, this block may have to be repeated during labor.

Fetal bradycardia is a worrisome com plication that occurs with approximately 15 percent of paracervical blocks (Rosen, FIGURE 25-2 Local infiltration of the pudendal nerve. Transvaginal technique showing 2002). Bradycardia usually develops within the needle extended beyond the needle guard and passing through the sacrospinous 10 minutes and may last up to 30 minutes.

ligament to reach the pudendal nerve.

protrude beyond its tip, and the needle is pushed beyond the introducer tip into the mucosa. A mucosal wheal is made with 1 mL of I-percent lidocaine solution or an equivalent dose of another local anesthetic (see Table 25-4). To guard against intravascular infusion, aspiration is attempted before this and all subsequent injections. The needle is then advanced until it touches the sacrospinous ligament, which is iniltrated with 3 mL of lidocaine. he needle is advanced farther through the ligament. As the needle pierces the loose areolar tissue behind the ligament, resistance against the plunger drops. Another 3 mL of solution is injected in this region. Next, the needle is withdrawn into the introducer, which is moved to a point just above the ischial spine. The needle is inserted through the mucosa and a inal 3 mL is deposited. The procedure is then repeated on the other side.

Within 3 to 4 minutes of injection, a successful pudendal block will allow pinching of the lower vagina and posterior vulva bilaterally without pain. If delivery occurs before the pudendal block becomes efective and an episiotomy is indicated, then the fourchette, perineum, and adjacent vagina can be iniltrated with 5 to 10 mL of I-percent lidocaine solution directly at the planned episiotomy site. By the time of repair, the pudendal block usually has become efective.

Pudendal block usually does not provide adequate analgesia when delivery requires extensive obstetrical manipulation. Moreover, such analgesia is usually inadequate for women in whom complete visualization of the cervix and upper vagina or manual exploration of the uterine cavity is indicated.

Infrequently, complications may follow this block. As previously described, intravascular injection of a local anesthetic agent may cause serious systemic toxicity. Hematoma formation from perforation of a blood vessel is most likely when there is a coagulopathy (Lee, 2004). Rarely, severe infection may originate Doppler studies have shown a rise in the pulsatility index of the uterine arteries following paracervical blockade. These observations support the hypothesis of drug-induced arterial vasospasm as a cause of fetal bradycardia (Manninen, 2000). For these reasons, paracervical block is not used in situations of potential fetal compromise.

Epidural, spinal, or combined spinal-epidural techniques are the most common methods used for pain relief during labor and delivery. In the United States in 2008, epidural analgesia was used in nearly 70 percent of mothers during labor and had a success rate of 98.8 percent. Neuraxial analgesia was used even more often in operative vaginal deliveries and supported 84 percent of forceps deliveries and 77 percent of vacuum extractions (Osterman, 2011).

Anesthetic in this block can be given as a single dose, can be partnered with an epidural catheter as combined spinalepidural analgesia, or can be administered as a continuous infusion. Injection of a local anesthetic into the subarachnoid space to efect analgesia has long been used for delivery. Advantages include rapid analgesia onset, short duration of action, and high success rate. he subarachnoid space during pregnancy is smaller, which likely results from internal vertebral venous plexus engorgement. Thus, in parturients, the same amount of anesthetic agent in the same volume of solution produces a much higher blockade than in nonpregnant women.

The irst stage of labor requires a sensory block to the level of the umbilicus (Tlo)' During the second stage of labor and for operative vaginal delivery, a sensory block of 52 through S4 is usually adequate to cover pain from perineal stretching and/ or instrumentation. Analgesic options include continuous lumbar epidural analgesia, combined spinal-epidural, continuous spinal analgesia, and other blocks such as pudendal and paracervical blocks.

Local anesthetic agents are usually given to establish a sensory block to the desired dermatome level. They are almost exclusively used in conjunction with neuraxial opioids. he mechanism of action is a function of the administration route and lipid solubility. Analgesia is induced by absorption into the vascular system (supraspinal), actions on the dorsal horns, and direct spread in the cerebrospinal fluid to the brainstem. Highly-soluble lipid opioids such as fentanyl and sufentanil have a rapid onset of action. But, because they are absorbed into lipid membranes and the epidural vasculature, their duration of action is short. Hydrophilic solutions such as morphine, on the other hand, provide extended analgesia (Lavoie, 2013). he major advantages of using such a combination are the rapid onset of pain relie, a decrease in shivering, and less dense motor blockade. Side efects are common and include pruritus and urinary retention. Nalbuphine, 2.5 to 5 mg intravenously, can be used to treat pruritis without diminishing the analgesic efect.

A level of sensory blockade extending to the T 4 dermatome is desired for cesarean delivery. Depending on maternal size, 10 to 12 mg of bupivacaine in a hyperbaric solution or 50 to 75 mg of lidocaine hyperbaric solution is administered. The addition of opioid increases the rapidity of blockade onset, reduces shivering, and minimizes referred pain and other symptoms such as nausea and vomiting. The addition of a preservative-free morphine (Duramorph or Astramorph), 0.1 to 0.3 mg intrathecal or 2 to 4 mg epidural, provides pain control up to 24 hours postoperatively.

Hypotension. Shown in Table 25-5 are some of the more common adverse events associated with neuraxial analgesia. Importantly, obese women have signiicantly impaired ventilation, and thus close clinical monitoring is imperative (Vricella, 2011).

TABLE 25-5. Complications of Regional Analgesia

Uncommon Inadvertant intrathecal, subdural, or intravascular injection of local anesthetic drugs Neurologic injury

Hypotension is a common complication that may develop soon after injection of the local anesthetic agent. It is the consequence of vasodilatation from sympathetic blockade and is compounded by obstructed venous return due to uter ine compression of the great vessels. In the supine position, even in the absence of maternal hypotension measured in the brachial artery, placental blood flow may still be significantly reduced. Treatment includes uterine displacement by left lat eral patient positioning, intravenous crystalloid hydration, and intravenous bolus injections of ephedrine or phenyleph rine.

Ephedrine is a sympathomimetic drug that binds to X-and 0-receptors but also indirectly enhances norepinephrine release. It raises blood pressure by raising heart rate and cardiac output and by variably elevating peripheral vascular resistance. In early animal studies, ephedrine preserved uteroplacental blood flow during pregnancy compared with ai-receptor agonists. Accordingly, it had been the preferred vasopressor for obstetrical use. Phenylephrine is a pure a-agonist and elevates blood pressure solely through vasoconstriction. A metaanalysis of seven randomized trials by Lee (2002a) suggests that the safety profiles of ephedrine and phenylephrine are comparable. Following their systematic review of 14 reports, Lee (2002b) questioned whether routine prophylactic ephedrine is needed for elective cesarean delivery. Although fetal acidemia has been reported with prophylactic ephedrine use, this was not observed with prophylactic phenylephrine use (Ngan Kee, 2004).

High or Total Spinal Blockade. Most often, high or total spinal blockade follows administration of an excessive dose of local anesthetic or inadvertent injection into the subdural or subarachnoid space. Subdral injection manifests as a high but patchy block even with a small dose of local anesthetic agent, whereas subarachnoid injection typically leads to complete spinal blockade with hypotension and apnea. hese conditions must be immediately treated to prevent cardiac arrest. In the undelivered woman: (1) the uterus is immediately displaced laterally to minimize aortocaval compression; (2) efective ventilation is established, preferably with tracheal intubation; and (3) intravenous fluids and vasopressors are given to correct hypotension. If chest compressions are to be performed, the woman is placed in the left-lateral position to allow left uterine displacement.

Postdural Puncture Headache. Leakage of cerebrospinal fluid (CSF) from the dura mater puncture site can lead to postdural puncture or "spinal headache." Presumably, when the woman sits or stands, the diminished CSF volume creates traction on pain-sensitive central nervous system structures. Another mechanism may be the compensatory cerebral vasodilation in response to the loss of CSF-the Monro-Kellie doctrine (Mokri, 2001).

Rates of this complication can be reduced by using a small-gauge spinal needle and avoiding multiple punctures. In a prospective, randomized study of ive diferent spinal needles, Vallejo and associates (2000) concluded that Sprotte and Whitacre needles had the lowest risks of postdural puncture headaches. Sprigge and Harper (2008) reported that the incidence of postdural puncture headache was 1 percent in more than 5000 women undergoing spinal analgesia. Postdural puncture headaches are much less frequent with epidural blockade because the dura mater is not intentionally punctured. he incidence of inadvertent dural puncture with epidural analgesia approximates 0.2 percent (Introna, 2012; Katircioglu, 2008). here is no good evidence that placing a woman absolutely lat on her back for several hours is efective in preventing this headache.

Once headache develops, it is managed aggressively, as expectant management increases hospital-stay lengths and subsequent emergency-room visits (Angle, 2005). Conservative management, such as luid administration and bed rest, is largely inefective. If not efectively treated, postdural puncture headache can persist as a chronic headache (Webb, 2012).

Epidural blood patch is considered the gold standard for treatment. Typically, 10 to 20 mL of autologous blood obtained aseptically by venipuncture is injected into the epidural space. Further CSF leakage is halted by either mass efect or coagulation. Relief is almost always immediate, and complications are uncommon. The initial success rate of an epidural blood patch ranges from 61 to 73 percent (Paech, 2011). Performing a "prophylactic" blood patch is debatable and is thought not to be as efective as if performed after the headache develops (Scavone, 2004, 2015).

If a headache does not have the pathognomonic postural characteristics or persists despite treatment with a blood patch, other diagnoses are considered. Chisholm and Campbell (2001) described a case of superior sagittal sinus thrombosis that manifested as a postdural headache. Smarkusky and colleagues (2006) described pneumocephalus, which caused immediate cephalgia. Finally, intracranial and intraspinal subarachnoid hematomas have developed after spinal analgesia (Dawley, 2009; Liu, 2008).

Convulsions. In rare instances, postdural puncture cephalgia is associated with temporary blindness and convulsions. Shearer and associates (1995) described eight such cases associated with 19,000 regional analgesic procedures done at Parkland Hospital. It is presumed that these too are caused by CSF hypotension. Immediate treatment of seizures and a blood patch were usually efective in these cases.

Bladder Dysfunction. With neuraxial analgesia, bladder sensa tion is likely to be obtunded and bladder emptying impaired for several hours after delivery. As a consequence, bladder distention is a frequent postpartum complication, especially if appreciable volumes of intravenous luid are given. Millet and colleagues (2012) randomized 146 women with neuraxial analgesia to either intermittent or continuous bladder catheterizations and found that the intermittent method was associated with signiicantly higher rates of bacteriuria. That said, we do not recommend routine postpartum use of indwelling catheters following uncomplicated vaginal delivery.

Arachnoiditis and Meningitis. Local anesthetics are no longer preserved in alcohol, formalin, or other toxic solutes,

TABLE 25-6. Absolute Contraindications to Neuraxial Analgesia

Skin infection over site of needle placement and disposable equipment is usually used. hese practices, coupled with aseptic technique, have made meningitis and arachnoiditis rare (Centers for Disease Control and Prevention, 2010).

Contraindications to Neuraxial AnalgeSia

Shown in Table 25-6 are absolute contraindications. Obstetrical complications that are associated with maternal hypovolemia and hypotension-for example, severe hemorrhage-are contraindications (Kennedy, 1968).

Disorders of coagulation and defective hemostasis also preclude neuraxial analgesia use. Although no randomized studies guide the management of anticoagulation at the time of delivery, consensus opinion suggests that women given subcutaneous unfractionated heparin or low-molecular-weight heparin should be instructed to stop therapy when labor begins (Krivak, 2007). Subarachnoid puncture is also contraindicated if cellulitis involves the planned needle entry site. Many consider neurological disorders to be a contraindication, if for no other reason than that exacerbation of the neurological disease might be erroneously attributed to the anesthetic agent. Other maternal conditions, such as aortic stenosis or pulmonary hypertension, are also relative contraindications (Chap. 49, p.i948).

Severe preeclampsia is another comorbid condition in which markedly decreased blood pressure can be predicted when neuraxial analgesia is used. Wallace and associates (1995) randomly assigned 80 women with severe preeclampsia undergoing cesarean delivery at Parkland Hospital to receive general anesthesia or either epidural or combined spinal-epidural analgesia. Maternal and neonatal outcomes did not difer. Still, 30 percent of women given epidural analgesia and 22 percent of those given spinal-epidural blockade developed hypotension. he average reduction in mean arterial pressure ranges between 15 and 25 percent.

Relief of labor and childbirth pain, including cesarean delivery, can be accomplished by injection of a local anesthetic agent into the epidural or peridural space 25-3). his potential space contains areolar tissue, fat, lymphatics, and the internal vertebral venous plexus. This plexus becomes engorged during pregnancy such that the volume of the epidural space is appreciably reduced. Entry for obstetrical analgesia is usually through a lumbar intervertebral space. Although only

Spinal needle punctures the dura mater for injection 1 I:

FIGURE 25-3 Neuraxial analgesia: A. Combined spinal-epidural analgesia. B. Epidural analgesia.

one injection may be elected, usually an indwelling catheter is placed for subsequent agent boluses or infusion via a volumetric pump. he American College of Obstetricians and Gynecologists (2017 a) concludes that under appropriate physician supervision, labor and delivery nursing personnel who have been specifically trained in the management of epidural infusions should be able to adjust dosage and also discontinue infusions.

Complete analgesia for the pain of labor and vaginal delivery necessitates a block from the TIO to the S5 dermatomes (see Fig. 25-1). For cesarean delivery, a block extending from the T4 to the S1 derma tomes is desired. The efective spread of anesthetic depends on the catheter tip location; the dose, concentration, and volume of anesthetic agent used; and whether the mother is head-down, horizontal, or head-up (Setayesh, 2001). Individual variations in anatomy or presence of synechiae may preclude a completely satisfactory block.

Finally, the catheter tip may migrate from its original location during labor.

One example of the sequential steps and techniques for performance of epidural analgesia is detailed in Table 25-7. Before injection of the local anesthetic therapeutic dose, a test dose is given. The woman is observed for features of toxicity from intravascular injection and for signs of high or total blockade from subdural or subarachnoid injection. If these are absent, only then is a full dose given. Analgesia is maintained by intermittent boluses of similar volume or by small volumes delivered continuously by infusion pump (Halpern, 2009). Current pumps used for epidural analgesia ofer a programmed intermittent epidural bolus (PIEB) mode, which reduces the required concentration of local anesthetics, the degree of lower extremity motor blockade, and rates of operative vaginal delivery (Capogna, 2011). he addition of small doses of a short-acting narcotic-fentanyl or sufentanil-has been shown to improve analgesic eicacy while avoiding motor blockade (Chestnut,

TABLE 25-7. Technique for Labor Epidural Analgesia

Informed consent is obtained, and the obstetrician consulted Monitoring includes the following:

Blood pressure every 1 to 2 minutes for 15 minutes ater giving a bolus of local anesthetic Continuous matenal heart rate monitoring during analgesia induction

Hydration with 500 to 1000 mL of lactated solution The woman assumes a lateral decubitus or sitting position

The epidural space is identified with a loss-of-resistance technique The epidural catheter is threaded 3 to 5 cm into the epidural space

A test dose of 3 mL of 1.5% lidocaine with 1 :200,000 epinephrine or 3 mL of 0.25% bupivacaine with 1 :200,000 epinephrine is injected after careful aspiration to avert injection and after a uterine contraction. This minimizes the chance of confusing tachycardia that results from labor pain with tachycardia from intravenous injection of the test dose.

If the test dose is negative, 10-15 mL of 0.0625-0.125% bupivacaine are injected to achieve a sensory TlO level.

Ater 15 to 20 minutes, the block is assessed using loss of sensation to cold or pinprick. If no block is evident, the catheter is replaced. If the block is asymmetrical, the epidural catheter is withdrawn 0.5 to 1s.0 cm and an additional 5 to 10 mL of 0.0625-0.125% bupivacaine is injected. If the block remains inadequate, the catheter is replaced.

The woman is positioned in the lateral or semilateral position to avoid aortocaval compression.

Subsequently, maternal blood pressure is recorded every 5 to 15 minutes. The fetal heart rate is monitored continuously. The level of analgesia and intensity of motor blockade are assessed at least hourly.

Reproduced with permission from Glosten B: Local anesthetic techniques. In Chestnut DH (ed): Obstetric Anesthesia: 2nd ed. St Louis, Mosby, 1999.

1988). As with spinal blockade, close monitoring, including the level of analgesia, is imperative and must be performed by trained personnel. Appropriate resuscitation equipment and drugs must be available during administration of epidural analgesia.

Higher or Total Spinal Blockade. In general, complications with epidural analgesia are similar to those with spinal analgesia (see Table 25-5). Dural puncture with inadvertent subarachnoid injection may cause total spinal blockade. Sprigge and Harper (2008) cited an incidence of 0.91 percent recognized accidental dural punctures at the time of epidural analgesia in more than 18,000 women. Personnel and facilities must be immediately available to manage this complication as described earlier (p. 491). In other aspects, however, complications are unique and inherent to epidural analgesia use.

Inefective Analgesia. Using currently popular continuous epidural infusion regimens such as 0.125-percent bupivacaine with 2-�g/mL fentanyl, 90 percent of women rate their pain relief as good to excellent (Sharma, 1997). lternatively, a few women ind epidural analgesia to be inadequate for labor. In a study of almost 2000 parturients, Hess and associates (2001) found that approximately 12 percent complained of three or more episodes of pain or pressure. Risk factors for such breakthrough pain included nullipariry and heavier fetal weights. Dresner and colleagues (2006) also reported that epidural analgesia was more likely to fail as body mass index increased. If epidural analgesia is allowed to dissipate before another Injection of anesthetic drug, subsequent pain relief may be delayed, incomplete, or both.

In some women, epidural analgesia is insuicient for cesarean delivery. For example, in a Maternal Fetal Medicine Units (MFMU) Network study, 4 percent of women initially given epidural analgesia required a general anesthetic for cesarean delivery (Bloom, 2005). Also at times, perineal analgesia for delivery is diicult to obtain, especially with the lumbar epidural technique. When this situation is encountered, pudendal block or systemic analgesia or rarely general anesthesia may be added.

Hypotension. Sympathetic blockade from epidurally injected analgesic agents can cause hypotension and decreased cardiac output. Despite precautions, hypotension is the most frequent side efect and is severe enough to require treatment in a third of women (Sharma, 1997). According to Miller and coworkers (2013), hypotension is more common-20 percent-in women with an admission pulse pressure <45 mm Hg, compared with 6 percent in those whose pulse pressure is >45 mm Hg. In normal gravidas, hypotension induced by epidural analgesia usually can be prevented by rapid infusion of 500 to 1000 mL of crystalloid solution as described for spinal analgesia. Maintaining a lateral position also minimizes hypotension.

Maternal Fever. Fusi and colleagues (1989) observed that the mean temperature rose in laboring women given epidural analgesia. Subsequently, several randomized and retrospective cohort studies have confirmed that some women develop intrapartum fever following this procedure. Many studies are limited by inabiliry to control for other risk factors such as labor length, duration of ruptured membranes, and number of vaginal examinations. With this in mind, the frequency of intrapartum fever associated with epidural analgesia was found by Lieberman and O'Donoghue (2002) to be 10 to 15 percent above the baseline rate.

The two general theories concerning the etiology of maternal hyperthermia are maternaletal inection or dysregulation of body temperature. Dashe and coworkers (1999) studied placental histopathology in laboring women given epidural analgesia and identified intrapartum fever only when there was placental inflammation. This suggests that fever is due to infection. he other proposed mechanisms include alteration of the hypothalamic thermoregulatory set point; impairment of peripheral thermoreceptor input to the central nervous system, with selective blockage of warm stimuli; or imbalance between heat production and heat loss. Sharma (2014) randomized 400 nulliparas with labor epidural analgesia to receive cefoxitin 2 g prophylactically versus placebo. It was hypothesized that epidural-related fever was due to infection and that prophylactic antimicrobial use should significantly reduce the rate of fever. Approximately equal proportions-about 40 percentof women developed fever > 38°C during labor. This suggests that infection is unlikely to be the cause of fever.

Back Pain. An association between epidural analgesia and subsequent back pain has been reported by some but not all. In a prospective cohort study, Butler and Fuller (1998) reported that back pain after delivery was common with epidural analgesia, however, persistent pain was uncommon. Based on their systematic review, Lieberman and O'Donoghue (2002) concluded that available data do not support an association between epidural analgesia and development of de novo, long-term backache.

Miscellaneous Complications. A spinal or epidural hematoma is a rare complication of an epidural catheter (Grant, 2007). Epidural abscesses are equally infrequent (Darouiche, 2006). And uncommonly, the plastic epidural catheter can be sheared of (Noblett, 2007).

Most studies, including the ive from Parkland Hospital, report that epidural analgesia prolongs labor and increases the use of oxytocin stimulation (Table 25-8). Alexander and associates (2002) examined the efects of epidural analgesia on the Friedman (1955) labor curve described in Chapter 22 (p. 432). Compared with original Friedman criteria, epidural analgesia prolonged the active phase of labor by 1 hour. As further shown in Table 25-8, epidural analgesia also increased the need for operative vaginal delivery because of prolonged second-stage labor. But importantly, this led to no greater rates of adverse neonatal efects.

This association among epidural analgesia and prolonged second-stage labor and operative vaginal delivery has been attributed to anesthesia-induced motor blockade and resultant impaired matenal expulsive eforts. Craig and colleagues (2015) randomized 310 nulliparous women with labor epidural analgesia to bupivacaine plus fentanyl or fentanyl alone during second-stage labor. Epidural bupivacaine analgesia did cause motor blockade during the second stage, however, the duration of the second stage was not increased.

TABLE 25-8. Selected Labor Events in 2703 Nulliparous Women Randomized to Epidural Analgesia

First-stage duration 8.1 ± 5 7.5 ± 5 0.01s1 (hr)b

Second-stage 60 ± 56 47 ± 57 <0.001 duration (min) Oxytocin ater 641 (48) 546 (40) <0.001

Type of delivery

SVD 1027 (77) 11s22 (82) <0.001 Forceps 172 (l3) 101 (7) <0.001 Cesarean 140 (10.5) 141 (10.3) 0.92 aData are presented as n (%) or mean ± SD.

bFirst stage = initiation of analgesia to complete cervical dilatation.

SVD = spontaneous vaginal delivery.

Adapted with permission from Sharma SK, Mcintire DD,

Wiley J, et al: Labor analgesia and cesarean delivery. An individual patient meta-analysis of nulliparous women,

Anesthesiology. 2004 Jan;l 00(1 ):142-148.

Fetal Heart Rate. Hill and associates (2003) examined the efects of epidural analgesia with 0.25-percent bupivacaine on fetal heart rate patterns. Compared with intravenous meperidine, no deleterious efects were identified. Reduced beat-co-beat variability and fewer accelerations were more frequent sequelae in fetuses whose mothers received meperidine (Chap. 24, p. 462). Based on their systematic review, Reynolds and coworkers (2002) reported that epidural analgesia was associated with improved neonatal acid-base status compared with meperidine.

Cesarean Delivery Rates. A contentious issue in the past was whether epidural analgesia increased the risk for cesarean delivery. Supporting evidence for this view came from the era when dense blocks of local anesthetic agents were used that impaired motor function and therefore likely did contribute to higher cesarean delivery rates. As techniques were refined, however, many investigators came to believe that epidural administration of dilute anesthetic solutions did not increase cesarean delivery rates.

Several studies conducted at Parkland Hospital were designed to answer this and related questions. From 1995 to 2002, a total of 2703 nulliparas at term and in spontaneous labor were enrolled in ive trials to evaluate epidural analgesia techniques compared with methods of intravenous meperidine administration. he results from these are summarized in Figure 25-4 and show that epidural analgesia does not signiicantly raise cesarean delivery rates.

Timing of Epidural Placement

In several retrospective studies, epidural placement in early labor was linked to an increased risk of cesarean delivery

Ramin et ai, 1995

Sharma et ai, 1997 Gambling et ai, 1998

Lucas et ai, 2001

Sharma et ai, 2002

I OR (95% el) Force on Obstetrical Anesthesia (2016).I Epidural hematomas are rare, and inci 1.01 (0.79,e1.30) dence of nerve damage from a hematoma is estimated to be 1 in 150,000 (Grant, 2007). he American College of Obstetri 1.20 (0.73, 1.97) cians and Gynecologists (2016b) has conI cluded that selected women with platelet 0.77 (0.31e, 1.91e) counts of 80,000 to 100,000/LL may be

I candidates for regional analgesia. Caveats --: -1.13 (0.65, 1.97) include a stable platelet count, no acquired or congenital coagulopathy, normal plateI let function, no antiplatelet-specific drugs, 1.05 (0.68, 1.63) and anticoagulation parameters, describedI next, that are met. Counts between 50,000 0.81 (0.41e, 1.61e) and 80,000 require an individualizedI decision on risks and benefits (van Veen, 1.04 (0.81e,e1.34) 2010). Single-shot spinal anesthesia with a 25-gauge needle is less traumatic than epiI dural or combined spinal-epidural anesthe sia with a 17-or 18-gauge epidural needle 0.0 0.4 0.8 1.2 1.6 2.0 platelets in this range.

FIGURE 25-4 Results offive studies comparing the incidence of cesarean delivery in women given either epidural analgesia or intravenous meperidine. The individual

Anticoagulation. Women recelvmg odds ratios (ORs) with 95-percent confidence intervals (Cis) for each randomized study, coagulation therapy who are given regional as well as overall crude and adjusted ORs with 95-percent Cis, are shown. An OR <1o.0 analgesia are at increased risk for spinal cord favored epidural over meperidine analgesia. (Reproduced with permission from Sharma

SK, Mcintire DO, Wiley J, et al: Labor analgesia and cesarean delivery. An individual patient meta-analysis of nulliparous women, Anesthesiology. 2004 Jan;l00(1):142-148.) sion (Chap. 52, p. 1014). Our practice pat (Lieberman, 1996; Rogers, 1999; Seyb, 1999). These observations prompted at least ive randomized trials, which showed that timing of epidural placement has no efect on the risk of cesarean birth, forceps delivery, or fetal malposition (Chestnut, 1994a,b; Ohel, 2006; Wong, 2005, 2009). Thus, withholding epidural placement until some arbitrary cervical dilation has been attained is unsupportable and serves only to deny women maximal labor pain relief.

he relative safety of epidural analgesia is relected by the extraordinary earlier experiences reported by Crawford (1985) from the Birmingham Maternity Hospital in England. Similarly, there were no anesthesia-related maternal deaths among nearly 20,000 women who received epidural analgesia in the MFMU Network study cited earlier (Bloom, 2005). And, Ruppen and associates (2006) reviewed data from 27 studies involving 1.4 million pregnant women who received epidural analgesia. hey calculated risks of 1: 145,000 for deep epidural infection, 1: 168,000 for epidural hematoma, and 1 :240,000 for persistent neurological injury.

Thrombocytopenia. For epidural analgesia, contraindications are similar to those with spinal analgesia (see Table 25-6). Although low platelet counts are intuitively worrisome, the level at which epidural bleeding might develop is unknown according to the American Society of Anesthesiologists Task tern includes the following: 1.

Women receiving unfractionated heparin therapy should be able to receive regional analgesia if they have a normal activated partial thromboplastin time (aPTT).

2.

Women receiving prophylactic doses of unfractionated heparin or low-dose aspirin are not at increased risk and can be ofered regional analgesia.

3.

For women receiving once-daily, low-dose low-molecularweight heparin, regional analgesia should not be placed until 12 hours after the last injection.

4.

Low-molecular-weight heparin should be withheld for at least 2 hours after epidural catheter removal.

5.

he safety of regional analgesia in women receiving twicedaily low-molecular-weight heparin has not been studied suiciently. It is not known whether delaying regional analgesia for 24 hours after the last injection is adequate.

Severe Preeclampsia-Eclampsia. Potential concerns with epidural analgesia in women with severe preeclampsia include hypotension as well as hypertension from pressor agents given to correct hypotension. Additionally, pulmonary edema following infusion of large volumes of crystalloid is a potential risk. These are outweighed by disadvantages of general anesthesia. Tracheal intubation may be diicult because of upper airway edema. Moreover, general anesthesia can lead to severe, sudden hypertension that can cause pulmonary or cerebral edema or intracranial hemorrhage.

With improved techniques for infusion of dilute local anesthetics into the epidural space, most obstetricians and obstetrical anesthesiologists have come to favor epidural block ade for labor and delivery in women with severe preeclamp sia. here seems to be no argument that epidural analgesia for women with severe preeclampsia-eclampsia can be safely used cians (Lucas, 2001).

Women with severe preeclampsia have remarkably diminished intravascular volumes compared with unafected gravidas (Zeeman, 2009). Conversely, extravascular volume is increased because of the capillary leak caused by endothelial cell activation (Chap. 40, p. 717). his imbalance is manifested as pathological peripheral edema, proteinuria, ascites, and total lung water. For all of these reasons, aggressive volume replacement increases the risk for pulmonary edema, especially in the irst 72 hours postpartum. In one study, Hogg and associates (1999) reported that 3.5 percent of women with severe preeclampsia developed pulmonary edema when preloaded without a protocol limitation to volume. Importantly, this risk can be reduced or obviated with judicious prehydration-usually with 500 to 1000 mL of crystalloid solution. Speciically, in the study by Lucas and colleagues (2001), there were no instances of pulmonary edema among the women in whom the crystalloid preload was limited to 500 mL. Moreover, vasodilation produced by epidural blockade is less abrupt if the analgesia level is achieved slowly with dilute solutions of local anesthetic agents. This allows maintenance of blood pressure while simultaneously avoiding infusion of large crystalloid volumes.

he combination of spinal and epidural techniques has increased in popularity and may provide rapid and efective analgesia for labor and for cesarean delivery. An introducer needle is irst placed in the epidural space. A small-gauge spinal needle is then introduced through the epidural needle into the subarachnoid space-this is called the needle-throughneedle technique (see Fig. 25-3). A single bolus of an opioid, sometimes in combination with a local anesthetic, is injected into the subarachnoid space. The spinal needle is withdrawn, and an epidural catheter is then placed through the introducer needle. A subarachnoid opioid bolus results in the rapid onset of profound pain relief with virtually no motor blockade. he epidural catheter permits repeated analgesia dosing. Miro and associates (2008) compared epidural analgesia with combined spinal-epidural analgesia for labor in 6497 women and found the overall outcomes and complications to be similar for the two techniques. In a randomized comparison, however, Abrao and colleagues (2009) reported that combined spinal-epidural analgesia was associated with a greater incidence of fetal heart rate abnormalities related to uterine hypertonus. Beamon and coworkers (2014) reported similar results .

here is emerging interest in continuous spinal analgesia for relief of labor pain. Arkoosh (2008) randomized 429 laboring women to either continuous spinal or conventional epidural analgesia. Complication rates between these two neuraxial techniq ues did not difer. Tao and colleagues (2015) reported their experiences with 113 women. With a dilute bupivacaine solution for analgesia, they found no cases of peripheral nerve injury and a headache rate of2.6 percent. he utility of continuous spinal analgesia in labor and delivery remains to be further studied.

A local block is occasionally useful to augment an inadequate or "patchy" regional block that was given emergently. Rarely, local iniltration may be needed to perform an emergent cesarean delivery to save the life of a fetus in the absence of anesthesia support (Young, 2012).

In one technique, the skin is iniltrated along the proposed incision, and the subcutaneous, muscle, and rectus sheath layers are injected as the abdomen is opened. Up to a total of 70 mL of 0.5-percent lidocaine with 1 :200,000 epinephrine is prepared for iniltration. Injection of large volumes into the fatty layers, which are relatively devoid of nerve supply, is avoided to limit the total dose of local anesthetic needed.

A second technique involves a ield block of the major branches supplying the abdominal wall, to include the 10th, 11 th, and 12th intercostal nerves and the ilioinguinal and genitofemoral nerves (Nandagopal, 2001). As shown in 25-5, the former group of nerves is located at a point midway

FIGURE 25-5 Local anesthetic block for cesarean delivery. The first injection site is halfway between the costal margin and iliac crest in the midaxillary line to block the 10th, 11 th, and 12th intercostal nerves. A second injection at the external inguinal ring blocks branches of the genitofemoral and ilioinguinal nerves. These two sites are infiltrated bilaterally. The fifth and final site is along the line of proposed skin incision.

between the costal margin and iliac crest in the midaxillary line. he latter group is found at the level of the external inguinal ring. Only one skin puncture is made at each of the four sites (right and left sides). At the intercostal block site, the needle is directed medially, and injection is carried down to the fascia, avoiding injection of the subcutaneous fat. Approximately 5 to 8 mL of 0.5-percent lidocaine is injected. The procedure is repeated at a 45-degree angle cephalad and caudad to this line. he other side is then injected. At the ilioinguinal and genitofemoral sites, the injection is started at a site 2 to 3 cm lateral from the pubic tubercle at a 45-degree angle. Finally, the skin overlying the planned incision is injected.

Trained personnel and specialized equipment including alternative airways, video laryngoscopes, and fiberoptic intubation scopes are mandatory for the safe use of general anesthesia. A common cause of death cited for general anesthesia is failed intubation. This occurs in approximately 1 of every 400 general anesthetics administered to pregnant women (Kinsella, 2015). There is a growing trend to continue surgery with a supraglottic airway device, such as a laryngeal mask airway, in the event of a failed intubation (Mushambi, 2015). Because of these relatively greater morbidity and mortality rates, neuraxial analgesia is the preferred method of pain control and should be used unless contraindicated (see Table 25-6). Indeed, in two reports from the MFMU Network, 93 percent of more than 54,000 cesarean deliveries were performed using neuraxial analgesia (Bloom, 2005; Brookfield, 2013). A higher incidence of general anesthesia use for nonwhite women has been reported (Butwick,i2014).

Before anesthesia induction, several steps are taken to help minimize complication risks: 1.

Antacid administration shortly before anesthesia induction has probably lowered mortality rates from general anesthesia more than any other single practice. The American Society of Anesthesiologists Task Force on Obstetrical Anesthesia (2016) recommends timely administration of a nonparticulate antacid, an Hrreceptor antagonist, or metoclopramide. For many years, we have administered 30 mL of Bicitra-sodium citrate with citric acid-a few minutes before anesthesia induction by either general or major neuraxial block. If more than 1 hour has passed ater the first dose was given and anesthesia has not yet been induced, then a second dose is given.

2.

Lateral uterine displacement is also provided, as the uterus may compress the inferior vena cava and aorta when the mother is supine. With uterine displacement, the duration of general anesthesia has less efect on neonatal condition than if the woman remains supine.

3.

Preoxygenation is done because functional reserve lung capacity is reduced and the pregnant woman becomes hypoxemic more rapidly during periods of apnea. Obesity exacerbates this tendency (McClelland, 2009). To minimize hypoxia between the time of muscle relaxant injection and intubation, oxygen is introduced into the lungs in place of nitrogen. 1bis preoxygenation is accomplished by administering 100-percent oxygen via face mask for 2 to 3 minutes before anesthesia induction. In an emergency, four vital capacity breaths of 100-percent oxygen via a tight breathing circuit will provide similar beneit (Norris, 1985).

Almost all parturients are considered to have a full stomach, which necessitates a rapid-sequence induction. Namely, an intravenous anesthetic and rapid-onset muscle relaxant are simultaneously administered while cricoid pressure is applied by an assistant.

Of anesthetics, intravenous propofol or etomidate is widely used and ofers a smooth, rapid induction. Propofol is associated with a quick onset and recovery, and it may lower the incidence of nausea and vomiting. Since thiopental is no longer available, propofol is used as the primary agent for induction of general anesthesia with a reasonable safety record. Etomidate is the induction agent of choice for hemodynamically unstable parturients. Alternatively, ketamine can be used but is avoided in hypertensive women. For muscle relaxation, succinylcholine is an ultrafast-onset, short-acting agent commonly used in obstetrics. It ofers intense muscle relaxation to aid endotracheal intubation but also allows for the rapid return of spontaneous respiration in the case of failed intubation. Rocuronium is an alternative muscle relaxant if succinylcholine is contraindicated or unavailable. Its duration is much longer than succinylcholine unless its efect is reversed by sugammadex (Bridion), a specific binding agent recently approved by the FDA. To decrease the incidence of fetal respiratory depression, an intermediate or long-acting opioid is usually avoided upon induction of general anesthesia. The intense stimulation from direct laryngoscopy may worsen hypertension and tachycardia in certain women. Remifentanil, an ultrashort-acting narcotic, has been used during induction for cesarean deliveries with favorable maternal hemodynamics and fetal outcome (Heesen, 2013).

During induction and intubation, cricoid pressure is applied by a trained assistant to occlude the esophagus and thereby minimize regurgitation of the gastric contents-the Sellick maneuver. Positive mask ventilation during rapid sequence induction is typically avoided to lower the risk of increased intragastric pressure, which raises the risk of vomiting. Surgery should begin only after an airway is secured or, depending on the status of the mother and fetus, efective ventilation has been established.

Although uncommon, failed intubation is a major cause of anesthesia-related maternal mortality. A history of prior difficult intubation and a careful anatomical assessment of the neck and maxillofacial, pharyngeal, and laryngeal structures may help predict intubation complications. Even in cases in which the initial airway assessment was unremarkable, edema may develop intrapartum and present considerable challenges. Morbid obesity is another major factor for failed or diicult intubation. The American Society of Anesthesiologists Task Force on Obstetrical Anesthesia (2016) stresses the importance of appropriate preoperative preparation. This includes the immediate availability of specialized equipment such as diferent-shaped laryngoscopes, laryngeal mask airways, a fiberoptic bronchoscope, and a transtracheal ventilation set, as well as liberal use of awake oral intubation techniques.

Ideally, an operative procedure is initiated only after it has and that adequate ventilation can be accomplished. Even with an abnormal fetal heart rate pattern, cesarean delivery initiation will only serve to complicate matters if there is diicult or failed intubation. Frequently, the woman must be allowed to awaken and a diferent technique used, such as an awake intubation or regional analgesia.

Following failed intubation, the woman is ventilated by mask and cricoid pressure is applied to reduce the aspiration risk. Surgery may proceed with mask ventilation, or the woman may be allowed to awaken. In those cases in which the woman has been paralyzed and ventilation cannot be reestablished by insertion of an oral airway, by laryngeal mask airway, or by use of a iberoptic laryngoscope to intubate the trachea, then a life-threatening emergency exists. To restore ventilation, percuraneous or even open cricothyrotomy is performed and jet ventilation begun. Failed intubation drills have been recommended to optimize the response to such an emergency.

With the endotracheal tube secured, anesthesia is maintained with a halogenated agent, typically mixed with air or nitrous oxide. he most commonly used inhalational anesthetics in the United States include deslurane and sevolurane. Both have low solubility in blood and fat. As a result, they ofer faster onset and clearance than more traditional gases such as isolurane. In addition to providing amnesia, they produce profound uterine relaxation when given in high concentrations. his is advantageous when relaxation is a requisite, such as for internal podalic version of the second twin, for breech decomposition, or for replacement of the acutely inverted uterus. That said, unless the woman is alread) under general anesthesia, intravenous nitroglycerine is preferred by many in such situations.

he endotracheal tube may be safely removed only if the woman is conscious to a degree that enables her to follow commands and is capable of maintaining oxygen saturation with spontaneous respiration. Consideration is given to emptying the stomach via a nasogastric tube before extubation. As induction has become safer, extubation may now be relatively more perilous. Of 15 anesthesia-related deaths of pregnant women from 1985 to 2003 in Michigan, none occurred during induction. Five resulted from hypoventilation or airway obstruction during emergence, extubation, or recovery (Mhyre, 2007).

Massive gastric acidic inhalation may cause pulmonary insufficiency from aspiration pneumonitis. In the past, this was the most common cause of anesthetic deaths in obstetrics and therefore deserves special attention. To minimize this risk, antacids are given rourinely, intubation is accompanied by cricoid pressure, and regional analgesia is employed when possible.

According to the American Society of Anesthesiologists Task Force on Obstetrical Anesthesia (2016) and the merican College of Obstetricians and Gynecologists (2017b), data are insuicient regarding fasting times for clear liquids and the risk of pulmonary aspiration during labor. Recommendations are that modest amounts of clear liquids such as water, clear tea, black cofee, carbonated beverages, and pulp-free fruit juices be allowed in uncomplicated laboring women (Chap 22, p. 437). Obvious solid foods are avoided. A fasting period of 6 to 8 hours for solid food is recommended for uncomplicated parturients prior to undergoing elective cesarean delivery or puerperal tubal ligation.

O'Sullivan (2009) randomized 2426 low-risk nulliparas to consume either water and ice chips alone or small amounts of bread, biscuits, vegetables, fruits, yogurt, soup, and fruit juice. Approximately 30 percent of women in each arm of the study underwent cesarean delivery. No cases of aspiration occurred during the study, although approximately a third of women in each study arm vomited during labor or delivery. Epidural analgesia during labor was used in this study, although the authors did not report the type of anesthesia used for cesarean deliveries. Presumably, neuraxial analgesia was used, and this greatly minimized the pulmonary aspiration risk. Given the low prevalence of aspiration, this trial was not powered to measure whether feeding during labor was safe (Sperling, 2016).

In 1952, Teabeaut demonstrated experimentally that if the pH of aspirated fluid was <2.5, severe chemical pneumonitis developed. It was later demonstrated that the pH of gastric juice in nearly half of women tested intrapartum was <2.5 (Taylor, 1966). The right mainstem bronchus usually ofers the simplest pathway for aspirated material to reach the lung parenchyma, and therefore, the right lower lobe is most often involved. In severe cases, there is bilateral widespread involvement.

The woman who aspirates may develop evidence of respiratory distress immediately or several hours after aspiration, depending in part on the material aspirated and the severity of the response. Aspiration of a large amount of solid material causes obvious airway obstruction. Smaller particles without acidic liquid may lead to patchy atelectasis and later to bronchopneumonia.

When highly acidic liquid is inspired, decreased oxygen saturation along with tachypnea, bronchospasm, rhonchi, rales, atelectasis, cyanosis, tachycardia, and hypotension are likely to develop. At the injury sites, there is pulmonary capillary leakage and exudation of protein-rich fluid containing numerous erythrocytes into the lung interstitium and alveoli. his causes decreased pulmonary compliance, shunting of blood, and severe hypoxemia. Radiographic changes may not appear immediately, and these may be variable, although the right lung most often is afected. hus, chest radiographs alone should not be used to exclude aspiration.

he methods recommended for treatment of aspiration have changed appreciably in recent years, indicating that previous therapy was not very successful. Suspicion of aspiration of gastric contents demands close monitoring for evidence of pulmonary damage. Respiratory rate and oxygen saturation as measured by pulse oximetry are the most sensitive and earliest indicators of injury.

Inhaled luid should be immediately and thoroughly wiped from the mouth and removed from the pharynx and trachea by suction. Saline lavage may further disseminate the acid throughout the lung and is not recommended. If large particulate matter is inspired, bronchoscopy may be indicated to relieve airway obstruction. No convincing evidence supports that corticosteroid therapy or prophylactic antimicrobial administration is beneicial (Marik, 2001). If infection develops, however, then vigorous treatment is given. If acute respiratory failure develops, mechanical ventilation with positive end-expiratory pressure may be lifesaving (Chap. 47, p. 919).

patient satisfaction, minimizing side efects, aiding unctional capacity, and preventing prolonged hospital stays (Lavoie, 2013). In a prospective study, 96 percent of women reported pain immediately ater delivery (Eisenach, 2008). he incidence of persistent pain 1 and 2 years following cesarean delivery was reported to approximate 20 percent (Hannah, 2004; Kainu, 2010).

he American Society of Anesthesiologists (2016) recommends neuraxial opioids for postoperative analgesia. Although most cesarean deliveries in the United States are performed under neuraxial anesthesia, in certain situations a peripheral nerve block such as a transversus abdominis plane (TAP) block may be considered (McDonnell, 2007). hese include cases in which the parturient did not receive neuraxial opioids, underwent general anesthesia, or has persistent pain following neuraxial anesthesia. It is usually performed under ultrasound guidance and involves injection of a local anesthetic into the transversus abdominis plane between the internal oblique and transversus abdominis muscles. he nerves lying in this plane supply the anterior abdominal wall at the T 6 to L1 dermatomes. A metaanalysis of 31 controlled trials showed that ultrasoundguided TAP block marginally reduced opioid consumption at 6 hours following abdominal surgery (Baeriswyl, 2015).

Abrao KC, Francisco RP, Miyadahira S, et al: Elevation of uterine basal tone and fetal heart rate abnormalities after labor analgesia: a randomized controlled trial. Obstet Gynecol 113(10):41,2009

Alexander JM, Sharma SK, McIntire DD, et al: Epidural analgesia lengthens the Friedman active phase ofolabor. Obstet Gynecol 100:46,o2002

American College of Obstetricians and Gynecologists: Practice advisory: FDA warnings regarding use of general anesthetics and sedation drugs in young children and pregnant women. 2016a. Available at: http://www.acog.org/ About-ACOG/News-Room/Practice-Advisories/FDA-Warnings-Rega rding-Use-of-General-Anesthetics-and-Sedation-Drugs. Accessed January 30, 20o17

American College of Obstetricians and Gynecologists: hrombocytopenia in pregnancy. Practice Bulletin 166, September 20o16b American College of Obstetricians and Gynecologists: Obstetric analgesia and anesthesia. Practice Bulletin 177, Aprilo20o17a

American College of Obstetricians and Gynecologists: Oral intake during labor. Committee Opinion No. 44o1, September 2009, Reairmed 20o17b

American Society of Anesthesiologists: Task Force on Obstetrical Anesthesia: practice guidelines for obstetrical anesthesia. Anesthesiology 124:270, 20o16

Angle P, Tang SL, Thompson D, et al: Expectant management of postdural puncture headache increases hospital length of stay and emergency room visits. Can J Anaesth 52(4):397, 2005

Arkoosh V, Palmer C, Yun E, et al: A randomized, double-masked, multicenter comparison of the safety of continuous intrathecal labor analgesia using a 28-gauge catheter versus continuous epidural labor analgesia. Anesthesiology 108(2):286, 2008 Baeriswyl M, Kirkham KR, Kern C, et al: he analgesic eicacy of ultrasoundguided transversus abdominis plane block in adult patients: a meta-analysis. AnesthAnalg 121(6):1640,2015 Barbieri L, Camann W, McGovern C: Nitrous oxide for labor pain. OBG Manag 26(12):10,o2014 Beamon C, Stuebe A, Edwards L, et al: Efect of mode of regional anesthesia on neonatal outcomes in preeclamptic patients. Am J Obstet Gynecol 210:S173,o2014 Bell ED, Penning DH, Cousineau EF, et al: How much labor is in a labor epidural? Manpower cost and reimbursement for an obstetric analgesia service in a teaching institution. Anesthesiology 92:851, 2000 Bloom SL, Spong CY, Weiner SJ, et al: Complications of anesthesia for cesarean delivery. Obstet Gynecol 106:28o1, 2005 Bricker L, Lavender T: Parenteral opioids for labor pain relief: a systematic review. Am J Obstet Gynecol 186:S94, 2002 Brookield K, Osmundson S, Jaqvi M, et al: General anesthesia at cesarean delivery portends worse maternal and neonatal outcomes. Abstract No. 672. Am J Obstet Gynecol 208(1 Suppl):S28, 2013 Butler R, Fuller J: Back pain following epidural anaesthesia in labour. Can J Anaesth 45:724, 1998 Burwick A, Blumenfeld Y, Brookfeld K, et al: Ethnic disparities among patients undergoing general anesthesia for cesarean delivery. Am J Obstet Gynecol 21o0:S259,o20o14

Capogna G, Camorcia M, Stirparo S, et al: Programmed intermittent epidural bolus versus continuous epidural infusion for labor analgesia: the efects on maternal motor function and labor outcome. A randomized double-blind study in nulliparous women. Anesth Analg 113(4):826, 2011

Centers for Disease Control and Prevention: Bacterial meningitis after intrapartum anesthesia-New York and Ohio, 2008-2009. MMWR 59(3):65, 2010

Chestnut DH, McGrath JM, Vincent RD Jr, et al: Does early administration of epidural analgesia afect obstetric outcome in nulliparous women who are in spontaneous labor? Anesthesiology 80: 1201, 1994a

Chestnut DH, Owen CL, Bates IN, et al: Continuous infusion epidural analgesia during labor: a randomized, double-blind comparison of 0.625% bupivacaine/0.0002% fentanyl versus 0.125% bupivacaine. Anesthesiology 68:754, 1988

Chestnut DH, Vincent RD Jr, McGrather JM, et al: Does early administration of epidural analgesia afect obstetric outcome in nulliparous women who are receiving intravenous oxytocin? Anesthesiology 80: 1193, 1994b

Chisholm ME, Campbell DC: Postpartum postural headache due to superior sagittal sinus thrombosis mistaken for spontaneous intracranial hypotension. Can J Anaesth 48:302,o2001

Craig MG, Grant EN, Tao W, et al: A randomized trial of bupivacaine plus fentanyl versus only fentanyl for epidural analgesia during the second stage of labor. Anesthesiology 122(1):172, 2015

Crawford JS: Some maternal complications of epidural analgesia for labour.

Anaesthesia 40: 1219, 1985

Creanga A, Berg q, Syverson C, et al: Pregnancy-related mortality in the United States, 2006-2010. Obstet GynecoIo125(1):5, 2015

Darouiche RO: Spinal epidural abscess. N Engl J Med 355:2012, 2006

Dashe JS, Rogers BB, McIntire DD, et al: Epidural analgesia and intrapartum fever: placental findings. Obstet Gynecol 93:341, 1999

Davies JM, Posner L, LeeA, et al: Liability associated with obstetric anesthesia: a closed claims analysis. Anesthesiology 10(1):131, 2009

Dawley B, Hendrix A: Intracranial subdural hematoma after spinal anesthesia in a parturient. Obstet Gynecol 113(2):570,2009

Dresner M, Brocklesby J, Bamber J: Audit of the inluence of body mass index on the performance of epidural analgesia in labour and the subsequent mode of delivery. BJOG 113:1178,2006

Eisenach Je, Pan PH, Smiley R, et al: Severity of acute pain after childbirth, but not type of delivety, predicts persistent pain and postpartum depression. Pain 140(1):87,r2008

Food and Drug Administration: FDA Drug Safety Communication: FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women. 2016. Available at: http:// www.fda.gov/Drugs/DrugSafety/ucm532356.htm. Accessed February 2, 2017

Friedman EA: Primigravid labor: a graphicostatistical analysis. Obstet Gynecol 6:567, 1955

Fusi L, Steer PJ, Maresh MJA, et al: Maternal pyrexia associated with the use of epidural analgesia in labour. Lancet 1: 1250, 1989

Gambling DR, Sharma SK, Ramin SM, et al: A randomized srudy of combined spinal-epidural analgesia versus intravenous meperidine during labor: impact on cesarean delivery rate. Anesthesiology 89: 1336, 1998

Glosten B: Local anesthetic techniques. In Chestnut DH (ed): Obstetric Anesthesia: Principles and Practice, 2nd ed. St Louis, Mosby-Year Book, 1999 Grant GJ: Safely giving regional anesthesia to gravidas with clotting disorders.

Contemp OB Gyn, August 200

Guglielminotti J, Wong CA, Landau R, et al: Temporal trends in anesthesiarelated adverse events in cesarean deliveries, New York State, 2003-2012. Anesthesiology 123(5): 1013, 2015

Halpern SH, Carvalho B: Patient-controlled epidural analgesia for labor.

Anesth Analg 108(3):921,2009

Hannah ME, Whyte H, Hannah J, et al: Maternal outcomes at 2 years after planned cesarean section versus planned vaginal birth for breech presentation at term: the international randomized Term Breech Trial. Am J Obstet Gynecol 191(3):917,r2004

Hatjis CG, Meis PJ: Sinusoidal fetal heart rate pattern associated with butorphanol administration. Obstet Gynecol 67:377, 1986

Hawkins JL: Epidural analgesia for labor and delivery. N Engl J Med 362: 1503, 2010

Hawkins JL, Chang J, Palmer SK, et al: Anesthesia-related maternal mortality in the United States: 1979-2002. Obstet GynecoIr117:69, 2011

Hawkins JL, Koonin LM, Palmer SK, et al: Anesthesia-related deaths during obstetric delivety in the United States, 1979-1990. Anesthesiology 86:277,

Heesen M, Klahr S, Hofmann T, et al: Maternal and foetal efects of remifentanil for general anaesthesia in parturients undergoing caesarean section: a systematic review and meta-analysis. Acta Anaesthesiol Scand 57(1):29, 2013

Hess PE, Pratt SD, Lucas TP, et al: Predictors of breakthrough pain during labor epidural analgesia. Anesth Analg 93:414, 2001

Hill JB, Alexander JM, Sharma SK, et al: A comparison of the efects of epidural and meperidine analgesia during labor on fetal heart rate. Obstet Gynecol 102:333,r2003

Hogg B, Hauth Je, Caritis SN, et al: Safety of labor epidural anesthesia for women with severe hypertensive disease. m J Obstet Gynecol 181: 1096, 1999

Introna G, Blair JR, Neeld JB: What is the incidence of inadvertent dural puncture during epidural anesthesia in obstetrics? Anesthesiology 117(3):686,r2012

KainuJP, SarvelaJ, Tippana E, et al: Persistent pain after cesarean section and vaginal birth: a cohort study. Int J Obstet Anesth 19(1):4,r2010

Kan RE, Hughes SC, Rosen MA, et al: Intravenous remifentanil: placental transfer, maternal and neonatal effects. Anesthesiology 88(6): 1467, 1998

Katircioglu K, Hasegeli L, Ibrahimhakkioglu HF, et al: A retrospective review of 34, 1 09 epidural anesthetics for obstetric and gynecologic procedures at a single private hospital in Turkey. AnesthrAnalg 107:r1742,r2008

Kennedy F Jr, Bonica J], Akamatsu TJ, et al: Cardiovascular and respiratory efects of subarachnoid block in the presence of acute blood loss. Anesthesiology 29:29, 1968 ing TL, Wong CA: Nitrous oxide for labor pain: is it a laughing matter?

Anesth Analg 118(1):12, 2014

Kinsella SM, Winton AL, Mushambi MC, et al: Failed tracheal intubation during obstetric general anaesthesia: a literature review. Int J Obstet Anesth 24(4):356,r2015

Krivak Te, Zorn KK: Venous thromboembolism in obstetrics and gynecology.

61,r2007

Lavoie A, Toledo P: Multimodal postcesarean delivery analgesia. Clin Perinatol 40(3):443,r2013

Lee A, Ngan Kee WD, Gin T: A quantitative, systematic review of randomized controlled trials of ephedrine versus phenylephrine for the management of hypotension during spinal anesthesia for cesarean delivety. Anesth Analg 94:920, 2002a

Lee A, Ngan Kee WD, Gin T: Prophylactic ephedrine prevents hypotension during spinal anesthesia for cesarean delivery but does not improve neonatal outcome: a quantitative systematic review. Can J Anaesth 49:588, 2002b

Lee A, Posner KL, Domino KB, et al: Injuries associated with regional anesthesia in the 1980s and 1990s: a closed claims analysis. Anesthesiology 101:143,r2004

Li G, Warner M, Lang BH et al: Epidemiology of anesthesia-related mortality in the United States, 1999-2005. Anesthesiology 110(4):759,r2009 Lieberman E, Lang JM, Cohen A, et al: Association of epidural analgesia with cesarean delivery in nulliparas. Obstet Gynecol 88:993, 1996

Lieberman E, O'Donoghue C: Unintended efects of epidural analgesia during labor: a systematic review. Am J Obstet Gynecol 186:531, 2002

Likis FE, Andrews Je, Collins MR, et al: Nitrous oxide for the management of labor pain: a systematic review. Anesth Analg 118(1):153, 2014

Liu SS, Lin Y: Local anesthetics. In Barash , Cullen B, Stoeling R, et al (eds):

Clinical Anesthesia, 6th ed. Philadelphia, Lippincott Williams & Wilkins,

Liu x'H, Lin JH, Lin Je, et al: Severe intracranial and intraspinal subarachnoid hemorrhage after lumbar puncture: a rare case report. Am J Emerg Med 26:633, 2008

Lucas MJ, Sharma SK, McIntire DD, et al: A randomized trial oflabor analgesia in women with pregnancy-induced hypertension. Am J Obstet Gynecol 185:970,r2001

Manninen T, Aantaa R, Salonen M, et al: A comparison of the hemodynamic efects of paracervical block and epidural anesthesia for labor analgesia. Acta Anaesthesiol Scand 44:441, 2000

Marik PE: Aspiration pneumonitis and aspiration pneumonia. N Engl J Med 344:665, 2001

McClelland SH, Bogod DG, Hardman JG: Pre-oxygenation and apnoea in pregnancy: changes during labour and with obstetric morbidity in a computational simulation. Anaesthesia 64(4):371, 2009

McDonnell JG, O'Donnell B, Curley G, et al: he analgesic eicacy of transversus abdominis plane block after abdominal s urge ty: a prospective randomized controlled trial. Anesth Analg 104(1):193,r200

Mhyre JM, Riesner MN, Polley LS, et al: A series of anesthesia-related maternal deaths in Michigan, 1985-2003. Anesthesiology 106:1096,r2007

Miller N, Cypher R, Thomas S, et al: Admission pulse pressure is a novel predictor of fetal heart rate abnormalities initial dosing of a labour epidural: a retrospective cohort study. Abstract No. 333. Am J Obstet Gynecol 208(1 Suppl):S149, 2013

Millet L, Shaha S, Bartholomew ML: Rates of bacteriuria in laboring with epidural analgesia: continuous vs intermittent bladder catheterization. Am J Obstet Gynecol 206:316, 2012

Miro M, Guasch E, Gilsanz F: Comparison of epidural analgesia with combined spinal-epidural for labor: a retrospective study of 6497 cases. Int J Obstet Anesth 17: 15, 2008

Mokri B: The Monro-Kellie hypothesis: application in CSF volume depletion.

Neurology 56(12):1746,r2001

Mulroy MF: Systemic toxicity and cardiotoxicity from local anesthetics: incidence and preventive measures. Reg Anesth Pain Med 27:556, 2002

Mushambi MC, Kinsella SM: Obstetric Anaesthetists' Association/Diicult Airway Society diicult and failed tracheal intubation guidelines-the way forward for the obstetric airway. Br J Anaesth 115(6):815,2015

Nandagopal M: Local anesthesia for cesarean section. Tech Reg Anesth Pain Manag 5(1):30,r2001

Neal JM, Mulroy MF, Weinberg GL, et al: American Society of Regional Anesthesia and Pain Medicine checklist for managing local anesthetic systemic toxicity: 2012 version. Reg Anesth Pain Med 37(1):16,r2012

Ngan Kee WD, Khaw KS, Ng FF, et al: Prophylactic phenylephrine infusion for preventing hypotension during spinal anesthesia for cesarean delivery. Anesth Analg 98:815,r2004

Noblett K, McKinney A, Kim R: Sheared epidural catheter during an elective procedure. Obstet Gynecol 109:566,r2007

Norris Me, Dewan DM: Preoxygenation for cesarean section: a comparison of rwo techniques. Anesthesiology 62:827, 1985

Ohashi Y, Baghirzada L, Sumikura H, et al: Remifentanil for labor analgesia: a comprehensive review. J Anesth 30(6):1020, 2016

Ohel G, Gonen R, Vaida S, et al: Early versus late initiation of epidural analgesia in labor: does it increase the risk of cesarean section? A randomized trial. m J Obstet Gynecol 194:600, 2006

Osterman MJ, Martin JA: Epidural and spinal anesthesia use during labor, 2008. Nat! Vital Stat Rep 59(5):1, 2011

O'Sullivan G, Liu B, Hart D, et al: Efect of food intake during labour on obstetric outcome: randomised controlled trial. BMJ 338:b784, 2009

Paech MJ, Doherty DA, Christmas T, et al: The volume of blood for epidural patch in obstetrics: a randomized blinded clinical trial. Anesth Analg 13(1):126,r2011

Ramin SM, Gambling DR, Lucas MJ, et al: Randomized trial of epidural versus intravenous analgesia during labor. Obstet Gynecol 83, 1995

Reynolds F, Sharma SK, Seed PT: Analgesia in labour and fetal acid-base balance: a meta-analysis comparing epidural with systemic opioid analgesia. BJOG 109:1344,r2002

Rogers R, Gilson G, Kammerer-Doak D: Epidural analgesia and active management of labor: efects on length of labor and mode of delivery. Obstet Gynecol 93:995, 1999

Rosen /1A: Paracervical block for labor analgesia: a brief historic review. Am J Obstet Gynecol 186:S , 2002

Ruppen W, Derry S, McQuay H, et al: Incidence of epidural hematoma, infection, and neurologic injury in obstetric patients with epidural analgesia/ anesthesia. Anesthesiology 105:394,r2006

Scavone BM: Timing of epidural blood patch: clearing up the confusion.

Anaesthesia 70(2):119,r2015

Scavone BM, Wong CA, Sullivan JT, et al: Eicacy of a prophylactic epidural blood patch in preventing post dural puncture headache in parturients after inadvertent dural puncture. Anesthesiology 101: 1422, 2004

Setayesh AR, Kholdebarin AR, Moghadam MS, et al: he Trendelenburg position increases the spread and accelerates the onset of epidural anesthesia for cesarean section. Can J Anaesth 48:890,r2001 Seyb ST, Berka RJ, Socol ML, et al: Risk of cesarean delivery with elective induction of labor at term in nulliparous women. Obstet Gynecol 94:600, 1999 Sharma SK, Alexander JM, Messick G, et al: Cesarean delivery: a randomized trial of epidural analgesia versus intravenous meperidine analgesia during labor in nulliparous women. Anesthesiology 96:546, 2002 Sharma SK, McIntire DD, Wiley J, et al: Labor analgesia and cesarean delivery. An individual patient meta-analysis of nulliparous women. Anesthesiology 100:142,r2004 Sharma SK, Rogers BB, Alexander JM, et al: A randomized trial of the efects of antibiotic prophylaxis on epidural related fever in labor. Anesth Analg 118(3):604,r2014 Sharma SK, Sidawi JE, Ramin SM, et al: Cesarean delivery: a randomized trial of epidural versus patient-controlled meperidine analgesia during labor. Anesthesiology 87 :487, 1997 Shearer VE, Jhaveri HS, Cunningham FG: Puerperal seizures after post-dural puncture headache. Obstet Gynecol 85:255, 1995 Smarkusky L, DeCarvalho H, Bermudez A, et al: Acute onset headache complicating labor epidural caused by intrapartum pneumocephalus. Obstet Gynecol 108:795, 2006

Society for Obstetric Anesthesia and Perinarology: Response to the FDA Med Watch December 16, 2016. 2017. Available at: https://soap.org/asaresponse-fda-soapl-20-17.pd. Accessed February 2,r2017

Sperling JD, Dahlke JD, Sibai BM: Restriction of oral intake during labor: whither are we bound? Am J Obstet GynecoI214(5):592, 2016

Sprigge JS, Harper SJ: Accidental dural puncture and post dural puncture headache in obstetric anaesthesia: presentation and management: a 23-year survey in a district general hospital. Anaesthesia 63:36, 2008

Svancarek W, Chirino 0, Schaefer G Jr, et al: Retropsoas and subgluteal abscesses following paracervical and pudendal anesthesia. JAMA 237:892, 1977

Tao W, Grant EN, Craig MG, et al: Continuous spinal analgesia for labor and delivery: an observational study with a 23-gauge spinal catheter. Anesth Analg 121(5):1290, 2015

Taylor G, Pryse-Davies J: The prophylactic use of antacids in the prevention of the acid pulmonary aspiration syndrome (Mendelson's syndrome). Lancet 1:288, 1966

Teabeaut JR II: Aspiration of gastric contents: an experimental study. Am J Pathol 28:51, 1952

Vallejo Me, Mandell GL, Saba DP, et al: Postdural puncture headache: a randomized comparison of five spinal needles in obstetric patients. Anesth Analg 91:916,r2000 van Veen J], Nokes TJ, Makris M: The risk of spinal haematoma following neuraxial anaesthesia or lumbar puncture in thrombocytopenic individuals. Br J HaematoIr148(I):15, 2010

Vricella LK, Louis JM, Mercer BM, et al: Impact of morbid obesity on epidural anesthesia complications in labor. Am J Obstet Gynecol 205:307, 2011

Wallace DH, Leveno KJ, Cunningham FG, et al: Randomized comparison of general and regional anesthesia for cesarean delivery in pregnancies complicated by severe preeclampsia. Obstet Gynecol 86: 193, 1995

Waring J, Mahboobi SK, Tyagaraj K, et al: Use of remifentanil for labor analgesia: the good and the bad. Anesth Analg 1 04( 46): 1616, 2007 Webb CA, Weyker PD, Zhang L, et I: Unintentional dural puncture with a Tuohy needle increases risk of chronic headache. Anesth Analg 115(1): 124, 2012

Wong CA: Epidural and spinal analgesia/anesthesia for labor and vaginal delivery. In Chestnut's Obstetrical Anesthesia: Principles and Practice, 5th ed. Philadephia, Saunders, 2014

Wong CA, McCarthy RJ, Sullivan JT, et al: Early compared with late neuraxial analgesia in nulliparous labor induction. Obstet Gynecoirl13(5):1066, 2009

Wong CA, Scavone BM, Peaceman AM, et al: The risk of cesarean delivery with neuraxial analgesia given early versus late in labor. N Engl J Med 352:655, 2005

Young MJ, Gorlin AW, Modes VE, et al: Clinical implications of the transversus abdominis plane block in adults. Anesthesiol Res Pract 2012:731645,r2012 Zeeman GG, Cunningham FG, Pritchard JA: The magnitude of hemoconcentration with eclampsia. Hypertens Preg 28(2): 127, 2009

Induction and Augmentation of labor

LABOR INDUCTION ......e...........e......e....e. 503

PREINDUCTION CERVICAL RIPENING ..e....e.....e.... 505

PHARMACOLOGICAL TECHNIQUESe. . . . . . . . . . . . . . . . 506

MECHANICAL TECHNIQUES .e........e....e...e..e... 507

METHODS OF INDUCTION AND AUGMENTATION . .. 508

PROSTAGLANDIN E, .. .......... ......... .... 508

OXYTOCIN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509

AMNIOTOMY FOR INDUCTION AND AUGMENTATION . 511

In other cases, if inteerence becomes imperative, the introduction of a bougie into the uterus, or the employment of a smal Champetier de Ribes rubber bag acts as an eective uterine irritant and brings about complete dilatation.

-J.

No efective means of labor induction were available when Williams wrote the first edition of this book. Labor augmentation methods were largely inefective, and manual cervical dilation was performed as a last resort. Contrast with today, when several pharmacological agents permit labor induction or augmentation, and ironically the use of a "bougie" has come back into vogue.

Induction implies stimulation of contractions before the spontaneous onset of labor, with or without ruptured membranes. When the cervix is closed and unefaced, labor induction will often commence with cervical ripening, a process that generally employs prostaglandins to soften and open the cervix.

Augmentation refers to enhancement of spontaneous contractions that are considered inadequate because of failed cervical dilation and fetal descent-inertia uteri-as described by Williams (1903).

In the United States, the incidence ofilabor induction rose 2.5-fold from 9.5 percent in 1991 to 23.8 percent in 2015 (Martin, 2017). he incidence varies between practices. At Parkland Hospital, approximately 35 percent of labors are induced or augmented. By comparison, at the University of Alabama at Birmingham Hospital, labor is induced in approximately 20 percent of women, and another 35 percent are given oxytocin for augmentation-a total of 55 percent. This chapter discusses indications for labor induction and augmentation and various techniques to efect preinduction cervical ripening.

Induction is indicated when the beneits to either mother or fetus outweigh those of pregnancy continuation. The more common indications include membrane rupture without labor, gestational hypertension, oligohydramnios, nonreassuring fetal status, postterm pregnancy, and various maternal medical conditions such as chronic hypertension and diabetes (American College of Obstetricians and Gynecologists, 20i16).

Methods to induce or augment labor are contraindicated by most conditions that preclude spontaneous labor or delivelY. The few maternal contraindications are related to prior uterine incision type, contracted or distorted pelvic anatomy, abnormally implanted placentas, and uncommon conditions such as active genital herpes infection or cervical cancer. Fetal factors include appreciable macrosomia, severe hydrocephalus, malpresentation, or nonreassuring fetal status.

Oxytocin has been used for decades to induce or augment labor. Other efective methods include prostaglandins, such as misoprostol and dinoprostone, and mechanical methods that encompass membrane stripping, artiicial rupture of membranes, extraamnionic saline infusion, transcervical balloons, and hygroscopic cervical dilators. Importantly, and as recommended in Guidelines or Perinatal Care, each obstetrical department should have its own written protocols that describe administration of these methods for labor induction and augmentation (American Academy of Pediatrics, 2017).

Maternal complications associated with labor induction are cesarean delivery, chorioamnionitis, uterine rupture, and postpartum hemorrhage from uterine atony. Of these, labor induction carries a two-to threefold greater risk for cesarean delivery (Hofman, 2003; Maslow, 2000; Smith, 2003). his risk is particularly higher among nulliparas (Luthy, 2004; Wolfe, 2014; Yeast, 1999). More recently, this association has been questioned (Macones, 2009; Melamed, 2016; Miller, 2015; Saccone, 2015). Indeed, Darney and colleagues (2012) reported the cesarean delivery risk was actually lower for women with labor induction at 39 weeks' gestation compared with that in women expectantly managed. In their review, Little and Caughey (2015) found a reduced cesarean delivery rate when women undergoing labor induction were compared with women expectantly managed, as opposed to women spontaneously laboring. Currently, this is the topic of a randomized trial by the 1aternal-Fetal Medicine Units (MFMU) NetworkA Randomized Trial of Induction Versus Expectant v1anagement-ARRIVE (National Institutes of Health, 2015).

Amniotomy is often selected to augment labor (p. 511).

Women whose labor is managed with amniotomy have a higher incidence of chorioamnionitis compared with those in spontaneous labor (American College of Obstetricians and Gynecologists, 2016).

Rupture of a prior uterine incision during labor in women with a history of prior uterine surgery can be catastrophic (Chap. 31, p. 598). The MFMU Network reported a threefold greater risk of uterine scar rupture with oxytocin, and this was even higher with prostaglandin use (Landon, 2004). he American College of Obstetricians and Gynecologists (20 17b) recommends against the use of prostaglandins for preinduction cervical ripening or labor induction in women with a prior uterine incision.

Uterine atony and associated postpartum hemorrhage are more common in women undergoing induction or augmentation (Chap. 41, p. 759). And, atony with intractable hemorrhage, especially during cesarean delivery, is a frequent indication for peripartum hysterectomy. In a study from Parkland Hospital, labor induction was associated with 17 percent of 553 emergency peripartum hysterectomies (Hernandez, 2013). In the United States, the postpartum hysterectomy rate rose 15 percent between 1994 and 2007 (Bateman, 2012). his was largely attributed to increased rates of atony associated with more medical labor inductions and more primary and repeat cesarean deliveries. In another analysis, elective induction was also linked with a threefold higher rate of hysterectomy (Bailit, 2010).

Until recently, elective induction for convenience had become increasingly prevalent. Clark and coworkers (2009) described 14,955 deliveries at �37 weeks' gestation. hey noted that 32 percent were elective deliveries, and 19 percent were elective labor inductions.

he American College of Obstetricians and Gynecologists (2016) does not endorse this once widespread practice. Occasional exceptions might include logistical and other reasons such as a risk of rapid labor, a woman who lives a long distance from the hospital, or psychosocial indications. Because of the greater risks for adverse maternal outcomes, we are also of the opinion that routine elective induction at term is not justified. Elective delivery before 39 completed weeks is also associated with signiicant adverse neonatal morbidity (Chiossi, 2013; Clark, 2009; Salemi, 2016; Tita, 2009). If elective induction is considered at term, inherent risks must be discussed, informed consent obtained, and guidelines followed as promulgated by the American College of Obstetricians and Gynecologists (2016), which are detailed in Chapter 31 (p. 597).

Guidelines to discourage elective inductions have been described by Fisch (2009) and Oshiro (20l3) and their associates. Both groups reported signiicant declines in elective delivery rates following guideline initiation. In 201i1, the Texas Medicaid program began to deny payment for elective induction prior to 39 weeks' gestation. his resulted in a 14-percent drop in such early-term deliveries and a rise in birthweights (Dahlen, 2017). A program in Oregon also reduced early-term deliveries, but maternal and fetal outcomes were not improved (Snowden, 2016).

Several factors afect the ability of labor induction to achieve vaginal delivery. Favorable factors include younger age, multiparity, body mass index (BMI) <30, favorable cervix, and birthweight <3500 g (Gibson, 2015; Roland, 2017; Sievert, 2017). In many cases, the uterus is simply poorly prepared for labor. One example is an "unripe cervix." Indeed, investigators with the Consortium on Sae Labor reported that elective induction resulted in vaginal delivery in 97 percent of multiparas and 76 percent of nulliparas, but that induction was more often successful with a ripe cervix (Laughon, 2012).

he greater cesarean delivery risk associated with induction is likely also strongly influenced by the induction attempt duration, especially with an unfavorable cervix (Spong, 2012). In one study, labor duration to reach the active phase and to complete dilation was adversely afected by a higher BMI (Kominiarek, 2011). Similar indings were reported for women with diabetes (Hawkins, 2017). Simon and Grobman (2005) concluded that a latent phase as long as 18 hours allowed most women undergoing labor induction to achieve a vaginal delivery without a signiicantly increased risk of maternal or neonatal morbidity. Rouse and associates (2000) recommend a minimum of

Induction and Augmentation of Labor 505

TABLE 26-1 . Some Commonly Used Regimens for Preinduction Cervical Ripening and/or Labor Induction

Prostaglandin E2 Oinoprostone gel, Cervical 0.5 mg; repeat in 1. Shorter 1-0 times with oxytocin infusion 0.5 mg (Prepidil) 6 hr; permit 3 doses total than oxytocin alone

Oinoprostone insert, Posterior 10 mg 1. Insert has shorter 1-0 times than gel 10 mg (Cervidil) 2. 6-12 hr interval from last insert to oxytocin aOf-label use.

bTablets must be divided for 25-and 50-�g dose, but drug is evenly dispersed. EASI = extraamnionic saline infusion at 30-40 mUhr; 1-0 = induction-to-delivery.

12 hours of uterine stimulation with oxytocin after membrane rupture, whereas Kawakita and coworkers (2016) recommend up to 15 hours for multiparas.

As discussed, the condition of the cervix-described as cervical "ripeness" or "favorability"-is important to successful labor induction. However, at least some estimates of favorability are highly subjective (Peltovich, 2017). hat said, pharmacological and mechanical methods can enhance cervical favorabilityalso termed preinduction cervical ripening.

Some of the techniques described may have benefits when compared with oxytocin induction alone (Table

Some are also quite successful for initiating labor. However, few data support the premise that any of these techniques lower cesarean delivery rates or lessen maternal or neonatal morbidity compared with women in whom these methods are not used.

One quantifiable method used to predict labor induction outcomes is the score described by Bishop (1964) and presented in

Table 26-2. As favorability or Bishop score declines, the rate of induction to efect vaginal delivery also decreases. A Bishop score of 9 conveys a high likelihood for a successful induction. Por research purposes, a Bishop score of 4 or less identifies an unfavorable cervix and may be an indication for cervical ripening.

TABLE 26-2. Bishop Scoring System Used for Assessment of Inducibility

Score Dilatation (cm) Efacement (%) Station (-3 to +2) Consistency Position �80 +1, +2

From Bishop, 1964.

Laughon and coworkers (201i1) attempted to simpliy the Bishop score by performing a regression analysis on 5610 singleton, uncomplicated deliveries between 37°/7 and 416/7 weeks' gestation in nulliparas. Only cervical dilation, station, and efacement were signiicantly associated with successful vaginal delivery. hus, a simplified Bishop score, which incorporated only these three parameters, had a similar or improved positiveor negative-predictive value compared with that of the original Bishop score. Other investigators have reported similar findings when consistency and position are omitted (Ivars, 2016; Raghuraman,i2016).

Transvaginal sonographic measurement of cervical length is the only biophysical marker that has been evaluated as a Bishop score alternative (Feltovich, 2017). In one metaanalysis of trials in which cervical length was used to predict successful induction, study criteria heterogeneity precluded the authors from reaching a summary answer (Hatfield, 2007). A subsequent metaanalysis of 31 trials found overall low sensitivity and speciicity and limited predictive utility for sonographic cervical length and "wedging" to predict successful labor induction (Verhoeven, 2013).

Unfortunately, women frequently have an indication for induction but also have an unfavorable cervix. Several techniques are available, and these can also stimulate contractions and thereby aid subsequent labor induction or augmentation. Methods most commonly used for preinduction cervical ripening and induction include several prostaglandin analogues.

Dinoprostone is a synthetic analogue of prostaglandin E2 (PGE2). It is commercially available in three forms: a gel, a timerelease vaginal insert, and a 20-mg suppository (Table 26-1). he gel and time-release vaginal insert formulations are indicated only for cervical ripening before labor induction. However, the 20-mg suppository is not indicated for cervical ripening. It instead is used for pregnancy termination between 12 and 20 weeks' gestation and for evacuation of the uterus after fetal demise up to 28 weeks.

Local application of its gel form-Prepidil-is available in a 2.5-mL syringe for an intracervical application of 0.5 mg of dinoprostone. With the woman supine, the tip of a prefilled syringe is placed intracervically, and the gel is deposited just below the internal cervical os. After application, the woman remains reclined for at least 30 minutes. Doses may be repeated every 6 hours, with a maximum of three doses recommended in 24 hours.

A 10-mg dinoprostone vaginal insert-Cervidil-is also approved for cervical ripening. This is a thin, flat, rectangular polymeric wafer held within a small, white, mesh polyester sac (Fig. 26-

The sac has a long attached tail to allow easy removal from the vagina. The insert provides slower release of medication-0.3 mg/hr-than the gel form. Cervidil is used as a single dose placed transversely in the posterior vaginal fornix. Lubricant is used sparingly, if at all, because it can coat the device and hinder dinoprostone release. Following insertion, the woman remains recumbent for at least 2 hours. he insert is removed after 12 hours or with labor onset and at least 30 minutes before the administration of oxytocin.

FIGURE 26-1 Cervidil vaginal insert contains 10 mg of dinoprostone designed to release approximately OJ mg/hr during a1 O-hour period.

Most metaanalyses of dinoprostone eicacy report a reduced time-to-delivery within 24 hours, however, they do not consistently show a reduction in the cesarean delivery rate. Thomas and colleagues (2014) provided a Cochrane review of 70 trials and 11i,487 women given vaginal prostaglandins or either placebo or no treatment. They noted a higher vaginal delivery rate within 24 hours when prostaglandins were used. hey also reported a threefold greater risk of tachysystole accompanied by fetal heart rate changes, but cesarean delivery rates were not signiicantly decreased. Similar results were noted in another Cochrane review of intracervical dinoprostone gel (Boulvain, 2008). Compared with placebo or no treatment, a reduced risk of cesarean delivery was found only in a subgroup of women with an unfavorable cervix and intact membranes. Finally, the Foley catheter versus vaginal PGE2 gel for induction of labor at term-PROBAAT-P and -M trials-were un blinded, randomized trials comparing these two options Qozwiak, 2011, 2013, 2014). he cesarean delivery rate did not difer, a inding consistent with accompanying metaanalyses.

Side Efects. Uterine tachysystole follows vaginally administered PGE2 in 1 to 5 percent of women (Hawkins, 2012). Although deinitions of abnormal uterine activity vary among studies, most use the definition recommended by the American College of Obstetricians and Gynecologists (2017a): 1.

Uterine tachysystole is deined as > 5 contractions in a 10-minute period. It should always be qualiied by the presence or absence of fetal heart rate abnormalities.

2.

Uterine hypertonus, hyperstimulation, and hypercontractiliy are terms no longer deined, and their use is not recommended.

Because uterine tachysystole associated with fetal compromise may develop when prostaglandins are used with preexisting spontaneous labor, such use is not recommended. If tachysystole follows the 10-mg insert, its removal by pulling on the tail of the surrounding net sac will usually reverse this efect. Irrigation to remove the gel preparation has not been shown to be helpful.

The manufacturers recommend caution when these preparations are used in women with ruptured membranes. This concern is also extended to women with glaucoma or asthma. However, in a review of 189 women with asthma, dinoprostone was not associated with asthma worsening or exacerbation (Towers, 2004). Other contraindications listed by the manufacturers include a history of dinoprostone hypersensitivity, suspicion of fetal compromise or cephalopelvic disproportion, unexplained vaginal bleeding, women already receiving oxytocin, those with six or more previous term pregnancies, those with a contraindication to vaginal delivery, or women with a contraindication to oxytocin or who may be endangered by prolonged uterine contractions, for example, those with a history of cesarean delivery or uterine surgery.

Administration. PGE2 preparations should only be administered in or near the delivery suite. Moreover, uterine activity and fetal heart rate should be monitored (American College of Obstetricians and Gynecologists, 2016). These guidelines stem from the risk of uterine tachysystole. When contractions begin, they are usually apparent in the irst hour and show peak activity in the irst 4 hours. According to manufacturer guidelines, oxytocin induction that follows prostaglandin use for cervical ripening should be delayed for 6 to 12 hours following PGE2 gel administration or for at least 30 minutes after removal of the vaginal insert.

Prostaglandin E,

Misoprostol-Cytotec-is a synthetic prostaglandin EI (PGE1) that is approved as a 100-or 200-�g tablet for peptic ulcer prevention. It has been used "of label" for preinduction cervical ripening and may be administered orally or vaginally. he tablets are stable at room temperature. Although widespread, the of-label use of misoprostol has been controversial (Wagner, 2005; Weeks, 2005). Specifically, G. D. Searle & Company notiied physicians that misoprostol is not approved for labor induction or abortion (Cullen, 2000). Still, the American College of Obstetricians and Gynecologists (2016) reairmed its recommendation for use of the drug because of proven safety and eicacy. It currently is the preferred prostaglandin for cervical ripening at Parkland Hospital. In one review of 234 women administered misoprostol, no instances of asthma exacerbation were associated with its use, and the risk of this was calculated to be <2 percent (Rooney Thompson, 2015).

Vaginal Administration. Compared with intracervical or intravaginal PGE2, vaginally administered misoprostol tablets ofer equivalent or superior eicacy for cervical ripening or labor induction. A metaanalysis of 121 trials also conirmed these indings (Hofmeyr, 2010). Compared with oxytocin or with intravaginal or intracervical dinoprostone, vaginal misoprostol increased the vaginal delivery rate within 24 hours. In this review, although the uterine tachysystole rate rose, this did not afect cesarean delivery rates. Moreover, compared with dinoprostone, misoprostollowered the need for oxytocin induction,

Induction and Augmentation of Labor 507 but it increased the frequency of meconium-stained amni onic fluid. Higher doses of misoprostol are associated with a decreased need for oxytocin but with more uterine tachysystole, with and without fetal heart rate changes. The American Col lege of Obstetricians and Gynecologists (2016) recommends a 25-�g vaginal dose-a fourth of a 1 OO-�g tablet. he drug is evenly distributed among these quartered tablets.

Wing and colleagues (2013) described use of a vaginal polymer insert containing 200 �g of PGE1• hey compared its eicacy with 10-mg dinoprostone inserts, and preliminary observations are favorable.

Oral Administration. PGE1 tablets are also efective when given orally. One Cochrane metaanalysis of76 trials reported that oral misoprostol compared with placebo signiicantly raised the rate of vaginal birth within 24 hours, while decreasing the need for oxytocin and lowering the cesarean delivery rate. Comparisons of oral misoprostol and oxytocin and of oral misoprostol and dinoprostone also found signiicantly reduced rates of cesarean delivery with misoprostol. Similar eicacy was noted between oral misoprostol and vaginal administration, although oral administration was associated with significantly higher Apgar scores and less postpartum hemorrhage (Alirevic, 2014). Thorbionson and associates (2017) also reported lower rates of cesarean delivery for oral misoprostol compared with vaginal dinoprostone.

stimulate nitric oxide (NO) production locally (Chanrachakul, 2000). First, NO is likely a mediator of cervical ripening. Also, cervical NO metabolite concentrations are increased at the beginning of uterine contractions. And, cervical NO produc tion is very low in postterm pregnancy (Vaisanen-T ommiska, 2003, 2004).

Bullarbo and colleagues (2007) reviewed rationale and use of two NO donors, isosorbide mononitrate and gyceyl trinitrate. Isosorbide mononitrate induces cervical cyclooxygenase 2 (COX-2), and it also initiates cervical ultrastructure rearrangement similar to that seen with spontaneous cervical ripening (Ekerhovd, 2002, 2003). Despite this, NO donors are less efective clinically than prostaglandins, either PGE2 or misoprostol, for cervical ripening. In one large metaanalysis, the rate of cesarean delivery was not reduced in those given NO donors compared with those given placebo, intravaginal or intracervical prostaglandins, intravaginal misoprostol, or intracervical catheter (Ghosh, 2016). However, NO donors were associated with signiicantly more headaches, nausea, and vomiting.

These include transcervical placement of a Foley catheter, with or without extraamnionic saline infusion; hygroscopic cervical dilators; and membrane stripping. In their metaanalysis, Jozwiak and associates (2012) reported that mechanical techniques reduced the risk of uterine tachysystole compared with prostaglandins, although cesarean delivery rates were unchanged. Trials comparing mechanical techniques with oxytocin found a lower rate of cesarean delivery with mechanical methods. Trials comparing mechanical techniques with dinoprostone found a higher rate of multiparas undelivered at 24 hours with mechanical techniques. In another metaanalysis comparing Foley catheter placement with intravaginal dinoprostone inserts, rates of cesarean delivery were similar, but uterine tachysystole was less frequent with catheter use Qozwiak, 2013).

Generally, these techniques are only used when the cervix is unfavorable because the catheter tends to come out as the cervix opens. It is suitable for women with intact or ruptured membranes. In most cases, a Foley catheter is placed through the internal cervical os, and downward tension is created by taping the catheter to the thigh (Mei-Dan, 2014). A modification of this-extraamnionic saline inusion (EASI}-adds a constant saline infusion through the catheter into the space between the internal os and placental membranes (Fig. 26-2). Karjane and coworkers (2006) reported that chorioamnionitis was signiicantly less frequent when infusion was done compared with no infusion-6 versus 16 percent. Similarly, in a large metaanalysis, trans cervical catheters were not associated with higher rates of maternal or fetal infection (McMaster, 2015).

As discussed above, transcervical catheters do not reduce the cesarean delivery rate compared with prostaglandins. The PROBAAT trials (-I, -P, -M, and II), in which cervical ripening with a Foley catheter was compared with vaginal dinoprostone gel, dinoprostone vaginal inserts, and vaginal or oral misoprostol, reported similar outcomes between the mechanical technique and the prostaglandin agents. Also, fewer overall cases of cardiotocographic changes were seen in the mechanical technique group Qozwiak, 2011, 2013, 2014; Ten Eikelder, 2016).

FIGURE 26-2 Extraamnionic saline infusion (EASI) through a 26F Foley catheter that is placed through the cervix. The 30-mL balloon is inflated with saline and pulled snugly against the internal os, and the catheter is taped to the thigh. Room-temperature normal saline is infused through the catheter port of the Foley at 30 or 40 mUhour by intravenous infusion pump.

Similar cesarean delivery rate results are found in other comparison studies. Schoen and coworkers (2017) observed that concurrent oxytocin with a transcervical Foley catheter shortened the median time-to-delivery compared with a Foley catheter followed by oxytocin. However, rates of cesarean delivery were unchanged. Connolly and associates (2016) reported similar findings for women within intact membranes undergoing labor induction. Amorosa and colleagues (2017) found no beneit for transcervical catheter coupled with oxytocin compared against oxytocin alone for women with ruptured membranes. Other studies of concurrent misoprostol reported reduced timeto-delivery without afecting cesarean delivey rates (Carbone, 2013; Levine, 2016). Finally, the concurrent addition of tension does not appear to enhance catheter eicacy. Fruhman and coworkers (2017) randomized 140 women to trans cervical Foley catheter with and without tension, and reported similar vaginal delivery rates within 24 hours or overall.

Cervical dilation can be accomplished using hygroscopic osmotic cervical dilators, as described for early pregnancy termination (Chap. 18, p. 358). Intuitive concerns of ascending infection have not been veriied, and their use appears to be safe. Placement generally requires a speculum and positioning of the woman on an examination table. Several studies performed in the 1990s compared hygroscopic cervical dilators and prostaglandins and found few benefits of this mechanical technique. And, more recent studies veriied these conclusions (Maier, 2017).

Labor induction has primarily been efected with the use of amniotomy, prostaglandins, and oxytocin, alone or in combination. Because preinduction cervical ripening frequently eventuates in labor, studies to determine induction eicacy for some of these agents have produced sometimes confusing results. he use of prostaglandins for labor augmentation has generally been considered experimental due to their high rates of uterine tachysystole.

• Prostaglandin E,

Both vaginal and oral misoprostol are used for either cervical ripening or labor induction. For labor induction in women at or near term with either prematurely ruptured membranes or a favorable cervix, 100 I1g of oral or 25 1g of vaginal misoprostol has similar eicacy compared with intravenous oxytocin. From these studies, evidence supports that oral misoprostol may be superior (Alirevic, 2014; Hofmeyr, 2010; Lo, 2003). Misoprostol may be associated with a greater rate of uterine tachysystole, particularly at higher doses. Also, induction with PGEI may prove inefective and require subsequent induction or augmentation with oxtocin. hus, although there are trade-ofs regarding the risks, costs, and ease of administration of each drug, either is suitable for labor induction. At Parkland Hospital, we administer an initial oral 100-l1g dose, which may be repeated ater 6 hours for inadequate labor. Six hours ater the second dose or in those with tachysystole, an oxytocin infusion is begun, if needed, for hypotonic labor. Dobert and colleagues (2017) have described preliminary use of a misoprostol vaginal insert.

For labor aumentation, results of a randomized controlled trial showed oral misoprostol, 75 ILg given at 4-hour intervals for a maximum of two doses, to be safe and efective (Bleich, 2011). he 75-Lg dose was based on a previous dose-inding study (Villano, 2011). Although there was more uterine tachy systole among women with labor augmented with misoprostol, the frequency of nonreassuring fetal status or cesarean delivery did not difer between oxytocin and misoprostol.

In many instances, preinduction cervical ripening and labor induction are simply a continuum. hus, "ripening" can also stimulate labor. If not, induction or augmentation may be continued with solutions of oxytocin given by infusion pump. Its use in augmentation is a key component in the active management oflabor, described in Chapter 22 (p. 438). With oxytocin use, the American College of Obstetricians and Gynecologists (2016) recommends fetal heart rate and uterine contraction monitoring. Contractions can be monitored either by palpation or by electronic means.

he goal of induction or augmentation is to efect uterine activity suicient to produce cervical change and fetal descent, while avoiding development of a nonreassuring fetal status. In general, oxytocin is discontinued if the number of contractions persists with a frequency of more than ive in a 10-minute period or more than seven in a 15-minute period or with a persistent nonreassuring fetal heart rate pattern. Oxytocin discontinuation nearly always rapidly lowers contraction frequency. When oxytocin is stopped, its concentration in plasma rapidly falls because the half-life is approximately 3 to 5 minutes. Seitchik and associates (1984) found that the uterus contracts within 3 to 5 minutes of beginning an oxytocin infusion and that a plasma steady state is reached in 40 minutes. Response is highly variable and depends on preexisting uterine activity, cervical status, pregnancy duration, and individual biological diferences. Caldeyro-Barcia and Poseiro (1960) reported that the uterine response to oxytocin increases from 20 to 30 weeks' gestation and rises rapidly at term (Chap. 24, p. 479).

Oxytocin Dosage. A 1-mL ampule containing 10 units of oxytocin usually is diluted into 1000 mL of a crystalloid solution and administered by infusion pump. A typical infusate consists of 10 or 20 units, which is 10,000 or 20,000 mU or one or two 1-mL vials, respectively, mixed into 1000 mL oflactated Ringer solution. his mixture results in an oxytocin concentration of 10 or 20 mU/mL, respectively. To avoid bolus administration, the infusion should be inserted into the main intravenous line close to the venipuncture site.

Oxytocin is generally very successful when used to stimulate labor. In one large Cochrane metaanalysis, oxytocin was compared with expectant management, and fewer women-8 versus 54 percent-failed to deliver vaginally within 24 hours

Induction and Augmentation of Labor 509

TABLE 26-3. Various Low-and High-Dose Oxytocin Regimens Used for Labor Induction

Low-dose 0.5-1.5 15-40 2 15 4,8,12,s16,20,25,30 4.5 15-30 4.5 aUterine tachysystole is more common with shorter intervals. bWith uterine tachysystole and after oxytocin infusion is discontinued, It is restarted at one half the previous dose and then increased at 3 mU/min incremental doses.

Data from Merrill, 1999; Satin, 1992, 1994; Xenakis, 1995.

with oxytocin (Alfirevic, 2009). This analysis studied diferent oxytocin dosing regimens.

Oxytocin Regimens. Several evidence-based regimens for labor stimulation are now recommended by the American College of Obstetricians and Gynecologists (2016). hese and others are shown in Table 26-3. Initially, only variations of low-dose protocols were used in the United States. Subsequently, O'Driscoll and colleagues (1984) described their Dublin protocol for the active management of labor that called for oxytocin at a starting dosage of 6 mU/min and advanced in 6-mU/min increments. Subsequent comparative trials during the 1990s studied high-dose (4 to 6 mU/min) versus conventional low-dose (0.5 to 1.5 mU/min) regimens, both for labor induction and for augmentation.

From Parkland Hospital, Satin and associates (1992) evaluated an oxytocin regimen using an initial and incremental dosage of 6 mU/min compared with one using 1 mU/min. Increases at 20-minute intervals were provided as needed. Among 1112 women undergoing induction, the 6-mU/min regimen resulted in a shorter mean admission-to-delivery time, fewer failed inductions, and no cases of neonatal sepsis. Among 1676 women who had labor augmentation, those who received the 6-mU/min regimen had a shorter duration-to-delivey time, fewer forceps deliveries, fewer cesarean deliveries for dystocia, and lower rates of intrapartum chorioamnionitis or neonatal sepsis. With this protocol, uterine tachysystole was managed by oxytocin discontinuation followed by resumption when indicated and at half the stopping dosage. hereafter, the dosage was increased at 3 mU/min when appropriate, instead of the usual 6-mU/min increase used for women without tachysystole. No adverse neonatal efects were observed.

Xenakis and coworkers (1995) reported beneits using an incremen tal oxytocin regimen starting at 4 m U / min. In another study, 816 women were randomly assigned for labor induction and 816 for augmentation with incremental oxytocin gihen at either 1.5 or 4.5 mU/min (Merrill, 1999). Women randomized to the 4.5 mU/min dosage had signiicantly shorter mean durations of induction-to-second-stage labor and inductionto-delivery times. Nulliparas randomized to the 4.5 mU/min dosage had a signiicantly lower cesarean delivery rate for dystocia compared with those given 1.5 mU/min dosage-6 versus 12 percent. Thus, benefits favor higher-dose regimens of 4.5 to 6 mU/min compared with lower dosages of 0.5 to 1.5 mU/min.

In 1990 at Parkland Hospital, routine use of the 6-mU/min oxytocin beginning and incremental dosage was incorporated and continues through today. In other labor units, a 2-mU/min beginning and incremental oxytocin regimen is preferred and administered. With either regimen, dosages are employed for either labor induction or augmentation. Although a Cochrane metaanalysis of randomized and quasi-randomized trials comparing high-dose versus low-dose regimens for labor induction at term reported no benefit of higher dosing, the metaanalysis included studies judged to have high potential bias. The authors concluded that the results might be confounded by these poorquality studies (Budden, 2014).

Interval between Incremental Dosing. Intervals to increase oxytocin doses vary from 15 to 40 minutes (see Table 26-3). Satin and associates (1994) addressed this aspect with a 6-mU/ min regimen providing increases at either 20-or 40-minute intervals. Women assigned to the 20-minute interval regimen for labor augmentation had a significantly reduced cesarean delivery rate for dystocia compared with that for the 40-minute interval regimen-8 versus 12 percent. As perhaps expected, uterine tachysystole was significantly more frequent with the 20-minute escalation regimen.

Other investigators reported even more frequent incremental increases. F rigoletto (1995) and Xenakis (1995) and their coworkers gave oxytocin at 4 mU/min with increases as needed every 15 minutes. Merrill and Zlatnik (1999) started with 4.5 mU/min doses and increased this every 30 minutes. L6pez-Zeno and associates (1992) used 6 mU/min doses and 15-minute intervals. Thus, there are several acceptable oxytocin protocols that at least appear dissimilar. But, a comparison of protocols from two institutions indicates that this is not so: 1.

The Parkland Hospital protocol uses a starting dose of oxytocin at 6 mU/min, which is increased by 6-mU/min every 40 minutes, and employs flexible dosing based on uterine tachysystole.

2.

The University of Alabama at Birmingham Hospital protocol begins oxytocin at 2 mU/min and increases it as needed every 15 minutes to 4,8, 12, 16,i20,25, and 30 mU/min.

hus, although the regimens at first appear disparate, if there is no uterine activity, either regimen is delivering 12 mU/ min by 45 minutes into the infusion.

Maximal OxytOcin Dosage. The maximal efective dose of oxytocin to achieve adequate contractions in all women is diferent. Wen and colleagues (2001) studied 1151 consecutive nulliparas and found that the likelihood of progression to vaginal delivery decreased at and beyond an oxytocin dosage of 36 mU/min. Still, at a dosage of 72 mU/min, half of the nulliparas were delivered vaginally. Thus, if contractions are not adequate-less than 200 Montevideo units-and if the fetal status is reassuring and labor has arrested, an oxytocin infusion dose greater than 48 mU/min has no apparent risks.

Unless the uterus is scarred, uterine rupture associated with oxytocin infusion is rare, even in parous women. Flannelly and associates (1993) reported no cases of uterine ruptures, with or without oxytocin, in 27,829 nulliparas. here were eight instances of overt uterine rupture during labor in 48,718 parous women. Only one of these was associated with oxytocin use. A population-based retrospective review from Denmark reported a rupture rate of 3.3 per 100,000 women without prior cesarean, with the highest risk among multiparas (This ted, 2015). Our experiences from Parkland Hospital are that oxytocin induction and augmentation are associated with uterine rupture (Happe, 2017). During an 8-year period in which there were about 95,000 births, 15 women sufered a primary uterine rupture, and 14 of these cases were associated with oxytocin use. In half of these women, prostaglandins were also given before augmentation with oxytocin.

Oxytocin has amino-acid homology similar to arginine vasopressin and has signiicant antidiuretic action. When infused at doses of 20 mU/min or more, renal free water clearance drops markedly. If aqueous luids are infused in appreciable amounts along with oxytocin, water intoxication can lead to convulsions, coma, and even death. In general, if oxytocin is to be administered in high doses for a considerable period of time, its concentration should be increased rather than raising the flow rate of a more dilute solution. Consideration also should be given to use of crystalloids-either normal saline or lactated Ringer solution.

Contraction forces in spontaneously laboring women range from 90 to 390 Montevideo units (Chap. 24, p. 479). Caldeyro-Barcia (1950) and Seitchik (1984) with their coworkers found that the mean or median spontaneous uterine contraction pattern between 140 and 150 Montevideo units resulted in progression to vaginal delivery.

In the management of active-phase arrest, and with no contraindication to intravenous oxytocin, decisions must be made with knowledge of the safe upper range of uterine activity. Hauth and colleagues (1986) described an efective and safe protocol for oxytocin augmentation for active-phase arrest. With it, more than 90 percent of women achieved an average of at least 200 to 225 Montevideo units. They later reported that nearly all women in whom active-phase arrest persisted despite oxytocin generated more than 200 Montevideo units (Hauth, 1991). Importantly, despite no labor progression, no adverse maternal or perinatal efects were noted in those ultimately requiring cesarean delivery. here are no data regarding safety and eicacy of contraction patterns in women with a prior cesarean delivery, with twins, or with an overdistended uterus.

First-stage arrest of labor is deined as a completed latent phase and contractions exceeding 200 NIontevideo units for more than 2 hours without cervical change. Some have attempted to deine a more accurate duration for active-phase arrest (Spong, 2012). Arulkumaran and coworkers (1987) extended the 2-hour limit to 4 hours and reported a 1.3-percent cesarean delivery rate in women who continued to have adequate con tractions and progressive cervical dilation of at least 1 cm/hr. In another 4 hours of labor, half required cesarean delivery.

Rouse and colleagues (1999) prospectively managed 542 women at term with active-phase arrest and no other complications. Their protocol was to achieve a sustained pattern of at least 200 Montevideo units for a minimum of 4 hours. This time frame was extended to 6 hours if activity of 200 Montevideo units or greater could not be sustained. Almost 92 percent of these women were delivered vaginally. As discussed in Chapter 23 (p. 443), these and other studies support the practice of allowing an active-phase arrest of 4 hours (Rouse, 2001).

Zhang and coworkers (2002) analyzed labor duration from 4 cm to complete dilatation in 1329 nulliparas at term. They found that before dilation of 7 cm was reached, lack of progress for more than 2 hours was not uncommon in those who delivered vaginally. Alexander and associates (2002) reported that epidural analgesia prolonged active labor by 1 hour compared with duration of the active phase as deined by Friedman (1955). Consideration of these changes in the management oflabor, especially in nulliparas, may safely reduce the cesarean delivery rate.

As data have accrued, investigators have increasingly questioned the thresholds for labor arrest disorders established by Friedman and others in the 1960s. In particular, investigators with the Consortium on Sai Labor reported that half of cases of dystocia after labor induction occurred before 6 cm of cervical dilation (Boyle, 2013; Zhang, 2010c). Even for women with spontaneous labor, these researchers found that active-phase labor was more likely to occur at 6 cm, and after slow progress between 4 and 6 cm (Zhang, 2010a). Additionally, they reported that a 2-hour threshold for diagnosing arrest disorders may be too brief when cervical dilation is <6 em (Zhang, 201Ob). This is discussed in detail in Chapter 23 (p. 444). Importantly, however, these studies of data from the Collaborative Perinatal Project included only singleton term gestation with spontaneous onset of labor, vaginal delivery, and a normal perinatal outcome. By excluding abnormal outcomes, cesarean deliveries, and those who were more than 6 cm dilated upon arrival, the above studies that sought to redeine the labor curve

Induction and Augmentation of Labor 511 have been faulted for introducing biases that limit general use of these findings (Cohen, 20 15a, b).

Elective amniotomy with the intention of accelerating labor is often performed. Shown in Table 26-4, amniotomy at approximately 5-cm dilation accelerated spontaneous labor by 1 to 1 Y2 hours. Importantly, neither the need for oxytocin stimulation nor the overall cesarean delivery rate was increased. Although the incidences of mild and moderate cord compression patterns were raised following amniotomy, cesarean delivery rates for fetal distress were not higher. Most importantly, there were no adverse perinatal efects.

For labor induction, artificial rupture of the membranessometimes called surgical induction-can be used and always implies a commitment to delivery. The main disadvantage of amniotomy used alone for labor induction is the unpredictable and occasionally long interval until labor onset. hat said, in a randomized trial, Bakos and Backstrom (1987) found that amniotomy alone or combined with oxytocin was superior to oxytocin alone. Mercer and colleagues (1995) randomly assigned 209 women undergoing oxytocin induction to either early amniotomy at 1 to 2 cm or late amniotomy at 5 cm. Early amniotomy was associated with a 4-hour reduction in labor duration. With early amniotomy, however, the incidence of chorioamnionitis was elevated.

For labor augmentation, amniotomy is commonly performed when labor is abnormally slow. Rouse and associates (1994) found that amniotomy with oxytocin augmentation for arrested active-phase labor shortened the time to delivery by 44 minutes compared with that of oxytocin alone. Although amniotomy did not alter the delivery route, one drawback was that it significantly increased the incidence of chorioamnionitis.

Regardless of the indication, amniotomy is associated with a risk of cord prolapse. To minimize this risk, disengagement of the fetal head during amniotomy is avoided. Toward this goal, fundal or suprapubic pressure or both may be helpful. Some clinicians prefer to rupture membranes during a contraction. If the vertex is not well applied to the lower uterine segment, aNo effect on overall rate; cesarean delivery for fetal distress significantly increased. blncreased mild and moderate umbilical cord compression patterns.

NA = not assessed.

a gradual egress of amnionic fluid can sometimes be accomplished by several membrane punctures with a 26-gauge needle held with a ring forceps and with direct visualization using a vaginal speculum. In many of these, however, membranes tear and luid is lost rapidly. Because of the risk of cord prolapse or rarely abruption, the fetal heart rate is assessed before and immediately after amniotomy.

Labor induction by membrane "stripping" is a frequent practice. Several studies have suggested that membrane stripping is safe and lowers the incidence of postterm pregnancy without consistently raising the incidence of ruptured membranes, infection, or bleeding. Authors of one large metaanalysis found that membrane stripping reduced the number of women remaining undelivered after 41 weeks without elevating the infection risk. They concluded that eight women would need to undergo membrane stripping to avoid one labor induction. Downsides are discomfort and associated bleeding (Boulvain, 2005).

Alexander ]M, Sharma SK, McIntire 0, et al: Epidural analgesia lengthens the Friedman active phase oflabor. Obstet Gynecol 100(1):46,o2002

Alirevic Z, Maifel N, Weeks A: Oral misoprostol for induction of labour.

Cochrane Database Syst Rev 6:CD001338 2014

Alirevic Z, Kelly A], Dowswell T: Intravenous oxytocin alone for cervical ripening and induction of labour. Cochrane Database Syst Rev 4:CD003246, 2009

American Academy of Pediatrics, American College of Obstetricians and Gynecologists: Guidelines for Perinatal Care, 8th ed. Elk Grove Village, P, 2017

American College of Obstetricians and Gynecologists: Induction of labor. Practice Bulletin No. 107, August 2009, Reairmed 2016

American College of Obstetricians and Gynecologists: Intrapartum fetal heart rate monitoring: nomenclature, interpretation, and general management principles. Practice Bulletin No. 106,o] uly 2009, Reairmed 20o17 a

American College of Obstetricians and Gynecologists: Vaginal birth after previous cesarean delivery. Practice Bulletin 115, August 2010, Reairmed 20 17b

Amorosa ]M, Stoneo], Factor SH, et al: A randomized trial of Foley bulb for labor induction in premature rupture of membranes in nulliparas (FLIP). Am] Obstet GynecoI217(3):360.e1

Arulkumaran S, Koh CH, Ingemarsson I, et al: Augmentation of labourmode of delivery related to cervi metric progress. Aust N Z ] Obstet GynaecoIo27:304, 1987 Bailit ]L, Gregory KD, Reddy UM, et al: Maternal and neonatal outcomes by labor onset type and gestational age. Am ] Obstet Gynecol 202(3):245. el,o2010 Bakos 0, Backstrom T: Induction of labor: a prospective, randomized study into amniotomy and oxytocin as induction methods in a total unselected population. Acta Obstet Gynecol Scand 66:537, 1987 Bateman BT, Mhyre ]M, Callaghan WM, et al: Peripartum hysterectomy in the United States: nationwide 14 year experience. Amo] Obstet Gynecol 206(1):63.el,o2012 Bishop EH: Pelvic scoring for elective induction. Obstet GynecoIo24:266, 1964 Bleich AT, Villano KS, Lo ]Y, et al: Oral misoprostol for labor augmentation: a randomized controlled trial. Obstet GynecoIo118(6):1255, 2011 Boulvain M, Kelly A, Irion 0: Intracervical prostaglandins for induction of labour. Cochrane Database Syst Rev 1:CD006971, 2008 Boulvain M, Stan C, Irion 0: Membrane sweeping for induction of labour. Cochrane Database Syst Rev 1 :CD00045o1, 2005 Boyle A, Reddy UM, Landy H], et al: Primary cesarean delivery in the United States. Obstet GynecoIo122(1):33, 2013 Budden A, Chen L], Henry A: High-dose versus low-dose oxytocin infusion regimens for induction of labour at term. Cochrane Database Syst Rev 10:CD009701,o2014 Bullarbo M, Orrskog ME, Andersch B, et al: Outpatient vaginal administration of the nitric oxide donor isosorbide mononitrate for cervical ripening and labor induction postterm: a randomized controlled study. Amo] Obstet GynecoIo196:50.e1,o2007

Caldeyro-Barcia R, Alvarez H, Reynolds SR: A better understanding of uterine contractility through simultaneous recording with an internal and a seven channel external method. Surg Obstet Gynecol 91 :641, 1950

Caldeyro-Barcia R, Poseiro JJ: Physiology of the uterine contraction. Clin Obstet Gynecol 3:386, 1960

Carbone ]F, Tuuli MG, Fogertey P], et al: Combination of Foley bulb and vaginal misoprostol compared with vaginal misoprostol alone for cervical ripening and labor induction: a randomized controlled trial. Obstet Gynecol. 121:247,2013

Chanrachakul B, Herabutya Y, Punyavachira P: Potential eicacy of nitric oxide for cervical ripening in pregnancy at term. Int ] Gynaecol Obstet ,2000 Chiossi G, Lai Y, Landon MB, et al: Timing of delivery and adverse outcomes in term singleton repeat cesarean deliveries. Obstet Gynecol 121 (3) :561, 2013

Clark SL, Miller DO, Belfort MA, et al: Neonatal and maternal outcomes associated with elective term delivery. Amo] Obstet Gynecol 200(2): 156. el,o2009

Cohen WR, Friedman EA: Misguided guidelines for managing labor. Am ] Obstet GynecoIo212(6):753.e1, 2015a

Cohen R, Friedman A: Perils of the new labor management guidelines. Am ] Obstet Gynecolo212(4):420, 2015b

Connolly A, Kohari KS, Rekawek P, et al: A randomized trial of Foley balloon induction oflabor trial in nulliparas (FIAT-N). Am] Obstet Gynecol. 215:392.el,2016

Cullen M: Important drug warning concerning unapproved use of intravaginal or oral misoprostol in pregnant women for induction of labor or abortion. 2000. Available at: http://www.fda.gov/ohrms/dockets/dailys/OO/ NovOO/111500/cpOOO1.pdf. Accessed July 28,o2017

Dahlen HM, McCullough ]M, Fertig AR, et al: Texas Medicaid payment reform: fewer early elective deliveries and increased gestational age and birthweight. Health ff(Millwood) 36(3):460, 20o17

Darney BG, Snowden ]M, Cheng W, et al: Elective induction of labor at term compared with expectant management: maternal and neonatal outcomes. Obstet GynecoIo122:761, 2013

Dobert M, Brandsetter A, Heinrich W, et al: he misoprostol vaginal insert compared with oral misoprostol for labor induction in term pregnancies: a pair-matched case-control study. ] Perinatal Med June 26, 20o17 [Epub ahead of print]

Ekerhovd E, Bullarbo M, Andersch B, et al: Vaginal administration of the nitric oxide donor isosorbide mononitrate for cervical ripening at term: a randomized controlled study. Amo] Obstet GynecoIo189:o1692, 2003

Ekerhovd E, Weijdegard B, Brannstrom I, et al: Nitric oxide induced cervical ripening in the human: involvement of cyclic guanosine monophosphate, prostaglandin F2a, and prostaglandin E2• Amo] Obstet GynecoIo186:745, 2002

Feltovich H: Cevical evaluation. From ancient medicine to precision medi cine. Obstet GynecoIo130:51, 2017

Fisch ]M, English 0, Pedaline S, et al: Labor induction process improvement: a patient quality-of-care initiative. Obstet Gynecol 113(4):797,o2009 Flannelly GM, Turner M], Rassmussen M], et al: Rupture of the uterus in Dublin: an update.o] Obstet GynaecoIo13:440, 1993

Fraser W, Marcoux S, Moutquin ]M, et al: Efect of early amniotomy on the risk of dystocia in nulliparous women. N Engl] Med 328:1145, 1993 Friedman A: Primigravid labor: a graphicostatistical analysis. Obstet Gynecol 6:567, 1955

Frigoletto FD, Lieberman E, Lang ]M, et al: A clinical trial of active management oflabor. N Engl] Med 333:745, 1995

Fruhman G, Gavard ]A, Amon E, et al: Tension compared to no tension on a Foley trans cevical catheter for cervical ripening: a randomized controlled trial. Am] Obstet GynecoI216:67.e1, 2017

Garite T], Porto M, Carlson N], et al: he inluence of elective amniotomy on fetal heart rate patterns and the course of labor in term patients: a randomized study. Am] Obstet GynecoIo168:1827, 1993

Ghosh A, Lattey R, Kelly A]: Nitric oxide donors for cervical ripening and induction of labour. Cochrane Database Syst Rev 12:CD00690 1, 2016 Gibson KS, Waters TP: Measures of success: prediction of successful labor induction. Semin PerinatoIo39:475, 2015 Happe SK, Yule CS, Wells CE: Outcomes in pregnancies complicated by intrapartum uterine rupture. Unpublished data, 2017 Hatield AS, Sanchez-Ramos L, Kaunitz M: Sonographic cervical assessment to predict the success of labor induction: a systematic review with metaanalysis. Amo] Obstet Gynecol 197: 186, 2007 Hauth]C, Hankins GO, Gilstrap LC III: Uterine contraction pressures achieved in parturients with active phase arrest. Obstet Gynecol 78:344, 1991 Hauth ]c, Hankins GO, Gilstrap LC III: Uterine contraction pressures with oxytocin induction/augmentation. Obstet GynecoIo68:305, 1986 Hawkins ]S, Stephenson M, Powers B, et al: Diabetes mellitus: an independent predictor of duration of prostaglandin labor induction. ] Perinatol 37:488, 20o17

Hawkins ]S, Wing DA: Current pharmacotherapy options for labor induction.

Expert Opin Pharmacother 13(14):2005,2012

Hernandez ]S, Wendel GO ]r, Sheield]S: Trends in emergency peripartum hysterectomy at a single institution: 1988-2009. Amr] PerinatoIr30(5):365, 2013

Hofman MK, Sciscione AC: Elective induction with cervical ripening increases the risk of cesarean delivery in multiparous women. Obstet GynecoIr101:7S, 2003

Hofmeyr G], G.ilmezoglu M, Pileggi C: Vaginal misoprostol for cervical ripening and induction of labour. Cochrane Database Syst Rev 1 0:CD000941 , 2010

Ivars J, Garabedian C, Devos P, et al: Simpliied Bishop score including parity predicts successful induction of labor. Eur ] Obstet Gynecol Reprod Bioi 203:309,r2016

Jozwiak M, Bloemenkamp KW, Kelly AJ, et al: Mechanical methods for induction of labour. Cochrane Database Syst Rev 3:CD001233, 2012

Jozwiak M, Oude Rengerink K, Benthem M, et al: Foley catheter versus vaginal prostaglandin E2 gel for induction of labour at term (PROBAAT trial): an open-label, randomised controlled trial. Lancet 378(9809):2095,r201r1

Jozwiak M, Oude Rengerink K, Ten Eikelder ML, et al: Foley catheter or prostaglandin E2 inserts for induction of labour at term: an open-label randomized controlled trial (PROBAAT-P trial) and systematic review of literature. Eur J Obstet Gynecol Reprod Bioi 170(1):137, 2013

Jozwiak M, Ten Eikelder M, Rengerink KO, et al: Foley catheter versus vaginal misoprostol: randomized controlled trial (PROBAAT-M Study) and systematic review and meta-analysis of literature. Am J Perinatol 31: 145, 2014

Karjane NW, Brock EL, Walsh SW: Induction of labor using a Foley balloon, with and without extra-amniotic saline infusion. Obstet Gynecol 107:234, 2006

Kawakita T, Reddy UM, Iqbal SN, et al: Duration of oxytocin and rupture of membranes before diagnosing a failed induction of labor. Obstet Gynecol 128:373,r2016

Kominiarek A, Zhang J, Vanveldhuisen P, et al: Contemporaty labor patterns: the impact of maternal body mass index. Am J Obstet Gynecol 205(3):244.e1,r2011

Landon MB, Hauth JC, Leveno KJ, et al: Maternal and perinatal outcomes associated with a trial of labor ater prior cesarean delivery. N Engl J Med 351(25):2581,r2004

Laughon SK, Branch OW, Beaverr], et al: Changes in labor patterns over 50 years. Am J Obstet GynecoI206(5):419.e1, 2012

Laughon SK, Zhang J, Troendle ], et al: Using a simplified Bishop score to predict vaginal delivery. Obstet GynecoIr117(4):805, 2011

Levine LD, Downes L, Elovitz A, et al: Mechanical and pharmacologic methods of labor induction: a randomized controlled trial. Obstet Gynecol 128:1357,r2016

Little SE, Caughey AB: Induction of labor and cesarean: what is the true relationship? Clin Obstet Gynecol 58:269, 2015

Lo JY, Alexander JM, McIntire DO, et al: Ruptured membranes at term: randomized, double-blind trial of oral misoprostol for labor induction. Obstet Gynecolr101:685,r2003

Lopez-Zeno JA, Peaceman M, Adashek ]A, et al: A controlled trial of a program for the active management oflabor. N Engl J Med 326:450, 1992

Luthy DA, Malmgren ]A, Zingheim RW: Cesarean delivery after elective induction in nulliparous women: the phYSician efect. Amr] Obstet Gynecol 191:1511,r2004

Macones GA: Elective induction of labor: waking the sleeping dogma? Ann Intern Med 151 (4):281, 2009

Maier JT, Metz M, Watermann N, et al: Induction of labor in patients with an unfavorable cervix after a cesarean using an osmotic dilator versus vaginal prostaglandin. J Perinatal Med June 26, 2017 [Epub ahead of print]

Martin JA, Hamilton BE, Osterman MJ, et al: Births: final data for 2015. Natl Vital Stat Rep 66(1):1, 2017

Maslow AS, Sweeny AL: Elective induction of labor as a risk factor for cesarean delivery among low-risk women at term. Obstet GynecoIr95:917, 2000

McMaster K, Sanchez-Ramos L, Kaunitz M: Evaluation of a trans cevical Foley catheter as a source of infection: a systematic review and meta-analysis. Obstet GynecoIr126:539, 2015

Mei-Dan E, Walisch A, Valencia C, et al: Making cervical ripening EASI: a prospective controlled comparison of single versus double balloon catheters. J Matern Fetal Neonatal Med 27:1765,r2014

Melamed N, Ray JG, Geary M, et al: Induction of labor before 40 weeks is associated with lower rate of cesarean delivery in women with gestational diabetes mellitus. Am J Obstet GynecoI214:364, 2016

Mercer BM, McNanley T, O'Brien JM, et al: Early versus late amniotomy for labor induction: a randomized trial. Am J Obstet Gynecol 173: 1371, 1995

Merrill DC, Zlatnik FJ: Randomized, double-masked comparison of oxytocin dosage in induction and augmentation of labor. Obstet Gynecol 94:455, 1999

Induction and Augmentation of Labor 513

Miller NR, Cypher L, Foglia LM, et al: Elective induction oflabor compared with expectant management of nulliparous women at 39 weeks of gestation: a randomized controlled trial. Obstet GynecoIr126:1258, 2015

National Institutes of Health: ClinicaITrials.gov: a randomized trial of induction versus expectant management (ARRIVE). 2015. Available at: https:!1 c1inicaltrials.gov/ct2/show/NCT01990612. Accessed July 28,r2017

O'Driscoll K, Foley M, MacDonald 0: Active management of labor as an alternative to cesarean section for dystocia. Obstet Gynecol 63:485, 1984

Oshiro BT, Kowalewski L, Sappenfield W, et al: A multistate quality improvement program to decrease elective deliveries before 39 weeks of gestation. Obstet Gynecol 121(5):1025,r2013

Raghuraman N, Stout MJ, Young OM: Utility of the simpliied Bishop score in spontaneous labor. Am ] Perinatol 33: 1176, 2016

Roland e, Warshak CR, DeFranco EA: Success of labor induction for preeclampsia at preterm and term gestational ages. J Perinatol 37(6):636, 2017 Rooney Thompson M, Towers CV, Howard Be, et l: The use of prostaglandin El in peripartum patients with asthma. m J Obstet Gynecol 212:392.e 1, 2015 Rouse 0], McCullough e, Wren AL, et al: Active-phase labor arrest: a randomized trial of chorioamnion management. Obstet GynecoIr83:937, 1994 Rouse OJ, Owen J, Hauth J C: Active-phase labor arrest: oxytocin augmenta tion for at least 4 hours. Obstet Gynecol 93:323, 1999

Rouse OJ, Owen J, Hauth JC: Criteria for failed labor induction: prospective evaluation of a standardized protocol. Obstet Gynecol 96:671, 2000

Rouse OJ, Owen J, Savage KG, et al: Active phase labor arrest: revisiting the 2-hour minimum. Obstet Gynecol 98:550, 2001

Saccone G, Berghella V: Induction of labor at full term in uncomplicated singleton gestations: a systematic review and metaanalysis of randomized controlled trials. Am J Obstet GynecoIr213:629, 2015

Salemi ]L, Pathak EB, Salihu HM: Infant outcomes ater elective early-term delivery compared with expectant management. Obstet Gynecol 127:657, 2016

Satin AJ, Leveno KJ, Sherman ML, et al: High-dose oxytocin: 20-versus 40-minute dosage interval. Obstet Gynecol 83:234, 1994

Satin A], Leveno KJ, Sherman ML, et al: High-versus low-dose oxytocin for labor stimulation. Obstet Gynecol 80: 111, 1992

Schoen CN, Grant G, Berghella V, et al: Intracevical Foley catheter with and without oxytocin for labor induction: a randomized controlled trial. Obstet GynecoIr129:1046,r2017

Seitchik J, Amico J, Robinson AG, et al: Oxytocin augmentation of dysfunctional labor. IV. Oxytocin pharmacokinetics. Am J Obstet Gynecol 150:225, 1984

Sievert A, Kuper SG, Jauk VC: Predictors of vaginal delivery in medically indicated early preterm induction oflabor. Am J Obstet GynecoIr217(3):375.e1 Simon CE, Grobman WA: When has an induction failed? Obstet Gynecol 105:705,r2005

Smith M, Hofman MK, Sciscione A: Elective induction oflabor in nulliparous women increases the risk of cesarean delivery. Obstet Gynecolr101:45S, 2003

Snowden JM, Muoto I, Darney BG, et al: Oregon's hard-stop policy limiting elective early-term deliveries: association with obstetric procedure use and health outcomes. Obstet GynecoIr128:1389, 2016

Spong CY, Berghella V, Wenstrom KD, et al: Preventing the first cesarean delivery. Summary of a Joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Sociery for Maternal-Fetal Medicine, and American College of Obstetricians and Gynecologists Workshop. Obstet GynecoIr120(5):1181, 2012

Ten Eikelder ML, Oude Rengerink K, Jozwiak M, et al: Induction of labor at term with oral misoprostol versus a Foley catheter (PROBAAT-II): a multicenter randomized controlled non-inferioriry trial. Lancet 387:1619,r2016 histed DL, Mortensen LH, Krebs L. Uterine rupture without previous caesarean delivery: a population-based cohort study. Eur J Obstet Gynecol Reprod BioI. 195:151,r2015 homas J, Fairclough A, Kavanagh J, et al: Vaginal prostaglandin (PGE2 and PGF2a) for induction of labour at term. Cochrane Database SYSt Rev 6:CD003101,r2014

Thorbiornson A, Vladic T, Stjernholm V: Oral versus vaginal prostaglandin for labor induction. J Matern Fetal Neonatal Med 30:789,r2017

Tita AT, Landon MB, Spong CY, et al: Timing of elective repeat cesarean delivery at term and neonatal outcomes. N Engl J Med 360(2):111,r2009 Towers CV, Briggs GG, Rojas JA: he use of prostaglandin E2 in pregnant patients with asthma. Am J Obstet GynecoIr190(6):1777, 2004

UK Amniotomy Group: A multicentre randomised trial of amniotomy in spontaneous first labour at term. BJOG 101:307, 1994

Vaisanen-Tommiska M, Nuutila M, Aittomaki K, et al: Nitric oxide metabolites in cervical fluid during pregnancy: further evidence for the role of cevical nitric oxide in cervical ripening. Am J Obstet Gynecol 188:779, 2003

Vaisanen-Tommiska M, Nuutila M, Ylikorkala 0: Cervical nitric oxide release in women posnerm. Obstet Gynecol 103:657,r2004

Verhoeven Cj, Opmeer BC, Oei SG, et al: Transvaginal sonographic assessment of cervical length and wedging for predicting outcome of labor induction at term: a systematic review and meta-analysis. Ultrasound Obstet Gynecol. 42:500, 2013

Villano KS, Lo jY, Alexander jM: A dose-finding study of oral misoprostol for labor augmentation. Am j Obstet Gynecol 204(6):560.el, 2011

Wagner M: Of-label use of misoprostol in obstetrics: a cautionary tale. BjOG 112: 266,r2005

Weeks AD, Fiala C, Safar P: Misoprostol and the debate over of-label drug use. BjOG 112: 269, 2005

Wen T, Beceir A, Xenakis E, et al: Is there a maximum efective dose of Pitocin? Am j Obstet Gynecol 185:5212,r2001

Williams JW: Obstetrics: a Text-book for the Use of Students and Practitioners.

New York, o. Appleton and Co., 1903

Wing OA, Brown R, Plante A, et al: Misoprostol vaginal insert and time to vaginal delivery. A randomized controlled trial. Obstet Gynecolrl22(2 pt 1): 201, 2013

Wolfe H, Timofeev j, Tefera E, et al: Risk of cesarean in obese nulliparous women with unfavorable cervix: elective induction vs expectant management at term. Am j Obstet Gynecol. 211:53.e1, 2014

Xenakis EM, Langer 0, Piper jM, et al: Low-dose versus high-dose oxytocin augmentation of labor-a randomized trial. m j Obstet Gynecol 3: 1874, 1995

Yeast jO, Jones A, Poskin M: Induction of labor and the relationship to cesarean delivery: a review of 001 consecutive inductions. Am j Obstet Gynecol 180:628, 1999

Zhang j, Landy Hj, Branch OW, et al: Contemporary patterns of spontaneous labor with normal neonatal outcomes. Obstet Gynecol 116(6): 1281, 20 lOa Zhang j, Troendle j, Mikolajczyk R, et al: The natural history of the normal irst stage of labor. Obstet Gynecol 115 (4): 705, 201 Ob

Zhang j, Troendle j, Reddy UM, et al: Contemporary cesarean delivery practice in the United States. Am j Obstet Gynecol 203(4):326.el, 20lOc Zhang j, Troendle jF, Yancey MK: Reassessing the labor curve in nulliparous women. Am j Obstet Gynecol 187:824,r2002

As soon as the head appears at the vulva the physician should be ready to restrain its progress. He should hold his hand in such a manner as to be able to bring it immediatey into action, or in many instances the resistance of the vulva is unexpectedy overcome, and a single pain may be suicient to push the head suddeny through it with a resulting perineal tea.

-J. hitridge Williams (1903)

As described by Williams, the natural culmination of secondstage labor is controlled vaginal delivery of a healthy neonate with minimal trauma to the mother. Vaginal delivery is the preferred route of delivery for most fetuses, although various clinical settings may favor cesarean delivery. Of delivery routes, spontaneous vaginal vertex delivery poses the lowest risk of most maternal comorbidity, and comparisons with cesarean delivery are found in Chapter 30 (p. 568). Delivery is usually spontaneous, although some maternal or fetal complications may warrant operative vaginal delivery, described in Chapter 29 (p. 553). Last, a malpresenting fetus or multifetal gestation in many cases may be delivered vaginally but requires special techniques. These are described in Chapters 28 (p. 543) and 45 (p. 888).

he end of second-stage labor is heralded as the perineum begins to distend, the overlying skin becomes stretched, and the fetal scalp is seen through the separating labia. Increased perineal pressure from the fetal head creates reflexive bearing-down eforts, which are encouraged when appropriate. At this time, preparations are made for delivery. If the bladder is distended, catheterization may be necessary. Continued attention is also given to fetal heart rate monitoring. s one example, a nuchal cord oten tightens with descent and may lead to deepening variable decelerations.

During second-stage labor, pushing positions may vary. But for delivery, the dorsal lithotomy position is most common and often the most satisfactory. For better exposure, leg holders or stirrups are used. Corton and associates (2012) found no increased rates of perineal lacerations with or without their use. With positioning, legs are not separated too widely or placed one higher than the other. Within the leg holder, the popliteal region should rest comfortably in the proximal portion and the heel in the distal portion. he legs are not strapped into the stirrups, thereby allowing quick flexion of the thighs backward onto the abdomen should shoulder dystocia develop. Legs may cramp during second-stage pushing, and cramping is relieved by repositioning the afected leg or by brief massage.

Preparation for delivery includes vulvar and perineal cleansing. If desired, sterile drapes may be placed in such a way that only the immediate area around the vulva is exposed. Scrubbing, gowning, gloving, and donning protective mask and eyewear protect both the laboring woman and accoucheur from infectious agents.

• Delivery of the Head

By the time of perineal distention, the position of the occiput is usually known. In some cases, however, molding and caput formation may have precluded early accurate identification. At this time, careful assessment is again performed as described in Chapter 22 (p. 426). In most cases, position is directly occiput anterior (OA) or is rotated slightly oblique. But, in perhaps 5 percent, occiput posterior (OP) positioning persists.

With each contraction, the vulvovaginal opening is dilated by the fetal head to gradually form an ovoid and inally, an almost circular opening (Fig. 27-1). his encirclement of the largest head diameter by the vulvar ring is termed crowning. he perineum thins and may spontaneously lacerate. he anus becomes greatly stretched, and the anterior wall of the rectum can easily be seen through it.

Routine episiotomy is no longer recommended, and selective use aims to enlarge the vaginal opening for specific indications (p. 529). To limit spontaneous vaginal laceration, some perform antenatal massage of the perineal body to increase perineal distensibility or intrapartum perineal massage to widen the introitus for head passage. During massage with a lubricant, the perineum is grasped in the midline by both hands using the thumb and opposing ingers. Outward and lateral stretching to thin the perineum is repeatedly performed. But in randomized studies, this technique did not significantly prevent perineal laceration (Beckmann, 2013; Mei-dan, 2008; Stamp, 2001). Antepartum use of the Epi-No intravaginal pump balloon has a similar aim, but it also fails to prevent perineal trauma or levator injury (Brito, 2015; Kamisan Atan, 2016).

When the head distends the vulva and perineum enough to open the vaginal introitus to a diameter of 5 cm or more, a gloved hand may be used to support the perineum (Fig. 27-2). he other hand is used to guide and control the fetal head to deliver the smallest head diameter through the introitus and to

FIGURE 27-2 Delivery of the head. The mouth appears over the perineum.

avoid expulsive delivery. Slow delivery of the head may decrease lacerations (Laine, 2008). Overall, bracing the perineum lowers rates of anal sphincter injury compared with a "hands of' approach to delivery (Bulchandani, 2015; McCandlish, 1998).

Alternatively, if expulsive eforts are inadequate or expeditious delivery is needed, the modied Ritgen maneuvermay be employed or an episiotomy cut. With the modified maneuver, gloved ingers beneath a draped towel exert forward pressure on the fetal chin through the perineum just in front of the coccyx. Concurrently, the other hand presses against the occiput (Fig. 27-3). Originally described in 1855, the maneuver allows controlled fetal head delivery (Cunningham, 2008). It also favors neck extension so that the head passes through the introitus and over the perineum with its smallest diameters. Comparing the Ritgen maneuver with simple perineal support in 1623 women, Jonsson and colleagues (2008) found a similar incidence of third-and fourth-degree tears, defined later (p. 528).

FIGURE 27-1 Perineum is supported as the head crowns.

FIGURE 27-3 Modified Ritgen maneuver. Moderate upward pressure is applied to the fetal chin by the posterior hand covered by a sterile towel. The other hand applies occipital pressure.

• Delivery of the Shoulders

Following delivery of the fetal head, a inger is passed across the fetal neck to determine whether it is encircled by one or more umbilical cord loops. he nuchal cord incidence increases with gestational age and is found in nearly 25 percent of deliveries at term (Larson, 1997; Ogueh, 2006). If an umbilical cord coil is felt, it is slipped over the head if loose enough. If applied too tightly, the loop is cut between two clamps. Tight nuchal cords complicate approximately 6 percent of all deliveries but are not associated with worse neonatal outcome than those without a cord loop (Henry, 2013).

Following its delivery, the fetal head falls posteriorly, bringing the face almost into contact with the maternal anus. he occiput promptly turns toward one of the maternal thighs, and the head assumes a transverse position. This external rotation indicates that the bisacromial diameter, which is the distance between the shoulders, has rotated into the anteroposterior diameter of the pelvis.

Most often, the shoulders appear at the vulva just after external rotation and are born spontaneously. If delayed, extraction aids controlled delivery. The sides of the head are grasped with two hands, and genle downward traction is applied until the anterior shoulder appears under the pubic arch (Fig. 27-4). Next, by an upward movement, the posterior shoulder is delivered. During delivery, abrupt or powerful force is avoided to avert fetal brachial plexus injury.

he rest of the body almost always follows the shoulders without diiculty. With prolonged delay, however, its birth may be hastened by moderate outward traction on the head and moderate pressre on the uterine fundus. Hooking the fingers in the axillae is avoided. This can injure upper extremity nerves and produce a transient or possibly permanent paralysis. Immediately after delivery of the newborn, a gush of amnionic luid that is often blood-tinged but not grossly bloody usually follows.

Previously, immediate nasopharyngeal bulb suctioning of the newborn was routine to remove secretions. It was found, however, that suctioning of the nasopharynx may lead to neonatal bradycardia (Gungor, 2006). he current American Heart Association neonatal resuscitation recommendations eschew most suctioning immediately following birth-even with meconium present (Chap. 33, p. 620). And with meconium-stained luid, routine intubation for tracheal suction is not recommended for vigorous or for nonvigorous neonates. Suctioning is reserved for neonates who have obvious obstruction to spontaneous breathing or who require positive-pressure ventilation (Wyckof, 2015). For suctioning, options are bulb syringe or suction catheter aspiration and may include intubation and suctioning if the airway is obstructed.

FIGURE 27-4 Delivery of the shoulders. A. Gentle downward traction to effect descent of the anterior shoulder. B. Delivery of the anterior shoulder completed. Gentle upward traction to deliver the posterior shoulder.

The umbilical cord is cut between two clamps placed 6 to 8 cm from the fetal abdomen, and later an umbilical cord clamp is applied 2 to 3 cm from its insertion into the fetal abdomen.

For term neonates, the timing of umbilical cord clamping remains debatable. Delayed umbilical cord clamping transfers a greater volume of blood to the newborn. A delay for up to 60 seconds may increase total body iron stores, expand blood volume, and decrease anemia incidence in the neonate (Andersson, 2011; Yao, 1974). his practice may be particularly valuable in populations in which iron deficiency is prevalent (Kc, 2017; World Health Organization, 2014).

Conversely, a higher hemoglobin concentration increases risks for hyperbilirubinemia and extended hospitalization for neonatal phototherapy (McDonald, 2013). Delayed cord clamping may also hinder timely and needed neonatal resuscitation. That said, early pilot studies are assessing the value of resuscitating newborns at the bedside to permit delayed clamping (Katheria, 2017; Winter 2017). Fortunately, in general, delayed umbilical cord clamping compared with early clamping does not worsen Apgar scores, umbilical cord pH, or respiratory distress caused by polycythemia. Regarding maternal outcomes, rates of postpartum hemorrhage are similar between early and delayed clamping groups (Andersson, 2013). Fewer data are available regarding cord "milking," in which the opera tor pushes blood through the cord toward the newborn. his clamping is clinically indicated (Upadhyay, 2013).

For the preterm neonate, delayed cord clamping has sev eral benefits. hese include higher red cell volume, decreased need for blood transfusion, and lower rates of intraventricu lar hemorrhage and of necrotizing enterocolitis (Backes, 2014;

Rabe, 2012). For neonates who require expedited resuscitation, cord milking may have beneits to quickly transfer volume (Al-Wassia, 2015; Katheria, 2015; Patel, 2014). Still, because of rapid blood volume changes, the American Heart Associa tion currently suggests against the routine use of cord milking for neonates born <29 weeks' gestation (Wyckof, 2015).

The American College of Obstetricians and Gynecologists (2017a) notes suicient evidence to support delayed umbili 30 to 60 seconds after birth. This opinion is also endorsed by the American Academy of Pediatrics (2017 a). The American

Heart Association guidelines advise that the practice may have resuscitation at birth (Wyckof, 2015).

In the absence of a pelvic architecture abnormalit) or asynclitism, the occiput transverse (OT) position is usually transitoly. Thus, unless contractions are hypotonic, the head usually spontaneously rotates to an OA posItion. If rotation ceases because of poor expulsive forces, vaginal deliveY usually can be accomplished readily in several ways. he easiest is manual rotation of the occiput either anteriorly to OA or less commonly, posteriorly to occiput posterior. If either is successful, Le Ray and coworkers (2007) reported a 4-percent cesarean delivery rate compared with a 60-percent rate in women in whom manual rotation was not successful. Some recommend rotation with Kielland forceps for the persistent OT position as outlined in Chapter 29 (p. 561). These forceps are used to rotate the occiput to the anterior position, and delivery is accomplished with the same forceps or by substitution with Simpson, Tucker-McLane, or similar forceps.

In some cases, pelvic shape leads to a persistent OT position that is not easily overcome. For example, a platypelloid pelvis is lattened anteroposteriorly and an android pelvis is heart shaped. With these, space may be inadequate for occipital rotation to either an anterior or posterior position (Fig. 2-17, p. 31). Because of these concerns, undue force is avoided if forceps delivery is attempted.

Approximately 2 to 10 percent of singleton term cephalic fetuses deliver in an occiput posterior (OP) position (Cheng, 2010). Many fetuses delivering OP are OA in early labor and relect malrotation during labor. Predisposing risks include epidural analgesia, nulliparity, greater fetal weight, and prior delivery with OP positioning (Cheng, 2006a; Gardberg, 2004; Lieberman, 2005). Regarding pelvic shape, an anthropoid pelvis and narrow subpubic angle can predispose (Barth, 2015; Ghi, 2016).

Women with a persistent OP position have higher associated rates of prolonged second-stage labor, cesarean delivery, and operative vaginal delivery. For women who deliver vaginally, rates of blood loss and of third-and fourth-degree lacerations are increased (Senecal, 2005).

plication rates then those born positioned OA. Cheng and coworkers (2006b) compared outcomes of 2591 women under going delivery with a persistent OP position with those of28,801 women whose newborns were delivered OA. Virtually every possible delivery complication was found more frequently with persistent OP position. Only 46 percent of these women deliv ered spontaneously, and the remainder accounted for 9 percent of cesarean deliveries performed. hese investigators also found that an OP position at delivery was associated with more adverse cord gases, birth trauma, Apgar scores <7, and intensive care nursery admission, among others. Similar results were reported by Ponkey (2003) and Fitzpatrick (2001) and their associates.

Methods to prevent persistent OP position and its associated morbidity have been investigated. First, digital examination for identiication of fetal head position can be inaccurate, and transabdominal sonography can be used to increase accuracy (Dupuis, 2005; Zahalka, 2005). The transducer is placed transversely just cephalad to the maternal mons pubis. In the sonogram, fetal orbits and nasal bridge lie ventrally, whereas the occiput apposes the lower sacrum. Such information may provide an explanation for prolonged second-stage labor or may identiy suitable candidates for rotation. Of other possible interventions, varying maternal position either antepartum or during labor does not appear to lower rates of persistent OP position (Desbriere, 2013; Kariminia, 2004; Le Ray, 2016).

The fetus in an OP position may be delivered either spontaneously or by operative vaginal delivery. First, if the bony pelvic outlet is roomy and the perineum is somewhat relaxed from prior deliveries, rapid spontaneous OP delivery will often take place. Conversely, if the perineum is resistant to stretch, secondstage labor may be appreciably prolonged. During each expulsive efort, the head is driven against the perineum to a much greater degree than when the head position is OA. This leads to greater rates of third-and fourth-degree lacerations (Groutz, 2011; Melamed, 2013).

In some cases, spontaneous vaginal delivery from an OP position does not appear feasible or expedited delivery is needed. Here, manual rotation with spontaneous delivery from an OA position may be preferred. This technique is described fully in Chapter 29 (p. 560). Successful rotation rates range from 47 to 90 percent. And, as would be expected, lower rates of cesarean delivery, vaginal laceration, and maternal blood loss follow rotation to OA position and vaginal delivery (Le Ray, 2005; Sen, 2013; Shafer, 2006, 2011). Disadvantageously, manual rotation is linked with higher cervical laceration rates. Thus, careful inspection of the cervix following rotation is mandatory.

For exigent delivery, forceps or vacuum device can be applied to a persistent OP position. This is often performed in conjunction with an episiotomy. Also, if the head is engaged, the cervix fully dilated, and the pelvis adequate, forceps rotation may be attempted for those with suitable skills. These operative vaginal techniques are detailed in Chapter 29 (p. 561).

Infrequently, protrusion of fetal scalp through the introitus is the consequence of marked elongation of the fetal head from molding combined with formation of a large caput succedaneum. In some cases, the head may not even be engaged-that is, the biparietal diameter may not have passed through the pelvic inlet. In these, labor is characteristically long and descent of the head is slow. Careful palpation above the symphysis may disclose the fetal head to be above the pelvic inlet. Prompt cesarean delivery is appropriate.

At Parkland Hospital, spontaneous delivery or manual rotation is preferred for management of persistent OP position. When needed, either manual rotation to OA position followed by forceps delivery or forceps delivery from the OP position is used. If neither can be completed with ease and safety, cesarean delivery is performed.

Following complete emergence of the fetal head during vaginal delivery, the remainder of the body may not rapidly follow. The anterior fetal shoulder can become wedged behind the symphysis pubis and fail to deliver using normally exerted downward traction and maternal pushing. Because the umbilical cord is compressed within the birth canal, this dystocia is an emergency. Several maneuvers, in addition to downward traction on the fetal head and neck, may be performed to free the shoulder. This requires a team approach, in which efective communication and leadership are critical.

Consensus regarding a speciic definition of shoulder dystocia is lacking. Some focus on whether maneuvers to free the shoulder are needed, whereas others use the head-to-body delivery time interval as deining (Beall, 1998). Spong and coworkers (1995) reported that the mean head-to-body delivery time in normal births was 24 seconds compared with 79 seconds in those with shoulder dystocia. These investigators proposed that a head-to-body delivery time >60 seconds be used to define shoulder dystocia. Currently, however, the diagnosis continues to rely on the clinical perception that the normal downward traction needed for fetal shoulder delivery is inefective.

Because of these difering deinitions, the incidence of shoulder dystocia varies. One recent review cites a clinically useful average of 1 percent of all deliveries (Ouzounian, 2016). The incidence has increased in recent decades, likely due to increasing fetal birthweight (MacKenzie, 2007; 0verland, 2014). Increased identiication and documentation may also raise the incidence (Kim, 2016).

In general, shoulder dystocia poses greater risk to the fetus than to the mother. The main maternal risks are serious perineal tears and postpartum hemorrhage, usually from uterine atony but also from lacerations (Gauthaman, 2016; Rahman, 2009). In contrast, significant neonatal neuromusculoskeletal injury and asphyxia are concerns. These specific injuries are described in Chapter 33 (p. 630). In one review of 1177 shoulder dystocia cases, brachial plexus injury was diagnosed in 11 percent and clavicular or humeral fracture in 2 percent (Chauhan, 2014). MacKenzie and associates (2007) reviewed 514 cases. Of the neonates, 7 percent showed evidence of acidosis at delivery, and 1.5 percent required cardiac resuscitation or developed hypoxic ischemic encephalopathy (HIE). In another review of 200 cases, rates of severe fetal acidosis and HIE were each 0.5 percent if delivery was completed within 5 minutes. These rates rose to 6 and 24 percent, respectively, with delivery delays �5 minutes (Leung, 2011a).

Fetal macrosomia, maternal obesity, prolonged second-stage labor, and a prior event raise risks for shoulder dystocia (Mehta, 2004; Overland, 2009; Schummers, 2015). Although these factors are clearly associated with this complication, identification of individual instances before the fact has proved to be impossible. The American College of Obstetricians and Gynecologists (2017 c) reviewed studies and concluded that: 1.

Most cases of shoulder dystocia cannot be accurately predicted or prevented.

2.

Elective induction of labor or elective cesarean delivery for all women suspected of having a macrosomic fetus is not appropriate.

3.

Planned cesarean delivery may be considered for the nondiabetic woman with a fetus whose estimated fetal weight is > 5000 g or for the diabetic woman whose fetus is estimated to weigh >4500 g.

There is a corresponding rise in the incidence of shoulder dystocia with increasing birthweight (Acker, 1985; 0verland, 2012; Stotland, 2004). Commonly cited maternal characteristics associated with increased fetal birthweight are obesity, postterm pregnancy, multiparity, and diabetes (Jolly, 2003; Koyanagi, 2013). The combination of fetal macrosomia and maternal diabetes mellitus escalates the frequency of shoulder dystocia (Langer, 1991; Nesbitt, 1998). This predisposition may stem from the fact that fetuses of diabetic women have larger shoulder and extremity circumferences and greater shoulder-to-head and chest-to-head size diferences relative to comparable-weight fetuses of nondiabetic mothers (McFarland, 1998; Modanlou, 1982). That said, translating these specific measurements into stand-alone sonographic clinical thresholds has shown poor predictive sensitivity (Burkhardt, 2014).

Preventively, early labor induction has yielded conflicting results. In one study, approximately 800 women with suspected macrosomic fetuses were randomized either to early induction between 37 and 39 weeks or to expectant care (Boulvain, 2015). Dystocia rates were lowered by two thirds in the intervention group, and neither group sufered brachial plexus injury. Although not measured, this practice is balanced against morbidity of early delivery. Moreover, the poor accuracy of antepartum fetal weight prediction should be considered as well (Hoopmann, 2010; Mlin, 2016; Noumi, 2005). In contrast, an earlier randomized study of 284 women showed that rates of shoulder dystocia were not lowered by early induction at 38 weeks (Gonen, 1997).

As previously discussed, cesarean delivery may be considered to prevent shoulder dystocia. hat said, Rouse and Owen (1999) concluded that a prophylactic cesarean delivery policy for macrosomic fetuses would require more than 1000 cesarean deliveries with attendant morbidity to avert a single permanent brachial plexus injury.

he risk of recurrent shoulder dystocia ranges from 1 to 13 percent (Bingham, 2010; Moore, 2008; Ouzounian, 2013). For many women with prior shoulder dystocia, a trial of labor may be reasonable. he American College of Obstetricians and Gynecologists (2017 c) recommends that estimated fetal weight, gestational age, maternal glucose intolerance, and severity of prior neonatal injury be evaluated and risks and benefits of cesarean delivery discussed with any woman with a history of

FIGURE 27-5 The McRoberts maneuver. The maneuver consists of removing the legs from the stirrups and sharply flexing the thighs up toward the abdomen. The assistant is also providing suprapubic pressure simultaneously (arrow).

shoulder dystocia. After discussion, either mode of delivery may be appropriate.

Because shoulder dystocia cannot be accurately predicted, clinicians should be well versed in its management principles. Because of ongoing cord compression with this dystocia, one goal is to reduce the head-to-body delivery time. This is balanced against the second goal, which is avoiding fetal and maternal injury from aggressive manipulations. Accordingly, an initial gentle attempt at traction, assisted by maternal expulsive eforts, is recommended. Adequate analgesia is certainly ideal. Some clinicians advocate performing a large episiotomy to provide room for manipulations. Episiotomy itself does not lower brachial plexus injury rates but raises third-and fourthdegree laceration rates (Gurewitsch, 2004; Paris, 2011; SagiDain, 2015). Episiotomy may be elected to complete needed maneuvers.

After gentle traction, various techniques can be used to free the anterior shoulder from its impacted position behind the symphysis pubis. A more detailed discussion of these and the topic is found in Cunningham and Gilstrap s Operative Obstetrics, 3rd edition (Cunningham, 2017). Of these, moderate suprapubic pressure can be applied by an assistant, while downward trac tion is applied to the fetal head. Pressure is applied with the heel of the hand to the anterior shoulder wedged above and behind the symphysis. The anterior shoulder is thus either depressed or rotated, or both, so the shoulders occupy the oblique plane of the pelvis. Here, the anterior shoulder can be freed.

The McRoberts maneuver is often selected next if additional steps are needed. The maneuver consists of removing the legs from the stirrups and sharply lexing them up toward the abdomen. Suprapubic pressure is often concurrently applied (Fig. 27-5). Gherman and associates (2000) analyzed the McRoberts maneuver using x-ray pelvimetry. hey found that the procedure caused straightening of the sacrum relative to the lumbar vertebrae, rotation of the symphysis pubis toward the maternal head, and a decrease in the angle of pelvic inclination. Although this does not increase pelvic dimensions, pelvic rotation cephalad tends to free the impacted anterior shoulder. Gonik and coworkers (1989) tested the McRoberts position objectively with laboratory models and found that the maneuver reduced the forces needed to free the fetal shoul der. If unsuccessful, most move next either to free the posterior shoulder or to rotate the bisacromial diameter into one of the oblique diameters of the maternal pelvis.

With delivey of the posterior shoulder, the accoucheur carefully sweeps the posterior arm of the fetus across its chest, followed by deliveY of the arm (Fig. 27-6). If possible, the operator's ingers are aligned parallel to the long axis of the fetal humerus to lower bone fracture risks. The shoulder girdle is then rotated into one of the oblique diameters of the pelvis with subsequent delivery of the anterior shoulder.

Of rotational maneuvers, Woods (1943) reported that by progressively rotating the posterior shoulder 180 degrees in a corkscrew fashion, the impacted anterior shoulder could be released. his is frequently referred to as the Woods corkscrew maneuver (Fig. 27-7). Rubin (1964) recommended two maneuvers. First, the fetal shoulders are rocked from side to side by applying force to the maternal abdomen. If this is not successful, the pelvic hand reaches the most easily accessible fetal shoulder, which is then pushed toward the anterior surface of the chest. This maneuver most oten abducts both shoulders, which in turn produces a smaller bisacromial diameter. This permits displacement of the anterior shoulder from behind the symphysis (Fig. 27-8).

If the above are initially unsuccessful, they may be repeated, and finally other methods may be elected. With an allours maneuver, also called the Gaskin maneuver, the parturient rolls onto her knees and hands. Here, downward traction against the head and neck attempts to free the posterior shoulder (Bruner, 1998). Challenges with this include immobility from regional analgesia and time lost in patient repositioning.

In some, the posterior arm is inaccessible for delivery. Cluver and Hofmeyr (2009) describedposterior axila sling traction to deliver the posterior arm. With this alternative method, a suction catheter is threaded under the axilla and both ends are brought together above the shoulder. Upward and outward traction on the catheter loop delivers the shoulder. In a small series of 19 cases, this maneuver was successful in 18 cases. However, neonatal injury included three cases of humeral fracture and one permanent and four transient cases ofErb palsy (Cluver, 2015).

FIGURE 27-6 Delivery of the posterior shoulder for relief of shoulder dystocia. A. The operator's hand is introduced into the vagina along the fetal posterior humerus. B.The arm is splinted and swept across the chest, keeping the arm flexed at the elbow. C. The fetal hand is grasped and the arm extended along the side of the face. The posterior arm is delivered from the vagina.

....�. i" Jr-.. �

FIGURE 27-7 Woods maneuver. The hand is placed behind the posterior shoulder of the fetus. The shoulder is then rotated in a corkscrew manner so that the impacted anterior shoulder is released.

FIGURE 27-8 The second Rubin maneuver. A. The bisacromial diameter is aligned vertically. B. The more easily accessible fetal shoulder (the anterior is shown here) is pushed toward the anterior chest wall of the fetus (arrow). Most often, this results in abduction of both shoulders, which reduces the bisacromial diameter and frees the impacted anterior shoulder.

Deliberate fracture of the anterior clavicle using the thumb to press it toward and against the pubic ramus can be attempted to free the shoulder impaction. In practice, however, deliberate fracture of a large neonate's clavicle is diicult. If successful, the fracture will heal rapidly and is usually trivial compared with brachial nerve injury, asphyxia, or death.

he Zavanelli maneuver involves replacement of the fetal head into the pelvis followed by cesarean delivery (Sandberg, 1985). Terbutaline, 0.25 mg, is given subcutaneously to produce uterine relaxation. he irst part of the maneuver consists of returning the head to an OA or OP position. The operator flexes the head and slowly pushes it back into the vagina. Cesarean delivery is then performed. Sandberg (1999) reviewed 103 reported cases. It was successful in 91 percent of cephalic cases and in all cases of breech head entrapments. Despite successful replacement, fetal injuries were common bur may have resulted from the multiple manipulations used before the Zavanelli maneuver (Sandberg, 2007).

Symphysiotomy, in which the intervening symphyseal cartilage and much of its ligamentous support is cut to widen the symphysis pubis, is described in Chapter 28 (p. 548). It has been used successfully for shoulder dystocia (Goodwin, 1997; Hartield, 1986). Maternal morbidity can be signiicant due to urinary tract injury. Cleidotomy consists of cutting the clavicle with scissors or other sharp instruments and is usually done for a dead fetus (Schramm, 1983).

Hernandez and Wendel (1990) suggest use of a shoulder dystocia drill to better organize emergency management: 1. Call for help-mobilize assistants and anesthesia and pediatric personnel. Initially, a gentle attempt at traction is made. Drain the bladder if it is distended.

2.

A generous episiotomy may be desired at this time to aford room posteriorly.

3.

Suprapubic pressure is used initially by most practitioners because it has the advantage of simplicity. Only one assistant is needed to provide suprapubic pressure, while normal downward traction is applied to the fetal head.

4.

The McRoberts maneuver requires two assistants. Each assistant grasps a leg and sharply lexes the maternal thigh toward the abdomen.

These maneuvers will resolve most cases of shoulder dystocia. If the above listed steps fail, the following steps may be attempted, and any of the maneuvers may be repeated: 5.

Delivery of the posterior arm is attempted. With a fully extended arm, however, this is usually diicult to accomplish.

6.

Woods screw maneuver is applied.

7.

Rubin maneuver is attempted.

The American College of Obstetricians and Gynecologists (2017c) has concluded that no one maneuver is superior to another in releasing an impacted shoulder or reducing the chance of injury. Performance of the McRoberts maneuver, however, is deemed a reasonable initial approach. In one review of more than 2000 cases, Hofman and colleagues (2011) noted an 84-percent success rate with posterior shoulder delivery and comparable rates of neonatal injury compared with other standard methods. This contrasts with a review of 205 cases, in which posterior shoulder delivery yielded greater neonatal injury rates than rotational methods (Leung, 201i1b). Spain and associates (2015) found that duration rather than a speciic maneuver increased neonatal injury.

Importantly, progression from one maneuver to the next should be organized and methodical. As noted, the urgency to relieve the dystocia should be balanced against potentially lnJurious traction forces and manipulations. Lerner and coworkers (201l) in their evaluation of 127 shoulder dystocia cases reported that all neonates without sequelae from shoulder dystocia were born by 4 minutes. Conversely, most depressed neonates-57 percent-had head-to-body delivery intervals >4 minutes. The percentage of depressed neonates rose sharply after 3 minutes.

Shoulder dystocia training and protocols using simulationbased education and drills has evidence-based support. These tools improve performance and retention of drill steps (Buerkle, 2012; Crofts, 2008; Grobman, 201l). Their use has translated into improved neonatal outcome in some, but not all, investigations (Crofts, 2016; Fransen, 2017; Kim, 2016; Walsh, 201l). The American College of Obstetricians and Gynecologists (2012) also has created a Patient Safety Checklist to guide the documentation process with shoulder dystocia.

In 2014, 0.7 percent of deliveries in the United States were planned home births and 0.2 percent were unplanned (MacDorman, 2016). Of unplanned births in a 15-year epoch in Norway, 69 of 6027 or 1.1 percent resulted in fetal or neonatal death. This high rate was attributable to infection, prematurity, and placental abruption (Gunnarsson, 2017). Multiparity and distance from the hospital were ascribed risks (Gunnarsson, 2014). In the United States, youth, lack of prenatal care, minority race, and lower educational attainment were associated risks for unplanned home birth (Declercq, 2010).

In contrast, the demographics of women choosing planned home birth in the United States favor those who are white, nonsmoking, self-pay, college-educated, and multiparous (MacDorman, 2016). As perceived beneits, planned delivery at home for those with low-risk pregnancies results in fewer medical interventions that include labor augmentation, episiotomy, operative vaginal delivery, and cesarean delivery (Bolten, 2016; Cheyney, 2014). Regarding the safety of planned home birth, data from randomized trial are lacking, and large observational studies derive from heterogeneous care systems, whose results may not be generalizable. For example, several developed countries deliver at home a large volume of carefully screened women, delivered by midwives with substantial training and in a setting closely integrated with the local health-care system (Birthplace in England Collaborative Group, 2011; de Jonge, 2015; Hutton, 2016). The level of such coordination in the United States is less uniform.

Overall, risks of home births in the United States are small but greater than those of hospital delivery. Midwife-attended home births carry a neonatal mortality risk of 1.3 per 1000 births. This is a nearly fourfold greater rate compared with midwife-attended hospital births. The most common underlying causes of death are those attributed to labor and delivery events, to congenital anomalies, and to infection. Of neonatal injuries, rates of neonatal seizure and serious neurological dysfunction are similarly elevated in home-birth groups (Grunebaum, 2013, 2014, 2017; Snowden, 2015; Wasden, 2016). Importantly, substantial risks attend home birth for those with prior cesarean delivery, with breech presentation, and with multifetal gestation (Cheyney, 2014; Cox, 2015). The American College of Obstetricians and Gynecologists (2017b) considers these to be absolute contraindications. Further, the College considers accredited hospitals and birthing centers to be the safest site for birth but recognizes the autonomy of the well-counseled patient.

As one option for pain relief, some women choose to spend part of first-stage labor in a large water tub. With this practice, one Cochrane review found lower rates of anesthesia block use and no greater adverse neonatal or maternal efects compared with traditional labor (Cluett, 2009).

For delivery, however, water birth carries greater concern for neonatal harm and without proven benefits. Case reports describe aspiration leading to fresh-water drowning (Pinette, 2004). The risk of cord avulsion during water birth approximates 3 per 1000 births, and stems primary from abruptly bringing the newborn out of the water (Schafer, 2014). Last, case reports also enumerate serious infections, which emphasize the need for rigorous sanitizing protocols. hat said, in most large studies comparing land and water births, overall maternal or neonatal infection rates are not increased (Bovbjerg, 2016; Burns, 2012; Thoeni, 2005). In sum, several reviews comment on study shortcomings and isolated complications but do not identiy definitive evidence for overall greater rates of neonatal harm from water birth in low-risk populations (Davies, 2015; Taylor, 2016). However, given the paucity of robust data and potential for serious complications, the American College of Obstetricians and Gynecologists (2016a) currently recommend that "birth occur on land, not in water."

This practice refers to medically unnecessary vulvar and perineal modification. In the United States, it is a federal crime to perform unnecessary genital surgery on a girl younger than 18 years. That said, forms of female genital mutilation are practiced in countries throughout Africa, the Middle East, and Asia. As many as 200 million women worldwide have undergone one of these procedures, and approximately 513,000 girls in the United States were at risk for this practice in 2012 (Goldberg, 2016; UNICEF, 2016). Cultural sensitivity is imperative, because many women may be ofended by the suggestion that they have been assaulted or mutilated (merican College of Obstetricians and Gynecologists, 2014).

The World Health Organization (2008) classifies genital mutilations into four types (Table 27-1). Long-term complications from surgery and its associated scarring include infertility, genital pain, diminished sexual quality of life, and propensity for urogenital infection (Almroth, 2005; Andersson, 2012; Nour, 2015). In general, women with significant symptoms following type III procedures are candidates for corrective surgery. Specifically, division of midline scar tissue to reopen the vulva is termed deinibulation.

Female genital mutilation has been associated with some adverse maternal and neonatal complications. The World

TABLE 27-1. World Health Organization Classification of Female Genital Mutilation

Type I Partial or total removal of the clitoris and/or prepuce

Type II Partial or total removal of the clitoris and the labia minora, with or without labia majora excision

Type III Partial or total labial minora and/or majora excision, followed by fusion of the wound, termed infibulation, to cover and narrow the vagina. With or without clitoridectomy

Type IV Pricking, piercing, incising, scraping, cautery, or other injury to female genitalia

Adapted from the World Health Organization, 2008.

Health Organization (2006, 2008) estimated that these proce dures increased perinatal morbidity rates by 10 to 20 per 1000.

Small increased risks for prolonged labor, cesarean delivery, and postpartum hemorrhage are also found (Berg, 2014; Chibber, 2011; Wuest, 2009). Importantly, the psychiatric consequences can be profound.

To prevent obstetrical complications, deinibulation can be performed either antepartum or intrapartum (Fig. 27-9) (Esu, 2017). In women not undergoing deinibulation, anal sphincter tear rates with vaginal delivery may be increased (Berggren, 2013; Rodriguez, 2016). In our experiences, intrapartum deinibulation in many cases allows successful vaginal delivery without major complications.

hese surgeries are performed with increasing frequency in reproductive-aged women, and thus pregnancy following these procedures is not uncommon. Logically, there are concerns for symptom recurrence following vaginal delivery, and high-quality data to aid evidenced-based decisions are limited. For women with prior stress urinary incontinence surgery, slightly greater protection against postpartum incontinence is gained by elective cesarean delivery (Pollard, 2012; Pradhan, 2013). Stated another way, most women with prior corrective surgery for incontinence can be delivered vaginally without symptom recurrence. Also, cesarean delivery is not always protective. Obviously, symptom recurrence and the need for additional vaginal surgery should be weighed against the surgical risk of cesarean delivery (Groenen, 2008). In those with prior surgeries for anal incontinence or pelvic organ prolapse, only scant information regarding outcomes is available. Such cases require individualization.

Rarely, delivery can be obstructed by extreme hydrocephaly, by body stalk anomaly, or by massive fetal abdominal enlargement from a greatly distended bladder, ascites, or organomegaly (Costa, 2012; Sikka, 2011). With milder forms of hydrocephaly, if the biparietal diameter is < 10 cm or if the head circumference is <36 cm, then vaginal delivery may be permitted (Anteby, 2003).

FIGURE 27-9 Deinfibulation. Although not shown here, lidocaine is first infiltrated along the planned incision if regional analgesia is not in place already. As protection, two fingers of one hand are insinuated behind the shelf created by fused labia but in front of the urethra and crowning head. The shelf is then incised in the midline. After delivery, the raw edges are sutured with rapidly absorbable material to secure hemostasis. (Reproduced with permission from Hawkins JS: Lower genital tract procedures. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 201o7.)

In rare cases in which neonatal death has occurred or is certain due to associated anomalies, vaginal delivery may be reasonable, but the head or abdomen must be reduced in size for delivery. Removal of luid by cephalocentesis or paracentesis with sonographic guidance can be performed intrapartum. As described on page 523, cleidotomy can shorten the bisacromial diameter. For hydrocephalic fetuses that are breech, cephalocentesis can be accomplished suprapubically when the aftercoming head enters the pelvis. Currently, these practices are more germane in developing countries.

• Delivery of the Placenta hird-stage labor begins immediately after fetal birth and ends with placental delivery. Goals include delivery of an intact placenta and avoidance of uterine inversion or postpartum hemorrhage. The latter two are grave intrapartum complications and constitute emergencies, as described in Chapter 41 (p. 755).

Immediately after newborn birth, uterine fundal size and consistency are examined. If the uterus remains irm and there is no unusual bleeding, watchful waiting until the placenta separates is the usual practice. Neither massage nor downward fundal pressure is employed, but the fundus is frequently palpated to ensure that it does not become atonic and illed with blood from placental separation. To prevent uterine inversion, umbilical cord traction must not be used to pul the placenta rom the uterus. Signs of separation include a sudden gush of blood into the vagina, a globular and firmer fundus, a lengthening of the umbilical cord as the placenta descends into the vagina, and elevation of the uterus into the abdomen. With the last, the placenta, having separated, passes down into the lower uterine segment and vagina. Here, its bulk pushes the uterine body upward.

These signs appear within minutes after newborn delivery, and the median time ranges from 4 to 12 minutes (Combs, 1991; Frolova, 2016; Shinar, 2016b). Once the placenta has detached from the uterine wall, the mother may be asked to bear down, and the intraabdominal pressure often expels the placenta into the vagina. These eforts may fail or may not be possible because of analgesia. After ensuring that the uterus is contracted irmly, the umbilical cord is kept slightly taut but is not pulled. Pressure is exerted by a hand wrapped around the fundus to propel the detached placenta into the vagina (Fig. 27-10). Concurrently, the heel of the hand exerts downward pressure between the symphysis pubis and the uterine fundus. This also aids inversion prevention. Once the placenta passes through the introitus, pressure on the uterus is relieved. The placenta is then gently lifted away. Care is taken to prevent placental membranes from being torn of and left behind. If the membranes begin to tear, they are grasped with a clamp and removed by gentle teasing (Fig. 27-11).

FIGURE 27-10 Expression of placenta. Note that the hand is not trying to push the fundus of the uterus through the birth canal! As the placenta leaves the uterus and enters the vagina, the uterus is elevated by the hand on the abdomen while the cord is held in position. The mother can aid in the delivery of the placenta by bearing down. As the placenta reaches the perineum, the cord is lifted, which in turn lifts the placenta out of the vagina.

FIGURE 27-11 Membranes that were somewhat adhered to the uterine lining are separated by gentle traction with ring forceps.

• Management of the Third Stage

Practices within the third stage of labor may be broadly considered as either expectant or active management. Expectant management involves waiting for placental separation signs and allowing the placenta to deliver either spontaneously or aided by nipple stimulation or gravity (World Health Organization, 2012). In contrast, active management of third-stage labor consists of early cord clamping, controlled cord traction during placental delivery, and immediate administration of prophylactic oxytocin. The goal of this triad is to limit postpartum hemorrhage (Begley, 2015; Jangsten, 2011; Westhof, 2013).

As noted earlier, delayed cord clamping does not increase postpartum hemorrhage rates, and thus early clamping is a less important component of this trio. Similarly, cord traction may also be less critical (Deneux-haraux, 2013; Du, 2014; Giilmezoglu, 2012). Uterine massage following placental delivery is recommended by many, but not all, to prevent postpartum hemorrhage. We support this with the caveat that evidence for this practice is not strong (Abdel-Aleem, 2010).

Therefore, utero tonics play an essential role to decrease postpartum blood loss. Choices include oxytocin (Pitocin), misoprostol (Cytotec), carboprost (Hemabate), and the ergots, namely ergonovine (Ergotrate) and methylergonovine (Methergine). In addition, a combination agent of oxytocin and ergonovine (Syntometrine) is used outside the United States. Also in other countries, carbetocin (Duratocin), a long-acting oxytocin analogue, is available and efective for hemorrhage prevention during cesarean delivery (Attilakos, 2010; Su, 2012). Of these, the World Health Organization (2012) recommends oxytocin as a first-line agent. Ergot-based drugs and misoprostol are alternatives in settings that lack oxytocin.

Utero tonics may be given before or after placental expulsion without afecting rates of postpartum hemorrhage, placental retention, or third-stage labor length (Soltani, 2010). If they are given before delivery of the placenta, however, they may entrap an undiagnosed, undelivered second (Win. hus, abdominal palpation should conirm no additional fetuses. Notably, this concern is less relevant with current widespread sonography use.

Synthetic oxytocin is identical to that produced by the posterior pituitary. Its action is noted at approximately 1 minute, and it has a mean half-life of 3 to 5 minutes. When given as a bolus, oxytocin can cause profound hypotension. Secher and coworkers (1978) reported that an intravenous bolus of 10 units of oxytocin caused a marked transient fall in blood pressure with an abrupt increase in cardiac output. Svansrrom and associates (2008) conirmed those findings. hese hemodynamic changes could be dangerous for women hypovolemic from hemorrhage or those with certain types of cardiac disease. Thus, oxytocin should be given as a dilute solution by continuous intravenous infusion or as an intramuscular injection.

Water intoxication can result from the antidiuretic action of high-dose oxytocin if administered in a large volume of electro lyte-free dextrose solution (Whalley, 1963). Thus, if oxytocin is to be administered in high doses for a considerable period of time, its concentration should be increased rather than increas ing the infusion flow rate.

Despite the routine use of oxytocin, no standard prophylactic dose has been established for its use following either vaginal or cesarean delivery. Our practice is to add 20 units (2 mL) of oxytocin per liter of infusate. his solution is administered after delivery of the placenta at a rate of 10 to 20 mUmin-200 to 400 mU/min-for a few minutes until the uterus remains irmly contracted and bleeding is controlled. he infusion rate then is reduced to 1 to 2 mUmin until the mother is ready for transfer from the recovery suite to the postpartum unit. The infusion is usually then discontinued. For women without intravenous access, 10 units of intramuscular oxytocin are injected.

Ergonovine and methylergonovine have similar activity levels in myometrium, and only methylergonovine is currently manufactured in the United States. These ergot alkaloid agents do not provide superior protection against postpartum hemorrhage compared with oxytocin. \10reover, safety and tolerability are greater with oxytocin (Liabsuetrakul, 2011). For these reasons, ergot alkaloid agents are considered second-line for prevention of postpartum hemorrhage. If selected, a 0.2-mg dose of methylergonovine is slowly given intravenously in a period not less than 60 seconds to avoid sudden hypertension (Novartis, 2012). Methylergonovine is relatively contraindicated in the hypertensive woman.

Misoprostol is a prostaglandin E, analogue, which has proved inferior to oxytocin for postpartum hemorrhage prevention (Tun:alp, 2012). However, in resource-poor settings that lack oxytocin, misoprostol is suitable for hemorrhage prophylaxis and is given as a single oral 600-�g dose (Mobeen, 2011; World Health Organization, 2012). Notably, although oxytocin is preferred for prevention of hemorrhage, ergot alkaloids and prostaglandins playia greater role in postpartum hemorrhage treatment, discussed in Chapter 41 (p. 759).

• Manual Removal of Placenta

In approximately 2 percent of singleton births, the placenta may not deliver promptly (Cheung, 2011). Three possibilities include pacenta adherens, in which uterine contractions are insu.cient to detach the placenta; lower uterine segment constriction and a detached but trapped placenta; or a morbidly adherent placenta. Consistent risks for retained placenta include stillbirth, prior cesarean delivery, prior retention, and preterm delivery (Belachew, 2014; Coviello, 2015; Endler, 2014; Nikolajsen, 2013). For the last, in one study with nearly 46,000 deliveries, analysis predicted that 90 percent of placentas would spontaneously deliver by 180 minutes for gestations at 20 weeks; 21 minutes at 30 weeks; and 14 minutes at 40 weeks (Dombrowski, 1995).

Postpartum hemorrhage can complicate a retained placenta, and bleeding risk accrues with third-stage length. Thus, in the absence of bleeding, some recommend expectant management for 30 minutes, whereas others use a 15-minute threshold (Cummings, 2016; Deneux-Tharaux, 2009; Shinar, 2016a). he World Health Organization (2012) cites a 60-minute threshold. Notably, if brisk bleeding ensues and the placenta cannot be delivered by standard technique, manual removal of the placenta is indicated (Fig. 27-12). When performed, some administer a single dose of intravenous antibiotics, however, one systematic review of observational studies found no beneits (Chibueze, 2015). Although the American College of Obstetricians and Gynecologists (2016c) concludes that data neither support nor refute this practice, the World Health Organization (2012) recommends prophylaxis. At our institution, we administer a single dose to women not already receiving antibiotics.

The hour immediately following delivery of the placenta is critical. During this time, lacerations are repaired. Although utero tonics are administered, postpartum hemorrhage as the result of uterine atony is most likely at this time. Hematomas may expand. Consequently, uterine tone and the perineum are frequently evaluated. The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (20 17b) recommend that maternal blood pressure and pulse be recorded immediately after delivery and every 15 minutes for the first 2 hours. The placenta, membranes, and umbilical cord are examined for completeness and for anomalies, as described in Chapter 6 (p. 111).

Lower genital tract lacerations may involve the cervix, vagina, or perineum. Those of the cervix and vagina are described in Chapter 41 (p. 763). Those of the perineum oten follow vaginal delivery, and most are irst-and second-degree lacerations. Lacerations are classified by their depth, and complete deinitions and visual examples are given in Figure 27-13. Of these, third-degree lacerations relect anal sphincter injury and are now subcategorized as: (3c) EAS plus internal anal sphincter (lAS) tears.

FIGURE 27-12 Manual removal of placenta. A. One hand grasps the fundus and the other hand is inserted into the uterine cavity and the fingers are swept from side to side as they are advanced. B. When the placenta detaches, it is grasped and removed.

FIGURE 27-13 1. First-degree perineal laceration: injury to only the vaginal epithelium or perineal skin. 2. Second-degree laceration: injury to perineum that spares the anal sphincter complex but involves the perineal muscles, which are the bulbospongiosus and superficial transverse perineal muscles. 3a.Third-degree laceration: <50 percent of the external anal sphincter (EAS) is torn. 3b.Third-degree laceration: >50 percent of the EAS is torn, but the internal anal sphincter (lAS) remains intact. 3c.Third-degree laceration: EAS and lAS are torn.

4. Fourth-degree laceration: the perineal body, entire anal sphincter complex, and anorectal mucosa are lacerated. (Reproduced with permission from Kenton K, Mueller M: Episiotomy and obstetric anal sphincter lacerations. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds):

Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 201o7.) hird-and fourth-degree lacerations are considered obstetrical anal sphincter injuries (OASIS), and their combined incidence varies from 0.5 to 5 percent (Blondel, 2016; Friedman, 2015).

ity, midline episiotomy, persistent OP position, operative vaginal delivery, Asian race, short perineal length, and increasing fetal birthweight (Ampt, 2013; Dua, 2009; Gurol-Urganci, 2013;

Landy, 2011). Mediolateral episiotomy is protective in most, but not all, studies Ganga, 2014; Raisanen, 2011; Shmueli, 2016).

Morbidity rates rise as laceration severity increases. Compared with simpler lacerations, anal sphincter injuries are associated with greater blood loss and puerperal pain. Wound disruption and infection rates are other risks (Goldaber, 1993; Lewicy-Gaupp, 2015). Stock and coworkers (2013) reported that approximately 7 percent of 909 OASIS lacerations had complications. Long term, anal sphincter injuries are linked with approximately doubled rates of fecal incontinence compared with vaginl delivery without OASIS (Evers, 2012; Gyhagen, 2014). Data on long-term dyspareunia are limited, and rates are increased in some but not all studies (MoS, 2008; Otero, 2006; Salim, 2014; Sundquist, 2012).

To ensure appropriate repair, identiication and correct categorization is essential. Diagnosis rates of OASIS improve with clinical experience (ndrews, 2006). Intrapartum endoanal ultrasound, performed in research studies, also boosts detection, and rates of clinically occult tears in primiparas range from 6 to 12 percent (Corton, 2013; Faltin, 2005; Ozyurt, 2015). hat said, few data currently support routine intrapartum endoanal sonography, and the American College of Obstetricians and Gynecologists (20 16b) does not recommended i t (Walsh, 2015).

Women with a prior OASIS have a higher recurrence rate compared with multiparas without prior OASIS (Baghestan, 2012; Edozien, 2014; Elfaghi, 2004). That said, the risk mirrors that of primiparas in the general population and is low (Basham, 2013; Boggs, 2014; Priddis, 2013). Fetal macrosomia and operative vaginal delivery are notable risks in this cohort of parturients and can influence counseling in future pregnancies. Speciically, patients may choose to deliver by cesarean to avoid repeat OASIS. his consideration may be most pertinent for those with prior postpartum anal incontinence, with OASIS complications requiring corrective surgery, or with psychological trauma (American College of Obstetricians and Gynecologists, 2016b). However, planned cesarean delivery is balanced against its associated operative risks discussed in Chapter 30 (p. 568).

In contrast to spontaneous lacerations, perineotomy is intended incision of the perineum. Episiotomy is incision of the pudendum-the external genital organs. In common parlance, however, the term episiotomy often is used synonymously with perineotomy, a practice that we follow here. Obstetrical textbooks and organizational guidelines difer considerably in their description of episiotomy techniques. Kalis and associates (2012) have presented a classification, and we agree with the need for terminology standardization.

Midline and mediolateral episiotomies are the two main types and vary by the angle of perineal incision. Involved structures mirror those found with second-degree laceration, and their repairs are analogous. The midline episiotomy begins at the fourchette, incises the perineal body in the midline, and ends well before the external anal sphincter is reached. he incision length varies from 2 to 3 cm depending on perineal length and degree of tissue thinning. The mediolateral episiotomy begins at the midline of the fourchette and is directed to the right or left at an angle 60 degrees of the midline (Fig. 27-14). This angle accounts for perineal anatomy distortion during crowning and ultimately yields an incision 45 degrees of the midline for suturing (El-Din, 2014; Kalis, 2011). The lateral episiotomy begins at point 1 to 2 cm lateral from the midline. It too is angled toward either the right or the left ischial tuberosity.

Before episiotomy, analgesia may be provided by existing labor regional analgesia, by bilateral pudendal nerve blockade, or by local infiltration of I-percent lidocaine. Some instead advocate 2.5-percent lidocaine-prilocaine cream (EMLA cream), but this requires application an hour before expected delivery, which may be logistically diicult (Franchi, 2009; Kargar, 2016).

If episiotomy is performed unnecessarily early, incisional bleeding may be considerable before delivery. If it is performed too late, lacerations will not be prevented. Typically, episiotomy is completed when the head is visible during a contraction to a diameter of approximately 4 cm, that is, crowning. When used in conjunction with forceps delivery, most perform an episiotomy after application of the blades.

Few data directly compare midline and mediolateral types. As noted, midline episiotomy has a greater likelihood of associated anal sphincter lacerations (Coats, 1980; de Leeuw, 2001). Shortterm rates of self-perceived pain and dyspareunia are similar or increased with mediolateral episiotomy (Fodstad, 2013, 2014; Sartore, 2004).

head crowns. Fingers are insinuated between the perineum and head. The incision begins in the midline and is directed toward the ipsilateral ischial tuberosity at an angle 60 degrees of the midline. (Reproduced with permission from Kenton K, Mueller M: Episiotomy and obstetric anal sphincter lacerations. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 2017.)

Even fewer studies compare lateral episiotomy to either mediolateral or midline. One randomized trial compared lateral and mediolateral tpes in nulliparas. Groups did not difer in pain scores, in sexual qulity of life, or in vaginal or perineal trauma, including OASIS (Karbanova, 2014a,b; Necesalova, 2016). The authors also reported that mediolateral episiotomies required less time and suture for the repair. Thus, among the three, mediolateral episiotomy may be the preferred incision to reduce OASIS rates.

In the past, routine episiotomy was practiced to avoid a ragged laceration and to limit postoperative pain and anal sphincter injury rates. But, a Cochrane review of randomized trials showed lower rates of severe perineal/vaginal trauma in women managed with a restrictive, that is, selective use of episiotomy for spontaneous delivery rather than with routine episiotomy Qiang, 2017). Importantly, this review did not discern between midline and mediolateral episiotomies.

The American College of Obstetricians and Gynecologists (20 16b) has concluded that restricted use of episiotomy is preferred to routine use. We are of the view that the procedure should be applied selectively for appropriate indications. Thus, episiotomy can be considered for indications such as shoulder dystocia, breech delivery, fetal macrosomia, operative vaginal deliveries, persistent OP positions, markedly short perineal length, and other instances in which failure to perform an episiotomy will result in signiicant perineal rupture. The final rule is that there is no substitute for surgical judgment and common sense.

FIGURE 27-15 Mediolateral episiotomy repair. A. The vaginal epithelium and deeper tissues are closed with a single, continuous, locking suture. The angle seems less acute now (approximately 45°) since the perineum is no longer distended. B. Ater the vaginal component of the laceration is repaired, deeper perineal tissues are reapproximated by a single, continuous, nonlocking suture. Small episiotomies may not require this deeper layer. C. With a similar continuous, non locking technique, the superficial transverse perineal and bulbospongiosus muscles are reapproximated. D. Last, the perineal skin is closed using a subcuticular stitch. (Reproduced with permission from Kenton K, Mueller M: Episiotomy and obstetric anal sphincter lacerations. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 201•7.)

With this new approach, epIsIotomy rates have dropped.

Oliphant and coworkers (2010) used the National Hospital Discharge Survey to analyze episiotomy rates between 1979 and 2006 in the United States. hey noted a 75-percent decline in the age-adjusted episiotomy rate. In the United States in 2012 episiotomy was performed in approximately 12 percent of vaginal births (Friedman, 2015).

Typically, perineal repairs are deferred until the placenta has been delivered. his policy permits undivided attention to the signs of placental separation and delivery. A further advantage is that the repair is not interrupted or disrupted by placenta delivery. his is especially true if manual removal must be performed. The major disadvantage is continuing blood loss until the repair is completed. Direct pressure from an applied gauze sponge will help to limit this volume.

For suitable repair, an understanding of perineal support and anatomy is necessary and is discussed in Chapter 2 (p. 19). Adequate analgesia is imperative, and women without regional analgesia can experience high levels of pain during perineal suturing. Again, locally injected lidocaine can be used solely or asia supplement to bilateral pudendal nerve blockade. In those with epidural analgesia, additional dosing may be necessary.

First-degree lacerations do not always require repair, and sutures are placed to control bleeding or restore anatomy. Here, few data guide suture selection, and ine-gauge absorbable or delayed-absorbable suture or adhesive glue is suitable.

Second-degree laceration correction as well as midline and mediolateral episiotomy repairs include similar steps. Namely, these close the vaginal epithelium and reapproximate the bulbospongiosus and supericial transverse perineal muscles during restoration of the perineal body (Figs. 27-15 and 27-16). For this, most studies support a continuous

FIGURE 27-16 Midline episiotomy repair. A. An anchor stitch is placed above the wound apex to begin a running, locking closure with 2-0 suture to close the vaginal epithelium and deeper tissues and reapproximate the hymeneal ring. B. A transition stitch redirects suturing from the vagina to the perineum. C. The superficial transverse perineal and bulbospongiosus muscles are reapproximated using a continuous, non locking technique with the same length of suture. This aids restoration of the perineal body for long-term support. D. The continuous suture is then carried upward as a subcuticular stitch. The final knot is tied proximal to the hymeneal ring. (Reproduced with permission from Kenton K, Mueller M: Episiotomy and obstetric anal sphincter lacerations. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 201•7.) suturing method, which is faster than placing interrupted sutures and, with few exceptions, yields less pain (Grant, 2001; Kettle, 2012; Kindberg, 2008; Valenzuela, 2009). Blunt needles are suitable and likely decrease the incidence of needle-stick injuries (El-Refaie, 2012; Mornar, 2008). Commonly used suture materials are 2-0 polyglactin 910 (Vicryl) or chromic catgut. With the former, a decrease in postsurgical pain and lower risk of wound dehiscence are cited as major advantages Qallad, 2016; Kettle, 2010). Closures with traditional polyglactin 910, however, occasionally require removal of residual suture from the repair site because of pain or dyspareunia. This disadvantage may be reduced by using a rapidly absorbed polyglactin 910 (Vicryl Rapide) (Bharathi, 2013; Kettle, 2002; Leroux, 2006).

For third-degree laceration repair, two methods are available to repair the external anal sphincter. The irst is an endto-end technique, which we prefer, and is shown in Figure 27-17. Initially, the cut ends of the external anal sphincter, which often retract, are isolated and brought to the midline. Importantly, the strength of this closure is derived from the connective tissue surrounding the sphincter-often called the capsule-and not the striated muscle. Thus, serial interrupted

FIGURE 27-17 In overview, with end-to-end approximation of the external anal sphincter (EAS), a suture is placed through the EAS muscle, and four to six simple interrupted 2-0 or 3-0 sutures of polyglactin 910 are placed at the 3, 6, 9, and 12 o'clock positions through the perisphincter connective tissue. To begin, disrupted ends of the striated EAS muscle and capsule are identified and grasped. The first suture is placed posteriorly to maintain clear exposure. Another suture is then placed inferiorly at the 6 o'clock position. The sphincter muscle fibers are next reapposed by a figure-of-eight stitch. Last, the remainder of the fascia is closed with a stitch placed anterior to the sphincter cylinder and again with once placed superior to it. (Reproduced with permission from

Kenton K, Mueller M: Episiotomy and obstetric anal sphincter lacerations. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative ObstetriCS, 3rd ed. New York, McGraw-Hili Education, 201o7.) sutures incorporate sphincter fibers and perisphincter connective tissue, to bring sphincter ends together. here are few evidence-based data to guide suture selection for sphincter repair, but delayed-absorbable material can provide sustained tensile strength during healing. This theory is supported by the above study by J all ad and coworkers (2016), which showed higher perineal breakdown rate following OASIS repair with chromic gut.

With the overlapping technique, the ends of the external anal sphincter are brought to the midline and lie atop one another. This method is only suitable for type 3c lacerations-those involving the external and internal anal sphincter. Two rows of mattress sutures travel through both sphincter ends to recreate the anal ring. In comparing the two methods, neither yields superior long-term anatomical or functional results (Farrell, 2012; Fernando, 2013; Fitzpatrick, 2000). Also with type 3c lacerations, the lAS is repaired before the EAS and is described next.

With fourth-degree laceration repairs, the torn edges of the rectal mucosa are reapproximated (Fig. 27-18). At a point 1 cm proximal to the wound apex, sutures are placed approximately 0.5 cm apart in the rectal muscularis and do not enter the ano rectal lumen. Clinicians oten use 4-0 polyglactin 910 or chromic gut for this running suture line. Some recommend a second reinforcing layer above this (Hale, 2007). If this is not done, then the next layer to cover the anorectal mucosa is formed by reapproximation of the internal anal sphincter. his running, nonlocking closure is completed with 3-0 or 4-0 suture (see Fig. 27-18B). Following any repair, needle and sponge counts are reconciled and recorded in the delivery note.

For reduction of infectious morbidity associated with anal sphincter lacerations, a single dose of antibiotic at the time of repair is recommended by the American College of Obstetricians and Gynecologists (20 16c). his practice is supported by evidence (Buppasiri, 2014; Duggal, 2008; Lewicky-Gaupp, 2015; Stock, 2013). A single dose of a secondgeneration cephalosporin is suitable, or clindamycin for penicillin-allergic women. With OASIS, postoperatively, stool softeners are prescribed for a week, and enemas and suppositories are avoided.

Unfortunately, normal function is not always ensured even with correct and complete surgical repair. Some women may experience continuing fecal incontinence caused by injury to the innervation of the pelvic Boor musculature (Roberts, 1990).

FIGURE 27-18 A. Suturing of the anorectal mucosa begins above the laceration apex using a continuous, non locking method with finegauge absorbable suture such as 3-0 or 4-0 chromic gut or polyglactin 910. Sutures are placed through the anorectal submucosa approximately 0.5 cm apart down to the anal verge. B. A second reinforcing layer uses 3-0 delayed-absorbable suture in a continuous, nonlocking fashion. This incorporate the torn ends of the internal anal sphincter (lAS), which can be identified as the glistening white fibrous structure lying between the anal canal submucosa and the fibers of the external anal sphincter. In many cases, the lAS retracts laterally and must be sought and retrieved for repair. (Reproduced with permission from Kenton K, Mueller M: Episiotomy and obstetric anal sphincter lacerations. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 201o7.)

Initially, locally applied ice packs help reduce swelling and allay discomfort (de Souza Bosco Paiva, 2016). In subsequent days, warm sitz baths aid comfort and hygiene. Additionally, a small squirt botde of warm water can cleanse the site after voiding or stooling. For pain, topical application of 5-percent lidocaine ointment was not efective in relieving episiotomy or perineal laceration discomfort in one randomized trial (Minassian, 2002). Oral analgesics containing codeine provide considerable relie. For lesser degree of discomfort, NSAID tablets can be given.

Because pain may signal a large vulvar, paravaginal, or ischiorectal fossa hematoma or perineal cellulitis, these sites should be examined carefully if pain is severe or persistent. Management of these complications is discussed in Chapters 37 and 41 (pp. 674 and 764). In addition to pain, urinary retention may complicate episiotomy recovery (Mulder, 2012, 2016). Its management is described in Chapter 36 (p. 660).

For those with second-degree lacerations or anal sphincter tears, intercourse is usually proscribed until after the irst puerperal visit at 6 weeks. Compared with women with intact perineum, those with perineal trauma show higher rates of delayed intercourse at 3 and 6 months, but not at 1 year (McDonald, 2015; Rldestad, 2008; Signorello, 2001).

Abdel-Aleem H, Singata M, Abdel-Aleem M, et al: Uterine massage to reduce postpartum hemorrhage after vaginal delivery. Int ] Gynaecol Obstet 111(1):32,r2010 Acker DB, Sachs BP, Friedman EA: Risk factors for shoulder dystocia. Obstet

Gynecol 66(6):762, 1985

Almroth L, Elmusharaf S, El Hadi N, et al: Primary infertility ater genital mutilation in girlhood in Sudan: a case-control study. Lancet 366:385, 2005

Al-Wassia H, Shah PS: Eicacy and safety of umbilical cord milking at birth: a systematic review and meta-analysis.]AMA Pediatr 169(1):18, 2015 American Academy of Pediatrics:

Delayed umbilical cord clamping after birth.

Pediatrics 0957,r2017a

American Academy of Pediatrics, American College of Obstetricians and Gynecologists: Guidelines for Perinatal Care, 8th ed. Elk Grove Village, AAP,r2017b

American College of Obstetricians and Gynecologists: Documenting shoulder dystocia. Patient Safety Checklist No.r6, August 2012

American College of Obstetricians and Gynecologists: Guidelines for Women's Health Care, 4th ed. Washington, ACOG, 2014

American College of Obstetricians and Gynecologists: Immersion in water during labor and delivery. Committee Opinion No. 679, November 2016a

American College of Obstetricians and Gynecologists: Prevention and management of obstetric lacerations at vaginal delivery. Practice Bulletin No. 165, July 2016b

American College of Obstetricians and Gynecologists: Prophylactic antibiotics in labor and delivery. Practice Bulletin No. 120, June 2011, Reairmed 2016c

American College of Obstetricians and Gynecologists: Delayed umbilical cord clamping after birth. Committee Opinion No. 684, January 2017a American College of Obstetricians and Gynecologists: Planned home birth.

Committee Opinion No. 697, April

American College of Obstetricians and Gynecologists: Shoulder dystocia. Practice Bulletin No. 178, November 2002, Reairmed May 2017c

Ampt A], Ford ]B, Roberts CL, et al: Trends in obstetric anal sphincter injuries and associated risk factors for vaginal singleton term births in New South Wales 2001-2009. Aust N Z] Obstet Gynaecol 53(1):9, 2013

Andersson 0, Hellstrom-Westas L, Andersson D, et al: Efect of delayed versus early umbilical cord clamping on neonatal outcomes and iron status at 4 months: a randomised controlled trial. BM] 343:d7157, 2011

Andersson 0, Hellstrom-Westas L, Andersson D, et al: Efects of delayed compared with early umbilical cord clamping on maternal postpartum hemorrhage and cord blood gas sampling: a randomized trial. Acta Obstet Gynecol Scand 92(5):567, 2013

Andersson SH, Rymer ], Joyce OW, et al: Sexual quality of life in women who have undergone female genital mutilation: a case-control study. B]OG 119(13):1606,r2012

Andrews V, Sultan AH, Thakar R, et al: Occult anal sphincter injuriesBmyth or reality? B]OG 113:195,r2006

Anteby EY, Yagel S: Route of delivery of fetuses with structural anomalies. Eur ] Obstet Gynecol Reprod Bioi 106(1):5,2003

Attilakos G, Psaroudakis 0, Ash], et al: Carbetocin versus oxytocin for the prevention of postpartum haemorrhage following caesarean section: the results of a double-blind randomised trial. B]OG 117(8):929,r2010

Backes CH, Rivera BK, Haque U, et al: Placental transfusion strategies in very preterm neonates: a systematic review and meta-analysis. Obstet Gynecol 124(1):4,r2014

Baghestan E, Irgens LM, Bordalll PE: Risk of recurrence and subsequent delivery after obstetric anal sphincter injuries. B]OG 119:62,r2012

Barth WH]r: Persistent occiput posterior. Obstet GynecoIr125(3):695, 2015

Basham E, Stock L, Lewicky-Gaupp C, et al: Subsequent pregnancy outcomes after obstetric anal sphincter injuries (OASIS). Female Pelvic Med Reconstr Surg 19(6):328,r2013

Beall MH, Spong C, McKay], et al: Objective definition of shoulder dystocia: a prospective evaluation. Am ] Obstet Gynecol 179:934, 1998

Beckmann MM, Stock OM: Antenatal perineal massage for reducing perineal trauma. Cochrane Database Syst Rev 4:CD005123, 2013

Begley CM, Gyte GM, Devane 0, et al: Active versus expectant management for women in the third stage of labour. Cochrane Database Syst Rev 3:CD007412,r2015

Belachew ], Cnattingius S, Mulic-Lurvica A, et al: Risk of retained placenta in women previously delivered by caesarean section: a population-based cohort study. B]OG 121(2):224,2014

Berg RC, Odgaard-]ensen ], Fretheim A, et al: An updated systematic review and meta-analysis of the obstetric consequences of female genital mutilation/cutting. Obstet Gynecol Int 2014:542859,2014

Berggren V, Gottvall K, Isman E, et al: Infibulated women have an increased risk of anal sphincter tears at delivery: a population-based Swedish register study of250,000 births. Acta Obstet Gynecol Scand 92(1):101, 2013

Bharathi A, Reddy DB, Kote GS: A prospective randomized comparative study of Vicryl Rapide versus chromic catgut for episiotomy repair. ] Clin Diagn Res 7(2):326, 2013

Bingham], Chauhan SP, Hayes E, et al: Recurrent shoulder dystocia: a review.

Obstet Gynecol Surv 65(3):183,r2010

Birthplace in England Collaborative Group, Brocklehurst P, Hardy P, et al:

Perinatal and maternal outcomes by planned place of birth for healthy women with low risk pregnancies: the Birthplace in England national prospective cohort study. BM] 343:d7400, 201r1

Blondel B, Alexander S, Bjarnad6ttir RI, et al: Variations in rates of severe perineal tears and episiotomies in 20 European countries: a study based on routine national data in Euro-Peristat Project. Acta Obstet Gynecol Scand 95(7):746,r2016

Boggs EW, Berger H, Urquia M, et al: Recurrence of obstetric third-degree and fourth-degree anal sphincter injuries. Obstet Gynecol 124(6): 1128,2014

Bolten N, de ]onge A, Zwagerman E, et al: Efect of planned place of birth on obstetric interventions and maternal outcomes among low-risk women: a cohort study in the Netherlands. BMC Pregnancy Childbirth 16(1):329,2016

Boulvain M, Senat MV, Perrotin F, et al: Induction of labour versus expectant management for large-for-date fetuses: a randomised controlled trial. Lancet 385(9987):2600,r2015

Bovbjerg ML, Cheyney M, Everson C: Maternal and newborn outcomes following waterbirth: The Midwives Alliance of North America Statistics Project, 2004 to 2009 Cohort.] Midwifery Womens Health 61(1):11, 2016

Brito LG, Ferreira CH, Duarte G, et al: Antepartum use of Epi-No birth trainer for preventing perineal trauma: systematic review. Int Urogynecol ] (10):1429, 2015

Bruner ]P, Drummond SB, Meenan AL, et al: All-fours maneuver for reducing shoulder dystocia during labor.] Reprod Med 43(5):439, 1998

Buerkle B, Pueth], Heler A, et al: Objective structured assessment of technical skills evaluation of theoretical compared with hands-on training of shoulder dystocia management: a randomized controlled trial. Obstet Gynecol 120(4):809,r2012

Bulchandani S, WattS E, Sucharitha A, et al: Manual perineal support at the time of childbirth: a systematic review and meta-analysis. B]OG 122(9):1r157,r2015

Buppasiri P, Lumbiganon P, Thinkhamrop ], et al: Antibiotic prophylaxis for third-and fourth-degree perineal tear during vaginal birth. Cochrane Database Syst Rev 10:CD005125, 2014

Burkhardt T, Schmidt M, Kurmanavicius], et al: Evaluation of fetal anthropometric measures to predict the risk for shoulder dystocia. Ultrasound Obstet Gynecol 43(1):77, 2014

Burns EE, Boulton MG, Cluett E, et al: Characteristics, interventions, and outcomes of women who used a birthing pool: a prospective observational study. Birth 39(3):192,r2012

Chauhan SP, Laye MR, Lutgendorf M, et al: A multicenrer assessment of 1,177 cases of shoulder dystocia: lessons learned. Am] Perinatol 31 (5):40 1, 2014

Cheng W, Hubbard A, Caughey AB, et al: The association between persistent fetal occiput posterior position and perinatal outcomes: an example of propensity score and covariate distance matching. An1] Epidemiol 171 (6):656, 2010

Cheng W, Shafer BL, Caughey AB: Associated factors and outcomes of persistent occiput posterior position: a retrospective cohort study from 1976 to 2001.] Matern Fetal Neonatal Med 19(9):563, 2006a

Cheng W, Shafer BL, Caughey AB: he association between persistent occiput posterior position and neonatal outcomes. Obstet Gynecol 107(4):837, 2006b

Cheung WM, Hawkes A, Ibish S: The retained placenta: historical and geographical rate variations.] Obstet GynaecoI31(1):3 ,2011

Cheyney M, Bovbjerg M, Everson C, et al: Outcomes of care for 16,924 planned home births in the United States: the Midwives Alliance of North America Statistics Project, 2004 to 2009. ] Midwifery Womens Health 59(1):1 ,2014

Chibber R, EI-Saleh E, El Harmi ]: Female circumcision: obstetrical and psychological sequelae continues unabated in the 21st century. ] Matern Fetal Neonatal Med 24(6):833,r2011

Chibueze EC, Parsons A], Ota E, et al: Prophylactic antibiotics for manual removal of retained placenta during vaginal birth: a systematic review of observational studies and meta-analysis. BMC Pregnancy Childbirth 15:313,r2015

Cluett ER, Nikodem VC, McCandlish RE, et al: Immersion in water in pregnancy, labour and birth. Cochrane Database Syst Rev 2:CDOOO Ill, 2009

Cluver CA, Hofmeyr G]: Posterior axilla sling traction: a technique for intractable shoulder dystocia. Obstet Gynecol 1r13(2 Pt 2):486, 2009

Cluver CA, Hofmeyr G]: Posterior axilla sling traction for shoulder dystocia: case review and a new method of shoulder rotation with the sling. Am ] Obstet GynecoIr212(6):784.e1, 2015

Coats PM, Chan KK, Wilkins M, et al: A comparison between midline and mediolateral episiotomies. B]OG 87:408, 1980

Combs CA, Laros K: Prolonged third stage of labor: morbidity and risk factors. Obstet Gynecol 77: 863, 1991

Corton MM, Lankford ]C, Ames R, et al: A randomized trial of birthing with and without stirrups. Amr] Obstet GynecoIr207(2):133.e1, 2012

Corton MM, McIntire DO, Twickler OM, et al: Endoanal ultrasound for detection of sphincter defects following childbirth. Int Urogynecol ] 24(4):627,r2013

Costa ML, Couto E, Furlan E, et al: Body stalk anomaly: adverse maternal outcomes in a series of21 cases. Prenat Diagn 32(3):264, 2012

Coviello EM, Grantz KL, Huang CC, et al: Risk factors for retained placenta.

Am] Obstet Gynecol 213(6):864.el, 2015

Cox K], Bovbjerg ML, Cheyney M, et al: Planned home YBAC in the United States, 2004-2009: outcomes, maternity care practices, and implications for shared decision making. Birth 42(4):299,r2015

Crofts ]F, Fox R, Ellis 0, et al: Observations from 450 shoulder dystocia simulations: lessons for skills training. Obstet Gynecol 112(4):906,2008

Crofts ]F, Lenguerrand E, Bentham GL, et al: Prevention of brachial plexus injury-12 years of shoulder dystocia training: an interrupted time-series study. B]OG 123(1):111,r2016

Cummings K, Doherty DA, Magann EF, et al: Timing of manual placenta removal to prevent postpartum hemorrhage: is it time to act? ] Matern Fetal Neonatal Med 29(24):3930,r2016

Cunningham FG: Shoulder dystocia. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hill Education, 2017 Cunningham FG: he Ritgen maneuver: another sacred cow questioned. Obstet Gynecol 112:210,r2008 Davies R, Davis 0, Pearce M, et al: The efect of waterbirth on neonatal mortaliry and morbidiry: a systematic review and meta-analysis. ]BI Database System Rev Implement Rep 13(10): 180, 2015 Declercq E, Macdorman MF, Menacker F, et al: Characteristics of planned and unplanned home births in 19 states. Obstet Gynecol 116(1):93,r2010 de ]onge A, Geerts CC, van der Goes BY, et al: Perinatal mortality and morbidity up to 28 days after birth among 743 070 low-risk planned home and hospital births: a cohort study based on three merged national perinatal databases. B]OG 122(5):720,r2015 de Leeuw ]W, Struijk Pc, Vierhout ME, et al: Risk factors for third degree perineal ruptures during delivery. B]OG 108(4):383,r2001 Deneux-Tharaux C, Macfarlane A, Winter C, et al: Policies for manual removal of placenta at vaginal delivery: variations in timing within Europe. B]OG 116(1):119,r2009

Deneux-haraux C, Sentilhes L, Maillard F, et al: Efect of routine controlled cord traction as part of the active management of the third stage oflabour on postpartum haemorrhage: multicetre randomised controlled trial (TRACOR). BM] 346:0541, 2013

Desbriere R, Blanc], Le Du R, et al: Is maternal posturing during labor eiciet in preventing persistet occiput posterior position? A randomized controlled trial. Am J Obstet GynecoI208(1):60.el, 2013 de Souza Bosco Paiva C, Junqueira Vasconcellos de Oliveira SM, Amorim Francisco A, et al: Length of perineal pain relief after ice pack application: a quasi-experimental study. Women Birth 29(2): 117, 2016

Dombrowski MP, Bottoms SF, Saleh AA, et al: Third stage of labor: analysis of duration and clinical practice. Am J Obstet Gynecol 172: 1279, 1995

Du Y, Ye M, Zheng F: Active management of the third stage oflabor with and without controlled cord traction: a systematic review and meta-analysis of randomized controlled trials. Acta Obstet Gynecol Scand 93(7):626, 2014

Dua A, Whitworth M, Dugdale A, et al: Perineal length: norms in gravid women in the irst stage of labour. Int Urogynecol ] Pelvic Floor Dysfunct 20(11):1361,r2009

Duggal N, Mercado e, Daniels K, et al: Antibiotic prophylaxis for prevention of postpartum perineal wound complications: a randomized controlled trial. Obstet Gynecolrlll(6):1268, 2008

Dupuis 0, Ruimark S, Corinne 0, et al: Fetal head position during the second stage of labor: comparison of digital vaginal examination and transabdominal ultrasonographic examination. Eur ] Obstet Gynecol Reprod Bioi 123(2):193,r2005

Edozien Le, Gurol-Urganci I, Cromwell DA, et al: Impact of third-and fourth-degree perineal tears at irst birth on subsequent pregnancy outcomes: a cohort study. B]OG 121(13):1695,2014

El-Din AS, Kamal MM, Amin MA: Comparison between two incision angles of mediolateral episiotomy in primiparous women: a randomised controlled trial. ] Obstet Gynaecol Res 40: 7, 2014

Elfaghi I, Johansson-Enste B, Rydhstroem H: Rupture of the sphincter ani: the recurrence rate in second delivery. B]OG Ill: 1361, 2004

EI-Refaie TA, Sayed KK, El-Shourbagy A, et al: Role of blunt suture needle in episiotomy repair at uncomplicated vaginal deliveries in reducing glove perforation rate: a randomized controlled trial. ] Obstet Gynaecol Res 38(5): 87,r2012

Endler M, Saltvedt S, Cnattingius S, et al: Retained placenta is associated with pre-eclampsia, stillbirth, giving birth to a small-for-gestational-age infant, and spontaneous preterm birth: a national register-based study. B]OG 121(12):1462,r2014

Esu E, Udo A, Okusanya BO, et al: Antepartum or intrapartum deinfibulation for childbirth in women with type III female genital mutilation: a systematic review and meta-analysis. It] Gynaecol Obstet 136 Suppl 1 :21, 2017

Evers Ee, Blomquist JL, McDermott Ke, et al: Obstetrical anal sphincter laceration and anal incontinence 5-10 years after childbirth. Am ] Obstet Gynecol 207(5):425.el, 2012

Faltin DL, Boulvain M, Floris LA, et al: Diagnosis of anal sphincter tears to prevent fecal incontinence: a randomized controlled trial. Obstet Gynecol 106:6,r2005

Farrell SA, Flowerdew G, Gilmour 0, et al: Overlapping compared with endto-end repair of complete third-degree or fourth-degree obstetric tears: three-year follow-up of a randomized controlled trial. Obstet Gynecol 120(4):803,r2012

Fernando RJ, Sultan AH, Kettle C, et al: Methods of repair for obstetric anal sphincter injury. Cochrane Database Syst Rev 12:CD002866, 2013

Fitzpatrick M, Behan M, O'Connell PR, et al: A randomized clinical trial comparing primary overlap with approximation repair of third-degree obstetric tears. Am ] Obstet Gynecol 183: 1220, 2000

Fitzpatrick M, McQuillan K, O'Herlihy C: InAuence of persistent occiput posterior position on delivery outcome. Obstet Gynecol 98(6): 1027, 2001 Fodstad K, Laine K, Staf AC: Diferent episiotomy techniques, postpartum perineal pain, and blood loss: an observational study. Int Urogynecol ] 24(5):865,r2013

Fodstad K, Staf AC, Laine K: Efect of diferent episiotomy techniques on perineal pain and sexual activity 3 months after delivery. Int Urogynecol J 25: 1629,r2014

Franchi M, Cromi A, Scarperi S, et al: Comparison between lidocaine-prilocaine cream (EMLA) and mepivacaine infiltration for pain relief during perineal repair after childbirth: a randomized trial. Am J Obstet Gynecol 201 (2): 186.e1, 2009

Fransen AF, van de Ven ], Schuit E, et al: Simulation-based team training for multi-professional obstetric care teams to improve patient outcome: a multicentre, cluster randomised controlled trial. B]OG 124(4):641,r201

Friedman AM, Ananth CV, Prendergast E, et al: Evaluation of third-degree and fourth-degree laceration rates as quality indicators. Obstet Gynecol 125(4):927,r2015

Frolova AI, Stout MJ, Tuuli MG, et al: Duration of the third stage oflabor and risk of postpartum hemorrhage. Obstet Gynecol (5):951,2016 Gardberg M, Stenwall 0, Laakkonen E: Recurrent persistent occipito-posterior position in subsequent deliveries. BJOG 111 (2): 170, 2004

Gauthaman N, Walters S, Tribe lA, et al: Shoulder dystocia and associated manoeuvres as risk factors for perineal trauma. Int Urogynecol J 27(4):571, 2016

Gherman RB, Tramont J, Muley P, et al: Analysis of McRoberts' maneuver by x-ray pelvimetry. Obstet Gynecol 95:43, 2000

Ghi T, Youssef A, Martelli F, et al: Narrow subpubic arch angle is associated with higher risk of persistent occiput posterior position at delivery. Ultrasound Obstet GynecoIr48(4):51r1, 2016

Goldaber KG, Wendel P], McIntire DO, et al: Postpartum perineal morbidity after fourth-degree perineal repair. Am] Obstet Gynecol 168:489, 1993

Goldberg H, Stupp P, Okoroh E, et al: Female genital mutilation/cutting in the United States: updated estimates of women and girls at risk, 20r12. Public Health Rep 131(2):340,r2016

Gonen 0, Rosen 0]0, Dolin Z, et al: Induction of labor versus expectant management in macrosomia: a randomized study. Obstet Gynecol 89:913, 1997

Gonik B, Allen R, Sorab J: Objective evaluation of the shoulder dystocia phenomenon: efect of matenal pelvic orientation on force reduction. Obstet Gynecol 74:44, 1989

Goodwin TM, Banks E, Millar LK, et al: Catastrophic shoulder dystocia and emergency symphysiotomy. Amr] Obstet Gynecol 1 :463, 199

Grat A, Gordon B, Mackrodat C, et al: The Ipswich childbirth study: one year follow up of altenative methods used in perineal repair. B]OG 108(1):34, 200r1

Grobman WA, Miller 0, Burke e, et al: Outcomes associated with introduction of a shoulder dystocia protocol. Am ] Obstet Gynecol 205(6):513, 2011

Groenen R, Vos MC, Willekes C, et al: Pregnancy and delivery after midurethral sling procedures for stress urinary incontinence: case reports and a review of literature. Int Urogynecol J Pelvic Floor Dysfunct 19(3):441, 2008

Groutz A, Hasson J, Wengier A, et al: Third-and fourth-degree perineal tears: prevalence and risk factors in the third millennium. Am ] Obstet Gynecol 204(4):347.e1,r2011

Grunebaum A, McCullough LB, Arabin B, et al: Underlying causes of neonatal deaths in term singleton pregnancies: home births versus hospital births in the United States. J Perinat Med 45(3):349,r2017

Grtinebaum A, McCullough LB, Sapra K], et al: Apgar score of 0 at 5 minutes and neonatal seizures or serious neurologic dysfunction in relation to birth setting. Am] Obstet GynecoI209(4):323.el, 2013

Grunebaum A, McCullough LB, Sapra K], et al: Early and total neonatal mortality in relation to birth setting in the United States, 2006-2009. Am J Obstet GynecoIr211:390.el, 2014

Gulmezoglu AM, Lumbiganon P, Landoulsi S, et al: Active management of the third stage of labour with and without controlled cord traction: a randomised, controlled, non-inferiority trial. Lancet 379(9827): 1721, 20r12

Gungor S, Kurt E, Teksoz E, et al: Oronasopharyngeal suction versus no suction in normal and term infants delivered by elective cesarean section: a prospective randomized controlled trial. Gynecol Obstet Invest 61 (1):9, 2006

Gunnarsson B, Fasting S, Skogvoll E, et al: Why babies die in unplanned out-of-institution births: an enquiry into perinatal deaths in Noway 19992013. Acta Obstet Gynecol Scand 96(3):326, 2017

Gunnarsson B, Smarason AK, Skogvoll E, et al: Characteristics and outcome of unplanned out-of-institution births in NOlway from 1999 to 2013: a crosssectional study. Acta Obstet Gynecol Scand 93(10): 1 003, 2014

Gurewitsch ED, Donithan M, Stallings SP, et al: Episiotomy versus fetal manipulation in managing severe shoulder dystocia: a comparison of outcomes. Am] Obstet GynecoIr191(3):91l, 2004

Gurol-Urganci I, Cromwell DA, Edozien LC, et al: Third-and fourth-degree perineal tears among primiparous women in England between 2000 and 2012: time trends and risk factors. BJOG 120(12):1516,r2013

Gyhagen M, Bullarbo M, Nielsen TF, et al: Faecal incontinence 20 years after one birth: a comparison between vaginal delivery and caesarean section. Int Urogynecolr] 25(10):141r1, 2014

Hale RW, Ling FW: Episiotomy: procedure and repair techniques. Washington, American College of Obstetricians and Gynecologists, 200

Hartield VJ: Symphysiotomy for shoulder dystocia. Am ] Obstet Gynecol 155:228, 1986

Hawkins ]S: Lower genital tract procedures. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 20r17

Henry E, Andres L, Christensen D: Neonatal outcomes following a tight nuchal cord.r] PerinatoIr33(3):231, 2013

Hernandez C, Wendel GD: Shoulder dystocia. In Pitkin M (ed): Clinical Obstetrics and Gynecology, Vol XXIII. Hagerstown, Lippincott, 1990 Hofman M: A comparison of obstetric maneuvers for the acute management of shoulder dystocia. Obstet Gynecolr119(part 1): 386,2011

Hoopmann M, Abele H, Wagner N, et al: Performance of 36 diferent weight estimation formulae in fetuses with macrosomia. Fetal Diagn Ther 27(4)204,r2010

Hutton EK, Cappelletti A, Reitsma AH, et al: Outcomes associated with planned place of birth among women with low-risk pregnancies. CIvlA] 188(5):E80, 2016 ]allad K, Steele SE, Barber MD: Breakdown of perineal laceration repair after vaginal delivery: a case-control study. Female Pelvic Med Reconstr Surg 22(4):276,r2016 ]ango H, Langhof-Roosr], Rosthoj 5, et al: vlodiiable risk factors of obstetric anal sphincter injury in primiparous women: a population-based cohort study. Am] Obstet GynecoIr210:59, 2014 ]angsten E, Mattsson A, Lyckestam I, et al: A comparison of active management and expectant management of the third stage of labour: a Swedish randomised controlled trial. B]OG 118(3):362,r2011

Jiang H, ian X, Carro Ii G, et al: Selective versus routine use of episiotomy for vaginal birth. Cochrane Database Syst Rev 2:CD000081, 2017

Jolly MC, Sebire N], Harris ]P, et al: Risk factors for macrosomia and its clinical consequences: a study of 350,311 pregnancies. Eur] Obstet Gynecol Reprod Bioi 111(l):9, 2003

Jonsson ER, Elfaghi I, Rydhstrom H, et al: Modified Ritgen's maneuver for anal sphincter injury at delivery: a randomized controlled trial. Obstet Gynecol 112:212, 2008

Kalis V, Laine K, de Leeuw ]W, et al: Classification of episiotomy: towards a standardisation of terminology. B]OG 119(5):522, 2012

Kalis V, Landsmanova], Bednarova B, et al: Evaluation of the incision angle of mediolateral episiotomy at 60 degrees. Int] Gynaecol Obstet 112:220, 2011

Kamisan Atan I, Shek L, Langer 5, et al: Does the Epi-No birth trainer prevent vaginal birth-related pelvic floor trauma? A multicentre prospective randomized controlled trial. B]OG 123(6):995, 2016

Karbanova], Rusavy Z, Betincova L, et al: Clinical evaluation of early postpartum pain and healing outcomes after mediolateral versus lateral episiotomy. Int] Gynaecol Obstet 127(2):152, 2014a

Karbanova ], Rusavy Z, Betincova L, et al: Clinical evaluation of peripartum outcomes of mediolateral versus lateral episiotomy. Int ] Gynaecol Obstet 124(1):72,r2014b

Kargar R, Aghazadeh-Nainie A, Khoddami-Vishteh HR: Comparison of the efects of lidocaine prilocaine cream (EMLA) and lidocaine injection on reduction of perineal pain during perineum repair in normal vaginal delivery.r] Family Reprod Health 10(1):21,r2016

Kariminia A, Chamberlain ME, Keogh], et al: Randomised controlled trial of efect of hands and knees posturing on incidence of occiput posterior position at birth. BM] 328(7438):490, 2004

Katheria AC, Brown MK, Faksh A, et al: Delayed cord clamping in newborns born at term at risk for resuscitation: a feasibility randomized clinical trial. ] Pediatr 187:313, 2017

Katheria AC, Truong G, Cousins L, et al: Umbilical cord milking versus delayed cord clamping in preterm infants. Pediatrics 136(1):61,2015

Kc A, Rana N, Milqvist M, et al: Efects of delayed umbilical cord clamping vs early clamping on anemia in infants at 8 and 12 months: a randomized clinical trial.]AMA Pediatr 171(3):264,2017

Kenton K, Mueller M: Episiotomy and obstetric anal sphincter lacerations. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hill Education,r201

Kettle C, Dowswell

T, Ismail M: Absorbable suture materials for primary repair of episiotomy and second degree tears. Cochrane Database Syst Rev 6:CD000006,r2010

Kettle C, Dowswell T, Ismail M: Continuous and interrupted suturing techniques for repair of episiotomy or second-degree tears. Cochrane Database Syst Rev 11:CD000947, 2012

Kettle C, Hills RK, Jones P, et al: Continuous versus interrupted perinel repair with standard or rapidly absorbed sutures after spontaneous vaginal birth: a randomized controlled trial. Lancet 359:2217,r2002

Kim T, Vogel I, Mackenthun SM, et al: Rigorous simulation training protocol does not improve maternal and neonatal outcomes from shoulder dystocia. Obstet Gynecolr127 Supplr1:3S, 2016

Kindberg S, Stehouwer M, Hvidman L, et al: Postpartum perineal repair performed by midwives: a randomized trial comparing two suture techniques leaving the skin unsutured. B]OG 115:472, 2008

Koyanagi A, Zhangr], Dagvadorj A, et al: Macrosomia in 23 developing countries: an analysis of a multicountry, facility-based, cross-sectional survey. Lancet 381(9865):476,r2013

Laine K, Pirhonen T, Rolland R, et al: Decreasing the incidence of anal sphincter tears during delivery. Obstet Gynecolr111:1053, 2008

Landy H], Laughon SK, Bailit ]L, et al: Characteristics associated with severe perineal and cervical lacerations during vaginal delivery. Obstet Gynecol 117(3):627,r2011

Langer 0, Berkus MD, Huf RW, et al: Shoulder dystocia: should the fetus weighing greater than or equal to 4000 grams be delivered by cesarean section? Am] Obstet Gynecolr165(4 Pt 1):831, 1991

Larson ]D, Rayburn F, Harlan L: Nuchal cord entanglements and gestational age. Am] Perinatal 14(9):555, 1997

Le Ray C, Carayol M, ]aquemin S, et al: Is epidural analgesia a risk factor for occiput posterior or transverse positions during labour? Eur ] Obstet Gynecol Reprod Bioi 123(1):22, 2005

Le Ray C, Lepleux F, De La Calle A, et al: Lateral asymmetric decubitus position for the rotation of occipita-posterior positions: multicenter randomized controlled trial EVADELA. Am] Obstet GynecoIr215(4):511.el, 2016

Le Ray C, Serres P, Schmitz T, et al: Manual rotation in occiput posterior or transverse positions: risk factors and consequences on the cesarean delivery rate. Obstet Gynecol 110(4):873,r2007

Lerner H, Durlacher K, Smith 5, et al: Relationship between head-to-body delivery interval in shoulder dystocia and neonatal depression. Obstet Gynecol 118(2 Pt 1):318,r2011

Leroux N, Bujold E: Impact of chromic catgut versus polyglactin 910 versus fast-absorbing polyglactin 910 sutures for perineal repair: a randomized, controlled trial. Am] Obstet GynecoIr194(6):1585, 2006

Leung Y, Stuart 0, Sahota DS: Head-to-body delivery interval and risk of fetal acidosis and hypoxic ischaemic encephalopathy in shoulder dystocia: a retrospective review. B]OG 118(4):474, 2011a

Leung Y, Stuart 0, Suen SS, et al: Comparison of perinatal outcomes of shoulder dystocia alleviated by diferent type and sequence of manoeuvres: a retrospective review. B]OG 118(8):985, 2011b

Lewicky-Gaupp C, Leader-Cramer A, Johnson LL, et al: Wound complications ater obstetric anal sphincter injuries. Obstet GynecoIr125(5):1088, 2015

Liabsuetrakul T, Choobun T, Peeyananjarassri K, et al: Prophylactic use of ergot alkaloids in the third stage of labour. Cochrane Database Syst Rev 2:CD005456, 2007, Reairmed 2011

Lieberman E, Davidson K, Lee-Parritz A, et al: Changes in fetal position during labor and their association with epidural analgesia. Obstet Gynecol 105(5 Pt 1):974, 2005

MacDorman MF, Declercq E: Trends and characteristics of United States outof-hospital births 2004-2014: new information on risk status and access to care. Birth 43(2):116,r2016

MacKenzie IZ, Shah M, Lean K, et al: Management of shoulder dystocia: trends in incidence and maternal and neonatal morbidity. Obstet Gynecol 110:1059,r2007

Malin GL, Bugg G], Takwoingi Y, et al: Antenatal magnetic resonance imaging versus ultrasound for predicting neonatal macrosomia: a systematic review and meta-analysis. B]OG 123(1):77,r2016

McCandlish R, Bowler U; Van Asten H, et al: A randomised controlled trial of care of the perineum during second stage of normal labour. B]OG 105(12):1262, 1998 McDonald A, Gartland 0, Small R, et al: Dyspareunia and childbirth: a prospective cohort study. B]OG 122(5):672,2015

McDonald 5], Middleton P, Dowswell T, et al: Efect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes. Cochrane Database Syst Rev 7:CD004074, 2013

McFarland MB, Trylovich CG, Langer 0: Anthropometric diferences in macrosomic infants of diabetic and nondiabetic mothers. ] Maternal Fetal Med 7(6):292, 1998

Mehta SH, Bujold E, Blackwell SC, et al: Is abnormal labor associated with shoulder dystocia in nulliparous women? Am] Obstet Gynecolr190( 6): 1604, 2004

Mei-dan E, Walfisch A, Raz I, et al: Perineal massage during pregnancy: a prospective controlled trial. Isr Med Assocr] 10(7):499, 2008

Melamed N, Gavish 0, Eisner M, et al: Third-and fourth-degree perineal tears-incidence and risk factors. ] Matern Fetal Neonatal Med 26(7):660, 2013

Minassian VA, ]azayeri A, Prien SO, et al: Randomized trial of lidocaine ointment versus placebo for the treatment of postpartum perineal pain. Obstet Gynecol 100: 1239, 2002

Mobeen N, Durocher ], Zuberi N, et al: Administration of misoprostol by trained traditional birth attendants ta prevent postpartum haemorrhage in homebirths in Pakistan: a randomised placebo-controlled trial. B]OG 118(3):353,r2011

Modanlou HD, Komatsu G, Dorchester W, et al: Large-for-gestational-age neonates: anthropometric reasons for shoulder dystocia. Obstet Gynecol 60:417,r1982

Moore HM, Reed SD, Batra M, et al: Risk factors for recurrent shoulder dystocia, Washington state, 1987-2004. Am] Obstet GynecoIr198:el6, 2008 Mornar S], Perlow JH: Blunt suture needle use in laceration and episiotomy repair at vaginal delivery. Am] Obstet Gynecol 198:e14, 2008

Mous M, Muller SA, de Leeuw]W: Long-term efects of anal sphincter rupture during vaginal delivery: faecal incontinence and sexual complaints. B]OG 115(2):234,r2008

Mulder FE, Oude Rengerink K, van der Post ]A, et al: Delivery-related risk factors for covert postpartum urinary retention after vaginal delivery. Int Urogynecol] 27(1):55, 2016

Mulder FE, Schofelmeer A, Hakvoort A, et al: Risk factors for POStpartum urinary retention: a systematic review and meta-analysis. B]OG 119(2):1440,r2012

Necesalova P, Karbanova], Rusavy Z, et al: Mediolateral versus lateral episiotomy and their efect on postpartum coital activity and dyspareunia rate 3 and 6 months postpartum. Sex Reprod Healthc 8:25, 2016

Nesbitt TS, Gilbert WM, Herrchen B: Shoulder dystocia and associated risk factors with macrosomic infants born in California. Am ] Obstet Gynecol 179:476,r1998

Nikolajsen S, L0kkegaard EC, Bergholt T: Reoccurrence of retained placenta at vaginal delivery: an observational study. Acta Obstet Gynecol Scand 92(4):421,r2013

Noumi G, Collado-Khoury F, Bombard A, et al: Clinical and sonographic estimation of fetal weight performed during labor by residents. Am] Obstet Gynecol 192(5):1407,2005

Nour NM. Female genital cutting: impact on women's health. Semin Reprod Med 330):41,r2015

Novartis: Methergine: prescribing information. 2012. Available at: http:// www.accessdata.fda.gov/drugsatfda_docs/labe1!20 12/00603 5s0781bl. pdf. Accessed October 26, 2016

Ogueh 0, I-Tarkait A, Vallerand D, et al: Obstetrical factors related to nuchal cord. Acta Obstet Gynecol Scand 85(7):810, 2006

Oliphant SS, Jones A, Wang L, et al: Trends over time with commonly performed obstetric and gynecologic inpatient procedures. Obstet Gynecol 116(4):926,r2010

Otero M, Boulvain M, Bianchi-Demicheli F, et al: Women's health 18 years after rupture of the anal sphincter during child-birth: II. Urinary incontinence, sexual function, and physical and mental health. Amr] Obstet Gynecol 194(5):1260, 2006

Ouzounian ]G: Shoulder dystocia: incidence and risk factors. Clin Obstet Gynecol 59(4):791, 2016

Ouzounian ]G, Korst LM, Miller DA, et al: Brachial plexus palsy and shoulder dystocia: obstetric risk factors remain elusive. Am ] Perinatol 30(4):303, 2013

Overland A, Spydslaug A, Nielsen CS, et al: Risk of shoulder dystocia in second delivery: does a history of shoulder dystocia matter? Am ] Obstet Gynecol 200(5):506.e1, 2009 0verland EA, Vatten L], Eskild A: Pregnancy week at delivery and the risk of shoulder dystocia: a population study of 2,014,956 deliveries. B]OG 1210):34,r2014 0verland EA, Vatten L], Eskild A: Risk of shoulder dystocia: associations with parity and ofspring birthweight. A population study of 1,914,544 deliveries. Acta Obstet Gynecol Scand 91(4):483, 2012

Ozyurt S, Aksoy H, Gedikbasi A, et al: Screening occult anal sphincter injuries in primigravid women after vaginal delivery with transperineal use of vaginal probe: a prospective, randomized controlled trial. Arch Gynecol Obstet 292(4):853, 2015

Paris E, Greenberg ]A, Ecker ]L, et al: Is an episiotomy necessary with a shoulder dystocia? Am] Obstet GynecoI205(3):217.e1, 2011 Patel S, Clark A, Rodriguez CE, et al: Efect of umbilical cord milking on morbidity and survival in extremely low gestational age neonates. Am ] Obstet GynecoIr211(5):519.el, 2014

Pinette MG, Wax ], Wilson E: he risks of underwater birth. Am ] Obstet Gynecol 190(5):1211,2004

Pollard ME, Morrisroe S, Anger ]T: Outcomes of pregnancy following surgery for stress urinary incontinence: a systematic review. ] Urol 187(6): 1966, 2012

Ponkey SE, Cohen AP, Hefner L], et al: Persistent fetal occiput posterior position: obstetric outcomes. Obstet Gynecol101(5 Pt 1):915,r2003

Pradhan A, Tincello DG, Kearney R: Childbirth after pelvic floor surgery: analysis of Hospital Episode Statistics in England, 2002-2008. B]OG 120(2):200,r2013

Priddis H, Dahlen HG, Schmied V, et al: Risk of recurrence, sub-sequent mode of birth and morbidity for women who experienced severe perineal trauma in a first birth in New South Wales between 2000-2008: a population based data linkage study. BMC Pregnancy Childbirth 13:89, 2013

Rabe H, Diaz-Rossello ]L, Duley L, et al: Efect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes. Cochrane Database Syst Rev 8:CD003248,r2012

Radestad I, Olsson A, Nissen E, et al: Tears in the vagina, perineum, sphincter ani, and rectum and first sexual intercourse ater childbirth: a nationwide follow-up. Birth 35:98, 2008

Rahmanr], Bhattee G, Rahman MS: Shoulder dystocia in a 16-year experience in a teaching hospital. ] Reprod Med 54(6):378, 2009

Raisanen S, Vehvilainen-]ulkunen K, Gissler M, et al: High episiotomy rate protects from obstetric anal sphincter ruptures: a birth register-study on delivery intervention policies in Finland. Scand ] Public Health 39(5):457, 2011

Roberts PL, Coller ]A, Schoetz D], et al: Manometric assessment of patients with obstetric injuries and fecal incontinence. Dis Colon Rectum 33: 16, 1990

Rodriguez MI, Seuc A, Say L, et al: Episiotomy and obstetric outcomes among women living with type 3 female genital mutilation: a secondary analysis. Reprod Health 130):131,2016

Rouse D], Owen ]: Prophylactic cesarean delivery for fetal macrosomia diagnosed by means of ultrasonography-a Faustian bargain? Am J Obstet Gynecol 181 :332, 1999

Rubin A: Management of shoulder dystocia.]AMA 189:835, 1964

Sagi-Dain L, Sagi S: he role of episiotomy in prevention and management of shoulder dystocia: a systematic review. Obstet Gynecol Surv 70(5):354, 2015

Salim R, Peretz H, Molnar R, et al: Long-term outcome of obstetric anal sphincter injury repaired by experienced obstetricians. Int ] Gynaecol Obstet 126(2):130,r2014

Sandberg EC: Shoulder dystocia: associated with versus caused by the Zavanelli maneuver. Am] Obstet Gynecol 1970): 115, 2007

Sandberg EC: The Zavanelli maneuver: 12 years of recorded experience. Obstet Gynecol 93:312, 1999

Sandberg EC: The Zavanelli maneuver: a potentially revolutionary method for the resolution of shoulder dystocia. Am ] Obstet Gynecol 152:479, 1985

Sartore A, De Seta F, Maso G, et al: The efects of mediolateral episiotomy on pelvic loor function after vaginal delivery. Obstet Gynecol 103(4):669, 2004

Schafer R: Umbilical cord avulsion in waterbirth.] Midwifery Womens Health 590):91,r2014

Schramm M: Impacted shoulders-a personal experience. Aust N Z ] Obstet Gynaecol 23:28, 1983

Schummers L, Hutcheon ]A, Bodnar LM, et al: Risk of adverse pregnancy outcomes by prep regnancy body mass index: a population-based study to inform prepregnancy weight loss counseling. Obstet Gynecol 125(1):133, 2015

Secher N], Arnso P, Wallin L: Haemodynamic efects of oxytocin (Syntocinon) and methylergometrine (Methergin) on the systemic and pulmonary circulations of pregnant anaesthetized women. Acta Obstet Gynecol Scand 57:97, 1978

Sen K, Sakamoto H, Nakabayashi Y, et al: Management of the occiput posterior presentation: a single institute experience. ] Obstet Gynaecol Res 39(1):160,r2013

Senecal ], Xiong X, Fraser WD, et al: Efect of fetal position on second-stage duration and labor outcome. Obstet Gynecol 105(4):763,r2005

Shafer BL, Cheng W, Vargas ]E, et al: Manual rotation of the fetal occiput: predictors of success and delivery. Am J Obstet Gynecol 194(5):e7, 2006

Shafer BL, Cheng W, Vargas ]E, et al: Manual rotation to reduce caesarean delivery in persistent occiput posterior or transverse position. ] Matern Fetal Neonatal Med 240):65,r201r1

Shinar S, Schwartz A, Maslovitz S, et al: How long is safe? Setting the cutof for uncomplicated third stage length: a retrospective case-control study. Birth 430):36,r2016a

Shinar S, Shenhav M, Maslovitz S, et al: Distribution of third-stage length and risk factors for its prolongation. Am] PerinatoI33(0):1023, 2016b

Shmueli A, Gabbay Benziv R, Hiersch L, et al: Episiotomy-risk factors and outcomes. ] Matern Fetal Neonatal Med 19: 1, 2016

Signorello LB, Harlow BL, Chekos AK, et al: Postpartum sexual functioning and its relationship to perineal trauma: a retrospective cohort study of primiparous women. Am] Obstet Gynecol 184:881,2001

Sikka P, Chopra S, Kalpdev A, et al: Destructive operations-a vanishing art in modern obstetrics: 25 year experience at a tertiary care center in India. Arch Gynecol Obstet 283(5):929,r201r1

Snowden JM, Tilden EL, Snyder J, et al: Planned out-of-hospital birth and birth outcomes. N Engl J vIed 373(27):2642,2015

Soltani H, Hutchon DR, Pouiose TA: Timing of prophylactic uterotonics for the third stage of labour after vaginal birth. Cochrane Database Syst Rev 8:CD006173,r2010

Spain JE, Frey HA, Tuuli MG, et al: Neonatal morbidity associated with shoulder dystocia maneuvers. m J Obstet Gynecol 212(3):353.e1, 2015

Spong CY, Beall M, Rodrigues D, et al: An objective definition of shoulder dystocia: prolonged head-to-body delivery intervals and/or the use of ancillary obstetric maneuvers. Obstet Gynecol 86:433, 1995

Stamp G, Kruzins G, Crowther C: Perineal massage in labour and prevention of perineal trauma: randomised controlled trial. BMJ 322(7297):1277, 2001

Stock L, Basham E, Gossett DR, et a1: Factors associated with wound complications in women with obstetric anal sphincter injuries (OASIS). m J Obstet Gynecol 208(4):32 .e1,2013

Stotland NE, Caughey AB, Breed EM, et al: Risk factors and obstetric complications associated with macrosomia. Int J Gynaecol Obstet 87(3):220, 2004 Su LL, Chong YS, Samuel M: Carbetocin for preventing postpartum haemor rhage. Cochrane Database Syst Rev 4:CD005457, 2012

Sundquist JC: Long-term outcome after obstetric injury: a retrospective study.

Acta Obstet Gynecol Scand 91(6):715,r2012

Svanstrom Me, Biber B, Hanes M, et al: Signs of myocardial ischaemia after injection of oxytocin: a randomized double-blind comparison of oxytocin and methylergometrine during caesarean section. Br J Anaesth 100:683, 2008 Taylor H, Kleine I, Bewley 5, et 1: Neonatal outcomes of waterbirth: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 101(4):F357, 2016

Thoeni A, Zech N, Moroder L, et al: Review of 1600 water births. Does water birth increase the risk of neonatal infection? J Matern Fetal Neonatal Med 17(5):357,r2005

Tun;alp 0, Hofmeyr GJ, Gulmezoglu M: Prostaglandins for preventing postpartum haemorrhage. Cochrane Database Syst Rev 8:CD000494, 2012

UNICEF: Female genital mutilation and cutting. 20r16. Available at: http:// data.unicef.org/topiclchild-protection/female-genital-mutilation-and-cutting.! Accessed October 24, 2016

Upadhyay A, Gothwal 5, Parihar R, et al: Efect of umbilical cord milking in term and near term infants: randomized control trial. Am J Obstet Gynecol 208(2):120.el, 2013

Valenzuela P, Saiz Puente MS, Valero JL, et al: Continuous versus interrupted sutures for repair of episiotomy or second-degree perineal tears: a randomised controlled trial. B]OG 11r6(3):436,r2009

Walsh JM, Kandamany N, Ni Shuibhne N, et al: Neonatal brachial plexus injury: comparison of incidence and antecedents between 2 decades. Am J Obstet GynecoIr204(4):324.e1, 2011

Walsh A, Grivell RM: Use of endoanal ultrasound for reducing the risk of complications related to anal sphincter injury after vaginal birth. Cochrane Database Syst Rev 1 O:CDO 1 0826, 2015

Wasden SW, Chasen ST, Perlman JM, et al: Planned home birth and the association with neonatal hypoxic ischemic encephalopathy. J Perinat Med November 19,r2016 [Epub ahead of print]

Westhof G, Cotter M1, Tolosa JE: Prophylactic oxytocin for the third stage of labour to prevent postpartum haemorrhage. Cochrane Database Syst Rev 10:CD001808,r2013

Whalley PJ, Pritchard JA: Oxytocin and water intoxication. JM1A 186:601, 1963 Winter J, Kattwinkel ], Chisholm e, et 1: ventilation of preterm infants during delayed cord clamping (VentFirst): a pilot study of feasibility nd safety. m ] PerinatoI34(2):1l1,r2017

Woods CE: A principle of physics is applicable to shoulder delivery. Am ] Obstet Gynecol 96, 1943

World Health Organization: Eliminating female genital mutilation. Geneva, World Health Organization, 2008

World Health Organization: Female genital mutilation and obstetric outcome: WHO collaborative prospective study in six African countries. Lancet 367: 1835, 2006

World Health Organization: Guideline: delayed umbilical cord clamping for improved maternal and infant health and nutrition outcomes. Geneva, World Health Organization, 2014

World Health Organization: WHO recommendations for the prevention and treatment of postpartum haemorrhage. Geneva, World Health Organization, 2012

Wuest 5, Raio L, Wyssmueller D, et al: Efects of female genital mutilation on birth outcomes in Switzerland. B]OG 116(9):1204,r2009

Wyckof MH, Aziz K, Escobedo MB, et al: Part 13: Neonatal resuscitation: 2015 American Heart Association guidelines update for cardiopulmonaIY resuscitation and emergency cardiovascular care. Circulation 132(18 Suppl 2):5543,r2015

Yao AC, Lind J: Placental transfusion. Am] Dis Child :128, 1974

Zahalka N, Sadan 0, Malinger G, et al: Comparison of transvaginal sonography with digital examination and transabdominal sonography for the determination of fetal head position in the second stage of labor. Am ] Obstet Gynecol 193:381,r2005

CLASSIFICATION OF BREECH PRESENTATIONS ....... 539

DIAGNOSIS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 540 ROUTE OF DELIVERYe. . . . . . . . . . . . . . . . . . . . . . . . . . . . 540

LABOR AND DELIVERY MANAGEMENTe. . . . . . . . . . . . . 543

PARTIAL BREECH EXTRACTION ................... 544

TOTAL BREECH EXTRACTIONe. . . . . . . . . . . . . . . . . . . . . 548 EXTERNAL CEPHALIC VERSION. . . . . . . . . . . . . . . . . . . . 549 extremities and buttocks. With a frank breech, lower extremities are flexed at the hips and extended at the knees, and thus the feet lie close to the head

With a complete breech, both hips are lexed, and one or both knees are also lexed (Fig. 28-2). With an incomplete breech, one or both hips are extended. As a result, one or both feet or knees lie below the breech, such that a foot or knee is lowermost in the birth canal (Fig. 28-3). A footling breech is an incomplete breech with one or both feet below the breech.

FIGURE 28-1 Frank breech presentation.

The essential prerequisite or the successful peormance of breech extraction lies in the complete dilatation of the cervix and the absence of any serious mechanical obstacle. It is true that in a certain number of cases extraction through an impeecty dilated cervix is possible, but this is usualy fected ony at the cost of deep cervical tears.

-J. Whitridge Williams (1903)

Near term, the fetus typically has spontaneously assumed a cephalic presentation. Conversely, if the fetal buttocks or legs enter the pelvis before the head, the presentation is breech. This fetal lie is more common remote from term, as earlier in pregnancy each fetal pole has similar bulk. At term, breech presentation persists in approximately 3 to 5 percent of singleton deliveries (Cammu, 2014; Lyons, 2015; Macharey, 2017).

he categories of frank, complete, and incomplete breech presentations difer in their varying relations between the lower

FIGURE 28-2 Complete breech presentation.

FIGURE 28-3 Incomplete breech presentation.

Of term breech fetuses, the neck may be extremely hyperextended in perhaps 5 percent, and the term stargazing etus is used (Cimmino, 1975). With these, fetal or uterine anomalies may be more prevalent and are sought if not previously identified (Phelan, 1983). With this hyperextension, vaginal delivery can result in injury to the cervical spinal cord. hus, if identified at term, this is an indication for cesarean delivery (Westgren, 1981). hat said, flexion itself may be implicated, s cses of spinal cord injury have been reported following uneventul cesarean delivery of such fetuses (Hernandez-Marti, 1984). With transverse lie and similar hyperextension of the fetal neck, the term iyingetus is applied.

Understanding the clinical settings that predispose to breech presentation can aid early recognition. Other than early gestational age, risk factors include extremes of amnionic fluid volume, multifetal gestation, hydrocephaly, anencephaly, structural uterine abnormalities, placenta previa, pelvic tumors, and prior breech delivery. One study found that following one breech delivery, the recurrence rate for a second breech presentation was 10 percent, and for a subsequent third breech it was 28 percent (Ford, 2010).

Leopold maneuvers to ascertain fetal presentation are discussed in Chapter 22 (p. 424). With the irst maneuver, the hard, round fetal head occupies the fundus. he second maneuver identifies the back to be on one side of the abdomen and the small parts on the other. With the third maneuver, if not engaged, the softer breech is movable above the pelvic inlet.

After engagement, the fourth maneuver shows the breech to be beneath the symphysis. he accuracy of this palpation varies (Lydon-Rochelle, 1993; Nassar, 2006). hus, with suspected breech presentation-or any presentation other than cephalic-sonographic evaluation is indicated.

During cervical examination with a frank breech, no feet are appreciated, but the fetal ischil tuberosities, sacrum, and anus are usually palpable. Ater urther fetal descent, the external genitalia may also be distinguished. When labor is prolonged, the fetal buttocks may become markedly swollen, rendering digital diferentiation of a face and breech diicult. In some cases, the anus may be mistaken for the mouth and the ischial tuberosities for the malar eminences. With careul examination, however, the inger encounters muscular resistance with the anus, whereas the hard, less yielding jaws are felt through the mouth. The finger, upon removal from the anus, may be stained with meconium. The mouth and malar eminences form a triangular shape, whereas the ischial tuberosities and anus lie in a straight line. With a complete breech, the feet may be felt alongside the buttocks. In footling presentations, one or both feet are inferior to the buttocks.

The fetal sacrum and its spinous processes are palpated to establish position. As with cephalic presentations, fetal position is designated to reflect the relations of the fetal sacrum to the maternal pelvis. Positions include left sacrum anterior (LSA) , right sacrum anterior (RSA), left sacrum posterior (LSP), right sacrum posterior (RSP), and sacrum transverse (ST).

Multiple factors aid determination of the best delivery route for a given mother-fetus pair. These include fetal characteristics, maternal pelvic dimensions, coexistent pregnancy complications, provider experience, patient preference, hospital capabilities, and gestational age.

Compared with their term counterparts, preterm breech fetuses have distinct complications related to their small size and immaturity. For example, rates of head entrapment, birth trauma, and perinatal mortality can be greater. Accordingly, separate dis cussions of term and preterm breech fetuses are more appropriate.

Current obstetrical thinking regarding vaginal delivery of the term breech fetus has been tremendously inluenced by results of the Term Breech Trial (Hannah, 2000). his trial included 1041 women randomly assigned to planned cesarean and 1042 to planned vaginal delivery. In the planned vaginal delivery group, 57 percent were actually delivered vaginally. Planned cesarean delivery was associated with a lower risk of perinatal mortality compared with planned vaginal delivery-3 per 1000 versus 13 per 1000. Cesarean delivery was also associated with a lower risk of "serious" neonatal morbidity-1.4 versus 3.8 percent. Short term maternal morbidity was similar between groups.

Critics of the Term Breech Trial emphasize that fewer than 10 percent of candidates underwent radiological pelvimetry. Also, most of the outcomes included in the "serious" neonatal morbidity composite did not actually portend long-term infant disability (Whyte, 2004).

Since that trial, however, additional data favoring cesarean delivery has come from the World Health Organization (Lumbiganon, 2010). From their evaluation of more than 100,000 deliveries from nine participating Asian countries, they reported improved perinatal outcomes for the term breech fetus with planned cesarean compared with planned vaginal delivery. Other studies have evluated neonatal outcome with cesarean delivery and also found lowered neonatal morbidity and mortality rates (Hartnack Tharin, 2011; Lyons, 2015; Rietberg, 2005; Vistad, 2015). From their metaanalysis, Berhan and Haileamlak (2016) calculate absolute risk of perinatal mortality to be 0.3 percent and of fetal birth trauma or neurological morbidity to be 0.7 percent.

In contrast, other studies support vaginal delivery as a suitable option at term (Hofmeyr, 2015a). he Presentation et Mode dAccouchement-PEMODA study-which translates as presentation and mode of delivery-showed no diferences in corrected neonatal mortality rates and neonatal outcomes according to delivery mode (Goinet, 2006). his French prospective observational study involved more than 8000 women with term breech singletons. Strict criteria were used to select 2526 of these for planned vaginal delivery, and 71 percent of that group were delivered vaginally. Similarly, data from the Lille Breech Study Group in France showed no excessive morbidity in term breech singletons delivered vaginally provided strict fetal biometric and maternal pelvimetry parameters were applied (Michel, 2011). Other smaller studies support these findings as long as guidelines are part of the selection process (Alarab, 2004; Giuliani, 2002; Toivonen, 2012).

Long-term evidence in support of vaginal breech delivery comes from Eide and associates (2005). These investigators analyzed intelligence testing scores of more than 8000 men delivered breech and ing vaginal or cesarean delivery. Also, a 2-year follow up from the velopmental delay between delivery groups (Whyte, 2004).

Despite evidence on both sides of the debate, at least in the

United States, rates of planned vaginal delivery attempts con tinue to decline. And as predicted, the number of skilled pro viders able to safely select and vaginally deliver breech fetuses continues to dwindle (Chinnock, 2007). Moreover, obvious ies diicult. In response, some institutions have developed birth simulators to improve resident competence in vaginal breech delivery (Deering, 2006; Maslovitz, 2007).

In contrast to the term breech fetus, there are no randomized trials regarding delivery of the preterm breech fetus. Moreover, study comparisons are oten made diicult by lumping, splitting, or overlapping of preterm gestational age groups. All that said, it would appear that for the preterm breech fetus, planned cesar ean delivery confers a survival advantage compared with planned vaginal delivery. Reddy and associates (2012) reported data from deliveries between 24 and 32 weeks' gestation. For breech fetuses within these gestational ages, attempting vaginal delivery yielded a low success rate, and those completed were associated with higher neonatal mortality rates compared with planned cesar ean delivery. Other investigations have reported similar findings (Bergenhenegouwen, 2014; Demirci, 2012; Muhuri, 2006).

For preterm fetuses in younger subgroups-23 to 28 weeksthe data are more conflicting, and some studies describe no improved survival rate with planned cesarean delivery (Bergenhenegouwen, 2015; Kayem, 2015; Thomas, 2016). Forperiviable etuses, deined by them as 20 to 256/7 weeks, a consensus workshop of perinatal organizations concluded that "available data do not consistently support routine cesarean delivery to improve perinatal mortality or neurological outcomes for early preterm infants" (Raju, 2014). A subsequent joint statement by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine (2017) suggested consideration for cesarean delivery for periviable fetuses beginning at 23°/7 weeks, with a recommendation for cesarean delivery at 25°1 weeks.

For more mature preterm breech fetuses, that is, between 32 and 37 weeks, again there are sparse data to guide delivery route selection. Bergenhenegouwen and coworkers (2015) studied more than 6800 breech deliveries in a subgroup between 32 and 37 weeks. With planned cesarean delivery, they found similar perinatal mortality rates but less composite mortality and severe morbidity. It appears in this subgroup that fetal weight rather than gestational age is likely more important. he Maternl-Fetal Nfedicine Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC) states that vaginal breech delivery is reasonable when the estimated fetal weight is >2500 g (Kotaska, 2009). There are especial concerns for delivery of the second noncephalic-presenting twin fetus that are discussed in Chapter 45 (p. 888).

In the United States, all these findings shape practice, and cesarean delivery is almost uniformly favored for the preterm breech fetus for which resuscitation is planned.

Increased rates of maternal and perinatal morbidity can be anticipated with breech presentations. For the mother, with either cesarean or vaginal delivery, genital tract laceration can be problematic. With cesarean delivery, added stretching of the lower uterine segment by forceps or by a poorly molded fetal head can extend hysterotomy incisions. With vaginal delivery, especially with a thinned lower uterine segment, delivery of the atercoming head through an incompletely dilated cervix or application of forceps may cause vaginal wall or cervical lacerations, and even uterine rupture. Manipulations may also extend an episiotomy, create deep perineal tears, and increase infection risks. Anesthesia suicient to induce appreciable uterine relaxation during vaginal delivery may cause uterine atony and in turn postpartum hemorrhage. Maternal death is rare, but rates appear higher in those with planned cesarean delivery for breech presentation-a case fatality rate of 0.47 maternal deaths per 1000 births (Schutte, 2007). Last, the risks associated with vaginal breech delivery are balanced against general cesarean delivery risks described in Chapter 30 (p. 568). Long-term, cesarean risks include those associated with repeated hysterotomy or with vaginal birth ater cesarean-VBAC-further described in Chapter 31 (p. 593).

For the fetus, prematurity and its complications are frequently comorbid with breech presentation. Rates of congenital anomalies are also greater (Cammu, 2014; Mostello, 2014). Compared with cephalic presentation, umbilical cord prolapse is more frequent with breech fetuses (Behbehani, 2016; Obeidat, 2010). Birth trauma can include fractures of the humerus, clavicle, and femur (Canpolat, 2010; Matsubara, 2008). In some cases, traction may separate scapular, humeral, or femoral epiphyses (Lamrani, 2011). Trauma is more common with vaginal births, but fetal trauma is also seen with cesarean deliveries.

Rare traumatic injuries may involve soft tissues. Brachial plexus injury and paralysis is one example (Foad, 2008). The spinal cord may be injured or even severed, or vertebrae fractured, especially if great force is employed (Vialle, 2007). Hematomas of the sternocleidomastoid muscles occasionally develop after delivery but usually disappear spontaneously. Last, genital injury may follow breech delivery (Saroha, 2015).

Some perinatal outcomes may be inherent to the breech position rather than delivery. For example, development of hip dysplasia is more common in breech compared with cephalic presentation and is unafected by delivery mode (de Hundt, 2012; Fox, 2010; Ortiz-Neira, 2012).

In many fetuses-especially those that are preterm-the breech is smaller than the atercoming head. Moreover, unlike cephalic presentations, the head of a breech-presenting fetus does not undergo appreciable molding during labor. Thus, if vaginal delivery is considered, fetal size, type of breech, and degree of neck lexion or extension are evaluated. In addition, pelvic dimensions are assessed to avoid head entrapment from cephalopelvic disproportion. Sonography and fetal pelvimetry are options.

Sonographic fetal evaluation will have been performed in most cases as part of prenatal care. If not, gross fetal abnormalities, such as hydrocephaly or anencephaly, can be rapidly ascertained with sonography. This will identiy many fetuses not suitable for vaginal delivery. It will also help to ensure that a cesarean delivery is not performed under emergency conditions for an anomalous fetus with no chance of survival.

Head flexion can usually also be determined sonographically, and for vaginal delivery, the fetal head should not be extended (Fontenot, 1997; Rojansky, 1994). If imaging is uncertain, then simple two-view radiography of the maternal abdomen is useful to define fetal head inclination. Sonographic identification of a nuchal arm may warrant cesarean delivery to avoid neonatal harm (Sherer, 1989).

he accuracy of fetal weight estimation by sonography is not altered by breech presentation (McNamara, 2012). Although variable, many protocols use fetal weights >2500 g and <3800 to 4000 g or evidence of growth restriction as exclusion criteria for planned vaginal delivery (Azria, 2012; Kotaska, 2009). Similarly, a biparietal diameter (BPD) >90 to 100 mm is often considered exclusionary (Giuliani, 2002; Roman, 2008).

Pelvimetry assesses the maternal bony pelvis before vaginal delivery, and one-view computed tomography (CT) , magnetic resonance (MR) imaging, or plain film radiography is suitable. Comparative data among these modalities for pelvimetry are lacking, but CT is favored due to its accuracy, low radiation dose, and widespread availability (homas, 1998). At Parkland Hospital, we use CT pelvimetry when possible to assess the critical dimensions of the pelvis (Chap. 2, p. 30). Although variable, some suggest specific measurements to permit a planned vaginal delivery: inlet anteroposterior diameter : 10.5 cm; inlet transverse diameter : 12.0 cm; and midpelvic interspinous distance : 10.0 cm (Azria, 2012; Vendittelli, 2006). Some have recommended maternalfetal biometry correlation. Appropriate values include: the sum of the inlet obstetrical conjugate minus the fetal BPD is : 15 mm; the inlet transverse diameter minus the BPD is :25 mm; and the midpelvis interspinous distance minus the BPD is :0 mm (Michel, 2011). With MR imaging, Hofmann and colleagues (2016) found vaginal delivery success rates of 79 percent in selected candidates if the interspinous distance exceeded 11 cm.

Currently, the American College of Obstetricians and Gynecologists (2016b) recommends that "the decision regarding the mode of delivery should depend on the experience of the health-care provider" and that "planned vaginal delivery of a term singleton breech fetus may be reasonable under hospitalspecific protocol guidelines." These guidelines have been echoed by other obstetrical organizations (Kotaska, 2009; Royal College of Obstetricians and Gynaecologists, 2006). Risks versus beneits are weighed and discussed with the patient. If possible, this is preferably done before admission. A diligent search is made for other complications, actual or anticipated, that might warrant cesarean delivery. Common circumstances are listed in Table

For a favorable outcome with any breech delivery, at the very minimum, the birth canal must be suiciently large to allow passage of the fetus without trauma. he cervix must be fully dilated, and if not, then a cesarean delivery nearly always is the more appropriate method of delivery if suspected fetal compromise develops.

TABLE 28-1 . Factors Favoring Cesarean Delivery of the Breech Fetus

Lack of operator experience

Patient request for cesarean delivery Large fetus: >3800 to 4000 g Apparently healthy and viable fetus either with active labor or with indicated delivery Severe fetal-growth restriction Fetal anomaly incompatible with vaginal delivery Prior perinatal death or neonatal birth trauma Incomplete or footling breech presentation Hyperextended head Pelvic contraction or unfavorable pelvic shape determined clinically or with pelvimetry Prior cesarean delivery

The conduct of both labor and delivery difer between cephalic and breech presentations. First, breech labor in general proceeds more slowly, but steady cervical progress is a positive indicator of adequate pelvic proportions (Lennox, 1998). Vaginal breech delivery is accomplished by one of three methods. With spontaneous breech delivery, the fetus is expelled entirely without any traction or manipulation other than support of the newborn. With partial breech extraction, the fetus is delivered spontaneously as far as the umbilicus, but the remainder of the body is delivered by provider traction and assisted maneuvers, with or without maternal expulsive eforts. With total breech extraction, the entire fetal body is extracted by the provider.

As with many other aspects of breech position, induction or augmentation of labor is controversial. Here again, data are limited and mostly retrospective. With labor induction, Burgos and coworkers (2017) reported equivalent vaginal delivery rates compared with spontaneous labor. With induction, however, they reported higher rates of neonatal intensive care unit admission. But, others have found similar perinatal outcome and cesarean delivery rates Qarniat, 2017; Marzouk, 2011). Finally, others described greater cesarean delivery rates with induction but similar neonatal outcomes (Macharey, 2016).

In many studies, successful vaginal delivery is associated with orderly labor progression. hus, some protocols avoid augmentation for the breech-presenting fetus, whereas others recommend it only for hypotonic contractions (Alarab, 2004; Kotaska, 2009). In women with a viable fetus, at Parkland Hospital, we attempt amniotomy induction but prefer cesarean delivery instead of pharmacological labor induction or augmentation.

On arrival to the labor unit, surveillance offetal heart rate and uterine contractions begins, and immediate recruitment of necessary staf includes: (1) a provider skilled in the art of breech extraction, an associate to assist with the delivery, (3) anesthesia personnel who can ensure adequate analgesia or anesthesia when needed, and an individual trained in newborn resuscitation. For the mother, intravenous access is obtained. his allows, if needed, emergency induction of anesthesia or maternal resuscitation following hemorrhage from lacerations or from uterine atony.

At admission, the status of the membranes and progression of labor are assessed. Knowledge regarding cervical dilatation, cervical efacement, and presenting part station is essential for preparation. If labor is too far advanced, pelvimetry may be unsafe if fetal expulsion in the radiology department is a pos sibility. This alone, however, should not force the decision for cesarean delivery. As mentioned, stepwise labor progression itself is a good indicator of pelvic adequacy (Biswas, 1993).

Sonographic assessment, described earlier, is completed. Ulti mately, the choice of abdominal or vaginal delivery is based on factors discussed earlier and listed in Table 28-1.

During labor, one-on-one nursing is ideal because of cord prolapse risks, and physicians must be readily available for such emergencies. Guidelines for monitoring the high-risk fetus are applied (Chap. 24, p. 478). For first-stage labor, while most clini cians prefer continuous electronic monitoring, the fetal heart rate is recorded at a minimum of every 15 minutes. A scalp electrode can be safely aixed to the buttock, but genitalia are avoided. If a nonreassuring fetal heart rate pattern develops, then a decision must be made regarding the necessity of cesarean delivery.

When membranes rupture, either spontaneously or artificially, the cord prolapse risk is appreciable and is increased when the fetus is small or when the breech is not frank. Therefore, vaginal examination is performed immediately following rupture, and special attention is directed to the fetal heart rate for the irst 5 to 10 minutes thereafter.

For women in labor with a breech presentation, continuous epidural analgesia is advocated by some. This may increase the need for labor augmentation and prolong second-stage labor (Chadha, 1992; Confino, 1985). hese potential disadvantages are weighed against the advantages of better pain relief and increased pelvic relaxation should extensive manipulation be required. Analgesia must be suicient for episiotomy, for breech extraction, and for Piper forceps application. Nitrous oxide plus oxygen inhalation can provide further relief from pain. If general anesthesia is required, it must be induced quickly.

Similar to vertex delivery, spontaneous expulsion of a breech fetus entails sequential cardinal movements. First, engagement and descent of the breech usually take place with the bitrochanteric diameter in one of the oblique pelvic diameters. The anterior hip usually descends more rapidly than the posterior hip, and when the resistance of the pelvic Boor is met, internal rotation of 45 degrees usually follows, bringing the anterior hip toward the pubic arch and allowing the bitrochanteric diameter to occupy the anteroposterior diameter of the pelvic outlet. If the posterior extremity is prolapsed, however, it, rather than the anterior hip, rotates to the symphysis pubis.

After rotation, descent continues until the perineum is distended by the advancing breech, and the anterior hip appears at the vulva. By lateral lexion of the fetal body, the posterior hip then is forced over the perineum, which retracts over the fetal buttocks, thus allowing the fetus to straighten out when the anterior hip is born (Fig. 28-4). he legs and feet follow the breech and may be born spontaneously or require aid.

FIGURE 28-4 The hips of the frank breech are delivering over the perineum. The anterior hip usually delivers first.

After the birth of the breech, there is slight external rotation, with the back turning anteriorly as the shoulders are brought into relation with one of the oblique diameters of the pelvis. The shoulders then descend rapidly and undergo internal rotation, with the bisacromial diameter occupying the anteroposterior plane. Immediately following the shoulders, the head, which is normally sharply flexed on the thorax, enters the pelvis in one of the oblique diameters and then rotates to bring the posterior portion of the neck under the symphysis pubis. The head is then born in flexion.

The breech may engage in the transverse diameter of the pelvis, with the sacrum directed anteriorly or posteriorly. he mechanism oflabor in the transverse position difers only in that internal rotation is through an arc of 90 rather than 45 degrees. Infrequently, rotation renders the back of the fetus to lie posteriorly instead of anteriorly. Such rotation is prevented if possible. Although the head can be delivered by allowing the chin and face to pass beneath the symphysis, the slightest traction on the body may cause extension of the head, which increases the diameter of the head that must pass through the pelvis.

With breech delivery, successively larger and less compressible parts are born. Thus, spontaneous expulsion is the exception, and vaginal delivery typically requires skilled provider participation for the fetus to navigate the birth canal. Noteworthy clinical pearls are provided by Yeomans (2017) in the third edition of Cunningham and Gilstrap s Operative Obstetrics.

First, with all breech deliveries, unless the perineum is considerably lax, an episiotomy is made and is an important adjunct to delivery. As discussed in Chapter 27 (p. 529), mediolateral episiotomy may be preferred for its lower associated risk of anal

FIGURE 28-5 To deliver the left leg, two fingers of the provider's left hand are placed beneath and parallel to the femur. The thigh is then slightly abducted and pressure from the fingertips in the popliteal fossa should induce knee flexion and bring the foot within reach. The foot is then grasped to gently deliver the entire leg outside the vagina. A similar procedure is followed on the right. (Figures 28-5 though 28-8: Reproduced with permission from Yeomans ER: Vaginal breech delivery. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New (ork, McGraw-Hili Education, 201o7.)

FIGURE 28-6 To deliver the body, thumbs are placed over the sacrum, and each index finger wraps over the top of the corresponding fetal iliac crest. Gentle downward traction is applied until the scapulas are clearly visible. (Reproduced with permission from Yeomans ER: Vaginal breech delivery. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 2017.)

FIGURE 28-7 A. After delivery of the first arm, 180-degree rotation of the fetal body brings the sacrum to a right sacrum transverse (RST) position. B. Fingers of the provider's hand extended over the right shoulder and parallel to the humerus. These sweep the arm downward across the chest and out. (Reproduced with permission from Yeomans ER: Vaginal breech delivery. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 201o7.) sphincter lacerations. Ideally, the breech is allowed to deliver spontaneously to the umbilicus. Delivery of the breech draws the umbilicus and attached cord into the pelvis. Therefore, once the breech has passed beyond the vaginal introitus, the abdomen, thorax, arms, and head must be delivered promptly either spontaneously or assisted.

The posterior hip will deliver, usually from the 6 o'clock position, and oten with suicient pressure to evoke passage of thick meconium (see Fig. 28-4). he anterior hip then delivers, followed by external rotation to a sacrum anterior position. The mother is encouraged to continue to push as the fetus descends until the legs are accessible. The legs are sequentially delivered by splinting the femur with the operator's fingers positioned parallel to the long axis of the femur, and by exerting pressure upward and laterally to sweep each leg away from the midline (Fig. 28-5).

Following delivery of the legs, the fetal bony pelvis is grasped with both hands. The fingers should rest on the anterior superior iliac crests and the thumbs on the sacrum. his minimizes the chance of fetal abdominal soft-tissue injury (Fig. 28-6). Maternal expulsive eforts are again used in conjunction with downward traction to afect delivery.

A cardinal rule in successul breech extraction is to employ steady, gentle, downward traction until the lower halves of the scapulas are delivered, making no attempt at delivery of the shoulders and arms until one axilla becomes visible. It makes little difference which shoulder is delivered irst, and two methods are suitable for their delivery. In the first method, with the scapulas visible, the trunk is rotated either clockwise or counterclocwise to bring the anterior shoulder and arm into view (Fig. 28-7). During delivery of the arm, fingers and hand are aligned parallel to the humerus and act to splint and prevent humeral fracture. he body of the fetus is then rotated 180 degrees in the reverse direction to bring the other shoulder and arm into position for delivery.

he second method is employed if trunk rotation is unsuccessful. With this maneuver, the posterior shoulder is delivered first. For this, the feet are grasped in one hand and drawn upward over the inner thigh of the mother (Fig. 28-8). The

FIGURE 28-8 Infrequently, the posterior arm must be delivered first. For this, the lower half of the fetal body is raised up and over the maternal groin. The provider's fingers are inserted under the posterior shoulder and aligned with the humerus. (Reproduced with permission from Yeomans ER: Vaginal breech delivery. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 2017.) hand enters over the shoulder, fingers are aligned parallel to the long axis of the humerus, and the fetal arm is swept upward. The posterior shoulder slides out over the perineal margin and is usually followed by the arm and hand. Then, by depressing the body of the fetus, the anterior shoulder emerges beneath the pubic arch, and the arm and hand usually follow spontaneously. After both shoulders are delivered, the back of the fetus tends to rotate spontaneously to the symphysis. Delivery of the head may then be accomplished.

During delivery, one or both fetal arms occasionally may lie across the back of the neck and become impacted at the pelvic inlet. With such a nuchal arm, delivery is more diicult and can be aided by rotating the fetus through a half circle in such a direction that the friction exerted by the birth canal will draw the elbow toward the face (Fig. 28-9). With a right nuchal arm, the body should be rotated counterclockwise, which rotates the fetal back toward the maternal right. With a left nuchal arm, the rotation is clockwise. If rotation fails to free the nuchal arm, it may be necessary to push the fetus upward to a roomier part of the pelvis. If the rotation is still unsuccessul, the nuchal arm oten is extracted by hooking a inger(s) over it and forcing the arm over the shoulder, and down the ventral surface for delivery of the arm. In this event, fracture of the humerus or clavicle is common.

Delivery of the Aftercoming Head

Mauriceau Maneuver. The fetal head is normally extracted with forceps or by one of several maneuvers. With any of these techniques, hyperextension of the fetal neck is avoided.

With the Mauriceau maneuver, the index and middle inger of one hand are applied over the maxilla, to flex the head, while

FIGURE 28-10 A. Delivery of the aftercoming head using the Mauriceau maneuver. Note that as the fetal head is being delivered, flexion of the head is maintained by suprapubic pressure provided by an assistant. B. Pressure on the maxilla is applied Simultaneously by the operator as upward and outward traction is exerted.

FIGURE 28-9 Reduction of a right nuchal arm is accomplished by rotating the fetal body 180 degrees counterclockwise, which directs the fetal back to the maternal right. Friction exerted by the birth canal will draw the elbow toward the face. (Reproduced with permission from Yeomans ER: Vaginal breech delivery. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 201•7.) the fetal body rests on the palm of the same hand and forearm (Fig. 28-10). Fetal legs straddle the forearm. Two ingers of the other hand then are hooked over the fetal neck and grasp the shoulders. Downward traction is concurrently applied until the suboccipital region appears under the symphysis. Gentle suprapubic pressure simultaneously applied by an assistant helps keep the head flexed. The body then is slightly elevated toward the maternal abdomen, and the mouth, nose, brow, and eventually the occiput emerge successively over the perineum. With this maneuver, the provider uses both hands simultaneously to exert continuous downward gentle traction while balancing forces between the fetal neck and maxilla to avoid neck hyperextension.

Forceps. Specialized forceps can be used to deliver the aftercoming head. Piper forceps, shown in Figure 28-11, or Laufe-Piper forceps may be applied electively or when the Mauriceau maneuver cannot be accomplished easily. The blades

FIGURE 28-11 Piper forceps for delivery of the aftercoming head. A. The fetal body is held elevated using a warm towel and the left blade of forceps is applied to the aftercoming head. B.The right blade is applied with the body still elevated. C. Forceps delivery of the aftercom ing head. Note the direction of movement shown by the arrow.

of the forceps are not applied to the aftercoming head until it has been brought into the pelvis by gentle traction, combined with suprapubic pressure, and is engaged. Suspension of the body of the fetus in a towel efectively holds the fetus up and helps keep the arms and cord out of the way as the forceps blades are applied.

Because the forceps blades are directed upward from the level of the perineum, some choose to apply them from a one-knee kneeling position. Piper forceps have a downward arch in the shank to accommodate the fetal body and lack a pelvic curve. This shape permits direct application of the cephalic curve of the blade along the length of the maternal vagina and fetal parietal bone. The blade to be placed on the maternal left is held in the provider's left hand. The right hand slides between the fetal head and left maternal vaginal sidewall to guide the blade inward and around the parietal bone. he opposite blade mirrors this application.

Once in place, the blades are articulated, and the fetal body rests across the shanks. The head is delivered by pulling gently outward and slightly raising the handle simultaneously. This rolls the face over the perineum, while the occiput remains beneath the symphysis until after the brow delivers. Ideally, the head and body move in unison to minimize neck hyperextension.

Modified Prague Maneuver. Rarely, the back of the fetus fails to rotate to the symphysis. The fetus still may be delivered using the modiied Prague maneuver. With this, two fingers of one hand grasp the shoulders of the back-down fetus from below while the other hand draws the feet up and over the maternal abdomen (Fig. 28-12).

FIGURE 28-12 Delivery of the aftercoming head using the modified Prague maneuver necessitated by failure of the fetal trunk to rotate anteriorly.

FIGURE 28-13 Duhrssen incision being cut at 2 o'clock, which is followed by a second incision at 10 o'clock. Infrequently, an additional incision is required at 6 o'clock. The incisions are so placed as to minimize bleeding from the laterally located cervical branches of the uterine artery. After delivery, the incisions are repaired as described in Chapter 41 (p.o763).

Head Entrapment. his emergency reflects either an incompletely dilated cervix or cephalopelvic disproportion. First, especially with a small preterm fetus, an incompletely dilated cervix can constrict around the neck and impede delivery of the aftercoming head. At this point, signiicant cord compression must be assumed, and time management is essential. With gentle traction on the fetal body, the cervix, at times, may be manually slipped over the occiput. If unsuccessful, then Diihrssen incisions may be necessary (Fig. 28-13). General anesthesia with halogenated agents or intravenous nitroglycerin is another option to aid lower uterine segment relaxation. As an extreme measure, replacement of the fetus higher into the vagina and uterus, followed by cesarean delivery, can rescue an entrapped breech fetus. This Zavaneli maneuver is classically performed to relieve intractable shoulder dystocia (Sandberg, 1988). However, case reports also have described its use for an entrapped aftercoming head (Sandberg, 1999; Steyn, 1994).

In cases with cephalopelvic disproportion and arrest of aftercoming head, the Zavanelli maneuver or symphysiotomy are options (Sunday-Adeoye, 2004; Wery, 2013). Using local analgesia, symphysiotomy surgically divides the intervening symphyseal cartilage and much of its ligamentous support to widen the symphysis pubis up to 2.5 cm (Basak, 2011). Lack of provider training and potentially serious maternal pelvic or urinary tract injury explain its rare use in the United States. That said, if cesarean delivery is not possible, symphysiotomy may be lifesaving for both mother and baby (Hofmeyr, 2012).

At times, total extraction of a complete or incomplete breech may be required. A hand is introduced through the vagina, and both fetal feet are grasped. he ankles are held with the middle finger lying between them. With gentle traction, the feet are brought through the introitus (Fig. 28-14). As the legs begin to emerge through the vulva, downward gentle traction is continued. As the legs emerge, successively higher portions are grasped, first the calves and then the thighs. When the breech appears at the vaginal outlet, gentle traction is applied until the hips are delivered. The thumbs are then placed over the sacrum and the fingers over the iliac crests. Breech extraction is then completed, as described for partial breech extraction (p. 544).

FIGURE 28-14 Complete breech extraction begins with traction on the feet and ankles.

If only one foot can be grasped, it can be brought down into the vagina and held with the appropriate hand, right hand for right foot and left hand for left foot (Yeomans, 2017). With the irst foot secure, the opposite hand is introduced, passed upward along the leg, and guided to locate the other foot. If the remaining hip is extended, the second foot is usually easily grasped and brought down. If the hip is lexed and knee extended, a finger is hooked into that groin, and traction will bring the lower half of the fetus down until the leg can be reached. For cesarean delivery, these total breech extraction maneuvers can be used to deliver a complete, incomplete, or footling breech through the hysterotomy incision.

During complete extraction of a frank breech, moderate traction is exerted by a finger in each groin and aided by a generous episiotomy. Once the breech is pulled through the introitus, the steps described for partial breech extraction are then completed (p. 544). These maneuvers are also used during cesarean delivery of a frank breech through a hysterotomy incision.

Rarely during vaginal delivery, a frank breech will require decomposition inside the uterine cavity. Attributed to Pinard (1889), this procedure converts a frank breech into a footling breech. It is accomplished more readily if the membranes have ruptured only recently. It becomes extremely diicult if amnionic luid is scant and the uterus is tightly contracted around the fetus. Pharmacological relaxation by general anesthesia or intravenous magnesium sulfate, nitroglycerin, or a betamimetic agent may be required. To begin, two ingers are carried up along one leg to externally rotate the hip by pressing on the medial side of the thigh parallel to the femur. Simultaneously, pressure in the popliteal fossa should prompt spontaneous knee flexion, which brings the corresponding foot into contact with the back of the provider's hand. he fetal foot then may be grasped and brought down.

With version, fetal presentation is altered by physically substituting one pole of a longitudinal presentation for the other, or converting an oblique or transverse lie into a longitudinal presentation. Manipulations performed through the abdominal wall that yield a cephalic presentation are termed external cephalic version. Manipulations accomplished inside the uterine cavity that yield a breech presentation are designated intenal podalic version. This latter procedure is reserved for delivery of a second twin and described in Chapter 45 (p. 890).

External cephalic version (ECy) reduces the rate of noncephalic presentation at birth (Hofmeyr, 2015b). For breech fetuses near term, the American College of Obstetricians and Gynecologists (2016a,b) recommends that version be ofered and attempted whenever possible. Its success rate averages about 60 percent (de Hundt, 2014). For women with a transverse lie, the overall success rate is significantly higher.

In general, ECV is attempted before labor in a woman who has reached 37 weeks' gestation. Before this time, breech pre sentation still has a high likelihood of correcting spontaneously.

And, if ECV is performed too early, time may allow a rever sion back to breech (Bogner, 2012). Last, if attempts at version cause a need for immediate delivery, complications of iatro genic late-preterm delivery generally are not severe.

Absolute contraindications to external version are few. It is contraindicated if vaginal delivery is not an option, such as with placenta previa. Another is multifetal gestation. Relative contraindications are early labor, oligohydramnios or rupture of membranes, known nuchal cord, structural uterine abnor malities, fetal-growth restriction, and prior abruption or its risks (Rosman, 2013). While many consider a prior cesarean delivery a contraindication, a few small studies found ECV was not asso ciated with uterine rupture (Burgos, 2014; Keepanasseril, 2017;

Weill, 2017). At Parkland Hospital, we do not attempt version in these women. More data from clinical studies are needed.

Several factors can improve the chances of a successful attempt. These include multiparity, unengaged presenting part, nonanterior placenta, nonobese patient, and abundant amnionic fluid (Kok, 2009, 2011; Velzel, 2015). To augment the last parameter, Burgos and coworkers (2014) administered a preprocedurali2-L intravenous luid bolus. While this improved amnionic luid volume, it did not increase version success rates.

Patient counseling includes a discussion regarding small but real risks for placental abruption, preterm labor, and fetal compromise. Rarely, uterine rupture, fetomaternal hemorrhage, alloimmunization, amnionic luid embolism, and even death may also complicate attempts at external version. hat said, fetal deaths are rare, serious complication rates are typically very low, and emergent cesarean rates are 0.5 percent or less (Grootscholten, 2008; Rodgers, 2017). And even after successful EC, several reports suggest that the cesarean delivery rate does not completely revert to the baseline for vertex presentations. Specifically, dystocia, malpresentation, and nonreassuring fetal heart patterns may be more common in these fetuses completing successful version (Chan, 2004; de Hundt, 2014; Vezina, 2004).

ECV should be carried out in an area that has ready access to a facility equipped to perform emergency cesarean delivery (American College of Obstetricians and Gynecologists, 20 16a). Because of the risk for surgical intervention, intravenous access is obtained, and patients abstain from eating for 6 or more hours. Sonographic examination is performed to conirm nonvertex presentation, document amnionic fluid volume adequacy, exclude obvious fetal anomalies if not done previously, and identiy placental location and fetal spine orientation. Preprocedural external monitoring is performed to assess fetal heart rate reactivity. Anti-D immune globulin is given to Rh-D negative women. Tocolysis and regional analgesia may be elected, and rationale for these is provided in subsequent sections.

he woman is placed in left lateral tilt to aid utero placental perfusion, and Trendelenburg positioning helps during elevation of the breech. During the procedure, we prefer to monitor fetal heart motion sonographically. An abundant abdominal coating of ultrasound gel permits this and also minimizes painful skin friction (Vallikkannu, 2014).

A forward roll of the fetus usually is attempted first. One or two providers may participate, and one hand grasps the head. he fetal buttocks are then elevated from the maternal pelvis and displaced laterally (Fig. 28-15). The buttocks are then gently guided toward the fundus, while the head is simultaneously directed toward the pelvis. If the forward roll is unsuccessful, a backward flip is attempted. ECV attempts are discontinued for excessive discomfort, persistently abnormal fetal heart rate, or after multiple failed attempts. Failure is not always absolute. Ben-Meir and colleagues (2007) reported a spontaneous version rate of 7 percent among 226 failed versions-2 percent among nulliparas and 13 percent among multiparas.

If ECV is successful, a nons tress test is repeated until a normal test result is obtained. If version is completed before 39 weeks' gestation, then awaiting spontaneous labor and fetal maturity is preferred. In some studies, immediate labor induction is linked to higher cesarean delivery rates (Burgos, 2015; Kuppens, 2013).

FIGURE 28-15 External cephalic version. With an attempted forward roll, clockwise pressure is exerted against the fetal poles.

To relax the uterus prior to an ECV attempt, existing evidence supports the use of tocolysis (American College of Obstetricians and Gynecologists, 2016a). Most data support the use of the beta-mimetics terbutaline and ritodrine (Cluver, 2015). In one such trial, Fernandez and coworkers (1996) reported that the success rate with subcutaneous terbutaline-52 percentwas significantly higher than without-27 percent. Our policy at Parkland Hospital is to administer 250 I1g of terbutaline subcutaneously to most women before attempted ECV. When maternal tachycardia-a known side efect of terbutaline-is noted, the attempt is begun. Data are limited and, in some cases nonsupportive, for alternate agents that include calciumchannel blockers, such as nifedipine; nitric oxide donors, such as nitroglycerin; the oxytocin-receptor antagonist atosiban; and another betamimetic salbutamol (Burgos, 2010; Hilton, 2009; Kok, 2008; Vani, 2009; Velzel, 2017; Wilcox, 2011).

Epidural analgesia coupled with tocolysis has been reported to increase version success rates compared with tocolysis alone (Goetzinger, 2011; Magro-Malosso, 2016). Moreover, rates of complications that include fetal heart rate aberrations, emergency cesarean delivery, or placental abruption were not greater with regional analgesia. Of randomized trials, spinal and epidural have both shown success (Khaw, 2015; Weiniger, 2010). Currently, the superior technique and best drugs to administer are unclear. In contrast, from limited data, intravenous sedation does not appear to improve success rates (Burgos, 2016; Khaw, 2015).

This is a traditional Chinese medicine technique that burns a cigarette-shaped stick of ground Artemisia vugaris-which is also known as mugwort or in Japanese as moxa. At the BL 67 acupuncture point, the stick is directly placed against the skin or indirectly heats an acupuncture needle at the site to increase fetal movement and promote spontaneous breech version (Ewies, 2002). It is performed usually between 33 and 36 weeks' gestation to permit a trial of ECV if not successful. Results from randomized controlled studies are conflicting (Bue, 2016; Coulon, 2014; Coyle, 2012; Sananes, 2016; Vas, 2013).

larab M, Regan C, O'Connell MP, et al: Singleton vaginal breech delivery at term: still a safe option. Obstet Gynecol 103:407, 2004 American College of Obstetricians and Gynecologists: External cephalic version. Practice Bulletin No. 161, February 2016a

American College of Obstetricians and Gynecologists: Mode of term in singleton breech delivery. Committee Opinion No. 340, July 2006, Reairmed 2016b

American College of Obstetricians and Gynecologists, Society for MaternalFetal Medicine: Periviable birth. Obstetric Care Consensus No.r6, October 2017

Azria E, Le Meaux JP, Khoshnood B, et al: Factors associated with adverse perinatal outcomes for term breech fetuses with planned vaginal delivery. Am J Obstet Gynecol 207(4):285.e1, 2012 Basak S, Kanungo S, Majhi C: Symphysiotomy: is it obsolete? J Obstet Gynaecol Res 37(7):770,r201r1

Behbehani S, Patenaude V, Abenhaim HA: Maternal risk factors and outcomes of umbilical cord prolapse: a population-based study. J Obstet Gynaecol Can 38(1):23, 2016

Ben-Meir A, Elram T, Tsafrir A, et al: The incidence of spontaneous version after failed external cephalic version. Am J Obstet Gynecol 196(2): 157,200

Bergenhenegouwen LA, Meertens LJ, Schaaf J, et al: Vaginal delivery versus caesarean section in preterm breech delivery: a systematic review. Eur J Obstet Gynecol Reprod Bioi 172: 1, 2014

Bergenhenegouwen L, Vlemmix F, Ensing S, et al: Preterm breech presentation: a comparison of intended vaginal and intended cesarean delivery. Obstet Gynecol 126(6):1223,r2015

Berhan Y, Haileamlak A: he risks of planned vaginal breech delivery versus planned caesarean section for term breech birth: a meta-analysis including observational studies. BJOG 123(1):49,r2016

Biswas A, Johnstone MJ: Term breech delivery: does x-ray pelvimetry help?

Aust N ZJ Obstet GynaecoI33:150, 1993

Bogner G, Xu F, Simbrunner C, et al: Single-institute experience, management, success rate, and outcome after external cephalic version at term. Int J Gynaecol Obstet 116(2):134,r2012

Bue L, Lauszus FF: Moxibustion did not have an efect in a randomised clinical trial for version of breech position. Dan Med J 63(2): A5199, 2016

Burgos J, Arana I, Garitano I, et al: Induction oflabor in breech presentation at term: a retrospective cohort study. J Perinat Med 45(3):299, 2017

Burgos J, Eguiguren N, Quintana E, et al: Atosiban vs. ritodrine as a tocolytic in external cephalic version at term: a prospective cohort study. J Perinat Med 38(1):23, 2010

Burgos J, Iglesias M, Pijoan Jr, et al: Probability of cesarean delivery after successful external cephalic version. Int J Gynaecol Obstet 131(2):192,r2015

Burgos J, Pijoan JI, Osuna C, et al: Increased pain relief with remifentanil does not improve the success rate of extenal cephalic version: a randomized controlled trial. Acta Obstet Gynecol Scand 95(5):547,r2016

Burgos J, Quintana E, Cobos P, et al: Efect of matenal intravenous Auid therapy on external cephalic version at term: a prospective cohort study. Am J Obstet GynecoI211(6):665.el, 2014

Cammu H, Dony N, Martens G, et al: Common determinants of breech presentation at birth in singletons: a population-based study. Eur J Obstet Gynecol Reprod Bioi 1 : 106, 2014

Canpolat FE, Kose A, Yurdakok M: Bilateral humerus fracture in a neonate after cesarean delivery. Arch Gynecol Obstet 281 (5):967, 2010

Chadha YC, Mahmood T A, Dick MJ, et al: Breech delivery and epidural analgesia. BJOG 99:96, 1992

Chan LY, TangJL, Tsoi KF, et al: Intrapartum cesarean delivery after successful external cephalic version: a meta-analysis. Obstet Gynecolrl04:155, 2004 Chinnock M, Robson S: Obstetric trainees' experience in vaginal breech deliv ery. Obstet Gynecol 110:900, 2007

Cimmino CV, Southworth LE: Persistent hyperextension of the neck in breech ("star-gazing fetus") and in transverse lie ("flying-fetus"): indication for cesar ean section. Am J Roentgenol Radium her Nucl Med , 1975

Cluver C, Gyte GM, Sinclair M, et al: Interventions for helping to turn term breech babies to head irst presentation when using external cephalic version. Cochrane Database Syst Rev 2:CDOOOI84, 2015

Conino E, rsmajovich B, Rudick V, et al: Extradural analgesia in the management of singleton breech delivery. Br J Anaesth 57:892, 1985

Coulon C, Poleszczuk M, Paty-Montaigne MH, et al: Version of breech fetuses by moxibustion with acupuncture: a randomized controlled trial. Obstet Gynecol 124(1) :32, 2014

Coyle ME, Smith CA, Peat B: Cephalic version by moxibustion for breech presentation. Cochrane Database Syst Rev 5:CD003928, 2012

Deering S, Brown J, Hodor J, et al: Simulation training and resident performance of singleton vaginal breech delivery. Obstet Gynecol (1): 86, 2006 de Hundt M, Velzel J, de Groot C], et al: Mode of delivery after successful external cephalic version: a systematic review and meta-analysis. Obstet Gynecol 123(6):1327,r2014 de Hundt M, Vlemmix F, Bais J M, et l: Risk factors for developmental dysplasia of the hip: a meta-analysis. Eur J Obstet Gynecol Reprod Bioi 165(1):8, 2012 Demirci 0, Tugrul AS, Turgut A, et al: Pregnancy outcomes by mode of delivery among breech births. Arch Gynecol Obstet 285(2):297,r2012 Eide MG, 0yen N, Skjaerven R, et al: Breech delivery and intelligence: a population-based study of8,738 breech infants. Obstet Gynecol 105(1):4, 2005

Ewies A, Olah KS: he sharp end of medical practice: the use of acupuncture in obstetrics and gynecology. BJOG 109(1): 1, 2002

Fernandez CO, Bloom S, Wendel G: A prospective, randomized, blinded comparison of terbutaline versus placebo for singleton, term external cephalic version. Am J Obstet Gynecol 174:326, 1996

Foad SL, Mehlman CT, Ying J: The epidemiology of neonatal brachial plexus palsy in the United States. J Bone Joint Surg Am 90(6): 1258,2008

Fontenot T, Campbell B, Mitchell-Tun E, et al: Radiographic evaluation of breech presentation: is it necessary? Ultrasound Obstet Gynecol 10:338, 1997

Ford JB, Roberts CL, Nassar N, et al: Recurrence of breech presentation in consecutive pregnancies. BJOG 117(7):830,r2010

Fox AE, Paton RW: he relationship between mode of delivery and developmental dysplasia of the hip in breech infants: a four-year prospective cohort study. J Bone Joint Surg Br 92(12):1695,r2010

Giuliani A, Scholl WMJ, Basver A, et al: vlode of delivery and outcome of 699 term singleton breech deliveries at a single center. Am J Obstet Gynecol 187: 1694, 2002

Goetzinger KR, Harper LM, Tuuli MG, et al: Efect of regional anesthesia on the success rate of external cephalic version: a systematic review and metaanalysis. Obstet Gynecol 118(5):1137,r2011

Goinet F, Carayol M, Foidart JM, et al: Is planned vaginal delivery for breech presentation at term still an option? Results of an observational prospective srvey in France and Belgium. Am J Obstet Gynecol 194(4): 1002,r2006

Grootscholten K, Kok M, Oei SG, et al: External cephalic version-related risks: a meta-analysis. Obstet Gynecol 112(5): 1143, 2008

Hannah ME, Hannah WJ, Hewson SA, et al: Planned caesarean section versus planned vaginal birth for breech presentation at term: a randomised multicentre trial. Lancet 356:1375,r2000

Hartnack 111arin JE, Rasmussen S, Krebs L: Consequences of the Term Breech Trial in Denmark. Acta Obstet Gynecol Scand ):767,r201r1

Henandez-Marti M, Dal Canto MC, Kidd JM: Evidence of spinal cord injury in an infant delivered by cesarean section. A case report. Childs Brain 11(3):197,r1984

Hilton J, Allan B, Swaby C, et al: Intravenous nitroglycerin for external cephalic version: a randomized controlled trial. Obstet Gynecol 114(3):560, 2009 Hofmann J, Thomassen K, Stumpp P, et al: New MRI criteria for successful vaginal breech delivery in primiparae. PLoS One 11(8):eOI61028, 2016 Hofmeyr GJ, Hannah M, Lawrie TA: Planned caesarean section for term breech delivery. Cochrane Database SYSt Rev :CDOOO 166, 2015a Hofmeyr GJ, Kulier R, West HM: Extenal cephalic version for breech presentation at term. Cochrane Database Syst Rev 4:CD000083, 201r5b

Hofmeyr GJ, Shweni PM: Symphysiotomy for feto-peh-ic disproportion.

Cochrane Database Syst Rev 10:CD005299, 2012

Janiat A, Eluard V, Martz 0, et al: Induced labour at term and breech presentation: Experience of a level lIB French maternity. J Gynecol Obstet Hum Reprod 46(7):597, 201

Kayem G, Com baud V, Lorthe E, et al: Mortality and morbidity in early preterm breech singletons: impact of a policy of planned vaginal delivelY. Eur J Obstet Gynecol Reprod Bioi 192:61, 2015

Keepanasseril A, Anand K, Soundara Raghavan S: Matched cohort study of external cephalic version in women with previous cesarean delivery. Int J Gynaecol Obstet 9,r2017

Khaw KS, Lee SW, Ngan Kee WD, et al: Randomized trial of anaesthetic interventions in external cephalic version for breech presentation. Br J Anaesth 114(6):944,r2015

Kok M, Bais JM, van Lith JM, et al: Nifedipine as a uterine relaxant for external cephalic version: a randomized controlled trial. Obstet Gynecol 112(2 Pt 1):271,r2008

Kok M, Cnossen J, Gravendeel L, et al: Ultrasound factors to predict the orcome of external cephalic version: a meta-analysis. Ultrasound Obstet Gynecol 33(1):76, 2009

Kok M, van der Steeg JW, van der Post JA, et al: Prediction of success of external cephalic version after 36 weeks. Am J Perinatol 28(2): 103, 2011

Kotaska A, Menticoglou S, Gagnon R: SOGC clinical practice guideline: vaginal delivery of breech presentation: No. 226, June 2009. Int J Gynaecol Obstet 107(2):169,r2009

Kuppens SM, Hurron EK, Hasaart TH, et al: Mode of delivery following successful external cephalic version: comparison with spontaneous cephalic presentations at delivery. J Obstet Gynaecol Can 35(10):883, 2013

Lamrani YA, Maaroui M, Kamaoui I, et al: Neonatal distal femoral epiphyseal dislocation: an ultrasound diagnosis. J Med Ultrason 38(4):221, 2011 Lennox CE, Kwast BE, Farley TM: Breech labor on the WHO partograph. Int J Gynaecol Obstet 62(2): , 1998

Lumbiganon P, Laopaiboon M, Gulmezoglu M, et al: Method of delivelY and pregnancy ourcomes in Asia: the WHO global survey on maternal and perinatal health 2007-08. Lancet 375(9713):490,r2010

Lydon-Rochelle M, Albers L, GorwodaJ, et al: Accracy of Leopold maneuvers in screening for malpresentation: a prospective study. Birth 20:132, 1993 Lyons J, Pressey T, Bartholomew S, et al: Delivery of breech presentation at term gestation in Canada, 2003-201 1. Obstet GynecoIr125(5):1153, 2015

Macharey G, Gissler M, Rahkonen L, et al: Breech presentation at term and associated obstetric risks factors-a nationwide population based cohort study. Arch Gynecol Obstet 295(4):833,r2017

Macharey G, Ulander VM, Heinonen S, et al: Induction of labor in breech presentations at term: a retrospective observational study. Arch Gynecol Obstet 293(3):549,r2016

Magro-Malosso ER, Saccone G, Di Tommaso M, et al: Neuraxial analgesia to increase the success rate of external cephalic version: a systematic review and meta-analysis of randomized controlled trials. Am J Obstet Gynecol 215(3):276,r2016

Marzouk P, Arnaud E, Oury JF, et al: Induction of labour and breech presentation: experience of a French maternity ward. [French]. J Gynecol Obstet Bioi Reprod (Paris) 40(7):668, 2011

Maslovitz S, Barkai G, Lessing JB, et al: Recurrent obstetric management mistakes identiied by simulation. Obstet Gynecol 109(6): 1295, 2007

Matsubara S, Izumi A, Nagai T, et al: Femur fracture during abdominal breech delivery. Arch Gynecol Obstet 278(2):195,r2008

McNamaraJM, Odibo AO, Macones GA, et al: The efect of breech presentation on the accuracy of estimated fetal weight. Am J PerinatoIr29(5):353, 2012

Michel S, Drain A, Closset E, et al: Evaluation of a decision protocol for type of delivery of infants in breech presentation at term. Eur J Obstet Gynecol Reprod Bioi 158(2):194, 2011

Mostello 0, Chang JJ, Bai F, et al: Breech presentation at delivery: a marker for congenital anomaly? J Perinatol 34(1): 11, 2014

Muhuri PK, Macdorman MF, Menacker F: Method of delivery and neonatal mortaliry among very low birth weight infants in the United States. Matern Child Health J 10:47,r2006

Nassar N, Roberts CL, Cameron CA, et al: Diagnostic accuracy of clinical examination for detection of non-cephalic presentation in late pregnancy: cross sectional analytic study. BMJ 333:578, 2006

Obeidat N, Zayed F, Alchalabi H, et al: Umbilical cord prolapse: a lO-year retrospective study in two civil hospitals, North Jordan. J Obstet Gynaecol 30(3):257,r2010

Ortiz-Neira CL, Paolucci EO, Donnon T: A meta-analysis of common risk factors associated with the diagnosis of developmental dysplasia of the hip in newborns. Eur J RadioIr81(3):e344, 2012

Phelan JP, Bethel M, DeVore G, et al: Use of ultrasonography in the breech presentation with hyperextension of the fetal head. J Ultrasound Med 2(8):373, 1983

Pinard A: On version by external maneuvers. In Traite du Palper Abdominal.

Paris, Lauwereyns, 1889

Raju TN, Mercer BM, Burchfield OJ, et al: Periviable birth: executive summary of a joint workshop by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Academy of Pediatrics, and merican College of Obstetricians and Gynecologists. Obstet GynecoIr123(5):1083, 2014 Reddy UM, Zhang J, Sun L, et al: Neonatal mortality by attempted route of delivery in early preterm birth. Am J Obstet Gynecol 207(2): 117.e1, 2012 Rietberg CC, Elferink-Stinkens PM, Visser GH: The efect of the Term Breech Trial on medical intervention behaviour and neonatal outcome in he Netherlands: an analysis of35,453 term breech infants. BJOG 112(2):205,r2005 Rodgers R, Beik N, Nassar N, et al: Complications of external cephalic version: a retrospective analysis of 1121 patients at a tertiary hospital in Sydney. BJOG 124(5):767,r201 Rojansky N, Tanos V, Lewin A, et al: Sonographic evaluation of fetal head extension and maternal pelvis in cases of breech presentation. Acta Obstet Gynecol Scand 73:607, 1994 Roman H, Carayol M, Watier L, et al: Planned vaginal delivery of fetuses in breech presentation at term: prenatal determinants predictive of elevated risk of cesarean delivery during labor. Eur J Obstet Gynecol Reprod Bioi 138(1):14,r2008

Rosman AN, Guijt A, Vlemmix F, et al: Contraindications for external cephalic version in breech position at term: a systematic review. Acta Obstet Gynecol Scand 92(2):137,r2013 Royal College of Obstetricians and Gynaecologists: he management of breech presentation. RCOG Green Top Guidelines, No. 20b. London, 2006 Sananes N, Roth GE, issi GA, et al: Acupuncture version of breech presentation: a randomized sham-controlled single-blinded trial. Eur J Obstet Gynecol Reprod Bioi 204:24, 2016 Sandberg EC: The Zavanelli maneuver: 12 years of recorded experience. Obstet GynecoIr93:312, 1999

Sandberg EC: he Zavanelli maneuver extended: progression of a revolutionary concept. AmJ Obstet Gynecolr158(6 Pt 1):1347,r1988 Saroha M, Batra P, Dewan P, et al: Genital injuries in neonates following breech presentation. J Neonatal Perinatal Med 8(4):421, 2015 Schutte JM, Steegers A, Santema JG, et al: Maternal deaths after elective cesarean section for breech presentation in the Netherlands. Acta Obstet Gynecol Scand 86(2):240, 2007 Sherer OM, Menashe M, Palti Z, et al: Radiologic evidence of a nuchal arm in the breech-presenting fetus at the onset of labor: an indication for abdominal delivery. Am J PerinatoI6(3):353, 1989

Steyn W, Pieper C: Favorable neonatal outcome after fetal entrapment and partially successful Zavanelli maneuver in a case of breech presentation. Am J Perinatolrll:348, 1994 Sunday-Adeoye 1M, Okonta P, Twomey 0: Symphysiotomy at the Mater Misericordiae Hospital Afikpo, Ebonyi State of Nigeria (1982-1999): a review of 1013 cases. J Obstet GynaecoI24(5):525, 2004 Thomas PE, Petersen SG, Gibbons K: he influence of mode of birth on neonatal survival and maternal outcomes at extreme prematurity: a retrospective cohort study. Aust N Z J Obstet Gynaecol 56(1):60, 2016 homas SM, Bees NR, Adam EJ: Trends in the use of pelvimetry techniques. Clin RadioIr53(4):293, 1998

Toivonen E, Palomaki 0, Huhtala H, et al: Selective vaginal breech delivery at term-still an option. Acta Obstet Gynecol Scand 91 (10): 1177, 2012

Vallikannu N, Nadzratulaiman N, Omar SZ, et al: Talcum powder or aqueous gel to aid external cephalic version: a randomised controlled trial. BMC Pregnancy Childbirth 14:49,2014

Vani S, Lau SY, Lim BK, et al: Intravenous salbutamol for external cephalic version. Int J Gynecol Obstet 104(1):28, 2009

Vas J, Aranda-Regules JM, Modesto M, et al: Using moxibustion in primary healthcare to correct non-vertex presentation: a multicentre randomised controlled trial. Acupunct Med 31(1):31,r2013 Velzel J, Vlemmix F, Opmeer Be, et al: Atosiban versus fenoterol as a uterine relaxant for external cephalic version: a randomised controlled trial. BMJ 26:356,r2017 Velzel J, de Hundt M, Mulder FM, et al: Prediction models for successful external cephalic version: a systematic review. Eur J Obstet Gynecol Reprod BioI 195:160,r2015

Vendittelli F, Pons Je, Lemery 0, et al: he term breech presentation: neonatal results and obstetric practices in France. Eur J Obstet Gynecol Reprod BioI 125(2):176,r2006

Vezina Y, Bujold E, Varin J, et al: Cesarean delivery after successful external cephalic version of breech presentation at term: a comparative study. Am J Obstet Gynecol 190:763,r2004

Vialle R, Pietin-Vialle C, Ilharreborde B, et al: Spinal cord injuries at birth: a multicenter review of nine cases. J Matern Fetal Neonatal Med 20(6):435, 2007

Vistad I, Klungs0yr K, Albrechtsen S, et al: Neonatal outcome of singleton term breech deliveries in N otway from 1991 to 2011. Acta Obstet Gynecol Scand 94(9):997, 2015

Weill Y, Pollack N: he eicacy and safery of external cephalic version after a previous caesarean delivery. Aust N Z J Obstet Gynaecol 57(3):323, 2017 Weiniger CF, Ginosar Y, Elchalal U, et al: Randomized controlled trial of external cephalic version in term multiparae with or without spinal analgesia. Br J Anaesth 104(5):613,r2010 Wery E, Le Roch A, Subtil 0: Zavanelli maneuver performed in a breech presentation. Int J Gynaecol Obstet 120(2):193,2013 Westgren M, Grundsell H, Ingemarsson I, et al: Hyperextension of the fetal head in breech presentation. A study with long-term follow-up. BJOG 88(2):101, 1981 Whyte H, Hannah ME, Saigal S, et al: Outcomes of children at 2 years after planned cesarean birth versus planned vaginal birth for breech presentation at term: the International Randomized Term Breech Trial. Am J Obstet GynecoIr191(3):864,r2004 Wilcox CB, Nassar N, RobertS CL: Efectiveness of nifedipine tocolysis to facilitate external cephalic version: a systematic review. BJOG 118(4):423,2011 Yeomans ER: Vaginal breech delivery. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hill Education, 2017

The most important function of orceps is traction exercised or the purpose of drawing the head through the genital tract. In not a ew cases, however, particulary in occipito-posterior presentations, its employment as a rotator is attended by most happy results.

-J. Whitridge Williams (1903)

Operative deliveries are vaginal deliveries accomplished with the use of forceps or a vacuum device. Once either is applied to the fetal head, outward traction generates forces that augment maternal pushing to deliver the fetus vaginally. he most important function of both devices is traction. In addition, forceps may also be used for rotation, particularly from occiput transverse and posterior positions.

According to the birth certiicate data from the National Vital Statistics Report, forceps-or vacuum-assisted vaginal delivery was used for 3.2 percent of births in the United States in 2014. his is a decline from 9.0 percent in 1990 (Hamilton, 2015). For these deliveries, a vacuum is disproportionately selected, and the vacuum-to-forceps delivery ratio is nearly 5: 1 (Merriam, 2017). In general, most of these attempts are successful. In 2006, only 0.4 percent of forceps trials in the United States and 0.8 percent of vacuum extraction attempts failed to result in vaginal delivery (Osterman, 2009).

If it is technically feasible and can be safely accomplished, termination of second-stage labor by traction instruments is indicated in any condition threatening the mother or fetus that is likely to be relieved by delivery. Some fetal indications include nonreassuring fetal heart rate pattern and premature placental separation (Schuit, 2012). In the past, forceps delivery was believed to be somewhat protective of the fragile preterm infant head. However, outcomes for neonates who 500 to 1500 g do not signiicantly difer if delivered spontaneously or by outlet forceps (Fairweather, 1981; Schwartz, 1983).

Some maternal indications include heart disease, pulmonary compromise, intrapartum infection, and certain neurological conditions. The most common are exhaustion and prolonged second-stage labor. However, a speciic maximum length beyond which all women should be considered for operative vaginal delivery has not been identiied (American College of Obstetricians and Gynecologists, 2016).

Operative delivery is generally performed from either a low or outlet station. Additionally, forceps or vacuum delivery should not be used electivey until the criteria for an outlet delivery have been met. In these circumstances, operative delivery is a simple and safe operation, although with some risk of maternal lower reproductive tract injury (Yancey, 1999).

Classiication for operative vaginal delivery is summarized in Table

It emphasizes that the two most important discriminators of risk for both mother and neonate are station and rotation. Station is measured in centimeters, -5 to 0 to +5.

TABLE 29-' . Operative Vaginal Delivery Prerequisites and Classification According to Station and Rotationa

Outlet forceps Scalp is visible at the introitus without separating the labia

Fetal head is at or on perineum

Head is OA or OP or

Head is right or left OA or OP position but rotation ;45 degrees

Low forceps (2 types) Leading point offetal skull is at station �+2 cm, and not on the pelvic floor, and: aClassification for the vacuum delivery system is the same as forforceps except that vacuum is used for traction but not rotation. bForceps, but not vacuum extractor, may be used for delivery of a face presentation with mentum anterior.

(Piper forceps may be used to deliver the head during breech delivery.

Zero station relects a line drawn between the ischial spines. Deliveries are categorized as outlet, low, and midpelvic procedures. High orceps, in which instruments are applied above 0 station, have noplace in contemporay obstetrics.

Once station and rotation are assessed, several prerequisites are met and are listed in Table 29-1. For vacuum extraction, fetuses should also be at least 34 weeks' gestation, and although infrequently used in the United States, fetal scalp blood sampling should not have been recently performed. Of requisites, ascertaining correct head position is essential, and the anatomy of the fetal skull is described in Figure

In unclear cases, sonography is useful to identiy fetal orbits and nasal bridge to aid orientation (Malvasi, 2014).

occiput posterior; OVD operative vaginal delivery.

Regional analgesia or general anesthesia is preferable for low forceps or midpelvic procedures, although pudendal blockade may prove adequate for outlet forceps. As discussed in Chapter 25 (p. 495), regional analgesia during labor does not appear to increase the risk for operative delivery (Halpern, 2004; Marucci, 2007; Wassen, 2014).

The bladder is emptied to provide additional pelvic space and minimize bladder trauma. Urinary retention and bladder dysunction are oten short-term efects offorceps and vacuum deliveries (Mulder, 2012; Pifarotti, 2014). Notably, episiotomy and epidural analgesia, both common associates, are also identified risks for urinary retention. Symptoms are brief and typically resolve with 24 to 48 hours ofpassive Foley catheter bladder drainage.

Biparietal diam.eter = 9.5 cm

Coronal suture --=./

FIGURE 29-1 Fetal head (A, B) at term showing fontanels, sutures, and various dimensions.

There is an increased risk of certain morbidities for both mother and fetus when operative delivery is employed. In general, these are related to the ease with which the delivery is accomplished.

In general, a higher station and/or greater degrees of rotation increase the chance of maternal or fetal injury. Morbidity is most properly compared with morbidity from cesarean delivery, and not with that from spontaneous vaginal delivery. his is the most appropriate comparator because the alternative to indicated operative delivery is cesarean delivery. For example, postpartum wound or uterine infection is more frequent in women following cesarean compared with operative vaginal delivery (Bailit, 2016; Halscott, 2015). Moreover, in a study of more than 1 million births, Spiliopoulos and associates (201i1) reported cesarean delivery, but not operative vaginal delivery, as a risk for peripartum hysterectomy.

he very conditions that lead to indications for operative delivery also increase the need for episiotomy and the likelihood of lacerations (de Leeuw, 2008). That said, forceps and vacuum deliveries are associated with higher rates of third-and fourthdegree lacerations as well s vaginal wall and cervical lacerations (Gurol-Urganci, 2013; Hirayama, 2012; Landy, 2011; Pergialiotis, 2014). These appear to occur more frequently with forceps compared with vacuum extraction, and especially if there is a midline episiotomy (Kudish, 2006; O'Mahony, 2010). Hagadorn-Freathy and coworkers (1991) reported a 13-percent rate of third-and fourth-degree episiotomy extensions and vaginal lacerations for outlet forceps, 22 percent for low forceps with less than 45-degree rotation, 44 percent for low forceps with more than 45-degree rotation, and 37 percent for midforceps deliveries.

In an efort to lower rates of third-and fourth-degree lacerations, and coincident with overall eforts to reduce routine episiotomy use, many advocate only indicated episiotomy with operative delivery. If episiotomy is required, a protective efect against these more extensive perineal lacerations may be aforded by mediolateral episiotomy (de Leeuw, 2008; de Vogel, 2012; Hirsch, 2008). Early disarticulation of forceps and cessation of maternal pushing during disarticulation can also be protective. Last, these injuries are more common with an occiput posterior position (Damron, 2004). Thus, manual or forceps rotation to an occiput anterior position and then subsequent traction delivery may decrease rates oflower reproductive tract injury (Bradley, 2013).

his term encompasses urinary incontinence, anal incontinence, and pelvic organ prolapse. Operative vaginal delivery has been suggested as a possible risk for each of these. Proposed mechanisms include structural compromise and/or pelvic loor denervation secondary to forces exerted during delivery.

Parity and speciically vaginal delivery are risk factors for urinary incontinence (Gyhagen, 2013; Rortveit, 2003). But, many studies do not support an increased risk compared with vaginal delivery alone (Gartland, 2016; Leijonhuvud, 2011;

MacArthur, 2016; Tahtinen, 2016).

Evidence linking anal incontinence with operative vaginal delivery is conlicting. Some studies show that anal sphincter disruption caused by higher-order episiotomy, but not delivery mode, is the main etiological factor strongly associated with anal incontinence (BoIs, 2010; Evers, 2012; Nygaard, 1997). In con trast, others directly link operative delivery with this complica tion (Dolan, 2010; Marthur, 2013). But, these studies may not be incongruous-recall that operative delivery is associated with increased rates of higher-order episiotomy. Importantly, several studies and reviews have not found cesarean delivery to be protec tive for anal incontinence (Nelson, 2010). Last, evidence linking pelvic organ prolapse with operative delivery also indicates mixed results (Gyhagen, 2013; Handa, 2012; Vo1l0yhaug, 2015).

hese injuries are more frequent with operative vaginal delivery than with cesarean delivery or spontaneous vaginal delivery. Injuries may be seen with either method. hey are more common with vacuum extraction, and types associated with this device include cephalohematoma, subgaleal hemorrhage, retinal hemorrhage, neonatal jaundice secondary to these hemorrhages, shoulder dystocia, clavicular fracture, and scalp lacerations. Cephalohematoma and subgaleal hemorrhage are both extracranial lesions described in Chapter 33 (p. 628). Forceps-assisted vaginal delivery has higher rates of facial nerve injury, brachial plexus injury, depressed skull fracture, and corneal abrasion (merican College of Obstetricians and Gynecologists, 2015; Demissie, 2004; Dupuis, 2005). For intracranial hemorrhage, some studies have associated vacuum extraction with higher rates, whereas others show similar rates with either of the two methods (Towner, 1999; Wen, 2001; Werner, 201l).

Comparing operative vaginal with cesarean delivery, rates of extracranial hematoma, skull fracture, facial nerve or brachial plexus injury, retinal hemorrhage, and facial or scalp laceration are lower with cesarean deliveY, and shoulder dystocia is eliminated. Importantly, however, fetal acidemia rates are not increased with operative delivery (Contag, 2010; Walsh, 2013). Intracranial hemorrhage rates are similar among newborns delivered by vacuum extraction, forceps, or cesarean delivery during labor (Towner, 1999). But, these rates are higher than among those delivered spontaneously or by cesarean delivery before labor. These authors suggest that the common risk factor for intracranial hemorrhage is abnormal labor. Werner and associates (2011), in their evaluation of more than 150,000 singleton deliveries, reported that forceps-assisted delivery was associated with fewer total neurological complications compared with vacuum-assisted or cesarean delivery. However, as a subset, subdural hemorrhage was signiicantly more frequent in both instrumental cohorts compared with neonates in the cesarean delivery group.

Comparing rotational operative delivery and second-stage cesarean delivery, maternal and neonatal morbidity rates are similar (Aiken, 2015; Bahl, 2013; Stock, 2013). For example, in their large series, Tempest and associates (2013) found similar morbidity rates among malpositioned fetuses during second-stage labor that underwent Kielland rotation, rotational vacuum extraction, or emergency cesarean delivery.

Comparing midforceps and cesarean delivery, reports of neonatal morbidity rates are from older studies and are conflicting. In the study by Towner and colleagues (1999), similar risks were reported for intracranial hemorrhage. Bashore and associates (1990) observed comparable Apgar scores, cord blood acid-base values, neonatal intensive care unit admission, and birth trauma between these two. In another study, however, Robertson and coworkers (1990) reported signiicantly higher rates of these adverse outcomes in the midforceps group. Hagadorn-Freathy and colleagues (1991) reported an increased risk for facial nerve palsy-9 percent-with midforceps delivery. In a recent report comparing low and midforceps procedures, Ducarme and coworkers (2015) found comparable morbidity rates.

Mechanisms of Acute Injury he types of fetal injury with operative delivery can usually be explained by the forces exerted. In cases of cephalohematoma or subgaleal hemorrhage, suction and perhaps rotation during vacuum extraction may lead to a primary vessel laceration. Intracranial hemorrhage may result from skull fracture and vessel laceration or from vessel laceration alone due to exerted forces. With facial nerve palsy, one of the forceps blades may compress the nerve against the facial bones. he higher rates of shoulder dystocia seen with vacuum extraction may result from the angle of traction. With the vacuum, this angle creates vector forces that actually pull the anterior shoulder into the symphysis pubis (Caughey, 2005). To explain brachial plexus injury, Towner and Ciotti (2007) proposed that as the fetal head descends down the birth canal, the shoulders may stay above the pelvic inlet. Thus, similar to shoulder dystocia at the symphysis, this "shoulder dystocia at the pelvic inlet" is overcome by traction forces but with concomitant stretch on the brachial plexus.

Evidence regarding long-term neurodevelopmental outcomes in children born by operative delivery is reassuring. In an older study, Seidman and colleagues (1991) evaluated more than 52,000 Israeli Defense Forces dratees at age 17 years and found that regardless of delivery mode, rates of physical or cognitive impairments were similar. Wesley and associates (1992) noted similar intelligence scores among 5-year-olds following spontaneous, forceps, or vacuum deliveries. Murphy and coworkers (2004) found no association between forceps delivery and epilepsy in a cohort of more than 21,000 adults. In their epidemiological review, O'Callaghan and colleagues (2011) found no association between cerebral palsy and operative delivery. Last, Bahl and associates (2007) noted that the incidence of neurodevelopmental morbidity was similar in those undergoing successul forceps delivery, failed forceps with cesarean delivery, or cesarean delivery without forceps.

Data regarding midforceps deliveries are for the most part reassuring. Broman and coworkers (1975) reported that infants delivered by midforceps had slightly higher intelligence scores at age 4 years compared with those of children delivered spontaneously. Using the same database, however, Friedman and associates (1977, 1984) analyzed intelligence scores at or after age 7 years. They concluded that children delivered by midforceps had lower mean intelligence quotients compared with those delivered by outlet forceps. In yet another report from this database, Dierker and colleagues (1986) compared long-term outcomes of children delivered by midforceps with those delivered by cesarean after dystocia. he strength of this study is the appropriateness of the control group. hese investigators reported that delivery by midforceps was not associated with neurodevelopmental disability. Last, Nilsen (1984) evaluated 18-year-old men and found that those delivered by Kielland forceps had higher intelligence scores than those delivered spontaneously, by vacuum extraction, or by cesarean.

If an attempt to perform an operative delivery is expected to be diicult, then it should be considered a trial. Moving the woman to an operating room for this attempt, which could be followed by immediate cesarean delivery if operative delivery fails, has merit. If forceps cannot be satisfactorily applied, then the procedure is stopped and either vacuum extraction or cesarean delivery is performed. With the former, if the fetus does not descend with traction, the trial should be abandoned and cesarean delivery performed.

With such caveats, cesarean delivery after an attempt at operative vaginal delivery was not associated with adverse neonatal outcomes if there was a reassuring fetal heart rate tracing (Alexander, 2009). A similar study evaluated 122 women who had a trial of midcavity forceps or vacuum extraction in a setting with full preparations for cesarean delivery (Lowe, 1987). Investigators found no significant diference in immediate neonatal or maternal morbidity compared with that of 42 women delivered for similar indications by cesarean but without such a trial. Conversely, in 61 women who had "unexpected" vacuum or forceps failure in which there was no prior preparation for immediate cesarean delivery, neonatal morbidity was higher.

Some factors associated with operative delivery failure are persistent occiput posterior position and birthweight >4000 g (Ben-Haroush, 2007; Verhoeven, 2016). However, Palatnik and associates (2016) found that risk factors poorly predicted success. In general, to avert morbidity with failed forceps or vacuum delivery, the American College of Obstetricians and Gynecologists (2015) cautions that these trials should be attempted only if the clinical assessment suggests a successful outcome. We also emphasize proper training.

Sequential instrumentation most often involves an attempt at vacuum extraction followed by one with forceps. his most likely stems from the higher completion rate with forceps compared with vacuum extraction noted earlier. This practice significantly increases risks for fetal trauma (Dupuis, 2005; Gardella, 2001; Murphy, 2011). Because of these adverse outcomes, the American College of Obstetricians and Gynecologists (2015) recommends against the sequential use of instruments unless there is a "compelling and justifiable reason."

As the rate of operative vaginal delivery has declined, so have opportunities for training (Fitzwater, 2015; Kyser, 2014). In

FIGURE 29-2 Simpson forceps have fenestrated blades, parallel shanks, and English lock. The cephalic curve accommodates the fetal head.

many programs, training in even low and outlet forceps proce dures has reached critically low levels. For residents completing training in 2015, the Accreditation Council for Graduate Med ical Education reported a median of only five forceps deliveries, and that for vacuum deliveries was 16.

Because traditional hands-on training has evolved, residency programs should have readily available skilled operators to teach these procedures by simulation as well as through actual cases (Skinner, 2017; Spong, 2012). And, the efectiveness of simulation training has been reported (Dupuis, 2006, 2009; Leslie, 2005). In one program, maternal and neonatal morbidity rates with operative delivery decreased after the implementation of a formal education program that included a manikin and pelvic model (Cheong, 2004). In another, a 59-percent increase in forceps deliveries over 2 years was related to a single experienced and proactive instructor assigned to teach forceps to residents in labor and delivery (Solt, 2011).

Forceps refers to the paired instrument, and each member of this pair is called a branch. Branches are designated left or right according to the side of the maternal pelvis to which they are applied (Fig. 29-2). Each branch has four components: blade, shank, lock, and handle (Fig. 29-3). Each blade has a toe, a heel, and two curves. Of these, the outward cephalic curve conforms to the round fetal head, whereas the upward pelvic curve corresponds more or less to the curve of the birth canal. Some blades have an opening within or a depression along the blade surface and are termed enestrated or pseudoenestrated, respectively. True fenestration reduces the degree of head slippage during forceps rotation. Disadvantageously, it can increase friction between the blade and vaginal wall. With pseudo fenestration, the forceps blade is smooth on the outer maternal side but indented on the inner fetal surface. he goal is to reduce head slipping yet improve the ease and safety of application and removal of forceps compared with pure fenestrated blades. In general, fenestrated blades are used for a fetus with a molded head or for rotation. In most situations, however, despite these subtle diferences any are appropriate.

he blades are connected to shanks, which may be parallel or overlapping. Locks are found on all forceps and help to connect

FIGURE 29-3 Luikart forceps have pseudofenestrated blades, overlapping shanks, sliding lock, tongue groove handles. The pelvic curve is marked in this example by the black line.

the right and left branches and stabilize the instrument. They can be located at the end of the shank nearest to the handles (English lock), at the ends of the handles (pivot lock), or along the shank (sliding lock). Although varied in design, handles, when squeezed, raise compression forces against the fetal head. hus, forces to consider include traction and compression.

Forceps blades grasp the head and are applied according to fetal head position. If the head is in an occiput anterior (OA) position, two or more fingers of the right hand are introduced inside the left posterior portion of the vulva and then into the vagina beside the fetal head. he handle of the left branch is grasped between the thumb and two fingers of the left hand (Fig. 29-4).

FIGURE 29-4 For OA or LOA positions, the left handle of the forceps is held in the left hand. The blade is introduced into the left side of the pelvis between the fetal head and the fingers of the operator's right hand.

FIGURE 29-5 Insertion arc of the blade. Importantly, the thumb of the right hand, guides the blade during placement, as shown in Figure 29-6.

he blade tip is then gently passed into the vagina between the fetal head and the palmar surface of the ingers of the right hand (Fig. 29-5). For application of the right blade, two or more ingers of the left hand are introduced into the right posterior portion of the vagina to serve as a guide for the right blade. his blade is held in the right hand and introduced into the vagina. With each blade, the thumb is positioned behind the heel, and most of the insertion force comes from this thumb (Fig. 29-6). If the head is positioned in a let OA (LOA) or right OA (ROA) position, then the lower of the two blades is typically placed irst. Mter positioning, the branches are articulated.

he blades are constructed so that their cephalic curve is closely adapted to the sides of the fetal head (Fig. 29-7). The fetal head is perfectly grasped only when the long axis of the blades corresponds to the occipitomental diameter (see Fig. 29-1). As a result, most of the blade lies over the lateral face. If the fetus is in an OA positi�n, then the concave arch of the blades is directed toward the sagittal suture. If the fetus is in an occiput posterior (OP) position, then the concave arch is directed toward the midline face.

Suboptimal blade placement can increase morbidity (Ramphul, 2015). For OA position, appropriately applied blades are equidistant from the sagittal suture, and each blade is equidistant from its adjacent lambdoidal suture. In the OP position, the blades are equidistant from the midline of the face and brow. Also for OP position, blades are symmetrically placed relative to the sagittal suture and each coronal suture. Applied in this way, the forceps should not slip, and traction may be applied most advantageously. With most forceps, if one blade is applied over the brow and the other over the occiput, the instrument cannot be locked, or if locked, the blades will slip of when traction is applied (Fig. 29-8).

With both branches in place, it should be an easy matter to articulate the handles, engage the lock, and correct asynclitism if present. Asynclitism is resolved by pulling and/or pushing each branch along the long axis of the instrument until the

FIGURE 29-6 In applying the second blade, insertional force is generated mainly by the thumb. (Reproduced with permission from Yeomans ER: Operative vaginal delivery. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 201•7.) inger guards align. If necessary, rotation to OA position is performed before traction is applied (Fig. 29-9).

When it is certain that the blades are placed satisfactorily, then gentle, intermittent, downward and outward traction is exerted concurrent with maternal eforts until the perineum

FIGURE 29-7 A. The forceps are symmetrically placed and articulated. B.The vertex is OA. (Reproduced with permission from Yeomans ER: Operative vaginal delivery. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 201•7.)

FIGURE 29-8 Incorrect application of forceps. A. One blade over the occiput and the other over the brow. Forceps cannot be locked.

B.With incorrect placement, blades tend to slip of with traction.

begins to bulge. When the head is at 0 to + 2 of + 5 sta tion, the initial direction of traction is quite posterior, almost toward the Roor. With head descent, the vector of forces changes continuously (Fig. 29-10). As a teaching tool for this, a Bill axis traction device can be attached over the finger guards of most forceps. he instrument has an arrow and indicator line. When the arrow points directly to the line, traction is

FIGURE 29-9 A. If LOA, the vertex is rotated (arrow) from this position to OA (B). (Reproduced with permission from Yeomans ER: Operative vaginal delivery. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 201o7.)

FIGURE 29-10 With low forceps, the direction of gentle traction for delivery of the head is indicated (arrow). The vector changes with fetal descent.

along the path of least resistance. With traction, as the vulva is distended by the occiput, an episiotomy may be performed if indicated. Additional horizontal traction is applied, and the handles are then gradually elevated. As the handles are raised, the head is extended. During the birth of the head, mechanisms of spontaneous delivery should be simulated as closely as possible.

The force produced by the forceps on the fetal skull is a function of both traction and compression by the forceps, as well as friction produced by maternal tissues. It is impossible to ascertain the amount of force exerted by forceps for an individual patient. Traction should therefore be intermittent, and the head should be allowed to recede between contractions, as in spontaneous labor. Except when urgently indicated, as in severe fetal bradycardia, delivery should be suiciently slow, deliberate, and gentle to prevent undue head compression. It is preferable to apply traction only with each uterine contraction. Maternal pushing will augment these eforts.

After the vulva has been well distended by the head, the delivery may be completed in several ways. Some clinicians keep the forceps in place to control the head. If this is done, however, the blade volume adds to vulvar distention, thus from that in which they were originally placed. The fingers of the right hand, covered by a sterile towel, bolster the perineum. The thumb is placed directly on the head to prevent sudden egress. (Reproduced with permission from Yeomans ER: Operative vaginal delivery. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 201o7.) increasing the likelihood of laceration or necessitating a large episiotomy. To prevent this, the forceps may be removed, and delivery is then completed by maternal pushing (Fig. 29-11). Importantly, if blades are disarticulated and removed too early, the head may recede and lead to a prolonged delivery. Delivery in some cases may be aided by addition of the modiied Ritgen maneuver.

Prompt delivery may at times become necessary when the small occipital fontanel is directed toward one of the sacroiliac synchondroses. In these right OP (ROP) or left OP (LOP) positions, the fetal head is often imperfectly lexed. With OP positions, second-stage labor can be lengthened. In these cases, the head may spontaneously deliver OP, may be manually or instrumentally rotated to an OA position, or may be delivered OP by forceps or vacuum.

With manual rotation, an open hand is inserted into the vagina. The palm straddles the sagittal suture of the fetal head. The operator's ingers wrap around one side of the fetal face and thumb extends along the other side. If the occiput is ROP, rotation is clockwise to bring it to an ROA or OA position (Fig. 29-12).

/�(, _A.V\..IA...._ ./�...._/' B FIGURE 29-12 A. Manual rotation using the left hand, palm-up, to rotate from ROP. B. The head is flexed and destationed during clockwise rotation to reach an OA pOSition. (Reproduced with permission from Yeomans ER: Operative vaginal delivery. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 201o7.)

FIGURE 29-14 Kielland forceps. The characteristic features are minimal pelvic curvature (A), sliding lock (8), and light weight.

With LOr position, rotation is counterclockwise. hree actions are performed simultaneously between contractions. The irst is fetal head flexion to provide a smaller diameter for rotation and subsequent descent. Second, slight destationing of the fetal head moves the head to a level in the maternal pelvis with sufficient room to complete the rotation. Importantly, destationing should not be confused with disengaging the fetal head, which is proscribed. Concurrently, some prefer to also place the other hand externally on the corresponding side of the maternal abdomen to pull the fetal back up toward the midline in synchrony with the internal rotation. Le Ray and colleagues (2007, 2013) reported a success rate of greater than 90 percent with manual rotation. Barth (2015) provides an excellent summary of this technique.

Manual rotations are most easily completed in multiparas. If manual rotation cannot be easily accomplished, application of forceps blades to the head in the posterior position and delivery from an or position may be the safest procedure. In many cases, the cause of a persistent or position and of the diiculty in accomplishing rotation is an anthropoid pelvis. his architecture opposes rotation and predisposes to posterior delivery (Fig. 2-17, p. 31).

With forceps delivery from an or position, downward and outward traction is applied until the base of the nose passes under the symphysis (Fig. 29-13). he handles are then slowly elevated until the occiput gradually emerges over the upper margin of the perineum. he forceps are directed downward again, and the nose, mouth, and chin successively emerge from the vulva.

or delivery causes greater distention of the vulva, and a large episiotomy may be needed. or deliveries have a higher incidence of severe perineal lacerations and extensive episiotomy compared with OA positions (de Leeuw, 2008; Pearl, 1993). Also, newborns delivered from or positions have a higher incidence ofErb and facial nerve palsies, 1 and 2 percent, respectively, than those delivered from OA positions. As expected, rotations to OA ultimately decrease perineal delivery trauma (Bradley, 2013).

Last, for forceps rotations from an or to OA position, the Kielland instruments are preferred because they have a less pronounced pelvic curve (Fig. 29-14). Cunningham and Gilstrapis

FIGURE 29-13 Outlet forceps delivery from an OP position. The head should be flexed ater the bregma passes under the symphysis.

Operative Obstetrics, 3rd edition, ofers a more detailed description of this Kielland forceps procedure (Yeomans, 2017).

With occiput transverse (OT) positions, rotation is required for delivery. With experienced operators, high success rates with minimal maternal morbidity can be achieved (Burke, 2012; Stock, 2013). Either standard forceps, such as Simpson, or specialized forceps, such as Kielland, are employed. With Kielland forceps, each handle has a small knob, and branches are placed so that this knob faces the occiput. he station of the fetal head must be accurately determined to be at, or preferably below, the level of the ischial spines, especially in the presence of extreme molding.

Kielland described two methods of applying the anterior blade. In our example, placement with a left OT (LOT) position is described. With the wandering method, the anterior blade is first introduced into the posterior pelvis (Fig. 29-15). The blade is then arched around the face to an anterior position. To permit this sweep of the blade, the handle is held close to the maternal left buttock throughout the maneuver. he second blade is introduced directly posteriorly, and the branches are locked.

After checking the application, the handles of the Kielland forceps are pulled slightly to the patient's right to increase fetal head lexion and create a smaller diameter for rotation. he irst and second fingers of the left hand are placed over the inger guards with the palm against the handles. his palm faces the maternal left. Concurrently, the first two ingers of the operator's right hand are placed against the anterior lambdoid suture. he fetal head is then destationed approximately 1 cm. For rotation in a counterclockwise direction, the wrist of the left hand supinates, to direct this palm upward. Simultaneously, two ingers of the right hand press on the edge of the right parietal bone that borders the lambdoid suture. This ensures that the fetal head turns with the blades and does not slip.

he second type of blade application introduces the anterior blade with its cephalic curve directed upward to curve under

A B c FIGURE 29-15 A. Application of the right branch of the Kielland forceps to a head in LOT position. The knob on this branch (colored blue) will ultimately face the occiput. B. The right branch is wandered to its final position behind the symphysis. C. Insertion ofthe left branch of the Kielland forceps directly posterior along the hollow of the sacrum. This branch is inserted to the maternal right of the anterior branch to aid in engaging the sliding lock. (Reproduced with permission from Yeomans ER: Operative vaginal delivery. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 201•7.) the symphysis. After it has been advanced far enough toward the upper vagina, it is turned on its long axis through 180 degrees to adapt the cephalic curvature to the head.

With either application, after rotation completion, the operator may choose from two acceptable methods for delivery. In one, the operator applies traction on the Kielland forceps using a bimanual grip described previously for conventional forceps (p. 559). When the posterior fontanel has passed under the subpubic arch, the handles can be elevated to the horizontal. Raising the handles above the horizontal may cause vaginal sulcus tears because of the reverse pelvic curve (Dennen, 1955). Alternatively, the Kielland forceps can be removed after rotation and replaced with conventional forceps. With this approach, moderate traction is first employed to seat the head before switching instruments.

With a mentum anterior face presentation, forceps can be used to efect vaginal delivery. The blades are applied to the sides of the head along the occipitomental diameter, with the pelvic curve directed toward the neck. Downward traction is exerted until the chin appears under the symphysis. hen, by an upward movement, the face is slowly extracted, with the nose, eyes, brow, and occipur appearing in succession over the anterior margin of the perineum. Forceps should not be applied to the mentum posterior presentation because vaginal delivey is impossible except in vey smal ttuses.

With vacuum delivery, suction is created within a cup placed on the fetal scalp such that traction on the cup aids fetal expulsion. In the United States, vacuum extractor is the preferred term, whereas in Europe it is commonly called a vento use (Fig. 29-16). heoretical beneits of this tool compared with forceps include simpler requirements for precise positioning on the fetal head and avoidance of space-occupying blades within the vagina, thereby mitigating maternal trauma.

Vacuum devices contain a cup, shaft, handle, and vacuum generator. Vacuum cups may be metal or hard or soft plastic, and they may also difer in their shape, size, and reusability. In the United States, nonmetal cups are generally preferred, and there are two main types. he soft cup is a pliable bell-shaped dome, whereas the rigid type has a firm flattened mushroomshaped cup and circular ridge around the cup rim (Table 29-2). When compared, rigid mushroom cups generate significantly more traction force (Hofmeyr, 1990; Muise, 1993). With or positions or with asynclitism, the flatter cup also permits improved placement at the flexion point, which is typically less accessible with these head positions. The trade-of is that the flatter cups have higher scalp laceration rates. Thus, many manufacturers recommend soft bell cups for more straightforward OA deliveries.

Several investigators have compared outcomes with various rigid and soft cups. Metal cups provide higher success rates but greater rates of scalp injuries, including cephalohematomas -�..--A

FIGURE 29-16 Vacuum delivery systems. A. The Kiwi OmniCup contains a handheld vacuum-generating pump, which is attached via flexible tubing to a rigid plastic mushroom cup. B. The Mityvac Mystic II MitySoft Bell Cup has a soft bell cup attached by a semirigid shaft to a handheld pump.

TABLE 29-2. Vacuum Cups for Operative Vaginal Delivery "Reusable cups. bSuitable for occiput posterior positions or asynclitism. (For extractions through a hysterotomy incision during cesarean delivery.

(O'Mahony, 2010). In another study, Kuit and coworkers (1993) found that the only advantage of the soft cups was a lower incidence of scalp injury. hey reported a 14-percent episiotomy extension rate with both rigid and pliable cups. In a review, Vacca (2002) concluded that there were fewer scalp lacerations with the soft cup, but that the rate of cephalohematomas and subgaleal hemorrhage was similar between soft and rigid cups. Importantly, high-pressure vacuum generates large amounts of force regardless of the cup used (Duchon, 1998) .

Aside from the cup, the shaft that connects the cup and handle may be lexible or semiflexible. Tubing-like flexible shafts may be preferred for OP positions or asynclitic presentation to permit better seating of the cup. Last, the vacuum generator may be handheld and actuated by the operator or may be held and operated by an assistant.

An important step in vacuum extraction is proper cup placement over the lexion point. his pivot point maximizes traction, minimizes cup detachment, lexes but averts twisting the fetal head, and delivers the smallest head diameter through the pelvic oudet. This improves success rates, lowers fetal scalp injury rates, and lessens perineal trauma because the smallest fetal head diameter distends the vulva (Baskett, 2008).

The lexion point is found along the sagittal suture, approximately 3 cm in front of the posterior fontanel and approximately 3em 6em /II -_ ...._-\ o\ I\ I\\ ........"------,///�

FIGURE 29-17 Drawing demonstrates correct cup placement at the flexion point. Along the sagittal suture, this spot lies 3 cm from the posterior fontanel and 6 cm from the anterior fontanel.

6 cm from the anterior fontanel. Because cup diameters range from 5 to 6 cm, when properly placed, the cup rim lies 3 cm from the anterior fontanel (Fig. 29-17). Placement of the cup more anteriorly on the fetal cranium-near the anterior fontanel-should be avoided as it leads to cervical spine extension during traction unless the fetus is small. Such placement also delivers a wider fetal head diameter through the vaginal opening. Last, asymmetrical placement relative to the sagittal suture may worsen asynclitism. For elective use, cup placement in OA positions is seldom diicult. In contrast, when the indication for delivery is failure to descend caused by occipital malpositionwith or without asynclitism or deflexion-cup positioning can be diicult.

During cup placement, maternal soft tissue entrapment predisposes the mother to lacerations and virtually ensures cup dislodgement, colloquially called a "pop of." Thus, the entire cup circumference should be palpated both before and after the vacuum has been created and again prior to traction to exclude such entrapment. Gradual vacuum creation is advocated by some and is generated by increasing the suction in increments of 0.2 kg/cm2 every 2 minutes until a total negative pressure of 0.8 kg/cm2 is reached 29-3). hat said, other studies have shown that negative pressure can be increased to 0.8 kg/cm2 in <2 minutes without a signiicant diference in eicacy or in maternal and fetal outcomes (Suwannachat, 2011, 2012) .

TABLE 29-3. Vacuum Pressure Conversions 100 10 3.9 1.9 0.l3 200 20 7.9 3.9 0.27 300 30 11.8 5.8 OA1 400 40 15.7 7.7 0.54 500 50 19.7 9.7 0.68 600 60 23.6 11s.6 0.82

Once suction is created, the instrument handle is grasped, and traction is initiated. Similar to forceps delivery, traction angles mirror that in Figure 29-10. Eforts are intermittent and coordinated with maternal expulsive eforts. Manual torque to the cup is avoided as it can cause cup displacement or cephalohematomas and, with metal cups, "cookie-cutter"-type scalp lacerations. hus, OA oblique positions are corrected not by rotation, but solely by downward outward traction. During pulls, the operator should place the nondominant hand within the vagina, with the thumb on the extractor cup and one or more ingers on the fetal scalp. So positioned, descent of the presenting part can be judged and the traction angle can be adjusted with head descent. In addition, the relationship of the cup edge to the scalp can be assessed to help detect cup separation.

Between contractions, some physicians will lower the suction levels to decrease rates of scalp injury, whereas others will maintain suction in cases with a nonreassuring fetal heart rate to aid rapid delivery. No diferences in maternal or fetal outcome were noted if the level of vacuum was decreased between contractions or if an efort was made to prevent fetal loss of station (Boill, 1997). Once the head is extracted, the vacuum pressure is relieved and the cup removed.

Vacuum extraction should be considered a trial. Without early and clear evidence of descent toward delivery, an alternative delivery approach should be considered. As a general guideline, progressive descent should accompany each traction attempt. Neither data nor consensus are available regarding the number of pulls required to efect delivery, the maximum number of cup pop-ofs that can be tolerated, or optimal total duration of the procedure. Some manufacturers have recommendations regarding these in their instructional literature (Clinical Innovations, 2016; CooperSurgical, 2011).

During a vacuum extraction trial, cup dislodgement due to technical failure or less than optimal placement should not be equated with dislodgement under ideal conditions of exact cup placement and optimal vacuum maintenance. hese cases may merit either additional attempts at placement or, alternatively, a trial of forceps (Ezenagu, 1999; Williams, 1991). he least desirable cases are those in which traction without progress or multiple disengagements occur following correct cup application and appropriate traction. As with forceps, clinicians should embrace a willingness to abandon attempts at vacuum extraction if satisfactory progress is not made (American College of Obstetricians and Gynecologists, 2015).

Accreditation Council for Graduate Medical Education: Obstetrics and

Gynecology Case Logs. 20o15. Available at: http://www.acgme.org/Portals/ 0/PDFs/220_NationaLReport_Program_ Version.pdf. Accessed May 11o, 20o16 Aiken AR, Aiken CE, Alberry MS, et al: Management of fetal malposition in the second stage of labor: a propensity score analysis. Amo] Obstet Gynecol 212(3):355.e1,o2015

Alexander ]M, Leveno K], Hauth ]C, et al: Failed operative vaginal delivery.

Obstet GynecoIo114(5):1017, 2009 American College of Obstetricians and Gynecologists, Society for Maternal

Fetal Medicine: Safe prevention of the primary cesarean delivery. Obstetric

Care Consensus No.o1, March 2014, Reairmed 2016

American College of Obstetricians and Gynecologists: Operative vaginal delivery. Practice Bulletin No. 154, November 2015

Bahl R, Patel R, Swingler R, et al: Neurodevelopmental outcome at 5 years after operative delivery in the second stage of labor: a cohort study. Am ] Obstet GynecoIo197:147, 2007

Bahl R, Van de Venne M, Macleod M, et al: Maternal and neonatal morbidity in relation to the instrument used for mid-cavity rotational operative vaginal delivery: a prospective cohort study. B]OG 120(12):1526,o2013

Bailit ]L, Grobman WA, Rice IM, et al: Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Am] Obstet GynecoI214(5):638.e1, 2016

Barth H ]r: Persistent occiput posterior. Obstet GynecoIo125(3):695, 2015 Bashore A, Phillips WH ]r, Brinkman CR III: A comparison of the morbidity of midforceps and cesarean delivety. Am] Obstet GynecoIo162(6): 1428, 1990

Baskett TF, Fanning CA, Young DC, et al: A prospective observational study of 1000 vacuum assisted deliveries with the OmniCup device. ] Obstet Gynaecol Can 30(7):573, 2008

Ben-Haroush A, Melamed N, Kaplan B, et al: Predictors of failed operative vaginal delivery: a single-center experience. Amo] Obstet Gynecol 197:308. e1,o2007

Bofill ]A, Rust OA, Schorr S], et al: A randomized trial of two vacuum extraction techniques. Obstet Gynecol89(5 Pt 1):758, 1997

BoIs EM, Hendriks E], Berghmans BC, et al: A systematic review of etiological factors for postpartum fecal incontinence. Acta Obstet Gynecol Scand 89(3):302,o2010

Bradley MS, Kaminski R], Streitman DC, et al: Efect of rotation on perineal lacerations in forceps-assisted vaginal deliveries. Obstet Gynecolol22(1): 132, 2013

Broman SH, Nichols PL, Kennedy WA: Preschool IQ: prenatal and early developmental correlates. Hillsdale, L. Erlbaum Associates, 1975

Burke N, Field K, Mujahid F, et al: Use and safety of Kielland's forceps in current obstetric practice. Obstet Gynecol 120(4):766,o2012 Caughey AB, Sandberg PL, Zlatnik MG, et al: Forceps compared with vacuum.

Rates of neonatal and maternal morbidity. Obstet Gynecol 106:908,2005

Cheong YC, Abdullahi H, Lashen H, et al: Can formal education and training improve the outcome of instrumental delivery? Eur ] Obstet Gynecol 113:139,o2004

Clinical Innovations: Kiwi complete vacuum delivery system instructions for use. Available at: http://clinicalinnovations.com/wp-content/ uploads/2015/03/Kiwi-IFU.pdf. Accessed May 13, 2016

Contag SA, Clifton RG, Bloom SL, et al: Neonatal outcomes and operative vaginal delivery versus cesarean delivery. Am] PerinatoI27(6):493, 2010

CooperSurgical: Mityvac vacuum-assisted delivery. 2011. Available at: http:// www.coopersurgical.com/Products/DetaiIlMi tyvac-Vacuum -AssistedDelivery-Pumps-and-Accessories. Accessed May 13, 2016

Damron DP, Capeless EL: Operative vaginal delivery: a comparison of forceps and vacuum for success rate and risk of rectal sphincter injury. Am ] Obstet Gynecol 191:907,o2004 de Leeuwo]W, de Wit C, Kuijken ]P, et al: Mediolateral episiotomy reduces the risk for anal sphincter injury during operative vaginal delivery. B]OG 115:104,o2008

Demissie K, Rhoads GG, Smulian ]C, et al: Operative vaginal delivery and neonatal and infant adverse outcomes: population based retrospective analysis. BM] 329(7456):24,o2004

Dennen EH: Forceps Delivery. Philadelphia, F.A. Davis Company, 1955 de Vogel], van der Leeuw-van Beek A, Gietelink 0, et al: The efect of a mediolateral episiotomy during operative vaginal delivery on the risk of developing obstetrical anal sphincter injuries. Am] Obstet GynecoI206(5):404, 2012

Dierker L], Rosen MG, Thompson K, et al: Midforceps deliveries: long-term outcome of infants. Am] Obstet Gynecol 154:764, 1986

Dolan LM, Hilton P: Obstetric risk factors and pelvic loor dysfunction 20 years ater first delivery. Int Urogynecol] Pelvic Floor Dysfunct 21:535, 2010

Ducarme G, Hamel ]F, Bouet PE, et al: Maternal and neonatal morbidity after attempted operative vaginal delivery according to fetal head station. Obstet GynecoIo126(3):521,o2015

Duchon MA, DeMund MA, Brown RH: Laboratory comparison of modern vacuum extractors. Obstet Gynecol 72: 155, 1998

Dupuis 0, Moreau R, Pham MT: Assessment of forceps blade orientations during their placement using an instrumented childbirth simulator. B]OG 116(2):327, 2009

Dupuis 0, Moreau R, Silveira R, et al: A new obstetric forceps for the training of junior doctors: a comparison of the spatial dispersion of forceps blade trajectories between junior and senior obstetricians. m ] Obstet Gynecol 194: 1524, 2006

Dupuis 0, Silveira R, Dupont C, et al: Comparison of "instrument-associated" and "spontaneous" obstetric depressed skull fractures in a cohort of 68 neonates. Am] Obstet GynecoIo192(1):165, 2005

Evers EC, Blomquist JL, McDermott KC, et al: Obstetrical anal sphincter laceration and anal incontinence 5-10 years after childbirth. Am J Obstet GynecoIr207(5):425.e1,r2012

Ezenagu LC, Kakaria R, Bofill JA: Sequential use of instruments at operative vaginal delivery: is it safe? Am J Obstet Gynecol 180: 1446, 1999 Faiweather 0: Obstetric management and follow-up of the very low-birthweight infant. J Reprod Med 26:387, 1981

Fitzwater JL, Owen J, Ankumah NA, et al: Nulliparous women in the second stage of labor: changes in delivery outcomes berween rwo cohorts from 2000 and 2011. Obstet GynecoIr126(1):81, 2015

Friedman A, Sachtleben MR, Bresky PA: Dysfunctional labor, 12. Long-term efects on the fetus. Am J Obstet GynecoIr127:779, 1977

Friedman EA, Sachtleben-Murray MR, Dahrouge 0, et al: Long-term efects of labor and delivery on ofspring: a matched-pair analysis. Am J Obstet Gynecol 150:941, 1984

Gardella C, Taylor M, Benedetti T, et al: The efect of sequential use of vacuum and forceps for assisted vaginal delivery on neonatal and maternal outcomes. Am J Obstet Gynecol 185(4):896,2001

Gartland 0, MacArthur C, Woolhouse H, et al: Frequency, severiry and risk factors for urinary and faecal incontinence at 4 years postpartum: a prospective cohort. BJOG 123(7):1203,r2016

Gurol-Urganci I, Cromwell DA, Edozien LC, et al: hird-and fourth-degree perineal tears among primiparous women in England between 2000 and 2012: time trends and risk factors. BJOG 120(12):1516,r2013

Gyhagen M, Bullarbo M, Nielsen T, et al: The prevalence of urinary incontinence 20 years after childbirth: a national cohort study in singleton primiparae after vaginal or caesarean delivery. BJOG 120:144,r2013

Hagadorn-Freathy AS, Yeomans ER, Hankins GO: Validation of the 1988 ACOG forceps classiication system. Obstet Gynecol 77:356, 1991

Halpern SH, Muir H, Breen W, et al: A multicenter randomized controlled trial comparing patient-controlled epidural with intravenous analgesia for pain relief in labor. Anesth Analg 99(5):1532,2004

Halscott TL, Reddy UM, Landy HJ, et al: Maternal and neonatal outcomes by attempted mode of operative delivery from a low station in the second stage of labor. Obstet GynecoIr126(6):1265, 2015

Hamilton BE, Martin JA, Osterman MJ, et al: Births: final data for 2014. Nat!

Vital Stat Rep 64(12):1, 2015

Handa L, Blomquist JL, McDermott KC, et al: Pelvic floor disorders after vaginal birth: efect of episiotomy, perineal laceration, and operative birth. Obstet Gynecol 119(2 Pt 1):233,2012

Hirayama F, Koyanagi A, Mori R, et al: Prevalence and risk factors for thirdand fourth-degree perineal lacerations during vaginal delivery: a multicountry study. BJOG 119(3):340,2012

Hirsch E, Haney EI, Gordon TE, et al: Reducing high-order perineal laceration during operative vaginal delivery. AmJ Obstet GynecoIr198(6):668.e1, 2008

Hofmeyr GJ, Gobetz L, Sonnendecker EW, et al: New design rigid and soft vacuum extractor cups: a preliminary comparison of traction forces. BJOG 97(8):681, 1990

Kudish B, Blackwell S, Mcneeley SG, et al: Operative vaginal delivery and midline episiotomy: a bad combination for the perineum. Am J Obstet Gynecol 195(3):749,r2006

Kuit JA, Eppinga HG, Wallenburg HCS, et al: A randomized comparison of vacuum extraction delivery with a rigid and a pliable cup. Obstet Gynecol 82:280, 1993

Kyser L, Lu X, Santillan 0, et al: Forceps delivery volumes in teaching and nonteaching hospitals: are volumes suicient for physicians to acquire and maintain competence? Acad Med 89(1):71, 2014

Landy HJ, Laughon SK, Bailit JL, et al: Characteristics associated with severe perineal and cervical lacerations during vaginal delivery. Obstet Gynecol 117(3):627,r201r1

Leijonhuvud A, Lundholm C, Cnattingius S, et al: Risks of stress urinary incontinence and pelvic organ prolapse surgery in relation to mode of childbirth. Am J Obstet GynecoI204(1):70.e1, 2011

Le Ray C, Deneux-haraux C, Khireddine I, et al: Manual rotation to decrease operative delivery in posterior or transverse positions. Obstet Gynecol 122(3):634,r2013

Le Ray C, Serres P, Schmitz T, et al: Manual rotation in occiput posterior or transverse positions. Obstet Gynecol 110:873, 200

Leslie KK, Dipasqule-Lehnerz P, Smith M: Obstetric forceps training using visual feedback and the isometric strength testing unit. Obstet Gynecolr1 05:377,2005 Lowe B: Fear of failure: a place for the trial of instrumental delivery. BJOG 94:60, 1987

MacArthur C, Wilson 0, Herbison P, et al: Faecal incontinence persisting after childbirth: a 12-year longitudinal study. BJOG 120(2):169,r2013

MacArthur C, X ilson 0, Herbison P, et al: Urinary incontinence persisting after childbirth: extent, delivery history, and efects in a 12-year longitudinal cohort study. Prolong Study Group. BJOG 123(6):1022,r2016

Malvasi A, Tinelli A, Barbera A, et al: Occiput posterior position diagnosis: vaginal examination or intrapartum-sonography? A clinical review. J Matern Fetal Neonatal Med 27(5):520,r2014

Marucci M, Cinnella G, Perchiazzi G, et al: Patient-requested neuraxial analgesia for labor: impact on rates of cesarean and instrumental vaginal delivery. Anesthesiology 106(5):1035, 2007

Merriam A, Ananth CV, Wright JD, et al: Trends in operative vaginal delivery, 2005-2013: a population-based study. BJOG 124(9):1365,2017

Muise L, Duchon A, Brown RH: he efect of artificial caput on performance of vacuum extractors. Obstet GynecoI81(2):170, 1993

Mulder F, Schofelmeer M, Hakvoort R, et al: Risk factors for postpartum urinary retention: a systematic review and meta-analysis. BJOG 119(12): 1440, 2012 Murphy OJ, Libby G, Chien P, et al: Cohort study offorceps delivery and the risk of epilepsy in adulthood. Am J Obstet Gynecol 191 :392, 2004

Murphy OJ, Macleod M, Bahl R, et al: A cohort study of maternal and neonatal morbidiry in relation to use of sequential instruments at operative vaginal delivery. Eur J Obstet Gynecol Reprod Bioi 156(1):41,r2011

Nelson L, Furner SE, Westercamp M, et al: Cesarean delivery for the prevention of anal incontinence. Cochrane Database Syst Rev 2:CD006756, 2010 Nilsen ST: Boys born by forceps and vacuum extraction examined at 18 years of age. Acta Obstet Gynecol Scand 63:549, 1984

Nygaard IE, Rao SS, Dawson JD: Anal incontinence after anal sphincter disruption: a 30-year retrospective cohort study. Obstet Gynecol 89:896, 199

O'Callaghan ME, MacLennan AH, Gibson CS, et al: Epidemiologic associations with cerebral palsy. Obstet GynecoIr118(3):576, 2011

O'Mahony F, Hofmeyr GJ, Menon V: Choice of instruments for assisted vaginal delivery. Cochrane Database Syst Rev 11:CD005455, 2010

Osterman MJ, Martin JA, Menacker F: Expanded health data from the new birth certificate, 2006. Nat! Vital Stat Rep 58(5):1, 2009

Palatnik A, Grobman WA, Hellendag MG, et al: Predictors offailed operative vaginal delivery in a contemporary obstetric cohort. Obstet Gynecol 127(3): 501,r2016

Pearl ML, Roberts JM, Laros RK, et al: Vaginal delivery from the persistent occiput posterior position: influence on maternal and neonatal morbidiry. J Reprod Med 38:955, 1993

Pergialiotis V, Vlachos 0, Protopapas A, et al: Risk factors for severe perineal lacerations during childbirth. Int J Gynaecol Obstet 125(1):6,r2014

Pifarotti P, Gargasole C, Folcini C, et al: Acute post-partum urinary retention: analysis of risk factors, a case-control study. Arch Gynecol Obstet 289(6):1249,r2014

Ramphul M, Kennelly MM, Burke G, et al: Risk factors and morbidiry associated with suboptimal instrument placement at instrumental delivery: observational study nested within the Instrumental Delivery & Ultrasound randomised controlled trial ISRCTN 72230496. BJOG 122(4):558,r2015

RobertSon PA, Laros RK, Zhao L: Neonatal and maternal outcome in lowpelvic and mid-pelvic operative deliveries. Am J Obstet Gynecol 162: 1436, 1990

Rorrveit G, Dalrveit AK, Hannestad YS, et al: Urinary incontinence after vaginal delivery or cesarean section. N Engl J Med 348:9000, 2003

Schuit E, Kwee A, Westerhuis ME, et al: A clinical prediction model to assess the risk of operative delivery. BJOG 119(8):915,r2012

Schwartz DB, Miodovnik M, Lavin JP Jr: Neonatal outcome among low birth weight infants delivered spontaneously or by low forceps. Obstet Gynecol 62:283, 1983

Skinner S, Davies-Tuck M, Wallace E, et al: Perinatal and maternal outcomes after training residents in forceps before vacuum instrumental birth. Obstet Gynecol 130(1):151,r2017

Seidman OS, Laor A, Gale R, et al: Long-term efects of vacuum and forceps deliveries. Lancet 337:1583, 1991

Solt I, Jackson S, Moore T, et al: Teaching forceps: the impact of proactive faculry. Am J Obstet Gynecol 204(5):448.e1, 2011

Spiliopoulos M, Kareti A, Jain NJ, et al: Risk of peripartum hysterectomy by mode of delivery and prior obstetric history: data from a population-based study. Arch Gynecol Obstet 283(6):1261, 2011

Spong CY, Berghella V, Wenstrom KD, et al: Preventing the first cesarean delivery: summary of a Joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, and American College of Obstetricians and Gynecologists X orkshop. Obstet GynecoIr120(5):1181, 2012

Stock SJ, Josephs K, Farquharson S, et al: Matenal and neonatal outcomes of successful Kielland's rotational forceps delivery. Obstet GynecoIr121(5): 1032,r2013

Suwannachat B, Laopaiboon M, Tonmat S, et al: Rapid versus stepwise application of negative pressure in vacuum extraction-assisted vaginal delivery: a multicentre randomised controlled non-inferiority trial. BJOG 118(10): 1247,r2011

Suwannachat B, Lumbiganon P, Laopaiboon M: Rapid versus stepwise negative pressure application for vacuum extraction assisted vaginal delivery. Cochrane Database Syst Rev 8:CD006636, 2012

Tahtinen RNf, Cartwright R, Tsui JF, et al: Long-term impact of mode of delivery on stress urinary incontinence and urgency urinary incontinence: a systematic review and meta-analysis. Eur Urol 70(1):148, 2016

Tempest N, Hart A, Walkinshaw S, et al: A re-evaluation of the role of rotational forceps: retrospective comparison of maternal and perinatal outcomes following diferent methods of birth for malposition in the second stage of labor. BJOG 7,r2013

Towner 0, Castro NlA, Eby-Wilkens E, et al: Efect of mode of delivery in nulliparous women on neonatal intracranial injuY. N Engl J /Ied 341: 1 09, 1999

Towner DR, Ciotti MC: Operative vaginal delivery: a cause of birth injury or is it? Clin Obstet Gynecol 50(3):563, 2007

Vacca A: Vacuum-assisted delivery. Best Pract Res Clin Obstet Gynaecol 16:17,r2002

Verhoeven CJ, Nuij C, Janssen-RolfCR, et al: Predictors for failure of vacuumassisted vaginal delivery: a case-control study. Eur J Obstet Gynecol Reprod Bioi 200:29, 2016

Voll0yhaug I, M0rkved S, Salvesen 0, et al: Forceps delivery is associated with increased risk of pelvic organ prolapse and muscle trauma: a cross-sectional study 16-24 years after irst delivery. Ultrasound Obstet Gynecol 46(4): 487,r2015

Walsh CA, Robson M, McAulife FM: Mode of delivery at term and adverse neonatal outcomes. Obstet Gynecol 121 (1): 122, 2013

Wassen MM, Hukkelhoven CW, Scheepers He, et al: Epidural analgesia and operative delivery: a ten-year population-based cohort study in The Netherlands. Eur J Obstet Gynecol Reprod Bioi 183: 125, 2014

Wen SW, Liu S, Kramer MS, et al: Comparison of maternal and infant outcomes between vacuum extraction and forceps deliveries. Am J Epidemiol 153(2):103,r2001

Werner EF, Janevic TM, IIIuzzi J, et al: Mode of delivery in nulliparous women and neonatal intracranial injury. Obstet Gynecol 118(6): 1239,r2011 Wesley B, Van den Berg B, Reece EA: The effect of operative vaginal delivery on cognitive development. Am J Obstet Gynecol 166:288, 1992

Williams MC, Knuppel A, O'Brien WF, et al: A randomized comparison of assisted vaginal delivery by obstetric forceps and polyethylene vacuum cup. Obstet Gynecol 78:789,r1991

Yancey MK, Pierce B, Schweitzer 0,et al: Observations on labor epidural analgesia and operative delivery rates. Am J Obstet Gynecol 180(2 Pt 1):353, 1999

Yeomans ER: Operative vaginal delivery. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 2017

CESAREAN DELIVERY IN THE UNITED STATES . .. ... 567

CESAREAN DELIVERY RISKS ......... . . .... .. 568

PATIENT PREPARATION .... .. . . .. ... ... 569

CESAREAN DELIVERY TECHNIQUE . . . ........... 571

LAPAROTOMY ........ .... . .... ... .. .. 571

HYSTEROTOMY .. ..... .. ... ..... .. . .. . 573

PERIPARTUM HYSTERECTOMY ... ......... ...... 580

POSTOPERATIVE CARE . . . . . . . . . . . . . . . . . . . . . . . . . 585 ?he anterior suace of the uterus is opened longitudinaly along its midline. ?his is best accomplished by making an incision a ew centimetres long with a scapel, and then rapidy enlarging it with the scissors to 16 or 18 centimetres. ?he membranes are then rupture, the child is seized by one oot and rapidy extracted -]. Whitridge Williams (1903)

From the above description, cesarean technique has evolved during the past century. For example, preference for classical hysterotomy has given way to low transverse incision. Evidence-based data now guide many surgical steps and are presented throughout this chapter.

Of deinitions, cesarean delivey defines the birth of a fetus via laparotomy and then hysterotomy. This definition is not applied to removal of the fetus from the abdominal cavity in the case of uterine rupture or with abdominal pregnancy. Rarely, hysterotomy is performed in a woman who has just died or in whom death is expected soon-postmortem orperimortem cesarean delivery (Chap. 47, p. 931).

In some instances, abdominal hysterectomy is indicated following delivery. When performed at the time of cesarean delivery, the operation is termed cesarean hysterectomy. If done within a short time after vaginal delivery, it is termedpospartum hysterectomy. Peripartum hysterectomy is a broader term that combines these two. In most cases, hysterectomy is total, but supracervical hysterectomy is an option. The adnexa are not usually removed. In most instances, a simple or type I hysterectomy is performed. However, for women with invasive cervical cancer, radical hysterectomy removes the uterus, parametrium, and proximal vagina to achieve tumor excision with negative margins. Also, for cases of placenta percreta that extend toward the pelvic sidewall, similar radical excision of the parametrium may be needed.

In the United States, the cesarean delivery rate rose from 4.5 percent in 1970 to 32.9 percent in 2009. Following this peak, the rate has trended slightly downward, and it was 32.0 percent in 2015 (Martin, 2017). Some indications for performing cesarean delivery are shown in Table

More than 85 percent of these operations are performed for four reasollSprior cesarean delivery, dystocia, fetal jeopardy, or abnormal fetal presentation. The latter three compose the main indications for primary cesarean delivery (Barber, 2011; Boyle, 2013).

The reasons for persistently significant cesarean rates are not completely understood, but some explanations include the following: 1.

Women are having fewer children, thus, a greater percentage of births are among nulparas, who are at increased risk for cesarean delivery.

2.

The average maternal age is rising, and older women, especially nulliparas, have a higher risk of cesarean delivery.

TABLE 30-1 . Some Indications for Cesarean Delivery

HIV human immunodeficiency virus; HSV herpes simplex virus.

3.

he use of electronic etal monitoring is widespread. This practice is associated with an increased cesarean delivery rate compared with intermittent fetal heart rate auscultation. Fetal distress accounts for only a minority of all cesareans. In many more cases, concern for an abnormal or "nonreassuring" fetal heart rate tracing prompts cesarean delivery.

4.

Most fetuses presenting breech are now delivered by cesarean.

5.

he frequency of operative vaginal delivery has declined.

6.

Rates of labor induction continue to rise, and induced labor, especially among nulliparas, raises the cesarean delivery rate.

7.

Obesi, which is a cesarean delivery risk, has reached epidemic proportions.

8.

Rates of cesarean delivery in women with preeclampsia have increased, whereas labor induction rates for these patients have declined.

9.

he rate of vaginal birth ater cesarean-BAC-has decreased from a high of 28 percent in 1996 and was 11 percent in 2014 (Hamilton, 2015).

10.

Elective cesarean deliveries are increasingly being performed for various indications that include maternal request, concern for pelvic loor injury associated with vaginal birth, and reduction of etal injury rates.

11.

Assisted reproductive technoloy is more widely used than in the past and is associated with greater cesarean delivery rates (Reddy, 2007).

12.

Mapractice litigation related to fetal injury during spontaneous or operative vaginal delivery continues to contribute to the present cesarean delivery rate.

To provide accurate informed consent, understanding both maternal and neonatal risks and beneits with surgery is essential. In broad terms, cesarean delivery has higher maternal surgical risks for the current and subsequent pregnancies compared with spontaneous vaginal birth. his is balanced against lower rates of perineal injury and short-term pelvic floor disorders. For the neonate, cesarean delivery ofers lower rates of birth trauma and stillbirth but greater rates of initial respiratory diiculties.

For the mother, death attributable solely to cesarean delivery is rare in the United States. Even so, numerous studies attest to increased mortality risks. Clark and colleagues (2008), in a review of nearly 1.5 million pregnancies, found maternal mortality rates of 2.2 per 100,000 cesarean deliveries compared with 0.2 per 100,000 vaginal births. In a metaanalysis of 203 studies, Guise and coworkers (2010) reported a maternal mortality rate of 13 per 100,000 with elective repeat cesarean delivery compared with 4 per 100,000 women undergoing a trial of labor after prior cesarean.

Similar to mortality rates, the frequencies of some maternal complications are increased with all cesarean compared with vaginal deliveries. Villar and associates (2007) reported that maternal morbidity rates increased twofold with cesarean compared with vaginal delivery. Principal among these are infection, hemorrhage, and thromboembolism. In addition, anesthetic complications, which also rarely include death, have a greater incidence with cesarean compared with vaginal delivery (Cheesman, 2009; Hawkins, 201l). Adjacent organs infrequently may be injured, which is described in detail on page 583.

Women who undergo a cesarean delivery are much more likely to be delivered by a repeat operation in subsequent pregnancies. For women undergoing subsequent cesarean, the maternal risks just described are even greater (Cahill, 2006; Marshall, 2011; Silver, 2006).

As an advantage, cesarean delivery is associated with lower rates of urinary incontinence and pelvic organ prolapse than is vaginal birth (Glazener, 2013; Gyhagen, 2013a,b; Handa, 2011; Leijonhuvud, 2011). Rates of anal incontinence appear uninluenced by delivery route (Fritel, 2007; Nelson, 2010). Protective advantages persist to some degree over time, but cesarean delivery is not totally protective. Moreover, longitudinal studies suggest that initial pelvic floor advantages gained from cesarean delivery are lost as women age (Dolan, 2010; MacArthur, 2011, 2013; Nelson, 2010). To address this, the National Institutes of Health (2006) held a conference on cesarean delivery on maternal request. It summarized that stress urinary incontinence rates after elective cesarean delivery are lower than those following vaginal delivery. However, the duration of this protection is unclear, particularly in older and multiparous populations. This same panel considered the evidence implicating vaginal delivery in other pelvic loor disorders to be weak and not favoring either delivery route.

Cesarean delivery is associated with a lower rate of fetal trauma (Linder, 2013; Moczygemba, 2010). lexander and colleagues (2006) found that fetal injury complicated 1 percent of cesarean deliveries. Skin laceration was most common, but others included cephalohematoma, clavicular fracture, brachial plexopathy, skull fracture, and facial nerve palsy. Cesarean deliveries following a failed operative vaginal delivery attempt had the highest injury rate, whereas the lowest rate-0.5 percentoccurred in the elective cesarean delivery group. hat said, Worley and colleagues (2009) noted that approximately a third of women who were delivered at Parkland Hospital entered spontaneous labor at term, and 96 percent of these delivered vaginally without adverse neonatal outcomes.

Some evidence shows higher asthma and allergy rates in those delivered by cesarean. With the hope to improve neonatal microbiota, swabbing the newborn mouth with a gauze that was incubated in the maternal vagina 1 hour before surgery is described in preliminary studies. However, the American College of Obstetricians and Gynecologists (2017 e) does not encourage this practice due to few data and the potential for transmission of harmful organisms.

Some women request elective cesarean delivery. Data regarding the true incidence of cesarean delivey on matenal request (CDMR) are poor. Rate estimates range from 1 to 8 percent in the United States (Barber, 2011; Declercq, 2005; Gossman, 2006; Menacker, 2006).

Reasons for the request include pelvic floor protection, convenience, fear of childbirth, and reduced risk of fetal injury. Data to address these concerns are slowly accruing. One study of more than 66,000 Chinese parturients compared outcomes of those who elected planned vaginal or primary cesarean delivery (Liu, 2015). Short-term serious maternal morbidity and neonatal mortality rates were similar. For the newborns, rates of birth trauma, infection, and hypoxic ischemic encephalopathy were low in both groups but statistically lower with cesarean delivery. Respiratory distress syndrome rates were greater in the CMDR cohort. A smaller study comparing these two routes of delivery support these findings (Larsson, 2011).

he debate surrounding CDMR includes these medical points, the concept of informed free choice by the woman, and the autonomy of the physician in ofering CMDR. During the National Institutes of Health panel (2006) cited above, participants noted that most of the maternal and neonatal outcomes examined had insuicient data to permit recommendations. Despite this, the panel was able to draw a few conclusions, which are echoed by the American College of Obstetricians and Gynecologists (2017a). Namely, CMDR should not be performed before 39 weeks' gestation unless fetal lung maturity is conirmed. Cesarean delivery is ideally avoided in women desiring several children because of placental implantation abnormalities and cesarean hysterectomy risks. Finally, CMDR should not be motivated by the unavailability of efective pain management.

No nationally recognized standard of care currently dictates the acceptable time interval to begin cesarean delivery. Previously, a 30-minute decision-to-incision interval was recommended. In studying this, Bloom and coworkers (2001) found that 69 percent of 7450 cesareans performed in labor commenced more than 30 minutes after the decision to operate. In a second study, Bloom and colleagues (2006) evaluated cesarean deliveries performed for emergency indications. They reported that failure to achieve a cesarean delivery decision-to-incision time of less than 30 minutes was not associated with a negative neonatal outcome. A subsequent systematic review echoed this inding (ToIcher, 2014). Despite this, when faced with an acute, catastrophic deterioration in fetal condition, cesarean delivery usually is indicated as rapidly as possible, and thus purposeful delays are inappropriate. he American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017) recommend that facilities giving obstetrical care should have the ability to initiate cesarean delivery in a time frame that best incorporates maternal and fetal risks and beneits.

Obtaining informed consent is a process and not merely a medical document (American College of Obstetricians and Gynecologists, 2015). The conversation should enhance a woman's awareness of her diagnosis and contain a discussion of medical and surgical care alternatives, procedure goals and limitations, and surgical risks. For women with a prior cesarean delivery, the option of a trial of labor should be included for suitable candidates. lso, in those desiring permanent sterilization or intrauterine device insertion, consenting for these can be completed concurrently.

n informed patient may decline a particular recommended intervention, and a woman's decision-making autonomy must be respected. In the medical record, clinicians should document her reasons for refusal and should note that the intervention's value and the health consequences of not proceeding with it have been explained.

For Jehovah's Witnesses, informed consent discussions regarding blood products ideally begin early in pregnancy. Acceptable blood products vary widely among individual women, and a preoperative checklist of approved products allows superior preparation (Hubbard, 2015; Husarova, 2016). In general, red cells, white cells, platelets, and plasma are viewed as primary blood components and are eschewed. However, certain clotting factors or cell fractions may be acceptable (Lawson, 2015). Before and after surgery, iron, folate, and, if necessary, erythropoietin are accepted agents to help maximize hemoglobin levels. Perioperatively, phlebotomy should be limited, and pediatric collection tubes are preferable. Intraoperative options include treatment of atony to limit blood loss; topical hemostatic agents, tranexamic acid, and desmopressin to promote clot formation; red blood cell salvage or acute normovolemic hemodilution to provide autologous donation; and controlled hypotensive anesthesia, uterine artery embolization, occlusive vascular balloons, and temporary aortic compression for uncontrolled bleeding (Belfort, 2011; vlason, 2015).

• Timing of Scheduled Cesarean Delivery

Adverse neonatal sequelae from neonatal immaturity with elective delivery before 39 completed weeks are appreciable (Clark, 2009; Tita, 2009). To avoid these, assurance of fetal maturity before scheduled elective surgery is essential as outlined by the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017) and discussed in Chapter 31 (p. 597). To assist with this and other components of cesarean delivery planning, the American College of Obstetricians and Gynecologists (2011, 20 14b) has created Patient Safety Checklists to be completed before the planned surgery.

If cesarean delivery is scheduled, a sedative may be given at bedtime the night before surgery. In general, no other sedatives, narcotics, or tranquilizers are administered until after the fetus is born. In one small randomized trial, no benefits were gained from a presurgical enema (Lurie, 2012). Solid food intake is stopped at least 6 to 8 hours before the procedure. Uncomplicated patients may have moderate amounts of clear liquids up to 2 hours before surgery (American Society of Anesthesiologists, 2016). his comports with Enhanced Recovery After Surgery (ERAS) protocols that strive to maintain anabolic homeostasis and advocate clear carbohydrate drinks up to 2 hours before scheduled surgery and early postoperative feeding (Ljungqvist, 2017). Although evidence supports an ERAS approach for many procedures, data specifically addressing this for cesarean delivery are scarce (Wrench, 2015).

The woman scheduled for repeat cesarean delivery typically is admitted the day of surgery and evaluated by the obstetrical and anesthesia teams. Recently performed hematocrit and indirect Coombs test are reviewed. If the latter is positive, then availability of compatible blood must be ensured.

As discussed in Chapter 25 (p. 490), regional analgesia is preferred for cesarean delivery. An antacid is given shortly before regional analgesia or induction of general anesthesia. One example is Bicitra, 30 mL orally in a single dose. This minimizes the lung injury risk from gastric acid aspiration. Once the woman is supine, a wedge beneath the right hip and lower back creates a left lateral tilt to aid venous return and avoid hypotension. Data are insuicient to determine the value of fetal monitoring before scheduled cesarean delivery in women without risk factors. Our practice is to obtain a 5-minute tracing prior to elective cases. At minimum, fetal heart sounds should be documented in the operating room prior to surgery.

Of urther preparations, hair removal at the surgical site does not lower surgical site infection (SSI) rates (Kowalski, 2016). However, if hair is obscuring, it is removed the day of surgery by clipping, which is associated with fewer SSIs than shaving (Tanner, 2011). Chemical depilation the night before surgery compared with clipping has similar SSI rates (Lefebvre, 2015). An electrosurgical grounding pad is placed near the surgical incision and typically on the lateral thigh. n indwelling bladder catheter is typically placed at Parkland Hospital to collapse the bladder away from the hysterotomy incision, to avert urinary retention secondary to regional analgesia, and to allow accurate postoperative urine measurement. Small studies show that catheterization may be withheld in hemodynamically stable women to minimize urinary infections (Abdel-Aleem, 2014; Li, 2011; Nasr, 2009).

he risk of venous thromboembolism is increased with pregnancy and almost doubled in those undergoing cesarean delivery Oames, 2006). Accordingly, for all women not already receiving thromboprophylaxis, the American College of Obstetricians and Gynecologists (2017d) recommends initiation of pneumatic compression hose before cesarean delivery. These are usually discontinued once the woman ambulates. Recommendations between organizations vary, and the American College of Chest Physicians suggests only early ambulation for women without risk factors who are undergoing cesarean delivery (Bates, 2012). For women already receiving prophylaxis or those with increased risk factors, they support escalation of prophylaxis. Last, the Royal College of Obstetricians and Gynaecologists (2015) are the most conservative and suggest pharmacological prophylaxis for the largest proportion of patients. hese various methods and recommendations are discussed in Chapter 52 and are shown in Table 52-6 (p. 1020).

Some women scheduled for cesarean delivery have concurrent comorbidity that requires specific management in anticipation of surgery. Among others, these include insulin-requiring or gestational diabetes, coagulopathy or thrombophilia, chronic corticosteroid use, and signiicant reactive airway disease. Surgical preparations are discussed in the respective chapters covering these topics.

Cesarean delivery is considered a clean contaminated case, and postoperative febrile morbidity is common. Numerous goodquality trials show that a single dose of an antibiotic given at the time of cesarean delivery signiicantly decreases infectious morbidity (Smaill, 2014). Although more obvious for women undergoing unscheduled cesarean delivery, this practice also pertains to women undergoing elective surgery (American College of Obstetricians and Gynecologists, 2016). Depending on drug allergies, most recommend a single intravenous dose of a 3-lactam antibiotic-either a cephalosporin or extended-spectrum penicillin. A 1-g dose of cefazolin (Ancd) is an eicacious and cost-efective choice. Additional doses are considered in cases with blood loss > 1500 mL or with duration longer than 3 hours. Recommen dations for the best dose in obese parturients are conflicting (Ahmadzia, 2015; Maggio, 2015; Swank, 2015; Young, 2015).

levels with a 2-g dose for cesarean deliveries lasting 1.5 hours.

women if surgeries were longer (Grupper, 2017).

A growing body of evidence supports extending the antibiotic spectrum (Andrews, 2003; Tita, 2008). One large randomized trial added azithromycin, 500 mg intravenously, to standard prophylaxis prior to cesarean delivery for women in labor or with ruptured membranes (Tita, 2016). Rates of wound infection and endometritis were signiicantly lower in the extended-spectrum group compared with those in the standard prophylaxis cohort.

In pregnant women with a history of infection with methicillin-resistant Staphylococcus aureus (MRSA), a single dose of vancomycin added to the standard prophylaxis for cesarean deliveries can be elected. Decolonization plays a limited role but may be considered prior to a planned cesarean delivery in women with known MRSA colonization (American College of Obstetricians and Gynecologists, 2016).

Significant penicillin or cephalosporin allergy, which manifests by anaphylaxis, angioedema, respiratory distress, or urticaria, merits prophylaxis with a single 600-mg intravenous dose of clindamycin combined with a weight-based dose of an aminoglycoside as an alternative. A 900-mg clindamycin dose is used for obese patients.

Antibiotic administration before surgical incision lowers postoperative infection rates without adverse neonatal efects compared with drug administration after umbilical cord clamping (Mackeen, 2014b; Sullivan, 2007; Witt, 2011). Prophylaxis is ideally administered within the 60 minutes prior to the start of planned cesarean delivery. For emergent delivery, antibiotics are given as soon as feasible.

Preoperative preparation of the abdominal wall skin is efective to prevent wound infection. Either chlorhexidine or povidone-iodine solutions are suitable (Hadiati, 2014; Ngai, 2015; Springel, 2017). In studies that found a diference, chlorhexidine was favored, and this is our practice (Menderes, 2012; Tuuli, 2016a). In addition, preoperative vaginal cleansing with a povidone-iodine scrub has been evaluated in small randomized trials (Haas, 2014; Caissutti, 2017). Some showed lower rates of metritis, especially for those with ruptured membranes or active labor, but not lower rates of wound infection (Haas, 2010; Memon, 2011; Yildirim, 2012). Some recommend preoperative vaginal cleansing, bur we do not do this at Parkland Hospital.

Antibiotic prophylaxis against infective endocarditis is not recommended for most cardiac conditions-exceptions are women with cyanotic heart disease, prosthetic valves, or both (American College of Obstetricians and Gynecologists, 2016). Regimens selected for routine cesarean infection prophylaxis will also serve as appropriate endocarditis coverage (Chap. 49, p. 965).

Glycemic control in diabetics lowers wound infection rates and is emphasized in Chapter 57 (p. 1105). Smoking is another modiiable risk, and its mitigation is especially helpful for morbidly obese women (Alanis, 2010; Avila, 2012; Shree, 2016). Intraoperative normothermia lowers wound infection rates in general surgery and is a Surgical Care Improvement Project measure (Kurz, 1996; he Joint Commission, 2016). his tenet might logically be extrapolated to cesarean delivery, although deinitive studies are lacking (Carpenter, 2012). Perioperative supplementation with high-concentration inspired oxygen does not lower wound infection rates (Duggal, 2013; Klingel, 2013).

he Joint Commission (2013) established a protocol to prevent surgical errors. For cesarean delivery, all relevant documents are veriied immediately before surgery, and a "time out" is completed. The "time out" requires attention of the entire team to confirm that the patient, site, and procedure are correct. Important discussions also include introduction of the patient-care team members, veriication of prophylactic antibiotics, estimation of procedure length, and communication of anticipated complications. Additionally, requests for special instrumentation should be addressed preoperatively to prevent potential patient compromise and intraoperative delays.

An instrument, sponge, and needle count before and after surgery is crucial to surgical safety. If counts are not reconciled, radiographic imaging for retained foreign objects is obtained (American College of Obstetricians and Gynecologists, 20 14a).

With minor variations, surgical performance of cesarean delivery is comparable worldwide. Most steps are founded on evidence-based data, and these have been reviewed by Dahlke and associates (2013). As with all surgery, a clear understanding of relevant anatomy is essential, and this is described and illustrated in Chapter 2 (p. 14).

In obstetrics, a suprapubic transverse incision or a midline vertical one is chosen for laparotomy. Transverse abdominal entry is by either Pfannenstiel or Maylard incisions. Of all these, the Pfannenstiel incision is selected most frequently for cesarean delivery.

Transverse incisions follow Langer lines of skin tension.

Thus, compared with vertical ones, Pfannenstiel incisions ofer superior cosmesis and lower incisional hernia rates. Use of the Pfannenstiel incision, however, is often discouraged for cases in which a large operating space is essential or in which access to the upper abdomen may be needed. With transverse incisions, because of the layers created during incision of the internal and external oblique aponeuroses, purulent fluid can collect between these. Therefore, some favor a midline vertical incision for cases with high infection risks. Emergent entry is typically faster with vertical incision during primary and repeat cesarean delivery (Wylie, 2010). Last, neurovascular structures, which include the ilioinguinal and iliohypogastric nerves and supericial and inferior epigastric vessels, are often encountered with transverse inCISIons. Logically, bleeding, wound hematoma, and neurological disruption may more frequently complicate these incisions compared with vertical ones. he best incision for the morbidly obese parturient is unclear (Smid, 2016). As discussed in Chapter 48 (p. 943), our preference with very obese women is a periumbilical midline vertical incision.

he Maylard incision difers mainly from the Pfannenstiel in that the bellies of the rectus abdominis muscle are transected horizontally to widen the operating space. It is technically more diicult due to its required muscle cutting and isolation and ligation of the inferior epigastric arteries, which lie laterally to these muscle bellies.

Once access is gained, metal handheld retractors provide exposure for hysterotomy. A few small randomized studies have evaluated postcesarean wound infection rates with a disposable plastic barrier retractor (Alexis-O). Results showing benefit are contradictory (Hinkson, 2016; Scolari Childress, 2016; heodoridis, 2011).

With the Pfannenstiel incision, the skin and subcutaneous tissue are incised using a low, transverse, slightly curvilinear incision. his is made at the level of the pubic hairline, which is typically 3 cm above the superior border of the symphysis pubis. The incision is extended laterally suiciently to accommodate delivery-12 to 15 cm is typical.

Sharp dissection is continued through the subcutaneous layer to the fascia. The supericial epigastric vessels can usually be identiied halway between the skin and fascia, several centimeters from the midline, and are coag ulated. If lacerated, these may be suture ligated with 3-0 plain gut suture or coag ulated with an electro surgical blade.

he fascia is then incised sharply at the midline. he anterior abdominal fascia is typically composed of two visible layers, the aponeurosis from the external oblique muscle and a fused layer containing aponeuroses of the internal oblique and transverse abdominis muscles. Ideally, the two layers are individually incised during lateral extension of the fascial incision. The inferior epigastric vessels usually lie outside the lateral border of the rectus abdominis muscle and beneath the fused aponeuroses of the internal oblique and transverse abdominis muscles. hus, although infrequently required, extension of the fascial incision further laterally may cut these vessels. With extension, these vessels are best identiied and coagulated or ligated to prevent bleeding and vessel retraction.

Once the fascia is incised, the inferior fascial edge is grasped with Kocher clamps and elevated by an assistant as muscle either bluntly or sharply until the superior border of the symphysis pubis is reached. Next, the superior fascial edge is grasped and again, separation of fascia from the rectus muscle is completed. Blood vessels coursing between the sheath and muscles are clamped, cut, and ligated, or they are coagulated with an electrosurgery blade. Meticulous hemostasis is imperative to lower rates of incisional hematoma and infection. he fascial separation progresses cephalad and laterally to create a semicircular area above the transverse incision with a radius of approximately 8 cm. This will vary depending on fetal size. he rectus abdominis and pyramidalis muscles are then separated in the midline, irst superiorly and then inferiorly, by sharp and blunt dissection to expose the transversalis fascia and peritoneum.

he transversalis fascia and preperitoneal fat are bluntly dissected away to reach the underlying peritoneum. The peritoneum near the upper end of the incision is opened carefully, either bluntly or by elevating it with two hemostats placed approximately 2 cm apart. his upper site lowers cystotomy risks. The tented fold of peritoneum between the clamps is examined and palpated to ensure that omentum, bowel, or bladder is not adjacent. he peritoneum is then incised. The peritoneal incision is extended superiorly to the upper pole of the fascial dissection and downward to just above the peritoneal relection over the bladder. Importantly, in women with prior intraabdominal surgery, including cesarean delivery, omentum or bowel may be adhered to the undersurface of the peritoneum. In women with obstructed labor, the bladder may be pushed cephalad almost to the level of the umbilicus.

the operator separates the fascial sheath FIGURE 30-1 The loose peritoneum above the bladder reflection is grasped with forceps from the underlying rectus abdominis and incised with Metzenbaum scissors,

This incision begins 2 to 3 cm above the superior margin of the symphysis. It should suiciently long to allow fetal delivery, and 12 to 15 cm is typical. Sharp or electrosurgical blade dissection through the subcutaneous layers ultimately exposes the anterior rectus sheath. A small opening is made sharply with scalpel in the upper half of the linea alba. Placement here helps avoid potential cystotomy. Index and middle ingers are placed beneath the fascia to elevate it, and the fascial incision is extended irst superiorly and then inferiorly with scissors. Midline separation of the rectus muscles and pyramidalis muscles and peritoneal entry are similar to those with the Pfannenstiel incision.

Most often, the lower uterine segment is incised transversely as described by Kerr in 1921. Occasionally, vertical incision conined solely to the lower uterine segment may be elected (Kronig, 1912). In contrast, a classical incision begins as a low-vertical incision, which is then extended cephalad into the active portion of the uterine corpus. Last, a fundal or even posterior incision may be selected for cases with placental accrete syndromes.

For most cesarean deliveries, this incision is preferred. Compared with a classical incision, it is easier to repair, causes less incision-site bleeding, and promotes less bowel or omentum adherence to the myometrial incision. Located in the inactive segment, it also is less likely to rupture during a subsequent pregnancy.

Before any hysterotomy, the surgeon palpates the fundus to identiy degrees of uterine rotation. The uterus may be rotated so that one round ligament is more anterior and closer to the midline. In such cases, the uterus can be

FIGURE 30-2 This peritoneal edge is elevated and incised laterally.

bladder is gently separated from the underlying lower uterine segment with blunt or sharp dissection within this vesicouterine space (Fig. 30-3). This bladder lap creation efectively moves the bladder away from the planned hysterotomy site. It also helps prevent bladder laceration if an unintended inferior hysterotomy extension occurs during fetal delivery.

In general, this caudad separation of bladder does not exceed 5 cm and usually is less. However, in instances in which cesarean hysterectomy is planned or anticipated, extended caudad dissection is recommended to aid total hysterectomy and decrease the risk of cystotomy.

manually reoriented and held to permit centering of the incision. This avoids incision extension into and laceration of the adjacent uterine artery. A moist sponge may be used to pack protruding bowel away from the operative ield.

he relection of peritoneum at the upper margin of the bladder and overlying the lower uterine segment is grasped in the midline with forceps and incised transversely with scissors (Fig. 30-1). Following this initial incision, scissors are inserted between peritoneum and lower uterine segment. Open scissors are pushed laterally from the midline on each side. This transverse peritoneal incision extends almost the full length of the lower uterine segment. As the lateral margin on each side is approached, the scissors are directed slightly cephalad (Fig. 30-2). The lower FIGURE 30-3 Cross section shows blunt dissection of the bladder of the uterus to edge of peritoneum is elevated, and the expose the lower uterine segment.

FIGURE 30-4 The myometrium is incised with shallow strokes to avoid cutting the fetal head.

FIGURE 30-5 After entering the uterine cavity, the incision is extended laterally with fingers or with bandage scissors (inset).

Some surgeons do not create a bladder lap. The main advantage is a shorter skin incision-to-delivery time. However, data supporting this practice are limited (O'Neill, 2014; Tuuli, 2012).

Uterine Incision. The uterus is entered through the lower uterine segment. Digital palpation to find the physiological border between irmer upper segment myometrium and the more flexible lower segment can guide placement. The bladder flap incision can also serve as a guide, and a hysterotomy site near this line is often selected.

For women with advanced or complete cervical dilatation, the hysterotomy is placed relatively higher. Failure to adjust increases the risk of lateral extension of the incision into the uterine arteries. It may also lead to incision of the cervix or vagina rather than the lower uterine segment. Such incisions into the cervix can distort postoperative cervical anatomy.

The uterus can be incised by various techniques. Each is initiated by using a scalpel to transversely incise the exposed lower uterine segment for 1 to 2 cm in the midline (Fig. 30-4). Repetitive shallow strokes avoid fetal laceration. As the myometrium thins, a fingertip can then bluntly enter the uterine cavity. Once the uterus is opened, the hysterotomy is lengthened by simply spreading the incision, using lateral and slightly upward pressure applied with each index inger 30-5). Some evidence also supports widening the lower-uterine-segment incision instead with ingers pulling in opposition in a cephalocaudad direction (Cromi, 2008; Xodo, 2016).

Alternatively, if the lower uterine segment is thick and unyielding, cutting laterally and then slightly upward with bandage scissors will lengthen the incision. Importantly, when scissors are used, the index and midline fingers of the nondominant hand should be insinuated beneath the myometrium and above fetal parts to prevent fetal laceration. Comparing blunt and sharp expansion of the initial uterine incision, blunt stretch is associated with fewer unintended incision extensions, shorter operative time, and less blood loss. However, the rates of infection and need for transfusion do not difer (ASIClOglu, 2014; Saad, 2014).

The uterine incision is made large enough to allow delivery of the fetus without tearing into the uterine vessels that course along the lateral uterine margins. If the placenta is encountered in the incision line, it must be either detached or incised. Placental function is thereby compromised, and thus delivery is performed expeditiously.

At times, a low transverse hysterotomy is selected but provides inadequate room for delivery. In such instances, one corner of the hysterotomy incision is extended cephalad into the contractile portion of the myometrium-a J incision. If this is completed bilaterally, a U incision is formed. Last, some prefer instead to extend in the midline-a T incision. As expected, each has higher intraoperative blood loss (Boyle, 1996; Patterson, 2002). Moreover, as these extend into the contractile portion, a trial of labor is more likely to be complicated by uterine rupture in future pregnancies.

Delivey of the Fetus. In a cephalic presentation, a hand is slipped into the uterine cavity between the symphysis and fetal head. The head is elevated gently with the ingers and palm through the incision. Once the head enters the incision, delivery may be aided by modest transabdominal fundal pressure (Fig. 30-6).

After a long labor with cephalopelvic disproportion, the fetal head may be tightly wedged in the birth canal. Release of an impacted fetal head raises the risk of hysterotomy extension, of associated blood loss, and of fetal skull fracture. In

FIGURE 30-6 Delivery of the fetal head.

this situation, there are three considerations for delivery. First, a "push" method may be used. With this, upward pressure exerted by a hand in the vagina by an assistant will help to dislodge the head and allow its delivery above the symphysis.

If this is anticipated, a patient in frog-leg position may allow easier vaginal access.

Second, as an alternative, a "pull" method grasps the fetal legs to bring them through the hysterotomy. he fetus is then delivered by traction as one would complete a breech extraction.

ized trials and retrospective cohort studies (Berhan, 2014; J eve, 2016; Nooh, 2017). A low vertical hysterotomy incision, which will give more room for the "pull" technique, may be selected. If a low transverse incision has already been made, then this can be extended to a J-, U-, or T-incision as previously discussed.

The third method is use of the "fetal pillow," which is a distensible intravaginal balloon that when inflated, elevates the fetal head. The device is available outside the United States, but evidence for its eicacy is limited (Safa, 2016; Seal, 2016).

Conversely, in women without labor, the fetal head may be unmolded and without a leading cephalic point. The round head may be diicult to lift through the uterine incision in a relatively thick lower segment that is unattenuated by labor. In such instances, either forceps or a vacuum device may be used to deliver the fetal head (Fig. 30-7).

fter head delivery, a inger should be passed across the fetal neck to determine whether it is encircled by one or more umbilical cord loops. If present, these are slipped over the head. The head is rotated to an occiput transverse position, which aligns the fetal bisacromial diameter vertically. The sides of the head are grasped with two hands, and gentle downward traction is applied until the anterior shoulder enters the hysterotomy incision (Fig. 30-8). Next, by upward movement, the posterior shoulder is delivered. During delivery, abrupt or powerful force is avoided to avert brachial plexus injury. With steady outward traction, the rest of the body then readily follows. Gentle fundal pressure may aid this.

With some exceptions, current American Heart Association neonatal resuscitation recommendations eschew suctioning immediately following birth, even with meconium present (Wyckof, 2015). A fuller discussion of this and delayed umbilical cord clamping is found in Chapter 27 (p. 518). he umbilical cord is clamped, and the newborn is given to the team member who will conduct resuscitative eforts as needed.

Comparing elective cesarean under neuraxial anesthesia and spontaneous vaginal deliveries, studies show that the need for neonatal resuscitation is not practically signiicant between the two (Atherton, 2006; Gordon, 2005; Jacob, 1997). he American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017) recommend that "a qualiied person who is skilled in neonatal resuscitation should be in the delivery room." At Parkland Hospital, pediatric nurse practitioners attend uncomplicated, scheduled cesarean deliveries. Notably, as anticipated neonatal risks rise, so too should the resuscitative skills of the attendants (Wyckof, 2015).

To promote breastfeeding, the American College of Obstetricians and Gynecologists (2017b) recommends skin-to-skin contact between newborn and mother in the delivery room.

FIGURE 30-7 A.The first cesarean forceps blade is placed. B. Slight upward and outward traction is used to lit the head through the incision.

Although most randomized trials focus on vaginal birth, several small studies support such contact following cesarean delivery, and this our practice (Moore, 2016; Stevens, 2014).

After birth, an intravenous infusion containing two ampules or 20 units of oxytocin per liter of crystalloid is infused at 10 mLlmin. Some prefer higher infusion dosages, however, nondilute boluses are avoided because of associated hypotension (Roach, 2013). Once the uterus contracts satisfactorily, the rate can be reduced. An alternative is carbetocin-a longer-acting oxytocin derivative that is not available in the United Statesthat provides suitable, albeit more expensive, hemorrhage prophylaxis Qin, 2016). Ergot-alkaloids are second-tier agents and carry hypertensive side efects. Carboprost, a IS-methyl derivative of prostaglandin F2> is another second-tier agent used to treat uterine atony. Some but certainly not all studies indicate that misoprostol appears to perform similarly to oxytocin (Chaudhuri, 2014; Conde-Agudelo, 2013). Finally, some recommend the use of tranexamic acid added to a standard oxytocin infusion to decrease blood loss (Simonazzi, 2016; Wang, 2015). Its antifibrinolytic action and efects on thromboembolism rates in pregnant surgical patients are unclear. Larger trials are needed before widespread use. Additional discussions of all these agents are found in Chapter 41 (p. 759).

Delivey of the Placenta. he uterine incision is observed for any vigorously bleeding sites. These should be quickly clamped with Pennington or ring forceps. Although some surgeons may prefer , manual removal of the placenta, spontaneous delivery prompted by some cord traction may reduce the risk of operative blood loss and infection (Anorlu, 2008; Baksu, 2005). Fundal massage may

FIGURE 30-8 The anterior (A) and then the posterior (B) shoulder are delivered.

begin as soon as the fetus is delivered to hasten placental separation and delivery (Fig. 30-9).

Immediately after delivery and quick gross inspection of the placenta, the uterine cavity is suctioned and wiped out with a gauze sponge to remove avulsed membranes, vernix, and clots. In the past, double-gloved fingers or ring forceps placed through the hysterotomy incision were used to dilate an ostensibly closed cervix. his practice does not reduce infection rates from potential hematometra and is not recommended (Kirscht, 2017; Liabsuetrakul, 2011).

Uterine Repair. Ater placental delivery, the uterus is lited through the incision and onto the draped abdominal wall, and the fundus is covered with a moistened laparotomy sponge. We favor this and believe a relaxed, atonic uterus can be recognized quickly and massage applied. Incision and bleeding points are more easily visualized and repaired, especially if there have been extensions. Adnexal exposure is superior, and thus, tubal sterilization is easier. Instead, some clinicians prefer to close the hysterotomy with the uterus in situ. Comparing these two approaches, febrile morbidity, pain, and blood loss are not signiicantly diferent (Walsh, 2009; Zaphiratos, 2015).

Before hysterotomy closure, previously clamped large vessels may be ligated separately or incorporated within the running incision closure. IUD insertion, if planned, is completed prior to hysterotomy closure (Chap. 38, p. 685). One angle of the uterine incision is grasped to stabilize and maneuver the incision. he uterine incision is then closed with one or two layers of continuous 0-or no. 1 absorbable suture (Fig. 30-10). Chromic catgut suture is used by many, but some prefer synthetic delayed-absorbable polyglactin 910 (Vicryl). In subsequent pregnancy, neither suture type has been shown superior by mitigating against greater rates of adverse pregnancy outcomes such as uterine incision rupture (CORONIS Collaborative Group, 2016). Single-layer closure is typically faster and is not associated with higher rates of infection or transfusion (CAESAR Study Collaborative Group, 2010; Dodd, 2014; Roberge, 2014). Moreover, most studies observed that the number of layers does not significantly afect complication rates in the next pregnancy (Chapman, 1997; CORONIS Collaborative Group, 2016; Durnwald, 2003; Roberge, 2011).

At Parkland Hospital, we use a one-layer uterine closure with chromic catgut. he initial suture is placed just beyond one angle of the uterine incision. A continuous, locking suture line for hemostasis is then performed, with each suture penetrating the full thickness of the myometrium. he suture line then extends to a point just beyond the opposite incision angle. If approximation is not satisfactory after a single layer or if bleeding sites persist, then more sutures are required. Either another layer of running suture is placed to achieve approximation and hemostasis, or individual bleeding sites can be secured with targeted figure-of-eight or mattress stitches.

FIGURE 30-9 Placenta bulging through the uterine incision as the uterus contracts. A hand gently massages the fundus to help aid spontaneous placental separation.

Traditionally, the peritoneum in the anterior cul-de-sac is approximated with a continuous 2-0 chromic catgut suture line. Multiple randomized trials suggest that omission of this step causes no postoperative complications (Grundsell, 1998; Irion, 1996; Nagele, 1996). If tubal sterilization is to be performed, it is completed as described in Chapter 39 (p. 702).

FIGURE 30-10 The cut edges of the uterine incision are approximated with a running, locking suture.

Following cesarean delivery, adhesions commonly form within the vesicouterine space or between the anterior abdominal wall and uterus. And, with each successive pregnancy, the percentage of afected women and adhesion severity rise (Morales, 2007; Tulandi, 2009). Adhesions can significantly lengthen incision-to-delivery time and total operative time (Rossouw, 2013; Sikirica, 2012). Although occurring infrequently, rates of cystotomy and bowel injury are also increased because of adhesive disease (Rahman, 2009; Silver, 2006).

Intuitively, scarring can be reduced by handling tissues delicately, achieving hemostasis, and minimizing tissue ischemia, infection, and foreign-body reaction. Most recent data on shortand long-term outcomes show no benefit to peritoneal closure (CAESAR Study Collaborative Group, 2010; CORONIS Collaborative Group, 2013, 2016; Kapustian, 2012). Similarly, most studies show no benefit from placement of an adhesion barrier at the hysterotomy site (Edwards, 2014; Kiefer, 2016).

Any laparotomy sponges are removed, and the paracolic gutters and cul-de-sac are gently suctioned of blood and amnionic fluid. Some surgeons irrigate the gutters and cul-de-sac, especially in the presence of infection or meconium. Routine irrigation in low-risk women, however, leads to greater intraoperative nausea but not to lower postoperative infection rates (Eke, 2016; Viney, 2012).

Prior to abdominal closure, correct sponge and instrument counts are verified. he rectus abdominis muscle bellies are allowed to fall into place. With significant diastasis, the rectus muscles may be approximated with one or two figure-of-eight sutures of 0 or no. 1 chromic gut suture. The overlying rectus fascia is closed by a continuous, nonlocking technique with a delayed-absorbable suture. In patients with a higher risk for infection, there may be theoretical value in selecting a monoilament suture here rather than braided material.

The subcutaneous tissue usually need not be closed if it is less than 2 em thick. With thicker layers, however, closure is recommended to minimize seroma and hematoma formation, which can lead to wound infection and/or disruption (Bohman, 1992; Chelmow, 2004). One recent metaanalysis found lower rates of seroma formation and of developing any wound complication with closure, but hematoma and wound infection rates were unafected (Pergialiotis, 2017). Addition of a subcutaneous drain does not prevent significant wound complications (Hellums, 2007; Ramsey, 2005).

Skin is closed with a running subcuticular stitch of 4-0 delayed-absorbable suture, with adhesive glue, or with staples. In comparison, final cosmetic results and infection rates appear similar, skin suturing takes longer, but wound separation rates are higher with metal staples (Basha, 2010; Figueroa, 2013; Mackeen, 2014a, 2015). Poliglecaprone 25 (NIonocryl) or polyglactin 910 (Vieryl) are both suitable (Tuuli, 2016b). Outcomes with 2-octyl cyanoacrylate adhesive (Dermabond) were equivalent to sutures for Pfannenstiel incisions (Daykan, 2017; Siddiqui, 2013). A sterile thin abdominal wound dress ing is suicient. In morbidly obese women, application of a prophylactic negative-pressure device atop the closed skin incision to prevent seroma and subsequent infection does not appear to lower wound complication rates (Hussamy, 2018; Smid, 2017).

The Pfannenstiel-Kerr technique just described has been used for decades. More recently, Joel-Cohen and Misgav Ladach techniques have been added (Holmgren, 1999). These difer from traditional Pfannenstiel-Kerr entry mainly by their initial incision placement and greater use of blunt dissection.

he Joel-Cohen technique creates a straight 10-cm transverse skin incision 3 em below the level of the anterior superior iliac spines (Olofson, 2015). he subcutaneous tissue layer is opened sharply 2 to 3 em in the midline. This is carried down, without lateral extension, to the fascia. A small transverse incision is made in the fascia, and curved Mayo scissors are pushed laterally on each side and beneath intact subcutaneous fat to incise the fascia. With this incision completed, an index finger from each hand is inserted between the rectus abdominis muscle bellies and beneath the fascia. One finger is moved cranially and the other caudally, in opposition, to separate the bellies and further open the fascial incision. hen, a finger from each hand hooks under each belly to stretch the muscles laterally. The peritoneum is entered sharply, and this incision is sharply extended cephalocaudad. Entry with the Misgav Ladach technique difers in that the peritoneum is entered bluntly (Holmgren, 1999).

Modiications to the Joel-Cohen method abound. For emergency delivery, we begin along a line somewhat lower on the abdomen. For speed, we extend the fascial incision bluntly by hooking index fingers in the fascial incision's lateral angles and pulling laterally (Hofmeyr, 2009; Olofson, 2015). Index fingers insinuated between the rectus bellies then move cephalocaudad in opposition to stretch the incision. Blunt index-finger dissection enters the peritoneum, and again, cranial and caudad opposing stretch opens this layer. Last, all the layers of the abdominal wall are grasped manually and pulled laterally in opposition to further open the operating space.

These techniques have been associated with shorter operative times and with lower rates of intraoperative blood loss and postoperative pain (Mathai, 2013). They may, however, prove diicult for women with anterior rectus fibrosis and peritoneal adhesions (BoIze, 2013).

Indications. This incision is usually avoided because it encompasses the active upper uterine segment and thus is prone to rupture with subsequent pregnancies. Some indications stem from diiculty in exposing or safely entering the lower uterine segment. For example, a densely adhered bladder from previous surgery is encountered; a leiomyoma occupies the lower uterine segment; the cervix has been invaded by cancer; or massive maternal obesity precludes safe access to the lower uterine segment. A classical incision is also preferred for placenta previa with anterior implantation, especially those complicated by placenta accrete syndromes. In extreme cases of this, the typical classical hysterotomy may be placed even higher in the uterine body or posteriorly to avoid the placenta. As such, fetuses with cephalic presentation are then delivered in a manner similar to total breech extraction (Chap. 28, p. 548).

In other instances, fetal indications dictate the need. Transverse lie of a large etus, especially if the membranes are ruptured and the shoulder is impacted in the birth canal, usually necessitates a classical incision. A fetus presenting as a back-down transverse lie is particularly di.cult to deliver through a transverse uterine incision. In instances when the fetus is very small and breech, a classical incision may be preferable (Osmundson, 2013). In such cases, the poorly developed lower uterine segment provides inadequate space for the manipulations required for breech delivery. Or, less commonly, the small fetal head may become entrapped by a contracting uterine fundus following membrane rupture. Last, with multiple fetuses, a classical incision again may provide suitable room for extraction of fetuses that may be malpositioned or preterm (Osmundson, 2015).

Uterine Incision and Repair. A vertical uterine incision is initiated with a scalpel beginning as low as possible and preferably within the lower uterine segment (Fig. 30-11). If adhesions, insu.cient exposure, a tumor, or placenta percreta preclude development of a bladder flap, then the incision is made above the level of the bladder. Once the uterus is entered with a scalpel, the incision is extended cephalad with bandage scissors until it is long enough to permit delivery of the fetus. With scissor use, the fingers of the nondominant hand are insinuated between the myometrium and fetus to prevent fetal laceration. As the incision is opened, numerous large vessels that bleed profusely are commonly encountered within the myometrium. The remainder of fetal and placental delivery mirrors that with a low transverse hysterotomy.

For incision closure, one method employs a layer of 0-or no. 1 chromic catgut with a running stitch to approximate the

FIGURE 30-11 An initial small vertical hysterotomy incision is made in the lower uterine segment. Fingers are insinuated between the myometrium and fetus to avoid fetal laceration. Scissors extend the incision cephalad as needed for delivery. (Reproduced with permission from Johnson DD: Cesarean delivery. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 201o7.) deeper length of the incision (Fig. 30-12). he outer layer of myometrium is then closed along its length with similar suture and with a running suture line. To achieve good approximation and to prevent the suture from tearing through the myometrium,

FIGURE 30-12 Classical incision closure. The deeper half (left) and superficial half (middle) of the incision are closed in a running fashion. The serosa is then closed (right). (Reproduced with permission from Johnson DD: Cesarean delivery. In Yeomans ER, Hoffman BL,

Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 201o7.) it is helpul to have an assistant compress the uterus on each side of the wound toward the midline as each stitch is placed.

Hysterectomy is most commonly performed to arrest or prevent hemorrhage from intractable uterine atony or abnormal placentation (Bateman, 2012; Hernandez, 2012; Owolabi, 2013). It is more often completed during or after cesarean delivery but may be needed following vaginal birth. If all deliveries are considered, the peripartum hysterectomy rate in the United States approximates 1 per 1000 births and has risen signiicantly during the past few decades (Bateman, 2012; Govindappagari, 2016). During a 25-year period, the rate of peripartum hysterectomy at Parkland Hospital was 1.7 per 1000 births (Hernandez, 2012). Most of this rise is attributed to the increasing rates of cesarean delivery and its associated complications in subsequent pregnancy (Bateman, 2012; Bodelon, 2009; Flood, 2009; Orbach, 2011). Of hysterectomies, approximately one half to two thirds are total, whereas the remaining cases are supracervical (Rossi, 2010; Shellhaas, 2009).

Major complications of peripartum hysterectomy include greater blood loss and risk of urinary tract damage. Blood loss is usually appreciable because hysterectomy is being performed for hemorrhage that frequently is torrential, and the procedure itself is associated with substantial bleeding. lthough many cases with hemorrhage cannot be anticipated, those with abnormal implantation are oten identiied antepartum. Preoperative preparations for placenta accreta are discussed in Chapter 41 (p. 781) and have also been outlined by the Society for Maternal-Fetal

FIGURE 30-14 The posterior leaf of the broad ligament adjacent to the uterus is perforated just beneath the fallopian tube, uteroovarian ligaments, and ovarian vessels.

FIGURE 30-13 The round ligaments are clamped, doubly ligated, FIGURE 30-15 The uteroovarian ligament and fallopian tube are and transected bilaterally. clamped and cut. The lateral pedicle is doubly ligated.

Medicine (2010) and American College of Obste tricians and Gynecologists (2017 c).

An important factor afecting the cesarean hysterectomy complication rate is whether the operation is performed electively or emergently.

tomy, rates of blood loss, blood transfusion, and urinary tract complications are lower that with emergent procedures (Briery, 2007; Glaze, 2008).

Total or supracervical hysterectomy is performed using standard operative techniques. Adequate exposure is essential, but initially, placement of a self-retaining retractor such as a Balfour is not necessary. Rather, satisfactory exposure is obtained with cephalad traction on the uterus by an assistant, along with handheld Richardson or Deaver retractors. he bladder lap is deflected downward to the level of the cervix if possible to permit total hysterectomy. In cases in which cesarean hysterectomy is planned or strongly suspected, extended bladder flap dissection is ideally completed before initial hysterotomy. Later attempts at bladder dissection may be obscured by bleeding, or excess blood may be lost while this dissection is performed.

After cesarean delivery, the placenta is typically removed. In cases of placenta accrete syndrome for which hysterectomy is already planned, the placenta is usually left undisturbed in situ. In either situation, if the hysterotomy incision is bleeding appreciably, it can be sutured or Pennington or sponge forceps can be applied for hemostasis. If bleeding is minimal, neither maneuver is necessary.

he round ligament is divided close to the uterus between clamps, and each pedicle is ligated (Fig. 30-13). Either 0 or no. 1 suture can be used in either chromic gut or delayedabsorbable material. he anterior leaf of the broad ligament is incised downward to meet the former bladder flap incision. he posterior leaf of the broad ligament adjacent to the uterus is bluntly or sharply perforated just beneath the fallopian tube, uteroovarian ligament, and ovarian vessels (Fig. 30-14). hese structures together are then divided between sturdy clamps placed close to the uterus 30-15). he lateral pedicle is doubly ligated. The medial clamp remains and is removed later with the entire uterine specimen. he posterior leaf of the broad ligament is incised toward the uterosacral ligaments (Fig. 30-16). Next, the bladder and attached peritoneal flap are further deflected and dissected as needed. If the bladder flap is unusually adhered, as it may be after previous hysterotomy incisions, careful sharp dissection may be necessary (Fig. 30-17).

Posterior leaf of broad ligament Uterosacral :n�s �

FIGURE 30-16 The posterior leaf of the broad ligament is divided inferiorly toward the uterosacral ligament.

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FIGURE 30-17 The bladder is dissected sharply from the lower uterine segment.

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FIGURE 30-18 The uterine vessels are clamped, and a third medial clamp helps prevent "back bleeding." Once divided, the lateral vascular pedicle is doubly ligated to ensure hemostasis.

Special care is required from this point on to avoid injury to the ureters, which pass beneath the uterine arteries. To help accomplish this, an assistant places constant traction to pull the uterus in the direction away from the side on which the uterine vessels are being ligated. he ascending uterine artery and veins on either side are identiied. These vessels are then clamped adjacent to the uterus. For security, some may prefer two lateral clamps as shown in Figure 30-18. he most medial clamp helps prevents back bleeding from the uterus and remains for later removal with the specimen. The uterine vessels are divided, and the lateral tissue pedicle is doubly suture ligated. After securing the uterine vessels on one side, the round ligament, adnexal pedicle, and uterine vessels are then addressed on the contralateral side.

With cesarean hysterectomy, it may be more advantageous in cases of profuse hemorrhage to rapidly double clamp and divide all of the vascular pedicles between clamps to gain hemostasis. The surgical team can then return to ligate all of the pedicles.

Even if total hysterectomy is planned, we find it technically easier in many cases to finish the operation after amputating the uterine fundus and placing Ochsner or Kocher clamps on the cervical stump for traction and hemostasis. Self-retaining retractors also may be placed at this time. To remove the cervix, the bladder is mobilized further if needed. This carries the ureters caudad as the bladder is retracted beneath the symphysis and will prevent laceration or suturing of the bladder during cervical excision and vaginal cuf closure.

FIGURE 30-19 The cardinal ligaments are clamped, incised, and ligated.

The cardinal ligament, the uterosacral ligaments, and the many large vessels these ligaments contain are clamped systematically with sturdy Heaney-type curved or straight clamps (Fig. 30-19). he clamps are placed as close to the cervix as possible, taking care not to include excessive tissue in each clamp. The tissue between the pair of clamps is incised, and the lateral pedicle is suture ligated. hese steps are repeated caudally and bilaterally until the level of the lateral vaginal fornix is reached on each side. In this way, the descending branches of the uterine vessels are clamped, cut, and ligated as the cervix is separated from the cardinal ligaments.

If the cervix is efaced and dilated considerably, its softness may obscure palpable identiication of the cervicovaginal junction. he junction location can be ascertained through a vertical uterine incision made anteriorly in the midline, either through the open hysterotomy incision or through an incision created at the level of the ligated uterine vessels. A finger is directed inferiorly through the incision to identiy the free margin of the dilated, efaced cervix. The contaminated glove is replaced. Another useful method to identiy the cervical margins in cases of planned hysterectomy is to transvaginally place four metal skin clips or brightly colored sutures at 12, 3, 6, and 9 o'clock positions on the cervical edges.

Immediately below the level of the cervix, a curved clamp is placed across the lateral vaginal fornix on each side, and the vagina is incised above the clamp (Fig. 30-20).The cervix is inspected to ensure that it has been completely removed. A transfixing suture is used for vaginal cuf closure as each clamp is removed. Interrupted stitches may be added to approximate the middle portion

FIGURE 30-20 A curved clamp is placed across the lateral vaginal fornix below the level of the cervix, and the tissue incised medially to the point of the clamp.

of the cuf Each lateral vaginal fornix is secured to the uterosac raliligaments to mitigate later vaginal prolapse. For cuf closure, some surgeons instead prefer to close the vagina by apposing the anterior and posterior vaginal walls with interrupted figure-of ll sites are examined carefully for bleeding. One technique is to perform a systematic bilateral survey from the fallopian tube and ovarian ligament pedicles to the vaginal vault and bladder lap. Bleeding sites are ligated with care to avoid the ureters. The abdominal wall normally is closed in layers, as previously described for cesarean delivery (p. 578).

To perform a subtotal nysterectomy, the uterine body is amputated immediately above the level of uterine artery ligation. The cervical stump may be closed with continuous or interrupted chromic catgut suture. Subtotal hysterectomy is often all that is necessary to stop hemorrhage. It may be preferred for women who would benefit from a shorter surgery or for those with extensive adhesions that threaten significant urinary tract injury.

Because of the large adnexal vessels and their close proximity to the uterus, it may be necessalY to remove one or both adnexa to obtain hemostasis. Briery and colleagues (2007) reported unilateral or bilateral oophorectomy in a fourth of cases. Preoperative counseling for anticipated hysterectomy should include this possibility.

hese injuries are rare during cesarean delivery. The bladder laceration rate approximates 2 per 1000 cesarean deliveries,

FIGURE 30-21 A running-lock suture approximates the vaginal wall edges.

whereas that for ureteral trauma nears 0.3 per 1000 cases (Giingordiik, 2010; Oliphant, 2014; Rajasekar, 1997). Bowel is damaged in about 1 in 1000 cesarean deliveries (Silver, 2006).

Bladder laceration most commonly occurs during blunt or sharp dissection in the vesicouterine space to create the bladder lap, during peritoneal cavity entry, and during hysterotomy (Phipps, 2005; Rahman, 2009). Risks are prior cesarean delivery; emergency cesarean delivery; comorbid adhesive disease; cesarean hysterectomy, especially cases with morbidly adherent placenta; and surgery in second-stage labor compared with irst-stage (Alexander, 2007; Silver, 2006; Yossepowitch, 2004).

Bladder injury is typically identified intraoperatively, and initially, a clear-luid gush or the Foley bulb may be seen. If cystotomy is suspected, it can be conirmed with retrograde instillation of infant formula or methylene-blue-stained saline through a Foley catheter into the bladder. Leakage of opaque milk or methylene blue aids in identiication of the laceration as well as delineation of its borders. The dome is lacerated in 95 percent of cases, and injuries at the trigone form the remainder (Phipps, 2005).

Prior to cystotomy repair, ureters are examined, and surveillance for urine jets from each oriice follows. This can be done directly through the cystotomy, if at the dome, or through a separate diagnostic extraperitoneal or retropubic cystotomy, if injury nears the trigone. Jet visualization can be assisted by 50 mg of methylene blue administered intravenously.

Once ureteral patency is conirmed, the bladder may be closed with a two-or three-layer running closure using a 3-0 absorbable or delayed-absorbable suture (Fig. 30-22). he first layer inverts the mucosa into the bladder. The bladder is then illed with a marker luid to demonstrate integrity of the repair. Leaking defects can be closed with interrupted reinforcing stitches. Subsequent layers reapproximate the bladder muscularis. Postoperative care requires continuous bladder drainage for 7 to 14 days to permit healing and minimize the risk of fistula formation. U ropathogen prophylaxis during this drainage is not required. Also, cystourethrography need not be routinely performed prior to catheter removal for a simple, �ingle laceration (Davis, 1999).

FIGURE 30-22 Cystotomy repair, A. The primary layer inverts the bladder mucosa with running or interrupted sutures of 3-0 delayedabsorbable or absorbable suture, B. Second and possibly a third layer approximate the bladder muscularis to reinforce the incision closure.

Larger lacerations in or near the trigone require careful attention. Specialists may be consulted, and in preparation, ureteral stents can be assembled. In these cases, ureteral oriices are directly inspected to document jets from both. If not seen, then stents may be passed through the cystotomy and into each oriice to conirm patency. Once this is confirmed, repair should not disrupt the ureteral orifices, and stents may remain to ensure ureteral patency.

U nrepaired cystotomy can manifest as hematuria, oliguria, abdominal pain, ileus, ascites, peritonitis, fever, urinoma, or istula. For diagnosis, retrograde cystography or abdominal computed tomography (CT) with cystography can be used (Tarney, 2013). Cystoscopy is also an option but may require an operating room. Once identified, prompt repair is indicated (Balgobin, 2017).

hese injuries occur most oten during repair of hysterotomy extensions into the broad ligament or vagina (Eisenkop, 1982). If ureteral injury is suspected, methylene blue is administered. The pelvis is directly inspected for dye extravasation, which suggests ureteral transection. Next, brisk dye-stained urine jets are sought from each oriice to exclude ureteral kinking or ligation. Oriice viewing may be via cystoscopy, if available; through a comorbid traumatic cystotomy; or through a diagnostic cystotomy. With sluggish or absent jets, consultation with a specialist is typically requested. A ureteral catheter is irst threaded to identiY a potential obstruction site and guide ureterolysis. Kinked or ligated ureters can be relieved by release of ensnaring sutures. Crush injuries are inspected to ensure vital tissue. In these cases, stents are let to avert ureteral stricture. A Foley cath�ter remains for 7 to 10 days, and the ureteral catheters are removed via cystoscopy ater 14 days. Intravenous pyelography (IVP) is usually not necessary before removal of the stent if it was placed as a precautionary measure ater relatively minor injury (Davis, 1999).

Crush injuries with devascularization, thermal injury, or transection require more extensive repair. If a healthy-appearing ureter can be reimplanted into the bladder without undue tension, then ureteroneocystostomy is preferable. For more proximal injuries, ureteroureterostomy, psoas hitch, or Boari lap creation may be needed. An explanation of these more extensive procedures is found in Cunningham and Gistrap s Operative Obstetrics, 3rd edition (Balgobin, 2017).

Unrecognized ureteral injury can mimic those of cystotomy with the addition of possible costovertebral angle tenderness. CT urography is a preferred initial diagnostic tool (Sharp, 2016). he duration of time from injury to identification directs repair. hose identified early are often suitable for immediate repair.

Serosal tears represent weak points in the small bowel. If obstruction develops postoperatively, these weak spots may perforate, leading to peritonitis. If serosal tears are few in number, they can be oversewn with either a ine absorbable or nonabsorbable suture (Davis, 1999). More signiicant lacerations are often repaired in consultation with a general surgeon or gynecologic oncologist.

During and after cesarean delivery, requirements for intravenous luids can vary considerably. Administered fluids consist of either lactated Ringer solution or a similar crystalloid solution with 5-percent dextrose. Typically, at least 2 L is infused during surgery. Blood loss with uncomplicated cesarean delivery approximates 1000 mL. he average-sized woman with a hematocrit of 30 percent or more and with a normally expanded blood and extracellular luid volume most often will tolerate blood loss up to 2000 mL without diiculty. Unappreciated bleeding through the vagina during the procedure, bleeding concealed in the uterus after its closure, or both commonly lead to underestimation.

Blood loss averages 1500 mL with elective cesarean hysterectomy, although this is variable (Pritchard, 1965). Most peripartum hysterectomies are unscheduled, and blood loss in these cases is correspondingly greater. Thus, in addition to close monitoring of vital signs and urine output, the hematocrit should be determined intra-or postoperatively as indicated.

he amount of vaginal bleeding is closely monitored for at least an hour in the immediate postoperative period. he uterine fundus is also identiied frequently by palpation to ensure that the uterus remains irmly contracted. Unfortunately, as conduction analgesia fades or the woman awakens from general anesthesia, abdominal palpation is likely to produce pain. A patient-controlled analgesia (PCA) pump can be efective. Once regional analgesia begins to fade or the woman becomes fully awake following general anesthesia, criteria for transfer to the postpartum ward include minimal bleeding, stable vital signs, and adequate urine output.

Analgesia, Vital Signs, Intravenous Fluids

Several schemes are suitable for postoperative pain control. One PCA regimen uses intravenous morphine given as needed as a I-mg dose with a 6-minute lockout interval and maximum dose of 30 mg in 4 hours. An additional 2-mg booster dose is permitted for a maximum of 2 doses. Alternatively, intramuscular (1M) meperidine, 50 to 75 mg every 3 to 4 hours, or 1M morphine, 10 to 15 mg every 3 to 4 hours, is suitable. In a trial using these options, Yost and associates (2004) found that morphine provided superior pain relief to meperidine and was associated with significantly higher rates of breastfeeding and continuation of newborn rooming in. Breastfeeding can be ini tiated the day of surgery. If the mother elects not to breastfeed, a binder that supports the breasts without marked compression usually will minimize discomfort.

After transfer to her room, the woman is assessed at least hourly for 4 hours, and thereafter at intervals of 4 hours. Deep breathing and coughing are encouraged to prevent atelectasis.

Vital signs, uterine tone, urine output, and bleeding are evalu ated. The hematocrit is routinely measured the morning after surgery. It is checked sooner if there was unusual blood loss or if there is hypotension, tachycardia, oliguria, or other evidence to suggest hypovolemia. If the hematocrit is decreased signii cantly from the preoperative level, the measurement is repeated and a search is instituted to identiy the cause. If the hematocrit stabilizes, the mother can be allowed to ambulate, and if there is little likelihood of further blood loss, iron therapy is preferred to transfusion.

Postpartum, the patient begins to mobilize and excrete her physiologically expanded extravascular volume. Thus, mainte sistent oral intake is reestablished. If urine output falls below 30 mLlhr, however, the woman should be reevaluated promptly.

The cause of the oliguria can range from unrecognized blood loss to an antidiuretic efect from infused oxytocin.

Women undergoing unscheduled cesarean delivery may have pathological retention or constriction of the extracellular fluid compartment caused by severe preeclampsia, sepsis syndrome, vomiting, prolonged labor without adequate fluid intake, or increased blood loss. Women with these complications are generally observed in the recovery room until stabilization is assured.

The Foley catheter most often can be removed by 12 hours postoperatively, or more conveniently, the morning after surgery. he prevalence of urinary retention following cesarean delivery approximates 3 to 7 percent (Chap. 36, p. 660). Failure to progress in labor and postoperative narcotic analgesia are identified risks (Chai, 2008; Kandadai, 2014; Liang, 2007).

In uncomplicated cases, liquids or solid food may be ofered within hours of surgery and advanced as tolerated (Guo, 2015). Some degree of adynamic ileus follows virtually every abdominal operation, but in most cases of cesarean delivery, it is negligible. Postoperative ileus symptoms include abdominal distention, gas pains, and an inability to pass flatus or stool. With persistent nausea and vomiting or with prolonged bowel function delay, radiological imaging may aid exclusion of bowel obstruction. A plain abdominal radiograph is a frequent first choice. However, in the general population, this study is diagnostic in only 50 to 60 percent of small bowel obstruction cases (Maglinte, 1997). Thus, a radiograph may best serve as a triage tool in cases in which ileus is the suspected diagnosis. Notably, an enlarged postpartum uterus can compress the rectosigmoid and prevent it from illing with gas. Thus, indings suggesting a distal colonic obstruction may confuse true cases of transient ileus (Kammen, 2000). In comparison, CT with intravenous contrast provides greater accuracy for small bowel obstruction. Oral contrast is concurrently given when SBO is a consideration (Katz, 2013). Last, although uncommon, an unrecognized bowel injury may be responsible for otherwise unexplained fever and poor bowel function. Here, CT may be most diagnostic of potential etiologies.

As treatment of ileus, intravenous luids compensate for poor oral intake and losses from emesis. Electrolyte imbalances are corrected to improve smooth muscle activity and avoid bowel edema. Nasogastric decompression is necessary only with persistent vomiting or severe distention.

For prevention, intraoperative goals strive to minimize bowel manipulation, avoid excess intravenous luids or profound hypovolemia, and limit surgery length (Bragg, 2015). Postoperatively, gum chewing enhances early bowel function recovery by nearly 7 hours after cesarean delivery (Zhu, 2014). Among studies, chewing was initiated immediately or up to 12 hours later, lasted 15 to 60 minutes, and was repeated in at least three sessions daily (Pereira Gomes Morais, 2016).

As discussed earlier, women undergoing cesarean delivery have an increased risk of venous thromboembolism compared with those delivering vaginally. Early ambulation lowers the thromboembolism risk. Walking to the bathroom begins, initially with assistance. Brief walks are encouraged, and ambulation can be timed so that a recently administered analgesic will minimize discomfort.

lthough not evidence based, we remove the surgical dressing after 24 hours and inspect the incision daily. One small randomized trial showed no wound healing diferences if removed at 6 hours (Peleg, 2016). By the third postpartum day, showering is not harmful to the incision. Prior to this, a plastic cover can maintain dryness during showers. If used, staples often are removed on the fourth day. Once removed, dressing strips (Steri-Strips) can be placed as needed for 1 week to reinforce skin edge integrity. If there is concern for supericial wound separation, staples remain in place for 7 to 10 days.

For uncomplicated cesarean delivery, the average hospitalization length is three to four days (Buie, 2010). Data from studies suggest that earlier discharge is feasible for properly selected women and newborns (Bayoumi, 2016; Tan, 2012). Protocols ideally include earlier reevaluation for neonatal jaundice.

Activities during the irst week should be restricted to selfcare and newborn care with assistance. Driving can be resumed when pain does not limit the ability to brake quickly and when narcotic medications are not in use. In women with cesarean delivery, intercourse was resumed in 44 percent by 6 weeks postpartum, in 81 percent by 3 months, and 97 percent at 1 year (McDonald, 2013). After the puerperium, the quality of sexual functioning does not difer between those undergoing spontaneous vaginal delivery or cesarean (Chang, 2015; Fehniger, 2013; Rogers, 2014). Rerurn to work is variable. Six weeks is commonly cited, although many women use the Family and Medical Leave Act to allow up to 12 weeks for recovery and newborn bonding.

Abdel-Aleem H, Aboelnasr MF, Jayousi TM, et al: Indwelling bladder catheterisation as part of intraoperative and postoperative care for caesarean section. Cochrane Database Syst Rev 4:CDO 1 0322, 2014

Ahmadzia HK, Patel EM, Joshi 0, et al: Obstetric surgical site infections: 2 grams compared with 3 grams of cefazolin in morbidly obese women. Obstet Gynecol 126(4): 08,2015

Alanis Me, Villers MS, Law TL, et al: Complications of cesarean delivery in the massively obese parturient. Am J Obstet Gynecol 203(3):271.e1, 2010 Alexander JM, Leveno KJ, Hauth J, et al: Fetal injury associated with cesarean delivery. Obstet Gynecol 108(4):885, 2006

Alexander JM, Leveno KJ, Rouse OJ, et al: Comparison of matenal and infant outcomes from primary cesarean delivery during the second compared with first stage oflabor. Obstet Gynecol 109(4):917,r2007

American Academy of Pediatrics, American College of Obstetricians and Gynecologists: Guidelines for Perinatal Care, 8th ed. Elk Grove Village, MP, 20r17

American College of Obstetricians and Gynecologists: Scheduling planned cesarean delivery. Patient Safety Checklist No.r3, December 2011

American College of Obstetricians and Gynecologists: Patient safety in the surgical environment. Committee Opinion No. 464, September 2010, Reaffirmed 2014a

American College of Obstetricians and Gynecologists: Preoperative planned cesarean delivery. Patient Safety Checklist No.r4, December 2014b American College of Obstetricians and Gynecologists: Informed consent.

Committee Opinion No. 439, August 2009, Reairmed 2015

American College of Obstetricians and Gynecologists: Prophylactic antibiotics in labor and delivery. Practice Bulletin No. 120, June 2011, Reairmed 2016 American College of Obstetricians and Gynecologists: Cesarean delivery on maternal request. Committee Opinion No. 559, April 20l3, Reairmed

American College of Obstetricians and Gynecologists: Optimizing support for breastfeeding as part of obstetric practice. Committee Opinion No. 658, February 2016, Reairmed 2017b

American College of Obstetricians and Gynecologists: Placenta accreta. Committee Opinion No. 529, July 2012, Reairmed 2017c

American College of Obstetricians and Gynecologists: Thromboembolism in pregnancy. Practice Bulletin No. 123, September 201r1, Reairmed 201 d American College of Obstetricians and Gynecologists: Vaginal seeding. Committee Opinion No. 725, November 201/e

American Society of Anesthesiologists: Task Force on Obstetrical Anesthesia: practice guidelines for obstetrical anesthesia. Anesthesiology 124:270, 2016

Andrews WW, Hauth JC, Cliver SP, et al: Randomized clinical trial of extended spectrum antibiotic prophylaxis with coverage for Ureaplasma urealyticum to reduce post-cesarean delivery endometritis. Obstet Gynecol 101(6):1183,r2003

Anorlu RI, Maholwana B, Hofmeyr GJ: Methods of delivering the placenta at caesarean section. Cochrane Database Syst Rev 3:CD004 3 , 2008

ASlclOglu 0, Giingordiik K, ASlClOglu BB, et al: Unintended extension of the lower segment uterine incision at cesarean delivery: a randomized comparison of sharp versus blunt techniques. Am J PerinatoI31(10):837, 2014

Atherton N, Parsons SJ, Mansfield P: Attendance of paediatricians at elective Caesarean sections performed under regional anaesthesia: is it warranted? J Paediatr Child Health 42(6):332, 2006

Avila C, Bhangoo R, Figueroa R, et al: Association of smoking with wound complications after cesarean delivery. J Matern Fetal Neonatal Med 25(8):1250,r2012 Baksu A, Kalan A, Ozkan A, et al: The efect of placental removal method and site of uterine repair on postcesarean endometritis and operative blood loss. Acta Obstet Gynecol Scand 84(3):266, 2005 Balgobin S: Urologic and gastrointestinal injuries. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hill Education, 2017 Barber EL, Lundsberg LS, Belanger K, et al: Indications contributing to the increasing cesarean delivery rate. Obstet Gynecol 118(1):29, 2011 Basha SL, Rochon ML, Quinones IN, et al: Randomized controlled trial of wound complication rates of subcuticular suture vs staples for skin closure at cesarean delivery. Am J Obstet GynecoIr203(3):285.e1, 2010 Bateman BT, Mhyre JM, Callaghan WM, et l: Peripartum hysterectomy in the United States: nationwide 14 year experience. Am J Obstet Gynecol 206(l):63.e1,r2012 Bates SM, Greer A, Middeldorp S, et al: VTE, thrombophilia, anti thrombotic therapy, and pregnancy: Antithrombotic herapy and Prevention of hrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141 (2 Suppl):e691S, 2012

Bayoumi YA, Bassiouny YA, Hassan A, et al: Is there a diference in the maternal and neonatal outcomes between patients discharged after 24 h versus 72 h following cesarean section? A prospective randomized observational study on 2998 patients. J \1aten Fetal Neonatal Med 29(8):1339, 2016

Belfort M, Koford S, Vaner M: Massive obstetric hemorrhage in a Jehovah's Witness: intraoperative strategies and high-dose erythropoietin use. Am J Perinatol , 201r1

Berhan Y, Berhan A: A meta-analysis of reverse breech extraction to deliver a deeply impacted head during cesarean delivery. Int J Gynaecol Obstet 124(2):99,r2014

Bloom SL, for the National Institute of Child Health and Human Development \1aternal-Fetal Medicine Units Cesarean Registry: Decision to incision times and infanc outcome. Am J Obstet Gynecol 185:S121, 2001

Bloom SL, Leveno KJ, Spong CY, et al: Decision-to-incision times and maternal and fetal outcomes. Obstet Gynecol 108(1):6,r2006

Bodelon C, Bernabe-Ortiz A, Schif MA, et al: Factors associated with peri partum hysterectomy. Obstet Gynecol 114(1): 115, 2009

Bohman VR, Gilstrap L, Leveno K, et al: Subcutaneous tissue: to close or not to close at cesarean section. Amr] Obstet Gynecol , 1992

Bolze PA, Massoud M, Gaucherand P, et al: What about the Misgav-Ladach surgical technique in patients with previous cesarean sections? Am J Perinatol 30(3):197, 2013

Boyle A, Reddy UM, Landy HJ, et al: PrimalY cesarean delivery in the United States. Obstet Gynecol 122(1):33,r2013

Boyle JG, Gabbe SG: T and J vertical extensions in low transverse cesarean births. Obstet Gynecol 87(2):238, 1996

Bragg 0, EI-Sharkawy AM, Psaltis E, et al: Postoperative ileus: recent developments in pathophysiology and management. Clin Nutr 34(3):367,r2015 Briery CM, Rose CH, Hudson T, et al: Planned vs emergent cesarean hys terectomy. Am] Obstet Gynecol 197(2):154.el, 2007

Buie VC, Owings MF, DeFrances CJ, et al: National Hospital Discharge Survey: 2006 summary. National Center for Health Statistics. Vital Health Stat 13(168):1,r2010

CAESAR Study Collaborative Group: Caesarean section surgical techniques: a randomised factorial trial (CAESAR). BJOG (11):1366,2010

Cahill AG, Stamilio OM, Odibo AO, et al: Is vaginal birth after cesarean (VBAC) or elective repeat cesarean safer in women with a prior vaginal delivery? Am ] Obstet Gynecol 195(4): 1143, 2006

Caissutti C, Saccone G, Zullo F, et al: Vaginal cleansing before cesarean delivery: a systematic review and meta-analysis Obstet Gynecol 130(3):527, 2017 Carpenter L, Baysinger CL: Maintaining perioperative normothermia in the patient undergoing cesarean delivery. Obstet Gynecol Surv 67(7):436, 2012

Chai AH, Wong T, Mak HL, et al: Prevalence and associated risk factors of retention of urine after caesarean section. 1m Urogynecol J Pelvic Floor Dysfunct 194(4):537,r2008

Chang SR, Chen KH, Ho HN, et al: Depressive symptoms, pain, and sexual dysfunction over the irst year following vaginal or cesarean delivery: a prospective longitudinal study. Int J Nurs Stud 52(9): 1433, 2015

Chapman SJ, Owen J, Hauth JC: One versus two-layer closure of a low transverse cesarean: the next pregnancy. Obstet Gynecol 89: 16, 1997

Chaudhuri P, Mandi S, Mazumdar A: Rectally administrated misoprostol as an alternative to intravenous oxytocin infusion for preventing post-partum hemorrhage after cesarean delivery. J Obstet Gynaecol Res 40(9):2023, 2014

Cheesman K, Brady]E, Flood P, et al: Epidemiology of anesthesia-related complications in labor and delivery, New York State, 2002-2005. Anesth Analg 109:1174,r2009

Chelmow 0, Rodriguez E], Sabatini MM: Suture closure of subcutaneous fat and wound disruption after cesarean delivery: a meta-analysis. Obstet Gynecol 103:974,r2004

Clark SL, Belfort MA, Dildy GA, et al: Matenal death in the 21st centlllY: causes, prevention, and relationship to cesarean delivery. Am J Obstet Gynecol 199(1):36.e1, 2008

Clark SL, Miller DO, Belfort A, et al: Neonatal and maternal outcomes associated with elective term delivery. Am J Obstet Gynecol 200(2): 156. el,r2009

Conde-Agudelo A, Nieto A, Rosas-Bermudez A, et al: Misoprostol to reduce intraoperative and postoperative hemorrhage during cesarean delivery: a systematic review and metaanalysis. Am J Obstet Gynecol 209(1 ):40.e1, 2013

CORON1S Collaborative Group, Abalos E, Addo V, et al: Caesarean section surgical techniques: 3 year follow-up of the CORONIS fractional, factorial, unmasked, randomised controlled trial. Lancet 388(10039):62,r2016

CORON1S Collaborative Group, Abalos E, Addo V, et al: Caesarean section surgical techniques (CORONIS): a fractional, factorial, unmasked, ran domised controlled trial. Lancet 382(9888):234,r2013

Cromi A, Ghezzi F, Di Naro E, et al: Blunt expansion of the low transverse uterine incision at cesarean delivery: a randomized comparison of 2 techniques. Am J Obstet Gynecol 199(3):292.el, 2008

Dahlke JD, Mendez-Figueroa H, Rouse OJ, et al: Evidence-based surgery for cesarean delivery: an updated systematic review. Am ] Obstet Gynecol 209(4):294,r2013

Davis JD: Management of injuries to the urinary and gastrointestinal tract during cesarean section. Obstet Gynecol Clin North Am 26(3):469, 1999

Daykan Y, Sharon-Weiner M, Pastenak Y, et al: Skin closure at cesarean delivery, glue versus subcuticular sutures: a randomized controlled trial. Am J Obstet GynecoIr216(4):406.el, 201

Declercq E, Menacker F, MacDorman M: Rise in "no indicated risk" primary caesareans in the United States, 1991-2001: cross sectional analysis. BM] 1,r2005

Dodd ]M, Anderson ER, Gates S, et al: Surgical techniques for uterine incision and uterine closure at the time of caesarean section. Cochrane Database Syst Rev 7:CD004732, 2014

Dolan LM, Hilton P: Obstetric risk factors and pelvic floor dysfunction 20 years after first delivery. Int Urogynecol] 21(5):535,r2010

Duggal N, Poddatoori V, Noroozkhani S, et al: Perioperative oxygen supplementation and surgical site infection after cesarean delivery: a randomized trial. Obstet GynecoIr122(1):79, 2013

Durnwald C, Mercer B: Uterine rupture, perioperative and perinatal morbidity after single-layer and double-layer closure at cesarean delivery. Am ] Obstet Gynecol 189:925,r2003

Edwards RK, Ingersoll M, Gerkin RD, et al: Carboxymethylcellulose adhesion barrier placement at primary cesarean delivery and outcomes at repeat cesarean delivery. Obstet Gynecol 123(5):923,r2014

Eisenkop SM, Richman R, Platt LD, et al: Urinary tract injury during cesarean section. Obstet GynecoIr60(5):591, 1982

Eke AC, Shukr GH, Chaalan TT, et al: Intra-abdominal saline irrigation at cesarean section: a systematic review and meta-analysis. J Maten Fetal Neonatal Med 29(10):1588,r2016

Fehniger ]E, Brown ]S, Creasman ]M, et al: Childbirth and female sexual function later in life. Obstet Gynecol 122(5):988,r2013

Figueroa 0, ]auk VC, Szychowski ]M, et al: Surgical staples compared with subcuticular suture for skin closure after cesarean delivery: a randomized controlled trial. Obstet Gynecol 121(1):33,2013

Flood M, Said S, Geary M, et al: Changing trends in peripartum hysterectomy over the last 4 decades. Amr] Obstet Gynecol 200(6):632.el, 2009

Fritel X, Ringa V, Varnoux N, et al: Mode of delivery and fecal incontinence at midlife: a study of 2,640 women in the Gazel cohort. Obstet Gynecol 110(1):31,r200

Glaze S, Ekwalanga P, RobertS G, et al: Peripartum hysterectomy: 1999 to 2006. Obstet Gynecol 111r(3):732,r2008

Glazener C, Elders A, Macarthur C, et al: Childbirth and prolapse: long-term associations with the symptoms and objective measurement of pelvic organ prolapse. B]OG 120(2):161,r2013

Gordon A, McKechnie EJ, Jefery H: Pediatric presence at cesarean section: justified or not? Am] Obstet Gynecol 193(3 pt 1):599,2005

Gossman GL, ]oesch ]M, Tanfer K: Trends in matenal request cesarean delivelY from 1991 to 2004. Obstet Gynecol 108: 1506, 2006

Govindappagari S, Wright JD, Ananth CV, et al: Risk of peripartum hysterectomy and cencer hysterectomy and delivery volume. Obstet Gynecol 128(6):1215,r2016

Grundsell HS, Rizk DE, Kumar M: Randomized study of non-closure of peritoneum in lower segment cesarean section. Acta Obstet Gynecol Scand 77:1r10, 1998

Grupper M, Kuti ]L, Swank ML, et al: Population pharmacokinetics of cefazolin in serum and adipose tissue from overweight and obese women undergoing cesarean delivery.] Clin Pharmacol 57(6):712,r2017

Guise ]M, Denman A, Emeis C, et al: Vaginal birth after cesarean: new insights on maternal and neonatal outcomes. Obstet Gynecol 115(6): , 2010

GLingorduk K, ASIClOglu 0, Celikkol 0, et al: Iatrogenic bladder injuries during caesarean delivery: a case control study. ] Obstet Gynaecol , 2010

Guor], Long S, Li H, et al: Early versus delayed oral feeding for patients after cesarean. Int] Gynaecol Obstet 128(2):100,r2015

Gyhagen M, Bullarbo M, Nielsen TF, et al: Prevalence and risk factors for pelvic organ prolapse 20 years after childbirth: a national cohort study in singleton primiparae after vaginal or caesarean delivery. BJOG 120(2): 152, 2013a

Gyhagen M, Bullarbo M, Nielsen TF, et al: he prevalence of urinary incontinence 20 years after childbirth: a national cohort study in singleton primiparae after vaginal or caesarean delivery. B]OG 120(2):144, 2013b

Haas OM, Morgan S, Contreras K: Vaginal preparation with antiseptic solution before cesarean section for preventing postoperative infections. Cochrane Database Syst Rev 12:CD007892, 2014

Haas OM, Pazouki F, Smith RR, et al: Vaginal cleansing before cesarean delivery to reduce postoperative infectious morbidiry: a randomized, controlled trial. Am] Obstet Gynecol 202(3):31O.el, 2010

Hadiati DR, Hakimi M, Nurdiati DS, et al: Skin preparation for preventing infection following caesarean section. Cochraneo' Database Syst Rev 9:CD007462,o2014

Hamilton BE, Martin JA, Osterman MJ, et al: Births: final data for 2014. Natl Vital Stat Rep 64(12):1, 2015

Handa L, Blomquist JL, Knoepp LR, et al: Pelvic Boor disorders 5-10 years after vaginal or cesarean childbirth. Obstet Gynecol 118(4):777,o2011 Hawkins JL, Chang J, Palmer SK, et al: Anesthesia-related maternal mortality in the United States: 1979-2002. Obstet GynecoIo117(1):69, 2011

Hellums EK, Lin MG, Ramsey PS: Prophylactic subcutaneous drainage for prevention of wound complications after cesarean delivety-a metaanalysis. Am J Obstet GynecoIo197(3):229, 2007

Hernandez JS, Nuangchamnong N, Ziadie M, et al: Placental and uterine pathology in women undergoing peripartum hysterectomy. Obstet Gynecol 119(6):1137,o2012

Hinkson L, SiedentopfJP, Weichert A, et al: Surgical site infection in cesarean sections with the use of a plastic sheath wound retractor compared to the traditional self-retaining metal retractor. Eur J Obstet Gynecol Reprod Bioi 203:232,o20o16

Hofmeyr JG, Novikova N, Mathai M, et al: Techniques for cesarean section.

Am J Obstet GynecoI201(5):431, 2009

Holmgren G, Sjoholm L, Stark M: he Misgav Ladach method for cesarean section: method description. Acta Obstet Gynecol Scand 78(7):615, 1999

Hubbard R, Waters JH, Yazer MH: Heterogeneity in blood product acceptance among antenatal patients of the Jehovah's Witness faith. Obstet Gynecol 126(5):974,o2015

Husarova V, Donnelly G, Doolan A, et al: Preferences of Jehovah's Witnesses regarding haematological supports in an obstetric setting: experience of a single university teaching hospital. Int J Obstet Anesth 25:53, 2016

Hussamy DJ, Wortman AC, Mclntire DD, et al: Closed incision negative pressure therapy (ciNPT) and post-operative wound morbidity in morbidly obese women undergoing cesarean delivety. Presented at the 38th Annual Meeting of the Society for Maternal-Fetal Medicine, Februaty 20o18

Irion 0, Luzuy F, Beguin F: Nonclosure of the visceral and parietal peritoneum at caesarean section: a randomised controlled trial. Br J Obstet Gynaecol 103:690, 1996

Jacob J, Phenninger J: Cesarean deliveries: When is a pediatrician necessaty?

Obstet GynecoIo89:217, 1997

James AH, Jamison MG, Brancazio LR, et al: Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol 194: 131o1, 2006

Jeve B, Navti OB, Konje JC: Comparison of techniques used to deliver a deeply impacted fetal head at full dilation: a systematic review and metaanalysis. BJOG 123(3):337,o2016

Jin B, Du Y, Zhang F, et al: Carbetocin for the prevention of postpartum hemorrhage: a systematic review and meta-analysis of randomized controlled trials. J Matern Fetal Neonatal Med 29(3):400, 2016

Johnson DD: Cesarean delivety. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hill Education, 2017 Kammen BF, Levine MS, Rubesin SE, et al: Adynamic ileus after caesarean section mimicking intestinal obstruction: indings on abdominal radiographs. Br J Radiol 73(873):951, 2000 Kandadai P, Kandadai V, Saini J, et al: Acute urinary retention ater cesarean delivery: a case-conttol study. Female Pelvic Med Reconstr Surg 20(5):276,o2014 Kapustian V, Anteby EY, Gdalevich M, et al: Efect of closure versus nonclosure of peritoneum at cesarean section on adhesions: a prospective randomized study. Am J Obstet GynecoI206(1):56.e1, 2012 Katz DS, Baker ME, Rosen MP, et al: ACR Appropriateness Criteria� suspected small-bowel obstruction. American College of Radiology, 1996, Reairmed 20o13 Kerr Jlvl: he lower uterine segment incision in conservative caesarean section. J Obstet Gynaecol Br Emp 28:4 5, 1921 Kiefer DG, Muscat Jc, Santorelli J, et al: Efectiveness and short-term safety of modiied sodium hyaluronic acid-carboxymethylcellulose at cesarean delivery: a randomized trial. Am J Obstet GynecoIo214(3):373.e1, 2016 Kirscht J, Weiss C, Nickol J, et al: Dilatation or no dilatation of the cervix during cesarean section (Dondi Trial): a randomized controlled trial. Arch Gynecol Obstet 295(1):39,o2017 Klingel ML, Patel SV: A meta-analysis of the efect of inspired oxygen concentration on the incidence of surgical site infection following cesarean section. Int J Obstet Anesth 22(2):104,o2013 Kowalski TJ, Kothari SN, Mathiason MA, et al: Impact of hair removal on surgical site infection rates: a prospective randomized noninferiority trial. J Am Coll Surg 223(5):704,o2016 Kronig B: Transperitonealer cervikaler Kaiserschnitt. In: Doderlein A, Kronig B (eds): Operative Gynakologie, 3rd ed. Leipzig, Thieme, 1912

Kurz A, Sessler DI, Lenhardt R: Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. Study of Wound Infection and Temperature Group. N Engl J Med 334(19):1209, 1996

Larsson C, Saltvedt S, Wiklund I, et al: Planned vaginal delivery versus planned caesarean section: short-term medical outcome analyzed according to intended mode of delivery. J Obstet Gynaecol Can 33(8):796, 20o11

Lawson T, Ralph C: Peri operative Jehovah's Witnesses: a review. Br J Anaesth 115(5):676,o2015

Lefebvre A, Saliou P, Lucet J C, et al: Preoperative hair removal and surgical site infections: network meta-analysis of randomized controlled trials. J Hosp Infect 91 (2): 100, 2015

Leijonhuvud A, Lundholm C, Cnattingius S, et al: Risks of stress urinary incontinence and pelvic organ prolapse surgery in relation to mode of childbirth. Am J Obstet GynecoI204(1):70.e1, 2011

Li L, Wen J, Wang L, et al: Is routine indwelling catheterisation of the bladder for caesarean section necessary? A systematic review. BJOG 118(4):400, 2011

Liabsuetrakul T, Peeyananjarassri K: Mechanical dilatation of the cervix at nonlabour caesarean section for reducing postoperative morbidity. Cochrane Database Syst Rev 11 :CD0080 19, 20o11

Liang Cc, Chang SD, Chang L, et al: Postpartum urinary retention ater cesarean delivery. Int J Gynaecol Obstet 99(3):229, 2007

Linder N, Linder I, Fridman E, et al: Birth trauma-risk factors and short-term neonatal outcome. J Matern Fetal Neonatal Med 26(15):149o1,o2013

Liu X, Landon MB, Cheng W, et al: Cesarean delivery on maternal request in China: what are the risks and beneits? Am J Obstet Gynecol 212(6): 817. e1,o2015

Ljungqvist 0, Scott M, Fearon KC: Enhanced recovery ater surgery: a review.

JAMA Surg 152(3):292,o2017

Lurie S, Baider C, Glickman H, et al: Are enemas given before cesarean section useful? A prospective randomized controlled study. Eur J Obstet Gynecol Reprod Bioi 163(1):27, 2012

MacArthur C, Glazener C, Lancashire R, et al: Exclusive caesarean section delivery and subsequent urinary and faecal incontinence: a 12-year longitudinal study. BJOG 118(8):1001,2011

MacArthur C, Wilson D, Herbison P, et al: Faecal incontinence persisting after childbirth: a 12 year longitudinal study. BJOG 120(2):169,o2013

Mackeen AD, Khalifeh A, Fleisher J, et al: Suture compared with staple skin closure after cesarean delivery: a randomized controlled trial Obstet Gynecol 123(6):1169,o2014a

Mackeen AD, Packard E, Ota E, et al: Timing of intravenous prophylactic antibiotics for preventing postpartum infectious morbidity in women undergoing cesarean delivery. Cochrane Database Syst Rev 12:CD009516, 20o14b

Mackeen AD, Schuster M, Berghella V: Suture versus staples for skin closure after cesarean: a metaanalysis. Am J Obstet GynecoIo212(5):621.e1, 2015

Maggio L, Nicolau DP, DaCosta M, et al: Cefazolin prophylaxis in obese women undergoing cesarean delivery: a randomized controlled trial. Obstet Gynecol 125(5):1205,o2015

Maglinte DD, Balthazar EJ, Kelvin FM, et al: he role of radiology in the diagnosis of small bowel obstruction. AJR Am J Roentgenol 168(5): 1171, 1997

Marshall NE, Fu R, Guise JM: Impact of multiple cesarean deliveries on maternal morbidity: a systematic review. Am J Obstet Gynecol 205(3):262.e1, 2011

Martin JA, Hamilton BE, Osterman MJ, et al: Births: final data for 2015. Nat!

Vital Stat Rep 66(1):1,o2017

Mason CL, Tran CK: Caring for the Jehovah's Witness parturient. Anesth Analg 121(6):1564, 2015

Mathai M, Hofmeyr GJ, Mathai NE: Abdominal surgical incisions for caesarean section. Cochrane Database Syst Rev 5:CD004453, 2013

McDonald EA, Brown SJ: Does method of birth make a diference to when women resume sex after childbirth? BJOG 120(7):823,o2013

Memon S, Qazi A, Bibi S,et al: Efect of preoperative vaginal cleansing with an antiseptic solution to reduce post caesarean infectious morbidity. J Pak Med Assoc 61(12):1179,o2011

Menacker F, Declercq E, Macdorman MF: Cesarean delivery: background, trends, and epidemiology. Semin Perinatol 30(5):235, 2006

Menderes G, Athar Ali N, et al: Chlorhexidine-alcohol compared with povidone-iodine for surgical-site antisepsis in cesarean deliveries. Obstet Gynecol 120(5):1037,o2012

Moczygemba CK, Paramsothy P, Meikle S, et al: Route of delivery and neonatal birth trauma. Am J Obstet GynecoI202(4):361.e1, 2010

Moore ER, Bergman N, Anderson Gc, et al: Early skin-to-skin contact for mothers and their healthy newborn infants. Cochrane Database Syst Rev 11:CD003519,o2016

Morales KJ, Gordon Me, Bates GW Jr: Postcesarean delivery adhesions associated with delayed delivery of infant. Am J Obstet Gynecol 196(5):461. e1,r2007

Nagele F, Karas H, Spitzer D, et al: Closure or nonclosure of the visceral peritoneum at cesarean delivery. AmJ Obstet GynecoIr174:1366, 1996

Nasr M, ElBigawy AF, Abdelamid E, et al: Evaluation of the use vs nonuse of urinary catheterization during cesarean delivery: a prospective, multicenter, randomized controlled trial. J PerinatoI29(6):416, 2009

National Institutes of Health: State-of-the-Science Conference Statement on Cesarean Delivery on Maternal Request. NIH Consens Sci Statements, 2006. Mar 27-29,r23(1):1,r2006

Nelson L, Furner SE, Westercamp M, et al: Cesarean delivery for the prevention of anal incontinence. Cochrane Database Syst Rev 2:CD006756, 2010

Ngai 1M, Van Arsdale A, Govindappagari S, et al: Skin preparation for prevention of surgical site infection after cesarean delivery: a randomized controlled trial. Obstet GynecoIr126(6):1251, 2015

Nooh M, Abdeldayem HM, Ben-Afan 0: Reverse breech extraction versus the standard approach of pushing the impacted fetal head up through the vagina in caesarean section for obstructed labour: a randomised controlled trial. J Obstet Gynaecol 37(4):459, 2017

Oliphant SS, Bochenska K, Tolge ME, et al: Maternal lower urinary tract injury at the time of cesarean delivery. Int Urogynecol J 25(12):1709, 2014 Olofsson P: Opening of the abdomen ad modum Joel Cohen, Joel-Cohen, Joel Joel-Cohen, or just Cohen? Acta Obstet Gynecol Scand 94(2) :224, 2015

O'Neill A, Egan G, Walsh CA, et al: Omission of the bladder lap at caesarean section reduces delivery time without increased morbidiry: a metaanalysis of randomised controlled trials. Eur J Obstet Gynecol Reprod BioI 174:20,r2014

Orbach A, Levy A, Wiznitzer A, et al: Peripartum cesarean hysterectomy: critical analysis of risk factors and trends over the years. J Matern Fetal Neonatal Med 24(3):480, 2011

Osmundson SS, Garabedian MJ, Lyell DJ: Risk factors for classical hysterotomy by gestational age. Obstet Gynecol 122:845,2013 Osmundson SS, Garabedian MJ, Yeaton-Massey A, et al: Risk factors for classical hysterotomy in rwin pregnancies. Obstet GynecoIr125(3):643, 2015

Owolabi MS, Blake E, Mayor MT, et al: Incidence and determinants of peripartum hysterectomy in the metropolitan area of the District of Columbia. J Reprod Med 58(3-4):167, 2013

Patterson LS, O'Connell CM, Baskett TF: Maternal and perinatal morbidity associated with classic and inverted T cesarean incisions. Obstet Gynecol 100(4):633, 2002

Peleg D, Eberstark E, Warsof SL, et al: Early wound dressing removal after scheduled cesarean delivery: a randomized controlled trial. Am J Obstet GynecoIr215(3):388.e1,r2016

Pereira Gomes Morais E, Riera R, Poririo GJ, et al: Chewing gum for enhancing early recovery of bowel function after caesarean section. Cochrane Database Syst Rev 10:CD011562, 2016

Pergialiotis V, Prodromidou A, Perrea DN, et al: The impact of subcutaneous tissue suturing at cesarean section on wound complications: a meta-analysis. BJOG 124(7):1018,r2017

Phipps MG, Watabe B, Clemons JL, et al: Risk factors for bladder injury during cesarean delivery. Obstet Gynecolr105(l):156, 2005

Pritchard JA: Changes in the blood volume during pregnancy and delivery.

Anesthesiology 26:393, 1965

Rahman MS, Gasem T, I Suleiman SA, et al: Bladder injuries during cesarean section in a university hospital: a 25-year review. Arch Gynecol Obstet 279(3):349, 2009

Rajasekar D, Hall M: Urinary tract injuries during obstetric intervention.

BJOG 104:731, 199

Ramsey PS, White M, Guinn DA, et al: Subcutaneous tissue reapproximation, alone or in combination with drain, in obese women undergoing cesarean delivery. Obstet Gynecolrl05(5 Pt 1):967,r2005

Reddy UM, Wapner RJ, Rebar RW, et al: Infertility, assisted reproductive technology, and adverse pregnancy outcomes: executive summary of a National Institute of Child Health and Human Development workshop. Obstet Gynecol 109(4):967,r2007

Roach MK, Abramovici A, Tita AT: Dose and duration of oxytocin to prevent postpartum hemorrhage: a review. Am J PerinatoI30(7):523, 2013

Roberge S, Chaillet N, Boutin A, et al: Single-versus double-layer closure of the hysterotomy incision during cesarean delivery and risk of uterine rupture. Int J Gynaecol Obstet 115(1):5, 2011

Roberge S, Demers S, Berghella V, et al: Impact of single-vs double-layer closure on adverse outcomes and uterine scar defect: a systematic review and metaanalysis. Am J Obstet GynecoI211(5):453, 2014

Rogers RG, Leeman LM, Borders N, et al: Contribution of the second stage of labour to pelvic loor dysfunction: a prospective cohort comparison of nulliparous women. BJOG 121(9):1145,2014

Rossi AC, ee H, Chmait H/ Emergency postpartum hysterectomy for uncontrolled postpartum bleeding: a systematic review. Obstet Gynecol 115 (3): 637, 2010 Rossouw IN, Hall 0, Harvey J: Time berween skin incision and delivery dur ing cesarean. Int J Gynaecol Obstet 121(1):82,r2013

Royal College of Obstetricians and Gynaecologists: Reducing the risk of venous thromboembolism during pregnancy and the puerperium. GreenTop Guideline No. 37a, April 2015

Saad AF, Rahman M, Costantine MM, et al: Blunt versus sharp uterine incision expansion during low transverse cesarean delivery: a metaanalysis. Am J Obstet GynecoIr211(6):684.e1, 2014

Safa H, Beckmann M: Comparison of maternal and neonatal outcomes from full-dilatation cesarean deliveries using the Fetal Pillow or hand-push method. Int J Gynaecol Obstet 135(3):281,2016

Scolari Childress M, Gavard JA, et al: A barrier retractor to reduce surgical site infections and wound disruptions in obese patients undergoing cesarean delivery: a randomized controlled trial. m J Obstet Gynecol 214(2):285. e1,r2016

Seal SL, Dey A, Barman Se, et al: Randomized controlled trial of elevation of the fetal head with a fetal pillow during cesarean delivery at full cervical dilatation. Int J Gynaecol Obstet 133(2):178,2016

Sharp HT, Adelman MR. Prevention, recognition, and management of urologic injuries during gynecologic surgery. Obstet Gynecol 127(6):1085, 2016

Shellhaas CS, Gilbert S, Landon MB, et al: he frequency and complication rates of hysterectomy accompanying cesarean delivery. Obstet Gynecol 114(2 Pt 1):224,r2009

Shree R, Park SY, Beigi RH, et al: Surgical site infection following cesarean delivery: patient, provider, and procedure-speciic risk factors. Am J PerinatoIr33(2):157,r2016

Siddiqui DS, Lacuna EM, Chen HY, et al: Skin closure of Pfannenstiel incision with Dermabond, staples, or suture during cesarean delivery: experience of a single attending. Am J PerinatoIr30(3):219, 2013

Sikirica V, Broder MS, Chang E, et al: Clinical and economic impact of adhesiolysis during repeat cesarean delivery. Acta Obstet Gynecol Scand 91(6):719,r2012

Silver M, Landon MB, Rouse OJ, et al: Maternal morbidity associated with multiple repeat cesarean deliveries. Obstet Gynecolr107:r1r226, 2006

Simonazzi G, Bisulli M, Saccone G, et al: Tranexamic acid for preventing postpartum blood loss ater cesarean delivery: a systematic review and meta-analysis of randomized controlled trials. Acta Obstet Gynecol Scand 95(1):28,r2016

Smaill FM, Grivell M: Antibiotic prophylxis versus no prophylaxis for preventing infection after cesarean section. Cochrane Database Syst Rev 10:CD007482,r2014

Smid Me, Dotters-Katz SK, Grace M, et al: prophylactic negative pressure wound therapy for obese women after cesarean delivery: a systematic review and meta-analysis. Obstet GynecoIr130(5):969, 2017

Smid Me, Smiley SG, Schulkin J, et al: he problem of the pannus: physician preference survey and a review of the literature on cesarean skin incision in morbidly obese women. Am J Perinatol 33(5):463, 2016

Society for Maternal-Fetal Medicine, Belfort A: Placenta accreta. Am J Obstet Gynecol 203(5):430, 2010

Springel EH, Wang Y, Sarfoh VM, et al: A randomized open-label controlled trial of chlorhexidine-alcohol vs povidone-iodine for cesarean antisepsis: the CAPICA trial. Am J Obstet GynecoI217(4):463.el, 2017

Stevens J, Schmied V, Burns E, et al: Immediate or early skin-to-skin contact after a Caesarean section: a review of the literature. Matern Child Nutr 10(4):456,r2014

Sullivan SA, Smith T, Chang E, et al: Administration of cefazolin prior to skin incision is superior to cefazolin at cord clamping in preventing postcesarean infectious morbidity: a randomized controlled trial. Am J Obstet Gynecol 196:455,r2007

Swank ML, Wing DA, Nicolau DP, et al: Increased 3-gram cefazolin dosing for cesarean delivery prophylxis in obese women. Am J Obstet Gynecol 213(3):415.e1,r2015

Tan PG, Norazilah MJ, Omar SZ: Hospital discharge on the first compared with the second day after a planned cesarean delivery: a randomized controlled trial. Obstet GynecoIr120(6):1273, 2012

Tanner J, Norrie P, Melen K: Preoperative hair removal to reduce surgical site infection. Cochrane Database Syst Rev 11 :CD004122, 2011

Tarney CM: Bladder injury during cesarean delivery. Curr Womens Health Rev 9(2):70,r2013

The Joint Commission: Facts about the universal protocol. 2013. Available at: http://www.jointcommission.org/ standards_information/ up.aspx. Accessed May 12,r2013

The Joint Commission: Surgical care improvement project core measure set. 2016. Available at: http://www.jointcommission.org/assets/ 1 /6/Surgical% 20Care%20Improvement%20Project. pdf. Accessed February 14, 2017 heodoridis TD, Chatzigeorgiou KN, Zepiridis L, et al: A prospective randomized study for evaluation of wound retractors in the prevention of incision site infections after cesarean section. C1in Exp Obstet Gynecol 38(1):57, 2011

Tita AT, Hauth ]C, Grimes A, et al: Decreasing incidence of postcesarean endometritis with extended-spectrum antibiotic prophylaxis. Obstet Gynecol 111(1):51,2008

Tita AT, Landon MB, Spong CY, et al: Timing of elective repeat cesarean delivery at term and neonatal outcomes. N Englr] Med 360(2): Ill, 2009 Tita AT, Szychowski ]M, Boggess K, et al: Adjunctive azithromycin prophy laxis for cesarean delivery. N Engl] Med 375(13):1231, 2016

Tolcher MC, Johnson RL, El-Nashar SA, et al: Decision-to-incision time and neonatal outcomes: a systematic review and meta-analysis. Obstet Gynecol 123(3):536,r2014

Tulandi T, Agdi M, Zarei A, Miner L, et al: Adhesion development and morbidiry after repeat cesarean delivery. m] Obstet Gynecol 201(1):56.e1, 2009

Tuuli MG, Liu], Stout M], et a1: A randomized trial comparing skin antiseptic agents at cesarean delivery. N Engl] vIed 374(7):647, 2016a

Tuuli MG, Odibo AO, Fogertey P, et al: Utility of the bladder lap at cesarean delivery: a randomized controlled trial. Obstet GynecoI119(4):815, 2012

Tuuli MG, Stout M], Martin S, et al: Comparison of suture materials for subcuticular skin closure at cesarean delivery. Am] Obstet Gynecol 215 (4) :490. el, 2016b

Villar ], Carroli G, Zavaleta N, et al: Maternal and neonatal individual risks and benefits associated with caesarean delivery: multicentre prospective study. B]M 335:1025, 2007

Viney R, Isaacs C, Chelmow D: Intra-abdominal irrigation at cesarean delivery: a randomized controlled trial. Obstet Gynecol 119(6): 11 06, 2012

Walsh CA, Walsh SR: Extraabdominal vs intraabdominal uterine repair at cesarean delivery: a metaanalysis. Amr] Obstet Gynecol 200(6):625. e1,r2009

Wang HY, Hong SK, Duan Y, et al: Tranexamic acid and blood loss during and after cesarean section: a meta-analysis.r] PerinatoIr35(10):818, 2015

Witt A, Doner M, Petricevic L, et al: Antibiotic prophylaxis before surgery vs after cord clamping in elective cesarean delivery: a double-blind, prospective, randomized, placebo-controlled trial. Arch Surg 146(12): 1404, 2011

Worley KC, Mcintire DD, Leveno K]: he prognosis for spontaneous labor in women with uncomplicated term pregnancies: implications for cesarean delivery on maternal request. Obstet Gynecol 113(4):812,r2009

Wrench I], Allison A, Galimberti A, et al: Introduction of enhanced recovery for elective caesarean section enabling next day discharge: a tertiary centre experience. Int] Obstet Anesth 24(2):124,2015

Wyckof MH, Aziz K, Escobedo MB, et 1: Part 13: Neonatal resuscitation: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 132(18 SuppI2):S543, 2015 Wylie B], Gilbert S, Landon MB, et al: Comparison of transverse and vertical skin incision for emergency cesarean delivery. Obstet GynecoIr115(6):1134, 2010

Xodo S, Saccone G, Cromi A, et a1: Cephalad-caudad versus transverse blunt expansion of the low transverse uterine incision during cesarean delivery. Eur] Obstet Gynecol Reprod BioI 202:75, 2016

Yildirim G, Gungorduk K, AsIClOgiu 0, et 1: Does vaginal preparation with povidone-iodine prior to caesarean delivery reduce the risk of endometritis? A randomized controlled trial.] Matern Fetal Neonatal Med 25(11):2316,r2012 Yossepowitch 0, Baniel ], Livne PM: Urological injuries during cesarean section: intraoperative diagnosis and management.r] UroIr172(1):196, 2004

Yost NP, Bloom SL, Sibley MK, et al: A hospital-sponsored quality improvement study of pain management after cesarean delivery. Amr] Obstet Gynecol 190:1341, 2004

Young OM, Shaik IH, Twedt R, et al: Pharmacokinetics of cefazolin prophylaxis in obese gravidae at time of cesarean delivery. Am ] Obstet Gynecol 213(4):541.e1,r2015 Zaphiratos V, George RB, Boyd ]c, et al: Uterine exteriorization compared with in situ repair for cesarean delivery: a systematic review and meta-analysis. Can] Anaesth 62(11):1209,r2015 Zhu P, Wang WJ, Zhang SL, et al: Efects of gum chewing on postoperative bowel motility after caesarean section: a meta-analysis of randomised controlled trials. B]OG 121(7):787,r2014 100 YEARS OF CONTROVERSY .e....e...e....e....e...e. 591

INFLUENCING FACTORS ....e. .e.. .e....e......e. 592

DELIVERY ROUTE RISKS . . ........e..... ..e... 593

CANDIDATES FOR TRIAL OF LABOR. . . . . . . . . . . . . . . 594

LABOR AND DELIVERY CONSIDERATIONS ..e..e...e.. 597

UTERINE SCAR ......e..e...e........ ... 598

MULTIPLE REPEAT CESAREAN DELIVERIESe. . . . . .. . . . 599

VAGINAL BIRTH AFTER CESAREAN-2017 . ...... 600

The occurrence of pregnancy ater a Caesarean section, however, is not always devoid of danger, cases have been reported in which the uterine cicatrix ruptured in the latter part of a subsequent gestation. It is also stated that the adhesions that sometimes orm between the uterus and the abdominal wall occasionaly exert a deleterious inluence in subsequent pregnancies.

-J. Whitridge Williams (1903)

From the above, there was an early appreciation for some of the major problems encountered in women with a prior cesarean delivery. Few issues in modern obstetrics have been as controversial as the management of these women. Indeed, the dangers associated with uterine rupture led to the oft-quoted remark by Cragin in 1916: "Once a cesarean, always a cesarean." As we reach the 100-year mark of Cragin's pronouncement, the issue remains largely unsettled.

By the beginning of the 20th century, cesarean delivery had become relatively safe. But, as women survived the first operation and conceived again, they were now at risk for rupture of the uterine scar. Still, the specter of rupture did not did not result in strict adherence to repeat cesarean delivery. Indeed, Eastman (1950) described a 30-percent postcesarean vaginal delivery rate at Johns Hopkins Hospital. he uterine rupture incidence was 2 percent and associated with a 1 O-percent maternal mortality rate. During the 1960s, observational studies suggested that vaginal delivery was a reasonable option (Pauerstein, 1966, 1969). Germane to this is that through the 1960s, the overall cesarean delivery rate approximated only 5 percent. Since then, as the primary cesarean rate escalated, the rate for repeat cesarean delivery followed (Rosenstein, 2013).

During the 1980s, a National Institutes of Health (NIH) Consensus Development Conference (1981) was convened, and it questioned the necessity of routine repeat cesarean delivery. With support and encouragement from the American College of Obstetricians and Gynecologists (1988, 1994), enthusiastic attempts were begun to increase the use of vaginal birth after cesa rea n-VBA. These attempts were highly successful, and VBAC rates increased from 3.4 percent in 1980 to a peak of 28.3 percent in 1996. These rates, along with a concomitant decline in total cesarean delivery rates for the United States, are shown in Figure 31-1.

As the vaginal delivery rate increased, so did reports of uterine rupture-related maternal and perinatal morbidity and mortality 1996; Sachs, 1999). These complications dampened prevailing enthusiasm for a trial of labor after cesarean section (TOLAC) and stimulated the American College of Obstetricians and Gynecologists (1998) to caution that such trials should be attempted only j:.:c)�00 .j!a:

FIGURE 31-1 Total, primary, and low-risk cesarean delivery (CS) rates and vaginal birth after previous cesarean (VBAC) rates in the United States, 1989-2015. Epochs denoted within rectangles represent contemporaneous ongoing events related to these rates. ACOG = American College of Obstetricians and Gynecologists; NIH = National Institutes of Health; PB = practice bulletin. (Data from Hamilton, 2015,2016; National Institutes of Health: NIH Consensus Development Conference, 2010.) in appropriately equipped institutions with physicians readiy available to provide emergency care. Less than a year later, the College (1999) recommended that physicians should be immediatey available. Many believe that this change ofone wordfrom readiy to immediatey available-was in large part responsible for the decade-long decline in national VBAC rates illustrated in Figure 31-1 (Cheng, 2014; Leeman, 2013).

Uddin and colleagues (2013) reported the proportion of women with a prior cesarean delivery who underwent TOLAC. This number peaked in 1995, when slightly more than half of all of these women chose this option. Since that time,

FIGURE 31-2 Percentage of births with trial of labor among all deliveries with a prior cesarean delivery and percentage ofsuccessful trials oflabor among all trials oflabor ater caesarean delivery in the United States, 1990-2009. TOLAC = trial of labor ater cesarean delivery; VBAC = vaginal birth after cesarean delivery. (Data from Uddin SFG, Simon AE: Rates and success rates oftrial of labor ater cesarean delivery in the United States, 1990-2009. Matern Child Health J 17:1309,2013.) the Oice of Medical Applications of Research (0MAR) convened an NIH Consensus Development Conference Panel (2010) to study the issues of VBAC. The panel report included a contemporaneous summary concerning the risks and benefits of repeat cesarean versus vaginal delivery. These indings are subsequently described along with summaries of current recommendations by various professional organizations. Importantly, data from California indicate that VBAC rates have not perceptibly increased since the 2010 NIH Consensus Conference (Barger, 2013).

For the woman who has had a previous cesarean delivery, planning for future pregnancies and the delivery route should begin with preconceptional counseling and be addressed once again early in prenatal care. Importantly, any decision is subject to continuing revisions as dictated by exigencies that arise during pregnancy. Assuming no mitigating circumstances, there are two basic choices. First, a TOAC ofers the goal of achieving VBA. If cesarean delivery becomes necessary during the trial, then it is termed a "failed trial oflabor." A second choice is elective repeat cesarean delivey (ERCD). his includes scheduled cesareandelivery as well as unscheduled but planned cesarean delivery for spontaneous labor or another indication.

he ultimate decision should weigh clinical factors known to influence TOLAC success as well as benefits and risks. As expected, these rates vary between institutions and providers. Factors that inluence a successful TOLAC are listed in Table

Finally, economic, staing, and medicolegal factors may shape the decision to ofer TOLAC.

the proportion of women attempting TOLAC declined to a nadir in 2006 of about 16 percent and has subsequently increased to 20 to 25 percent through 2009. These investigators further reported that the percentage of VBACs reached its peak in 2000 with approximately 70 percent ofwomen being successful, but this has subsequently declined to a nadir of 38 percent in 2008 (Fig. 31-2).

In reality, several other interrelated factors-both medical and nonmedicalhave undoubtedly contributed to declining VBAC rates. Because of their complexity and importance, the Eunice Kennedy Shriver National Institute of Child Health and Human Devel

TABLE 31-1. Some Factors That Influence a Successful Trial of Labor in a Woman with Prior Cesarean Delivery aMost consider these absolute contraindications. EGA = estimated gestational age.

As evidence mounted that the risk of uterine rupture might be greater than expected, the American College of Obstetricians and Gynecologists (1988, 1998, 1999, 2017a) issued updated Practice Bulletins supporting labor trials but also urging a more cautious approach. It is problematic that both options have risks and beneits to mother and fetus but that these are not always congruent.

Rates of uterine rupture and associated complications clearly are increased with TO LAC. Uterine rupture typically is classified as either (1) complete, when all layers of the uterine wall are separated, or (2) incomplete, when the uterine muscle is separated but the visceral peritoneum is intact. Incomplete rupture is also commonly referred to as uterine dehiscence. It is these risks that underpin most of the angst in attempting TOLAC. Despite this, some have argued that these factors should weigh only minimally in the decision because their absolute risk is low. One systematic review by Guise and colleagues (2010) concluded that the risk of uterine rupture was significantly elevated in women undergoing TOLAC-absolute risk of 0.47 percent and relative risk of 20.7-compared with those choosing ERCD.

he Maternal-Fetal Medicine Units Network conducted a prospective study at 19 academic centers (Landon, 2004). The outcomes of nearly 18,000 women attempting TOLAC were compared with more than 15,000 gravidas undergoing ERCD. The absolute risk of uterine rupture was 0.7 percent compared with no reported uterine ruptures in the ERCD cohort (Table 31-2). .10st studies suggest that the maternal mortaliy rate does not difer significantly between these two groups (Landon, 2004; Mozurkewich, 2000). But, the aforementioned systematic review by Guise (2010) found the

Single mother Classical or T incision Increased maternal age Prior rupture Macrosomic fetus Patient refusal Obesity Transfundal surgery Breech Obstetrical contraindication,

Multifetal pregnancy e.g., previa Preeclampsia Inadequate facilities risk of maternal death to be signiicantly reduced for women undergoing TOLAC compared with ERCD. In a retrospective Canadian cohort study, the maternal death rate for women undergoing ERCD was 5.6 per 100,000 cases compared with 1.6 per 100,000 for those attempting TOLAC (Wen, 2005).

Estimates of maternal morbidiy are also conflicting. he review by Guise (2010) observed no significant diferences in the risk of hysterectomy or transfusion. But, another metaanalysis reported that women undergoing TOLAC were approximately half as likely to require a blood transfusion or hysterectomy compared with those undergoing ERCD (Mozurkewich, 2000). Conversely, in the Network study, investigators observed that the risks of transfusion and infection were significantly greater for women attempting TOLAC (Landon, 2004). This disparity is also found among other studies. Notably, compared with a successful TOLAC, the risk of these major complications was ivefold greater with an attempted vaginal delivery that failed (Babbar, 2013; Rossi, 2008).

TOLAC is associated with significantly higher perinatal mortaliy rates compared with ERCD. he perinatal rate with TOLAC is 0.13 compared with 0.05 percent for ERCD, and the neonatal mortality rates are 0.i11 versus 0.06 percent, respectively (Guise, 2010). In another study of nearly 25,000 women with a prior cesarean delivery, the vaginal-delivery-related perinatal death risk was 1.3 per 1000 among 15,515 women electing TOLAC. Although this absolute risk is small, it is 11 times greater than the risk found in 9014 women with ERCD (Smith, 2002).

TOLAC also appears to be associated with a higher risk of hypoxic ischemic encephalopathy (HIE) than ERCD. The Network study reported the incidence of HIE at term to be 46 per 100,000 TOLACs compared with zero cases in women undergoing ERCD (Landon, 2004).

Uterine dehiscence 11s9 (0.7)

Hysterectomy 41 (0.2) 76 (0.5) 1.38 (1s.04-1.85) 0.77 (0.51-1s.17) .03 .22 aDenominator is 15,338 for the trial of labor group and 15,014 for the elective repeat cesarean delivery group.

confidence interval; HIE hypoxic ischemic encephalopathy; NA not applicablesNICHD = National Institute of Child Health and Human Development; NS = not significant.

Adapted from Landon, 2004.

In the systematic review, the absolute risk of transient tachypnea of the newborn was slightly higher with ERCD compared with TOAC-4.2 versus 3.6 percent (Guise, 2010). But, neonatal bag and mask ventilation were used more often in newborns delivered following TOAC than in those delivered by ERCD-5.4 versus 2.5 percent. Finally, there are no signiicant diferences in 5-minute Apgar scores or neonatal intensive care unit admission rates for newborns delivered by TO AC compared with those delivered by ERCD. Birth trauma from lacerations is more commonly seen in neonates born by ERCD.

Few high-quality data are available to guide selection of TO AC candidates. In a population-based cohort study of 41,450 women he type and number of prior cesarean deliveries are overriding factors in recommending TOAC. Women with one prior low-transverse hysterotomy have the lowest risk of symptomatic scar separation (Table 31-3). The highest risks are with prior vertical incisions extending into the fundus, such as that

TABLE 31 -3. Types of Prior Uterine Incisions and Estimated Risks for Uterine Rupture delivering in California hospitals, Gregory and colleagues (2008) Classical reported a TOAC success rate of74 percent when no maternal, T-shaped fetal, or placental complications were present. Several algorithms and nomograms have been developed to aid prediction, but none has demonstrated reasonable prognostic value (Grobman, 2007b, 2008,i2009; Macones, 2006; Metz, 2013; Srinivas, 2007). A predictive model for failed trial of labor, however, was found to be somewhat predictive of uterine rupture or dehiscence (Stanhope, 2013). Despite these limitations for precision, several points are pertinent to candidate evaluation and are described in the next sections. Current recommendations of the American College of Obstetricians and Gynecologists (2017 a) are that most women with one previous low-transverse hysterotomy are candidates, and if appropriate, they should be counseled regarding TOAC and ERCD options. Although not our practice, those with two prior low-transverse incisions may be considered.

aSee text for definition.

Data from the American College of Obstetricians and Gynecologists, 201s7a; Cahill, 20s1 Ob; Chauhan, 2002; Landon, 2006; Macones, 2005a,b; Martin, 1997; Miller, 1994; Sciscione, 2008; Society for Maternal-Fetal Medicine, 2012; Tahseen, 201s0.

FIGURE 31-3 Ruptured vertical cesarean delivery scar (arrow) identified at time of repeat cesarean delivery early in labor. The two black asterisks to the left indicate some sites of densely adhered omentum.

shown in Figure 3i1-3. Importantly, in some women, a classical scar will rupture before labor onset, and this can happen several weeks before term. In a review of 157 women with prior classical cesarean delivery, one woman had a complete uterine rupture before labor onset, whereas 9 percent had a uterine dehiscence (Chauhan, 2002).

he risk of uterine rupture in women with a prior vertical incision that did not extend into the fundus is unclear. Martin (1997) and Shipp (1999) and their coworkers reported that these low-vertical uterine incisions did not have an increased risk for rupture compared with low-transverse incisions. The American College of Obstetricians and Gynecologists (2017a) concluded that although evidence is limited, women with a prior vertical incision in the lower uterine segment without fundal extension may be candidates for TOLAC. This is in contrast to prior classical or T -shaped uterine incisions, which are considered by most as contraindications to labor.

Although there are few indications for a primary classical incision, 53 percent of women undergoing cesarean delivery between 24°/7 weeks and 256r weeks have such an incision (Osmundson, 20l3). By 28 weeks' gestation, the risk drops to 35 percent and declines to < 10 percent by 32 weeks. he likelihood of classical uterine incision is also increased by noncephalic presentations. In those instances-for example, preterm breech fetus with an undeveloped lower segment-the "low vertical" incision almost invariably extends into the active segment. Prior preterm cesarean delivery may result in a twofold increased risk for rupture (Sciscione, 2008). This may be in part explained by the greater likelihood with a preterm fetus of upward uterine incision extension. Lannon and coworkers (2015) compared 456 women with a prior periviable cesarean delivery with more than 10,000 women whose prior cesarean delivery occurred at term. hey observed uterine rupture in 1.8 percent in the prior periviable group versus 0.4 percent in the prior term group. Of the uterine ruptures in the periviable group, half were in women whose prior uterine incision was described as low transverse. Harper and associates (2009) did not confirm these findings.

There are also special considerations for women with uterine malformations who have undergone cesarean delivery. Earlier reports suggested that the uterine rupture risk in a subsequent pregnancy was greater than the risk in those with a prior low transverse hysterotomy and normally formed uterus (Ravasia, 1999). But, in a study of 103 women with miillerian duct anomalies, there were no cases of uterine rupture (Erez, 2007).

Given the wide range of risk for uterine rupture associated with the various uterine incision types, it is not surprising that most fellows of the American College of Obstetricians and

Gynecologists consider the type of prior incision to be the most important factor when considering a TOLAC (Coleman, 2005).

As discussed in Chapter 30 (p. 577), the low-transverse hysterotomy incision can be sutured in either one or two layers. A metaanalysis by Roberge and colleagues (2014) compared single-versus double-layer closure and locking versus unlocking suture for uterine closure. They reported that rates for uterine dehiscence or uterine rupture for these closures did not difer signiicantly. Single-layer closure and locked irst layer, however, was associated with a reduced myometrial thickness during subsequent sonographic measurement. In contrast, Bennich and coworkers (2016) reported that a double-layer closure did not increase the residual myometrial thickness when saline contrast sonography was done several months postpartum. At Parkland Hospital, we routinely close the lower-segment incision with one running, locking suture line.

Number of Prior Cesarean Incisions

At least three studies report a doubling or tripling of the rupture rate in women with two compared with one prior transverse hysterotomy (.1acones, 2005a; Miller, 1994; Tahseen, 2010). In contrast, analysis of the Network database by Landon and associates (2006) did not conirm this. Instead, they reported an insigniicant diference in the uterine rupture rate in 975 women with multiple prior cesarean deliveries compared with 16,915 women with a single prior operation-0.9 versus 0.7 percent, respectively. As discussed on page 599, other serious maternal morbidity increases along with the number of prior cesarean deliveries (Marshall, 2011).

Imaging of Prior Incision

Sonographic measurement of a prior hysterotomy incision has been used to predict the likelihood of rupture. Large defects in a nonpregnant uterus forecast a greater risk for subsequent rupture (Osser, 201i1). Naji and coworkers (20l3a,b) found that the residual myometrial thickness decreased as pregnancy progressed and that rupture correlated with a thinner scar. In a systematic review, women with a prior low-transverse cesarean incision underwent third-trimester sonographic evaluation (Jastrow, 2010a). Investigators concluded that the thickness of the lower uterine segment was a strong predictor for a uterine scar defect in women with prior cesarean delivery. They deined this segment as the smallest measurement between urine in the maternal bladder and amnionic luid. hat said, they could not ind an ideal threshold value to recommend TOLAC. his same group subsequently recruited 1856 women contemplating vaginal birth after a single low-transverse incision, and they sonographically measured lower uterine segment thickness by between 34 weeks and 39 weeks G as trow, 2016). hey grouped women into three risk categories for uterine rupture during TOLAC based on the measured segment value: high risk <2.0 mm; intermediate risk 2.0-2.4 mm; and low risk �2.5 mm. he TOAC rates were 9,42, and 61 percent in the three categories, respectively. Of the 984 TOLACs, there were no symptomatic uterine ruptures. Overall, data are limited, and this evaluation is currently not part of our routine practice.

Women who have previously sustained a uterine rupture are at greater risk for recurrence. As shown in Table 31-3, those with a previous low-segment rupture have up to a 6-percent recurrence risk, whereas prior upper segment uterine rupture confers a 9-to 32-percent risk (Reyes-Ceja, 1969; Ritchie, 1971). Fox and associates (2014) reported 14 women with prior uterine rupture and 30 women with prior uterine dehiscence. In 60 subsequent pregnancies, they reported no uterine ruptures or severe complications if women were managed in a standardized manner with cesarean delivery prior to labor onset.

Magnetic resonance imaging studies of myometrial healing suggest that complete uterine involution and restoration of anatomy may require at least 6 months (Dicie, 1997). To explore this further, Shipp and coworkers (2001) examined the relationship between interdelivery interval and uterine rupture in 2409 women with one prior cesarean delivery. There were 29 women with a uterine rupture-l.4 percent. Interdelivery intervalsi:;18 months were associated with a threefold greater risk of symptomatic rupture during a subsequent TOLAC compared with intervalsi> 18 months. Similarly, Stamilio and associates (2007) noted a threefold augmented risk of uterine rupture in women with an interpregnancy interval <6 months compared with one �6 months.

Prior vaginal delivery, either before or after a cesarean birth, improves the prognosis for a subsequent vaginal delivery with either spontaneous or induced labor (Aviram, 2017; Grinstead, 2004; Hendler, 2004; Mercer, 2008). Prior vaginal delivery also lowers the risk of subsequent uterine rupture and other morbidities (Cahill, 2006; Hochler, 2014; Zelop, 1999).

Women with a nonrecurring indication-for example, breech presentation-have the highest VBAC rate of nearly 90 percent (Wing, 1999). Those with a prior cesarean delivery for fetal compromise have an approximately 80-percent VBAC rate, and for those done for labor arrest, VBAC rates approximate 60 percent (Bujold, 2001; Peaceman, 2006). Prior second-stage cesarean delivery can be associated with second-stage uterine rupture in a subsequent pregnancy Gastrow, 2013).

Most studies show that increasing fetal size is inversely related to VBAC rates. he risk for uterine rupture is less robustly linked. Zelop and associates (2001) studied outcomes of almost 2750 women undergoing TOAC, and the rate of uterine rupture increased-albeit not signiicantly-with rising fetal weight. he rate was 1.0 percent for fetal weight <4000 g, 1.6 percent for >4000 g, and 2.4 percent for >4250 g. Similarly, Jastrow and colleagues (201 Ob) in a retrospective report of 2586 women with a prior low-transverse uterine incision, observed an elevated risk for a failed trial of labor, uterine rupture, shoulder dystocia, and perineal laceration associated with rising birthweights. Conversely, Baron and coworkers (2013) did not ind higher uterine rupture rates with birthweights >4000 g. With a preterm fetus, women who attempt a TOLAC have higher VBAC rates and lower rupture rates (Durnwald, 2006; Quinones, 2005).

Data supporting external cephalic version (ECV) for breech presentation are limited and are derived from small studies (Burgos, 2014; Weill, 2017). From thes;, ECV success and adverse event rates appear comparable to women without prior cesarean. The American College of Obstetricians and Gynecologists (2016) acknowledges this lack of robust data. At Parkland Hospital, we do not attempt ECV in those with a prior cesarean delivery.

Twin pregnancy does not appear to increase the risk of uterine rupture. Ford and associates (2006) analyzed 1850 women with twins and reported a 45-percent successful VBAC rate and a rupture rate of 0.9 percent. Similar studies by Cahill (2005) and Varner (2007) and their colleagues reported rupture rates of 0.7 to 1.1 percent and VBAC rates of 75 to 85 percent. According to the American College of Obstetricians and Gynecologists (2017a), women with twins and a prior low-transverse hysterotomy can safely undergo TO LAC.

Multiple studies have reported an inverse relationship between prep regnancy body mass index (BMI) and VBAC rates. Hibbard and coworkers (2006) reported the following rates: 85 percent with a normal BMI, 78 percent with a BMI between 25 and 30, 70 percent with a BMI between 30 and 40, and 61 percent with a BMI �40. Similar findings were reported by Juhasz and associates (2005).

Most women with a prior cesarean delivery and fetal death in the current pregnancy would prefer a vaginal delivery. Although fetal concerns are obviated, available data suggest that maternal risks are increased. Nearly 46,000 women with a prior cesarean delivery in the Network database had a total of209 fetal deaths at an average gestational age of32.8 weeks (Ramirez, 2010). There were 158 women who elected TOLAC, with a VBAC rate of 87 percent. In the entire TOLAC group, the uterine rupture rate was 2.4 percent. Of the 116 women who underwent an induction oflabor, there were five uterine ruptures (3.4 percent).

The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine (2017b) recommend delaying nonmedically indicated deliveries until 39 completed weeks of gestation or beyond. As shown in Figure 31-4, signiicant and appreciable adverse neonatal morbidity has been reported with elective delivery before 39 completed weeks (Chiossi, 2013; Clark, 2009). Thus, if ERCD is planned, it is essential that the fetus be mature.

The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017) have established the following guidelines for timing an elective cesarean delivery, and accurate gestational dating is suitable using any of these criteria.

1.

Sonographic measurements taken before 20 weeks' gestation support a gestational age :39 weeks.

2.

Fetal heart sounds have been documented for 30 weeks by Doppler ultrasound.

3.

A positive serum or urine �-human chorionic gonadotropin (hCG) test result has been documented for :36 weeks.

Because of uterine rupture risks for women undergoing TOLAC, the American Academy of Pediatricians and the American College of Obstetricians and Gynecologists (2017) recommend that such trials be undertaken only in facilities with staf immediately available to provide emergency care. Moreover, these centers should have a plan and resources for managing uterine rupture. Some argue that these provisions deny women full access to choices. For example, in an earlier survey of Ohio hospitals, 15 percent of Level I, 63 percent of Level II, and 100 percent of Level III institutions met these requirements (Lavin, 2002). Moreover, an obstetrical anesthesia workforce survey reported that due to stafing limitations, TOLAC was allowed in only 88 percent of hospitals with : 1500 annual deliveries, in 59 percent of those with 500 to 1499 deliveries, and in 43 percent of those with < 500 deliveries (Traynor, 2016). In some cases, women choose to attempt TOLAC at a birthing center or at home (Shields, 2017).

Labor induction is associated with a higher failure rate during TOLAC. The risks for uterine rupture, however, are less clear with induction or augmentation, with the exception of prostaglandin E1-misoprostol-which is contraindicated (American College of Obstetricians and Gynecologists, 2017a). Although most institutions are not so conservative, we do not induce or augment labor pharmacologically in women electing TOLAC at Parkland Hospital. Instead, we attempt induction only by amniotomy. Other considerations are to avoid induction or augmentation in women with an unknown prior incision type, an unfavorable cervix, or pregnancy >40 weeks.

Induction or augmentation of labor with oxytocin has been implicated in increased rates of uterine rupture in women undergoing TOLAC (Zelop, 1999). In the Network study reported by Landon and colleagues (2004), uterine rupture was more frequent in women induced with oxytocin alone-I.l percentthan in those in spontaneous labor-O.4 percent. Augmentation of labor was associated with uterine rupture in 0.9 percent. Among women in this trial without a prior vaginal delivery, the uterine rupture risk associated with oxytocin induction was 1.8 percent-a fourfold greater risk compared with spontaneous labor (Grobman, 2007a). In contrast, in one case-control study, induction was not associated with a higher risk for rupture (Harper, 2012a). Cahill (2008) and Goetzl (2001) and their coworkers reported a dose-related risk of rupture with oxytocin.

Various prostaglandin preparations commonly employed for cervical ripening or labor induction are discussed in Chapter 26 (p. 506). s a group, their safe use in women with a prior cesarean delivery is unclear because of conlicting data.

With misoprostol (PGE1), Wing and colleagues (1998)

FIGURE 31-4 Neonatal morbidity rates seen with 13,258 elective repeat cesarean deliveries. Any adverse outcome includes death. Sepsis includes suspected and proven. RDS = respiratory distress syndrome; IN = transient tachypnea of the newborn. (Data from Tita AT, Landon MB, Spong CY, et al: Timing of elective repeat cesarean delivery at term and neonatal outcomes. N Engl J Med 360(2):1o11,o2009.) compared it versus oxytocin for labor induction in women with a prior cesarean delivery. They terminated their trial after two of the irst 17 women assigned to misoprostol developed a uterine rupture. Other studies confirmed this, and most consider misoprostol to be contraindicated (American College of Obstetricians and Gynecologists, 2017 a).

Of other prostaglandins, studies to evaluate their use for induction are contradictory. Ravasia and coworkers (2000) compared uterine rupture in 172 women given PGE2 gel with 1544 women in spontaneous labor. The rupture rate was significantly greater in women treated with PGE2 gel-2.9 percent compared with 0.9 percent in those with spontaneous labor. Lydon-Rochelle and associates (2001) found similar results. However, in the Network study cited previously, the uterine rupture rate was 1.4 percent when any prostaglandin was used in combination with oxytocin (Landon, 2004). But, in the subgroup of 227 women in whom labor was induced with a prostaglandin alone, there were no ruptures. Similar findings were reported with intravaginal prostaglandins, which were not associated with a greater uterine rupture risk (Macones, 2005b). These latter investigators, along with Kayani and colleagues (2005), found that sequential use of a prostaglandin followed by oxytocin was associated with a threefold greater risk of rupture compared with spontaneous labor.

Studies concerning the use of a transcervical Foley catheter for cervical ripening and induction of labor in women with a prior cesarean delivery are limited (Ben-Aroya, 2002; Jozwiak, 2014). In a retrospective study of 2479 women with prior cesarean delivery, the uterine rupture risk using a transcervical Foley catheter for labor induction (1.6 percent) was not significantly greater than that with spontaneous labor (1.1 percent) or with using amniotomy with or without oxytocin (1.2 percent) (Bujold, 2004). In contrast, Hofman (2004) described 138 women who underwent preinduction cervical ripening with a Foley catheter compared with 536 women who entered labor spontaneously. They observed a significant and inordinately high uterine rupture risk during labor following Foley catheter cervical ripening compared with spontaneous onset of labor-6.5 versus 1.9 percent.

Concerns that epidural analgesia for labor might mask the pain of uterine rupture have not been veriied. Fewer than 10 percent of women with scar separation experience pain and bleeding, and fetal heart rate decel erations are the most likely sign (ieser, 2002). That said, Cahill and coworkers (2010a) documented that more frequent episodes of epidural dosing were associated with increasing uterine rupture rates.

VBAC rates are similar, and in some cases higher, among women with labor epidural analgesia compared with those using other forms of analgesia (Aviram,

Following VBAC, some clinicians routinely document the integrity of a prior scar by placing a hand through the dilated cervix and along the inner surface of the lower uterine segment. But routine uterine exploration is considered by others to be unnecessary. In a longitudinal study of 3469 women who had a VBAC, seven uterine dehiscences and one uterine rupture yielded an overall event rate of 0.23 percent (Silberstein, 1998). They concluded that trans cervical evaluation need only be performed in symptomatic patients.

Currently, the benefits of routine scar evaluation in the asymptomatic woman are unclear, however, surgical correction of a dehiscence is necessary if significant bleeding is encountered. Our practice is to routinely examine these prior hysterotomy sites. Any decision for laparotomy and repair takes into consideration the extent of the tear, whether the peritoneal cavity has been entered, and the presence of active bleeding.

Progress of labor in women attempting TOLAC is similar to normal labor, and no speciic pattern presages uterine rupture (Graseck, 2012; Harper, 2012b; Sondgeroth, 2017). Before hypovolemic shock develops, symptoms and physical findings in women with uterine rupture may appear bizarre unless the possibility is kept in mind. For example, hemoperitoneum from a ruptured uterus may result in diaphragmatic irritation with pain referred to the chest. This may direct one to a diagnosis of pulmonary or amnionic fluid embolism instead of uterine rupture. As shown in Figure 31-5, the most common sign of uterine rupture is a nonreassuring fetl heart rate pattern with variable decelerations that may evolve into late decelerations and bradycardia. In 36 cases of such rupture during TOLAC, there were fetal signs of uterine rupture in 24, maternal signs in eight, and a combination of maternal and fetal in three (Holmgren, 2012). Few women experience cessation of contractions following uterine rupture, and the use of intrauterine pressure catheters does not assist reliably in the diagnosis (Rodriguez, 1989).

2017; Shmudi, 2017). Perhaps related, almost a fourth of VBAC deliveries were completed with either forceps or vacuum (Inbar, 2017). he merican Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017) have concluded that epidural analgesia while pushing. The rupture apparently stimulated a reflex push, after which uterine tone may safely be used during TOLAC. diminished and fetal bradycardia worsened.

FIGURE 31-6 Maternal-Fetal Medicine Units Network: rates of some complications with increasing number of repeat cesarean deliveries. (Data from Silver RM, Landon MB, Rouse OJ, et al: Maternal morbidity associated with mUltiple repeat cesarean deliveries. Obstet Gynecol 207:1o226, 2006.)

In some women, the clinical appearance of uterine rupture mirrors that of placental abruption. In most, however, there is remarkably little appreciable pain or tenderness. Also, because most women in labor are treated for discomfort with either narcotics or epidural analgesia, pain and tenderness may not be readily apparent. The condition usually becomes evident because of fetal distress and occasionally because of maternal hypovolemia from concealed hemorrhage.

If the fetal presenting part has already entered the pelvis with labor, loss of station may be detected by pelvic examination. If the fetus is partly or totally extruded from the uterine rupture site, abdominal palpation or vaginal examination may be help ful to identiY the presenting part, which will have moved away from the pelvic inlet. A irm contracted uterus may at times be felt alongside the fetus. Sonography may be helpful.

With rupture and expulsion of the fetus into the peritoneal cavity, the chances for intact fetal survival are dismal, and reported mortality rates range from 50 to 75 percent. Fetal condition depends on the degree to which placental implantation remains intact, although this can change within minutes. With rupture, the only chance of fetal survival is aforded by immediate delivery-most often by laparotomy-otherwise, hypoxia is inevitable. If rupture is followed by total placental separation, then very few neurologically intact fetuses will be salvaged.

Thus, even in the best of circumstances, some etal outcomes wil be impaire. he Utah experiences are instructive here (Holmgren, 2012). Of the 35 laboring patients with uterine rupture, the decision-to-delivery time was < 18 minutes in 17, and none of these infants had an adverse neurological outcome. Of the 18 born > 18 minutes from decision time, the three infants with long-term neurological impairments were delivered at 31, 40, and 42 minutes. There were no deaths, thus severe neonatal neurological morbidity developed in 8 percent of this group of 35 women with uterine rupture.

In a study using the Swedish Birth Registry, Kaczmarczyk and coworkers (2007) found that the risk of neonatal death following uterine rupture was 5 percent. In the Network study cited earlier, seven of the 114 uterine ruptures associated with TOAC-6 percent-were complicated by development of neonatal HIE (Spong, 2007).

Maternal deaths from uterine rupture are uncommon. Of 2.5 million women who gave birth in Canada between 1991 and 2001, there were 1898 cases of uterine rupture, and four of these-0.2 percent-resulted in maternal death (Wen, 2005). In other regions of the world, however, maternal mortality rates are much higher. From rural India, the maternal mortality rate associated with uterine rupture was 30 percent (Chatterjee, 2007).

With complete rupture during TOAC, hysterectomy may be required. In selected cases, however, suture repair with uterine preservation may be performed. Sheth (1968) described outcomes from a series of 66 women in whom repair of a uterine rupture was elected rather than hysterectomy. hirteen of the 41 mothers who did not have tubal sterilization had a total of 21 subsequent pregnancies. Uterine rupture recurred in four of these-approximately 20 percent. Usta and associates (2007) reported similar results. In another study, however, women with a uterine dehiscence were not more likely to have a subsequent uterine rupture (Baron, 2014).

Because of the aforementioned concerns with TOAC, most women in the United States undergo ERCD. his choice has several signiicant maternal complications, and rates of these rise in women who have multiple repeat operations. The incidences of some common complications for women with one prior transverse cesarean delivery who undergo an ERCD were shown in Table 31-2. Of note, half of cesarean hysterectomies done at Parkland Hospital are in women with one or more prior cesarean deliveries (Hernandez, 2013).

The Network addressed issues of increased morbidity in a cohort of30,132 women who had from one to six repeat cesarean deliveries (Silver, 2006). he rates of some of the more frequent or serious complications are depicted in Figure 31-6. In addition, rates of bowel or bladder injury, admission to an intensive care unit or need for ventilator therapy, and maternal mortality, as well as operative and hospitalization length, showed significantly rising trends. Similar results have been reported by others (Nisenblat, 2006; Usta, 2005). More diicult to quantiY are risks for bowel obstruction and pelvic pain from peritoneal �.� c0 4 ..A 2�): E0u

First Second Third � Fifth (6201) (15,808) (6324) (347)

Number of repeat cesarean deliveries (Number of women)

TABLE 31-4. Some Recommendations of Professional Societies Concerning a Trial of Labor to Attempt VBAC

CD cesarean delivery; VBAC vaginal birth after cesarean.

adhesive disease, both of which increase with each successive cesarean delivery (Andolf, 2010; Mankuta, 2013).

Cook and colleagues (2013) from the United Kingdom Obstetric Surveillance System (UKOSS) described adverse sequelae of women with ive or more cesarean deliveries. These women had signiicantly higher rates of morbidity. Namely, the major hemorrhage rate increased 18-fold; visceral damage, 17 -fold; critical care admissions, IS-fold; and delivery <37 weeks, sixfold. Much of this morbidity was in the 18 percent who had a placenta previa or an accrete syndrome (Chap. 41, p. 773).

For providers and their patients, unfortunately, no large rndomized trials have compared outcomes of women with an intent to pursue either TOAC or ERCD. Most studies to date have compared actual routes of delivey rather than the intended route of delivery. hus, we agree with Scott (2011) regarding a "commonsense" approach. The woman-and her partner if she wishes-are encouraged to actively participate with her provider in informed consent. Counseling should include documentation of the prior uterine incision and discussion of risks, benefits, and success rates of TO AC or ERCD. This includes consideration of risks involving uture pregnancies. Ideally, counseling begins preconceptionally and continues throughout pregnancy, with lexible options extending up to delivery. For women who desire TOAC despite a factor that increases their speciic risk, additions to the consent form are recommended by the merican College of Obstetricians and Gynecologists (2017 a). Bonanno and colleagues (2011) have provided such an example. Brief synopses of professional society guidelines are shown in Table 31-4. Guidelines that tend to be more conservative are shown in Table 31-5.

TABLE 31 -5. Conservative Guidelines to Approach a Trial of Labor Following Cesarean Delivery

Early during prenatal care Develop preliminary plan Revisit at least each trimester Be willing to alter decision Have facilities availability

Review relative and absolute contraindications Reconsider risks as pregnancy progresses

Tread carefully: > 1 prior transverse CD, unknown incision, twins, macrosomia

Cautions for induction-unfavorable cervix, high station Consider AROM

Respect oxytocin-know when to quit Beware of abnormal labor progress Respect EFM pattern abnormalities

Know when to abandon a trial of labor

ACOG American College of Obstetricians and Gynecologists; AROM = artificial rupture of membranes;

American College of Obstetricians and Gynecologists (20l7a)

Society of Obstetricians and Gynaecologists of Canada (2005)

Royal College of Obstetricians and Gynaecologists (2007)

Offer to most women with one prior low-transverse incision; consider for t.IO prior low-transverse incisions

Offer to wornen with one prior transverse lowsegment cesarean delivery; withs> 1 prior CD then VBAC likely successful but increased risks

Discuss VB,\C option with women with prior low-segment cesarean delivery; decision between obstetrician and patient Safest with ability for immediate cesarean delivery; patients should be allowed to accept increased risk when not available

Should deliver in hospital in which timely cesarean delivery is available; approximate timeframe of 30 minutes

Suitable delivery suite with continuous care and monitoring; immediate cesarean delivery capability Not precluded: twins, macrosomia, prior lowvertical or unknown type of incision

Oxytocin or Foley catheter induction safe, but prostaglandins should not be used; macrosomia, diabetes, postterm pregnancy, twins are not contrai nd ications

Caution with twins and macrosomia

American Academy of Pediatrics, American College of Obstetricians and Gynecologists: Guidelines for Perinatal Care, 8th ed. Elk Grove Village, 2017

American College of Obstetricians and Gynecologists: Guidelines for vaginal delivery ater a previous cesarean birth. Committee Opinion No. 64, October 1988

American College of Obstetricians and Gynecologists: Vaginal delivery after previous cesarean birth. Committee Opinion No. 143, October 1994 American College of Obstetricians and Gynecologists: Vaginal birth ater previous cesarean delivery. Practice Bulletin No.r2, October 1998 American College of Obstetricians and Gynecologists: Vaginal birth after previous cesarean delivery. Practice Bulletin No.r5, ] uly 1999 American College of Obstetricians and Gynecologists: External cephalic version. Practice Bulletin No. 161, February 2016

American College of Obstetricians and Gynecologists: Vaginal birth after cesarean delivery. Practice Bulletin No. 184, November 2017a merican College of Obstetricians and Gynecologists, Society for MaternalFetal Medicine: Nonmedically indicated early-term deliveries. Committee Opinion No. 561, April 2013, Reairmed 2017b

Andolf E, Thorsell M, Kallen K: Cesarean delivery and risk for postoperative adhesions and intestinal obstruction: a nested case-control study of the Swedish Medical Birth Registry. Am] Obstet Gynecol 203:406.el, 2010

Aviram A, Hadar E, Gabbay-Benziv R, et al: Successful tolac in a population with a high success rate-what are the diferences? Abstract No. 923. Am ] Obstet GynecoIr216:S526, 2017

Babbar S, Chauhan S, Hammas I, et al: Failed trial of labor after cesarean delivery: indications for failure and peripartum complications. Abstract No. 818, Am] Obstet Gynecol208 (1 Suppl):S342, 2013

Barger MK, Dunn ]T, Bearman S, et al: A survey of access to trial of labor in California hospitals in 2012. BMC Pregnancy Childbirth 13:83,r2013

Baron], Weintraub AY, Eshkoli T, et al: he consequences of previous uterine scar dehiscence and cesarean delivery on subsequent births. Intr] Gynaecol Obstet 126(2):120,r2014

Baron], Weintraub A, Sergienko R, et al: Is vaginal delivery of a macrosomic infant after cesarean section really so dangerous? Abstract No. 799, Am ] Obstet Gynecolr208(1 Suppl):S335, 2013

Ben-Aroya Z, Hallak M, Segal 0, et al: Ripening of the uterine cervix in a post-cesarean parturient: prostaglandin E2 versus Foley catheter. ] Matern Fetal Neonatal Med 12(1):42r2002

Bennich G, Rudnicki M, Wilken-Jensen C, et al: Impact of adding a second layer to a single unlocked closure of a cesarean uterine incision: randomized controlled trial. Ultrasound Obstet GynecoIr47(4):417, 2016

Bonanno C, Clausing M, Berkowitz R: VBAC: a medicolegal perspective. Clin Perinatol 38:217, 2011

Bujold E, Blackwell SC, Gauthier R]: Cervical ripening with trans cervical Foley catheter and the risk of uterine rupture. Obstet Gynecol 103(1): 18 2004 Bujold E, Gauthier R]: Should we allow a trial oflabor after a previous cesarean for dystocia in the second stage of labor? Obstet Gynecol 98:652, 2001

Burgosr], Cobos P, Rodriguez L, et al: Is external cephalic version at term contraindicated in previous caesarean section? A prospective comparative cohort study. B]OG 121:230,r2014

Cahill A, Stamilio OM, Pare E, et al: Vaginal birth ater cesarean (VBAC) attempt in twin pregnancies: is it safe? Am] Obstet Gynecol 193: 1 050, 2005

Cahill AG, Odibo AO, Allswroth ]E, et al: Frequent epidural dosing as a marker for impending uterine rupture in patients who attempt vaginal birth after cesarean delivery. Amr] Obstet Gynecol 202:355.e1, 2010a

Cahill AG, Stamilio DM, Odibo A, et al: Is vaginal birth after cesarean (VBAC) or elective repeat cesarean safer in women with a prior vaginal delivery? Am ] Obstet Gynecol 195:1143,r2006

Cahill AG, Tuuli M, Odibo AO, et al: Vaginal birth ater caesarean for women with three or more prior caesareans: assessing safety and success. B]OG 117:422,r201Ob

Cahill AG, Waterman BM, Stamilio DM, et al: Higher maximum doses of oxytocin are associated with an unacceptably high risk for uterine rupture in patients attempting vaginal birth after cesarean delivery. Am ] Obstet Gynecol 199:32.e1, 2008

Chatterjee SR, Bhaduri S: Clinical analysis of 40 cases of uterine rupture at Durgapur Subdivisional Hospital: an observational study. ] Indian Med Assoc 105:510,r2007

Chauhan SP, Magann EF, Wiggs CD, et al: Pregnancy after classic cesarean delivery. Obstet Gynecol 100:946, 2002

Cheng Y, Snowden], Cottrell E, et al: Trends in proportions of hospitals with VBAC: impact of ACOG guidelines. Am] Obstet Gynecol 21 0:S241, 2014

Chiossi G, Lai Y, Landon MB, et al: Timing of delivery and adverse outcomes in term singleton repeat cesarean deliveries. Obstet Gynecol 121 :561, 2013

Clark SL, Miller DO, Belfort A, et al: Neonatal and maternal outcomes associated with elective term delivery. Am ] Obstet Gynecol 200(2): 156. el,r2009

Coleman VH, Erickson K, Schulkinr], et al: Vaginal birth after cesarean delivery.r] Reprod Med 50:261, 2005

Cookr], ]avis S, Knight M, et al: Multiple repeat caesarean section in the UK: incidence and consequences to mother and child. A national, prospective, cohort study. B]OG 120(1):85, 2013

Cragin E: Conservatism in obstetrics. N Y Med] 104: 1, 1916

Dicle 0, Kiiciikler C, Pirnar T: Magnetic resonance imaging evaluation ofincision healing after cesarean sections. Eur Radiol 7:31, 1997

Durnwald CP, Rouse 0], Leveno K], et al: he Maternal-Fetal Medicine Units Cesarean Registry: safety and eicacy of a trial oflabor in preterm pregnancy after a prior cesarean delivery. Am] Obstet Gynecol 195: 1119, 2006

Eastman N]: Williams Obstetrics, 10th ed. Appleton-Century-Crofts, New York, 1950

Erez 0, Dulder 0, Novack L, et al: Trial of labor and vaginal birth after cesarean section in patients with uterine millerian anomalies: a population-based study. Am] Obstet Gynecol 196:537.e1, 2007

Ford M, Bateman BT, Simpson LL: Vaginal birth ater cesarean delivery in twin gestations: a large, nationwide sample of deliveries. Amr] Obstet Gynecol 195:1138,r2006

Fox NS, Gerber RS, Mourad M, et al: Pregnancy outcomes in patients with prior uterine rupture or dehiscence. Obstet GynecoIr123(4):785, 2014 Goetzl L, Shipp TO, Cohen A, et al: Oxytocin dose and the risk of uterine rupture in trial of labor ater cesarean. Obstet Gynecol 97:381, 2001

Graseck AS, Odibo AO, Tuuli M, et al: Normal first stage of labor in women undergoing trial oflabor after cesarean delivery. Obstet GynecoIr119(4):732, 2012

Gregory KD, Korst LM, Fridman M, et al: Vaginal birth ater cesarean: clinical risk factors associated with adverse outcome. Am] Obstet Gynecol 198:452. e1,r2008

Grinstead], Grobman W A: Induction of labor after one prior cesarean: predictors of vaginal delivery. Obstet Gynecol 103:534,r2004

Grobman W A, Gilbert S, Landon MB, et al: Outcomes of induction of labor after one prior cesarean. Obstet Gynecolr109:262, 2007a

Grobman WA, Lai Y, Landon MB, et al: Can a prediction model for vaginal birth after cesarean also predict the probability of morbidity related to a trial oflabor? Am] Obstet Gynecol 200(1):56.e1, 2009

Grobman WA, Lai Y, Landon MB, et al: Development of a nomogram for prediction of vaginal birth ater cesarean delivery. Obstet Gynecol 109:806, 2007b

Grobman WA, Lai Y, Landon MB, et al: Prediction of uterine rupture associated with attempted vaginal birth ater cesarean delivery. Am ] Obstet GynecoIr199:30.e1,r2008

Guise ]M, Denman MA, Emeis C, et al: Vaginal birth after cesarean: new insights on maternal and neonatal outcomes. Obstet Gynecol 115: 1267, 2010

Hamilton BE, Martin ]A, Osterman M], et al: Births: inal data for 2014. Nat!

Vital Stat Rep 64(12):1, 2015

Hamilton BE, Martin ]A, Osterman M]: Births: preliminary data for 2015.

Nat! Vital Stat Rep 65(3):1, 2016

Harper LM, Cahill AG, Boslaugh S, et al: Association of induction of labor and uterine rupture in women attempting vaginal birth after cesarean: a survival analysis. Am] Obstet Gynecol 206:51.e 1, 2012a

Harper LM, Cahill AG, Roehl A, et al: he pattern oflabor preceding uterine rupture. Am] Obstet GynecoI207(3):210.e1, 2012b

Harper LM, Cahill AG, Stamilio DM, et al: Efect of gestational age at the prior cesarean delivery on maternal morbidity in subsequent VBAC attempt. Am] Obstet GynecoI200(3):276.e1, 2009

Hendler I, Bujold E: Efect of prior vaginal delivery or prior vaginal birth after cesarean delivery on obstetric outcomes in women undergoing trial of labor. Obstet Gynecol 104(2):2 3,r2004

Hernandez ]S, Wendel GO, Sheield ]S: Trends in emergency peripartum hysterectomy at a single institution: 1988-2009. Am] PerinatoI30:365, 2013

Hibbard ]U, Gilbert S, Landon MB, et al: Trial of labor or repeat cesarean delivery in women with morbid obesity and previous cesarean delivery. Obstet Gynecol 108: 125, 2006

Hochler H, Yafe H, Schwed P, et al: Safety of a trial of labor after cesarean delivery in grandmultiparous women. Obstet GynecoIr123:304, 2014

Hofman MK, Sciscione A, Srinivasana M, et al: Uterine rupture in patients with a prior cesarean delivery: the impact of cervical ripening. Am ] PerinatoIr21(4):217,r2004

Holmgren C, Scott ]R, Porter TF, et al: Uterine rupture with attempted vaginal birth after cesarean delivery. Obstet Gynecol 119:725,r2012

Inbar R, Mazaaki S, Kalter A, et al: Trial oflabour after caesarean (TO LAC) is associated with increased risk for instrumental delivery. ] Obstet Gynaecol 37(1):44,r2017

Jastrow N, Chailet N, Roberge S, et al: Sonographic lower uterine segment thickness and risk of uterine scar defect: a systematic review. J Obstet Gynaecol Can 32(4):321, 2010a

Jastrow N, Demers S, Chaillet N, et al: Lower uterine segment thickness to prevent uterine rupture and adverse perinatal outcomes: a multicenter prospective study. Am J Obstet Gynecol 215(5):604.e1, 2016

Jastrow N, Demers S, Gauthier Rl, et al: Adverse obstetric outcomes in women with previous cesarean for dystocia in second stage labor. Am J Perinatol 3,r2013

Jastrow N, Robere S, Gauthier RJ, et al: Efect of birth weight on adverse obstetric outcomes in vaginal birth after cesarean delivery. Obstet Gynecol 115(2):338,r2010b

Jozwiak M, Van De Lest H, Burger NB, et al: Cervical ripening with Foley catheter for induction of labor after cesarean section: a cohort study. Acta Obstet Gynecol Scand 93:296, 2014

Juhasz G, Gyami C, Gyami P, et al: Efect of body mass index and excessive weight gain on success of vaginal birth after cesarean delivery. Obstet Gynecol lO6:741, 2005 Kaczmarczyk M, Span�n P, Terry P, et al: Risk factors for uterine rupture and neonatal consequences of uterine rupture: a population-based study of successive pregnancies in Sweden. BJOG 114:1208,r2007 Kayani SI, lfirevic Z: Uterine rupture after induction of labour in women with previous caesarean section. BJOG 112:45r1,r2005 Kieser E, Baskett TF: A 10-year population-based study of uterine rupture. Obstet Gynecol 100:749,r2002 Landon MB, Hauth Jc, Leveno KJ, et al: Maternal and perinatal outcomes associated with a trial of labor after prior cesarean delivery. N Engl J Med 351 :2581, 2004 Landon MB, Leindecker S, Spong CY, et al: he IvfFMU Cesarean Registry: factors afecting the success of trial of labor after previous cesarean delivery. Am J Obstet Gynecol 193:1016,r2005 Landon MB, Spong CY, Thon E, et al: Risk of uterine rupture with a trial of labor in women with multiple and single prior cesarean delivery. Obstet Gynecol 108: 12, 2006 Lannon SM, Guthrie A, Vanderhoeven JP, et al: Uterine rupture risk after periviable cesarean delivery. Obstet Gynecol 125: 1 095, 2015 Lavin JP, DiPasquale L, Crane S, et al: A state-wide assessment of the obstetric, anesthesia, and operative team personnel who are available to manage the labors and deliveries and to treat the complications of women who attempt vaginal birth after cesarean delivery. Am J Obstet Gynecol 187:611, 2002 Leeman Uvl, Beagle M, Espey E, et al: Diminishing availability of trial of labor ater cesarean delivery in New Mexico hospitals. Obstet GynecoIr122:242, 2013 Lydon-Rochelle M, Holt VL, Easterling TR, et al: Risk of uterine rupture during labor among women with a prior cesarean delivery. N Engl J Med 345:3,r2001 Macones GA, Cahill A, Pare E, et al: Obstetric outcomes in women with two prior cesarean deliveries: is vaginal birth after cesarean delivery a viable option? Am J Obstet GynecoIr192:1223, 2005a Macones GA, Cahill AG, Stamilio DM, et al: Can uterine rupture in patients attempting vaginal birth ater cesarean delivery be predicted? Am J Obstet Gynecol 195:1148,2006 Macones GA, Peipert J, Nelson DB, et al: Maternal complications with vaginal birth after cesarean delivery: a multicenter study. Am J Obstet Gynecol 193: 1656, 2005b Mankuta D, Mansour M, Alon SA: Ivlaternal and fetal morbidity due to abdominal adhesions after repeated cesarean section. Abstract No. 792, Am J Obstet Gynecol 208(1 Suppl):S332, 2013 Marshall NE, Fu R, Guise JM: Impact of multiple cesarean deliveries on maternal morbidity: a systematic review. Am J Obstet GynecoI205:262.e1, 2011 Martin IN, Perry KG, Roberts WE, et al: The care for trial of labor in the patients with a prior low-segment vertical cesarean incision. Am J Obstet Gynecol 177: 144, 1997 McMahon MJ, Luther ER, Bowes WA J r, et al: Comparison of a trial of labor with an elective second cesarean section. N Engl J Med 335:689, 1996 Mercer BM, Gilbert S, Landon MB, et al: Labor outcomes with increasing number of prior vaginal births after cesarean delivery. Obstet Gynecol 111:285,r2008 Metz TD, Stoddard GJ, Henry E, et al: Simple, validated vaginal birth after cesarean delivery prediction model for use at the time of admission. Obstet Gynecol 122:571,r2013 Miller DA, Diaz FG, Paul RH: Vaginal birth after cesarean: a 10-year experience. Obstet GynecoIr84(2):255, 1994 Mozurkewich EL, Hutton EK: Elective repeat cesarean delivery versus trial of labor: a meta-analysis of the literature from 1989 to 1999. Am J Obstet Gynecol 183(5):1187,2000 Naji 0, Daemen A, Smith A, et al: Changes in cesarean section scar dimensions during pregnancy: a prospective longitudinal study. Ultrasound Obstet Gynecol 41(5):556, 2013a

Naji 0, Wynants L, Smith A, et al: Predicting successful vaginal birth after cesarean section using a model based on cesarean scar features examined using transvaginal sonography. Ultrasound Obstet Gynecol 41 (6):672, 2013b

National Institutes of Health: Consensus Development Conference of Cesarean Childbirth, September 1980. NIH Pub No. 82-2067, Bethesda, NIH, 1981

National Institutes of Health Consensus Development Conference Panel: National Institutes of Health Consensus Development conference statement: Vaginl birth after cesarean: new insights. March 8-10, 2010. Obstet Gyneco1r115:12 9,20lO

Nisenblat V, Barak S, Griness OB, et al: llaternal complications associated with multiple cesarean deliveries. Obstet Gynecol lO8:21, 2006 Osmundson SS, Garabedian MJ, Lyell OJ: Risk factors for classical hysterotomy by gestational age. Obstet Gynecol 122:845,r2013

Osser OV, Valentin L: Clinical importance of appearance of cesarean hysterotomy scar at transvaginal ultrasonography in nonpregnant women. Obstet Gynecol 117:525,r2011

Pauerstein CJ: Once a section, always a trial of labor? Obstet Gynecol 28:273, 1966 Pauerstein CJ, Karp L, Muher S: Trial oflabor after low segment cesarean section. S Med J 62:925, 1969

Peace man v!, Gersnoviez R, Landon MB, et al: he MFMU cesarean registry: impact of fetal size on trial of labor success for patients with previous cesarean for dystocia. Am J Obstet Gynecol 195:1127,2006

Quinones IN, Stamilio OM, Pare E, et al: he efect of prematurity on vaginal birth after cesarean delivery: success and maternal morbidity. Obstet Gynecol 105:519,r2005

Ramirez MM, Gilbert S, Landon MB, et al: Mode of delivery in women with antepartum fetal death and prior cesarean delivery. Am J Perinatol 27:825, 2010

Ravasia OJ, Brain PH, Pollard JK: Incidence of uterine rupture among women with mullerian duct anomalies who attempt vaginal birth after cesarean delivery. Am J Obstet Gynecol 7, 1999 Ravasia OJ, Wood SL, Pollard JK: Uterine rupture during induced trial of labor among women with previous cesarean delivery. Am J Obstet Gynecol 183:1176,r2000

Reyes-Ceja L, Cabrera R, Insfran E, et al: Pregnancy following previous uterine rupture: study of 19 patients. Obstet Gynecol 34:387, 1969 Ritchie EH: Pregnancy after rupture of the pregnant uterus: a report of 36 pregnancies and a study of cases reported since 1932. J Obstet Gynaecol Br Commonw 78:642, 1971 Roberge S, Demers S, Bergella V, et al: Impact of single-vs double-layer closure on adverse outcomes and uterine scar defect: a systematic review and metaanalysis. Am J Obstet Gynecol 211:453, 2014 Rodriguez MH, Masaki 01, Phelan JP, et al: Uterine rupture: are intrauterine pressure catheters useful in the diagnosis? Am J Obstet Gynecol 161 :666, 1989 Rosenstein MG, Kuppermann M, Gregorich SE, et al: Association between vaginal birth after cesarean delivery and primary cesarean delivery rates. Obstet Gynecol 122:lO10, 2013 Rossi AC, D'Addario V: Maternal morbidity following a trial of labor after cesarean section vs elective repeat cesarean delivery: a systematic review with metaanalysis. Am J Obstet Gynecol 199(3):224,2008 Royal College of Obstetricians and Gynaecologists: Birth after previous caesarean birth. Green-top Guideline No. 45, February 2007 Sachs BP, Koblin C, Castro A, et al: The risk of lowering the cesarean-delivery rate. N Engl J Med 340:5, 1999 Sciscione AC, Landon MB, Leveno KJ, et al: Previous preterm cesarean delivery and risk of subsequent uterine rupture. Obstet Gynecol 111 :648, 2008 Scott JR: Vaginal birth after cesarean delivery: a common-sense approach. Obstet Gynecol 118:342, 2011 Sheth SS: Results of treatment of rupture of the uterus by suturing. J Obstet Gynaecol Br Commonw 75:55, 1968 Shields M, Zwerling B, Cheng W: Outcomes of hospital versus out-ofhospital birth in vaginal birth after cesarean. Abstract No. 827. Am J Obstet Gynecol 216:S474, 2017 Shipp TO, Zelop CM, Repke JT, et al: Interdelivery interval and risk of symptomatic uterine rupture. Obstet Gynecol 97: 175, 2001 Shipp TO, Zelop CM, Repke JT, et al: Intrapartum uterine rupture and dehiscence in patients with prior lower uterine segment vertical and transverse incisions. Obstet Gynecol 94:735, 1999 Shmueli A, Salman L, Nassie 01, et al: he intriguing association between epidural anesthesia and mode of delivery among women in trial of labor after cesarean delivery. Abstract No. 949. Am J Obstet Gynecol 216:S536, 2017 Silberstein T, Wiznitzer A, Katz M, et al: Routine revision of uterine scar after cesarean section: has it ever been necessary? Eur J Obstet Gynecol Reprod BioI 78:29, 1998

Silver M, Landon MB, Rouse 0], et al: Maternal morbidity associated with multiple repeat cesarean deliveries. Obstet Gynecol 207: 1226, 2006

Smith GC, Pell ]P, Cameron AD, et al: Risk of perinatal death associated with labor after previous cesarean delivery in uncomplicated term pregnancies. ]AMA 287:2684, 2002

Society for Matenal-Fetal Medicine: Counseling and management of women with prior classical cesarean delivery. Conremp OB/GYN 57(6):26, 2012

Society of Obstetricians and Gynaecologists of Canada: SOGC clinical practice guidelines. Guidelines for vaginal birth after previous caesarean birth. Number 155 (replaces guideline Number 147), February 2005. Intr] Gynaecol Obstet 89(3):319, 2005

Sondgeroth KE, Stout M], Tuuli MG, et al: Does uterine resting tone have any clinical value in trial oflabor (TOLAC)? Abstract No. 829. Am] Obstet Gynecol 216:5475, 201

Spong CY, Landon MB, Gilbert 5, et al: Risk of uterine rupture and adverse perinatal outcome at term after cesarean delivery. Obstet Gynecol 110:801, 2007

Srinivas SK, Stamilio OM, Stevens E], et al: Predicting failure of a vaginal birth attempt after cesarean delivery. Obstet Gynecol 109:800, 2007

Stamilio OM, DeFranco E, Pare E, et al: Short inrerpregnancy inrerval. Risk of uterine rupture and complications of vaginal birth after cesarean delivery. Obstet Gynecol 110, 1075,2007

Stanhope T, El-Nasher 5, Garrett A, et al: Prediction of uterine rupture or dehiscence during trial of labor after cesarean delivery: a cohort study. Abstract No. 821, Amr] Obstet Gynecol 208(1 Suppi):S343, 2013

Tahseen 5, Griiths M: Vaginal birth after two caesarean sections (VBAC-2)a systematic review with meta-analysis of success rate and adverse outcomes of VBAC-2 versus VBAC-1 and repeat (third) caesarean sections. B]OG 117:5,r2010

Tita AT, Landon MB, Spong CY, et al: Timing of elective repeat cesarean delivery at term and neonatal outcomes. N Engl ] Med 360(2): Ill, 2009

Traynor A], Aragon M, Ghosh 0, et al: Obstetric Anesthesia Workforce Survey: a 30-year update. Anesth Analg 122(6):1939, 2016

Uddin SFG, Simon E: Rates and success rates of trial oflabor ater cesarean delivery in the United States, 1990-2009. Maten Child Health] 17:1309,2013 Usta 1M, Hamdi MA, Abu Musa A, et al: Pregnancy outcome in patients with previous uterine rupture. Acta Obstet Gynecol 86: 172, 2007

Usta 1M, Hobeika EM, Abu-Musa A, et al: Placenra previa-accreta: risk factors and complications. Am] Obstet Gynecol 193:1045,2005

Varner MW, Thon E, Spong CY, et al: Trial oflabor after one previous cesarean delivery for multifetal gestation. Obstet Gynecol 110:814, 2007

Weill Y, Pollack RN: The eicacy and safety of external cephalic version after a previous caesarean delivery. Aust N Z ] Obstet Gynaecol 57(3):323, 20r17

Wen SW, Huang L, Liston R, et al: Severe maternal morbidity in Canada, 1991-2001. CMA] 173:759,r2005

Wing DA, Lovett K, Paul RH: Disruption of prior uterine incision following misoprostol for labor induction in women with previous cesarean delivery. Obstet Gynecol 91 :828, 1998

Wing DA, Paul RH: Vaginal birth after cesarean section: selection and management. Clin Obstet GynecoIr42:836, 1999

Zelop CM, Shipp TO, Repke ]T, et al: Outcomes of trial of labor following previous cesarean delivery among women with fetuses weighing >4000 g. Am] Obstet Gynecol 185:903,2001

Zelop CM, Shipp TO, Repke ]T, et al: Uterine rupture during induced or augmented labor in gravid women with one prior cesarean delivery. Am ] Obstet Gynecol 181r:882, 1999

The Newborn

TRANSITION TO AIR BREATHING .................. 606

CARE IN THE DELIVERY ROOM .................... 607

EVALUATION OF NEWBORN CONDITION ............ 610

PREVENTIVE CARE.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613

ROUTINE NEWBORN CARE ....................... 614

Normaly the newy born child begins to cry almost immediatey ater its exit from the vulva. This act indicates the establishment of respiration, which is accompanied by important modications in the circulatory system.

-J. Whitridge Williams (1903)

In most instances at delivery, the newborn is healthy and vigorous, but at times, special care may be needed. For this reason, the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (20 17b) recommend that every birth should be attended by at least one qualified individual. This person should be skilled in the initial steps of newborn care and positive-pressure ventilation, and their only responsibility is management of the newborn. his usually is a pediatrician, nurse practitioner, anesthesiologist, nurse anesthetist, or specially trained nurse. However, in their absence, the responsibility for neonatal resuscitation falls to the obstetrical attendant. hus, obstetricians should be well versed in measures for immediate care of the newborn.

The number and qualiications of personnel who attend the delivery will vary depending on the anticipated risk, the number of babies, and the hospital setting. A qualiied team with full resuscitation skills should be present for high-risk deliveries and immediately available for every resuscitation (Wyckof, 2015). This team should not be on call at home or in a remote area of the hospital. Moreover, team training through frequent simulation practice is recommended for all who may be called to attend deliveries (Perlman, 2015).

Immediately following birth, the newborn must promptly convert from placental to pulmonary gas exchange. Pulmonary vascular resistance must fall, pulmonary perfusion must rapidly rise, and unique fetal vascular shunts must begin to close to separate the systemic and pulmonary circulations (Rudolph, 1979). These shunts include the patent ductus arteriosus and patent foramen ovale, described in Chapter 7 (p. 129). Lung aeration is not only critical for pulmonary gas exchange. Recent studies suggest that it is signiicantly responsible for initiating cardiovascular changes at birth (Hooper, 2016).

In utero, the fetal lungs are illed with amnionic luid, which must be cleared quickly for air breathing. This clearance occurs through various means, and the contributions of these mechanisms may depend on gestational age and mode of delivery. First, a large release of fetal adrenaline late in labor stimulates pulmonary epithelial cells to stop secreting and instead to start reabsorbing lung liquid as a result of sodium-channel activation (te Pas, 2008). The contribution of this mechanism is unlikely to be major, as blockade of the receptors for sodium channel activation reduces or delays but does not prevent lung liquid clearance at birth (O'Brodovich, 1990).

As a second method, mechanical forces aid lung fluid clearance during labor. Early reports described compression of the fetal thorax and abdomen as they passed through the birth canal leading to lung liquid expulsion (Karl berg, 1962; Saunders, 1978). By this mechanism, up to a third of lung liquid is expelled in a jet of luid from the nose and mouth once the respiratory tract is exposed to the lower outside pressure.

The Newborn 607

However, it may be that uterine contractions force a change in fetal posture leading to compression of the thorax and increased intrathoracic pressures. his prompts expulsion of lung liquid early in labor more so than the "vaginal squeeze" theory (Lines, 1997; te Pas, 2008; Vyas, 1981).

In a third mechanism, a significant amount of lung liquid is cleared after birth (Hooper, 2016). In animal studies, most lung aeration occurs during inspiration-within three to ive breaths after birth. But, no liquid clears between breaths (Hooper, 2007). Speciically, the transpulmonary pressure gradient during inspiration promotes movement of fluid into the interstitial tissue. From here, it is gradually cleared, probably by the pulmonary circulation and lymphatic vessls. It is possible for lung interstitial tissue pressure to rise to a point that luid can actually move back into the airspaces during expiration unless positive end-expiratory pressure opposes liquid reentry (Siew, 2009a,b). This may be a contributing factor in the development of transient tachypnea of the newborn.

As fluid is replaced by air, compression of the pulmonary vasculature is reduced considerably, and in turn, resistance to blood flow is lowered. With the fall in pulmonary arterial blood pressure, the ductus arteriosus normally closes.

High, negative intrathoracic pressures are required to permit the initial entry of air into the fluid-illed alveoli. Normally, from the irst breath after birth, progressively more residual air accumulates in the lung. And, with each successive breath, lower pulmonary opening pressure is required. In the normal mature newborn, by approximately the ifth breath, pressurevolume changes achieved with each respiration are very similar to those of the adult. hus, the breathing pattern shifts from shallow episodic inspirations characteristic of the fetus to regular, deeper inhalations (Chap. 17, p. 333).

As a last mechanism, surfactant, which is synthesized by the type II pneumocytes, lowers alveolar surface tension and helps maintain lung inlation by preventing alveolar collapse. Insuficient surfactant, which is common in preterm neonates, leads promptly to respiratory distress syndrome (Chap. 34, p. 636).

In utero, umbilical venous retun is the main source of preload for the left ventricle, particularly as fetal pulmonary blood flow is very low due to high pulmonary vascular resistance and is unable to provide suicient venous return to maintain left ventricular output (Hooper, 2015).

Clamping the umbilical cord reduces preload for the left ventricle and thus reduces cardiac output. Until the lungs aerate and pulmonary blood low increases, the reduced cardiac output will manifest as bradycardia. If cord clamping is delayed until after the lungs have aerated, the transition is smoother and cardiac ouput does not fall (Bhatt, 2013). This understanding has led to interest in delayed (physiological) cord clamping, especially if it can be done after successful inflation of the lung. Randomized trials are currently underway.

The International Liaison Committee on Resuscitation (ILCOR) updated its scientiic review for neonatal delivery room care and resuscitation (Perlman, 2015). The ILCOR scientiic review is used by the American Academy of Pediatrics and the American Heart Association to develop the neonatal resuscitation guidelines for North America (Wyckof, 2015).

Before and during delivery, careful consideration must be given to several determinants of neonatal well-being. hese include: (1) maternal health status; (2) prenatal complications, including any suspected fetal malformations; (3) gestational age; (4) labor complications; (5) duration of labor and ruptured membranes; (6) type and duration of anesthesia; (7) diiculty of delivery; and (8) medications given during labor and their dosages, administration routes, and timing.

When risk factors are present, neonatal resuscitation providers should be present for the delivery. This team readies equipment, ensures that adequate personnel are present, delegates roles and responsibilities, and considers contingency plans to stabilize the newborn. Four questions a neonatal provider will ask pertain to expected gestional age, amnionic fluid color, fetal number, and additional fetal risks. Several conditions are associated with a nonvigorous presentation. These may include immaturity, hypoxemia or acidosis from any cause, sepsis syndrome, recent drugs administered to the mother, and central nervous system developmental abnormalities. Those related to the respiratory tract are lung abnormalities, upper airway obstruction, pneumothorax, and meconium aspiration.

Ideally, obstetrical and pediatric teams discuss plans regarding umbilical cord management. Delayed cord clamping provides transfusion of placental blood to the newborn. In term infants, delay of cord clamping by 30 to 60 seconds raises hemoglobin levels at birth, improves iron stores during infancy, and enhances neurodevelopment at 4 years of age (Katheria, 2017). As discussed in Chapter 33 (p. 625), the only reported negative outcome of delayed cord clamping is hyperbilirubinemia, leading to a higher rate of phototherapy (American College of Obstetricians and Gynecologists, 2017a). In preterm neonates, delayed cord clamping reduces rates of blood transfusion, intraventricular hemorrhage, and necrotizing enterocolitis.

Delayed cord clamping should be performed in preterm and term newborns who do not require resuscitation at birth (American Academy of Pediatrics, 2017 a; American College of Obstetricians and Gynecologists, 2017a; Perlman, 2015). here should be no delay if a newborn requires resuscitation or if the placental circulation is disrupted by abruption, cord avulsion, or bleeding placenta previa or vasa previa.

Approximately 10 percent of newborns require some degree of active resuscitation to stimulate breathing, and 1 percent need extensive care. Perhaps not coincidentally, the risk of death for newborns delivered at home compared with those delivered in hospitals is increased two-to threefold (American College of Obstetricians and Gynecologists, 2017 d).

When deprived of adequate gas exchange, either before or after birth, neonates demonstrate a well-deined sequence of

FIGURE 32-1 Physiological changes associated with primary and secondary apnea in the newborn. bpm = beats per minute; HR = heart rate; MAP mean arterial pressure. (Adapted with permission from Kattwinkel J: Textbook of Neonatal Resuscitation, 6th ed. Elk Grove Village, American Academy of Pediatrics and American Heart Association, 2010.) events leading to apnea (Fig.

With oxygen deprivation and carbon dioxide (C02) elevation, there is a transient period of rapid breathing, and if it persists, breathing stops, which is termed primay apnea. This stage is accompanied by a fall in heart rate and loss of neuromuscular tone. Simple stimulation will usually reverse primary apnea. If oxygen deprivation and asphyxia persist, however, the newborn will develop deep gasping respirations, followed by seconday apnea. This latter stage is associated with a further decline in heart rate, fall in blood pressure, and loss of neuromuscular tone. Neonates in secondary apnea will not respond to stimulation and will not spontaneously resume respiratory eforts. Unless ventilation is assisted, death follows.

Clinically, primary and secondary apneas are indistinguishable, and thus, secondary apnea must be assumed. And, when a response to stimulation is not immediate, resuscitation with efective ventilation of the apneic newborn must be started quickly.

Immediately after birth and usually during the delay for umbilical cord clamping, newborn tone, respiratory efort, and heart rate are evaluated (Fig. 32-2). :Most term neonates are vigorous by 10 to 30 seconds after birth (Ersdal, 2012). For these, initial steps of warming the newborn can be done on the mother's chest or abdomen. Direct skin-to-skin contact with the mother and drying and covering the newborn with a warm blanket will help maintain euthermia (36.5 to 37.5°C). A vigorously crying newborn does not require routine oral suctioning (Carrasco, 1997; Gungor, 2006). Instead, bulb suctioning to remove secretions is best reserved for those who cannot clear secretions on their own due to apnea or copious secretions. Additional routine care steps include drying, gentle stimulation by rubbing the newborn's back, and continued observation during the transition period.

If not vigorous or if preterm, the neonate is carried to a prewarmed radiant warmer for the initial newborn care steps.

The initial wet birth blanket is removed to allow newborn drying. Cold stress is associated with multiple neonatal morbidities and mortality. Preterm infants are particularly vulnerable, and special steps to maintain euthermia include providing a warmer delivery room (>25°C), covering the neonatal head with either a plastic or wool hat, application of polyethylene plastic "ponchos" or wraps to slow evaporative heat losses, use of chemically activated thermal mattresses to reduce conductive heat loss, and administration of warm, humidified respiratory gases during respiratory stabilization (Perlman, 2015).

At the radiant warmer, newborns must be positioned to maximally open the airway, with mild extension of the neck. If the newborn is apneic or has copious secretions that it cannot clear, a bulb syringe or suction catheter may be used to clear the mouth and then the nose. Routine intubation and suctioning of meconium-stained amnionic luid is no longer recommended for the nonvigorous newborn (American College of Obstetricians and Gynecologists, 2017b; Perlman, 2015). Intubation and suction are reserved for suspected airway obstruction.

After completion of the initial stabilization steps, apnea, gasping respirations, or heart rate � 100 beats per minute (bpm) should prompt immediate administration of positivepressure ventilation with room air (Fig. 32-3). his should be started by 60 seconds of life, if not sooner, once the initial steps are completed.

Assisted ventilation by facemask at a rate of 40 to 60 breaths per minute is recommended. Oxygen saturation is monitored by pulse oximetry. Supplemental oxygen can be given in graduated, rising percentages to maintain oxygen saturation values within a normal range per minute of life. Adequate ventilation is best indicated by an improved heart rate. Colorimetric end-tidal carbon dioxide (ETC02) monitoring placed between the positive-pressure device and facemask serves as a helpful adjunct for detection of successful gas exchange during mask ventilation (Weiner, 2016).

If the heart rate remains � 100 bpm after 5 to 10 positive pressure breaths, the attempted ventilation is inadequate and corrective steps must be taken. These can be remembered by the pneumonic MR. SOPA (Table 32-1). The two most common problems are mask leak due to an inefective seal and malposition of the airway (Schmolzer, 2011). If corrective steps do not improve the heart rate, either intubation with an endotracheal tube or placement of a laryngeal mask airway is required.

If mask ventilation is inefective or prolonged, an alternative airway is placed. For tracheal intubation, a laryngoscope with a straight blade-size 0 for a preterm newborn and size 1 for a term neonate-is used. Gentle cricoid pressure may be useful. An increasing heart rate and ETC02 detection after several breaths are the primary methods of conirming intubation of the trachea and not the esophagus. One can also look for symmetrical chest wall motion; auscultate for equal breath sounds, especially in the axillae; and auscultate for the absence of breath sounds or gurgling over the stomach.

The Newborn 609

Once in place, the tube is used for tracheal suctioning only for a suspected obstructed airway. Otherwise, an appropriate positive-pressure device is attached to the endotracheal tube. Air pufs are delivered at a rate of 40 to 60 per minute with a force adequate to stabilize the heart rate. In term infants, opening pressures of 30 to 40 cm H20 typically will expand the alveoli without causing barotrauma. Once the lung is inflated, less pressure is typically needed (20 to 25 cm

H20). For preterm infants, pressures of 20 to 25 cm

Term?

Good tone?

Breathing/crying?

H20 are typically used. An increase in heart rate and peripheral oxygen saturation (Sp02) levels within acceptable ranges reflect a positive response.

FIGURE 32-2 Algorithm for resuscitation of the newborn based on the International Liaison Committee on Resuscitation scientific review and recommended by the American Academy of Pediatrics and American Heart Association (Perlman, 2015; Wyckoff, 2015). bpm = beats per minute; CPAP = continuous positive airway pressure; ECG = electrocardiogram; ETT = endotracheal tube; HR = heart FIGURE 32-3 Correct use of bag-and-mask ventilation. The head rate; IV = intravenous; PPV = positive-pressure ventilation; Sp02= should be in a sniffing position with the tip of the nose pointing to peripheral oxygen saturation; UVC = umbilical venous catheter. the ceiling. The neck should not be hyperextended.

Epinephrine measures (American Academy of Pediatrics, 2017). s shown in Table 32-2, each of five easily identiiable characteristics

Intravenously administered epinephrine is indicated if the heart heart rate, respiratory efort, muscle tone, relex irritability, andrate remains ;60 bpm after adequate ventilation and chest color-is assessed and assigned a value of 0, 1, or 2. In the curcompressions. The recommended intravenous dose is 0.01 to rently recommended expanded form, concurrent resuscitation 0.03 mg/kg. Epinephrine may be given through the endotracheal interventions are also recorded over time. he total score, based on tube if venous access has not been established, but its action is the sum of the five components, is determined in all neonates at 1less reliable (Kapadia, 2017). If given through the endotracheal and 5 minutes ater delivery. In those with a score <7, the scoretube, higher doses are employed-0.05 to 0.1 mg/kg.

may be calculated at urther 5-minute intervals until a 20-minute Discontinuation of Resuscitation Apgar score is assigned or resuscitation eforts are halted.

In an analysis of more than 150,000 newborns delivered at ILCOR concludes that it is reasonable to discontinue resusciParkland Hospital, Casey and associates (2001 b) assessed thetative eforts for a neonate who remains without a heartbeat signiicance of the 5-minute score for predicting survival durdespite at least 10 minutes of continuous and adequate resusciing the first 28 days of life. They found that in term neonates,tative eforts. Notably, the decision to continue or discontinue the risk of neonatal death was approximately 1 in 5000 for resuscitative eforts must be individualized (Perlman, 2015).

those with Apgar scores of 7 to 10. his risk compares with a mortality rate of 25 percent for term newborns with 5-minute scores ;3. Low 5-minute scores were comparably predictive of neonatal death in preterm neonates. These investigators con • Apgar Score cluded that the Apgar scoring system remains relevant for the he scoring system described by Dr. Virginia Apgar in 1953 prediction of neonatal survival. remains a useul clinical tool to classiY newborn health immeThere have been attempts to use Apgar scores to define diately after birth and to assess the efectiveness of resuscitative asphxial injury and to predict subsequent neurological

TABLE 32-2. 20-Minute Expanded Apgar Score

Respiration Absent Weak cry; hypo-Good, crying

Comments: Resuscitation

CPAP = continuous positive airway pressure; En = endotracheal tube; PPV = positive-pressure ventilation. Data from Weiner, 2016.

outcome-uses for which the Apgar score was never intended (Chap. 33, p. 624). Such associations are diicult to mea sure with reliability given that both asphyxial injury and low

Apgar scores are infrequent outcomes. For example, according to United States birth certiicate records for 2010, only 1.8 percent of newborns had a 5-minute score below 7 (Martin, 2012). Similarly, in a population-based study of more than 1 million term newborns in Sweden between 1988 and 1997, the incidence of 5-minute Apgar scores of �3 approximated 2 per 1000 (Thorngren-Jerneck, 2001).

Previously, many groups established erroneous definitions of asphyxia based solely on low Apgar scores. hese prompted the American College of Obstetricians and Gynecologists and American Academy of Pediatrics (2017f) to issue a series of joint opinions with important caveats regarding Apgar score limitations. Certain elements of the Apgar score are partially dependent on the physiological maturity of the newborn, and a healthy, preterm neonate may receive a low score only because of immaturity. Other influencing factors include fetal malformations, maternal medications, and infection. Therefore, it is inappropriate to use an Apgar score alone to diagnose asphyxia. Moreover, the Apgar score alone cannot establish hypoxia as the cause of cerebral palsy, as discussed in Chapter 33 (p. 624).

Blood taken from umbilical vessels may be used for acid-base studies to assess the metabolic status of the neonate. Blood collection is performed following delivery by immediately isolating a 10-to 20-cm segment of cord with two clamps placed near the neonate and another two clamps positioned nearer the placenta. The cord is then cut between the two proximal clamps and then the two distal clamps (Blickstein, 2007).

Arterial blood is drawn from the isolated cord segment into a 1-to 2-mL commercially prepared plastic syringe containing lyophilized heparin or a similar syringe that has been flushed with a heparin solution containing 1000 U/mL. Once sampling is completed, the needle is capped and the syringe transported, on ice, to the laboratory. Although eforts should be made for prompt transport, neither the pH nor partial pressure of CO2 (pC02) values change significantly in blood kept at room temperature for up to 60 minutes (Lynn, 2007). Mathematical models have been developed that allow reasonable prediction of birth acid-base status in properly collected cord blood samples analyzed as late as 60 hours after delivery (Chauhan, 1994). Acid-base measurements can show signiicant variances between diferent analyzing devices (vlokarami,r2012).

he fetus produces both carbonic and organic acids. Carbonic acid (H2C03) is formed by oxidative metabolism of CO2. he fetus usually rapidly clears CO2 through the placental circulation. If CO2 clearance is lowered, then carbonic acid levels rise. This often follows impaired placental exchange. When H2C03

The Newborn 61 1 rently rise, the result is respiratoy acidemia.

In contrast, organic acids primarily include lactic and 3-hydroxybutyric acids. Levels of these increase with persistent placental exchange impairment, and they result from anaero bic glycolysis. These organic acids are cleared slowly from fetal blood. When they accumulate, without a concurrent increase in H2C03, the result is metabolic acidemia. With the develop ment of metabolic acidemia, bicarbonate (HC03 -) levels drop because it is used to bufer the organic acid. A rise in H2C03 concentrations accompanied by greater organic acid levels, relected by decreased HC03 -levels, causes mixed respiratoy metabolic acidemia.

In the fetus, respiratory and metabolic acidemia and ultimately tissue acidosis are most likely part of a progressively worsening continuum. his is diferent from adult pathophysiology, in which distinct conditions result either in respiratory acidosis-for example, pulmonary disease, or in metabolic acidosis-for example, diabetes. In the fetus, the placenta serves as both the lungs and, to a certain degree, the kidneys. One principal cause of fetal acidemia is a drop in uteroplacental perfusion. This creates retention of CO2, that is, respiratory acidemia, and if protracted and severe enough, yields a mixed or metabolic acidemia.

Assuming that maternal pH and blood gases are normal, the actual pH of fetal blood is dependent on the proportion of carbonic and organic acids and the amount of bicarbonate, which is the major bufer in blood. This can best be illustrated by the Henderson-Hasselbalch equation: [base]pH = pK + Iog -or, pH = pK + Iog

For clinical purposes, HC03-represents the metabolic component and is reported in mEq/L. The H2C03 concentration reflects the respiratory component and is reported as the pC02 in mm Hg. Thus:

The result of this equation is a pH value. Because pH is a logarithmic term, it does not give a linear measure of acid accumulation. For example, a change in hydrogen ion concentration associated with a fall in pH from 7.0 to 6.9 is almost twice that which is associated with a fall in pH from 7.3 to 7.2. For this reason, the change in base-termed delta base-ofers a more linear measure of the degree of accumulation of metabolic acid (Armstrong, 2007). The delta base is a calculated number used as a measure of the change in bufering capacity of bicarbonate (HC03 -). he formula for calculating the base excess (BE) is as follows:

BE = 0.02786 X pC02 X lO(pH -6.,1) X 13.77 X pH -124.58 32-4 is a nomogram developed from which these can be calculated if only two parameters are known. For example, the HC03 -concentration declines with a metabolic acidemia as it is consumed to maintain a normal pH. A base deicit develops when the HC03-concentration drops below 6.8 reported for preterm neonates (Dick8 pH 015 ? ,:00 ,0ED 70 inson, 1992; Ramin, 1989; Riley, 7.2 7.1 Fetal oxygenation and pH generally decline during the course of normal 7.0 labor. Normal umbilical cord blood pH and blood gas values at delivery 6.9 60 in term newborns are summarized in

Table 32-3. Similar values have been 6.7 1993). he lower limits of normal pH in the newborn have been found to range from 7.04 to 7.10 (horp, 6.6 1996). Thus, these values should be 6 considered to deine neonatal acidemia. Even so, most fetuses will tol erate intrapartum acidemia with a 110 pH as low as 7.00 without incurring neurological impairment (Freeman, 1988; Gilstrap, 1989). That said, in FIGURE 32-4 Nomogram for determining the delta base. (Adapted with permission from Siggaarda study of newborns with a pH <7.0 Anderson 0: Blood acid-base alignment nomogram, Scand J (lin Lab Invest. 1963;15:21o1-7.) from Parkland Hospital, there were

TABLE 32-3. Umbilical Cord Blood pH and Blood Gas Values in Normal Term Newborns

Ramin, 1989a Riley, 1993b Kotaska, 201 Ob Kotaska, 2010e pH 7.28 (0.07) 7.27 (0.069) 7.26 (7.01n-7.39) 7.3 (7.05-7.39) Pco2 (mm Hg) 49.9 (14.2) 50.3(11n.1) 51 (30.9-85.8) 54 (37.5-79.5) HC03 -(mEq/L) 23.1 (2.8) 22.0 (3.6) Base excess (mEq/L) -3.6 (2.8) -2.7 (2.8) pH 7.34 (0.063) 7.31 (7.06-7.44) 7.34 (7.10-7.42) PC02 (mm Hg) 40.7 (7.9) 41 (24.9-70.9) 44 (29.1n-70.2) HC03 -(mEq/L) 21.4 (2.5) Base excess (mEq/L) -2.4 (2) aNewborns of selected women with uncomplicated vaginal deliveries. bNewborns of unselected women with vaginal deliveries.

(Data shown as mean (SO). dOata shown as range with 2.5 or 97.5 percentile. eCesarean delivery-labor not stated.

From Centers for Disease Control and Prevention, 201n2; Watson, 2006.

normal levels, and a base excess occurs when HC03 -values are above normal. Importantly, a mixed respiratory-metabolic acidemia with a large base deicit and a low HC03 -, for example 12 mmollL, is more often associated with a depressed neonate than is a mixed acidemia with a minimal base deficit and a more nearly normal HC03 -level.

The Newborn 61 3 inordinate proportions of neonatal deaths-8 percent, intensive care admissions-39 percent, intubations-14 percent, and seizures-13 percent (Goldaber, 1991). And, in a study from Oxford of more than 51,000 term newborns, the incidence of neonatal encephalopathy in those with a birth pH <7.0 was 3 percent (Yeh, 2012). Even those with who had normalrS-minute Apgar scores but an arterial cord pH values <7.0 had a significantly higher risk of morbidity that included respiratory distress, neonatal intensive care unit admission, and sepsis (Sabol, 2016). The speed of acidemia resolution after birth is associated with outcome (Casey, 2001a).

Acute interruption in placental gas exchange is accompanied by subsequent CO2 retention and respiratory acidemia. The most common antecedent factor is transient umbilical cord compres sion. Generally, respiratory acidemia is not harmful to the fetus (Low, 1994).

he degree to which pH is afected by pC02-the respira tory component of the acidosis-can be calculated. First, the upper normal neonatal pC02 of about 50 mm Hg is subtracted from the cord blood gas pC02 value. Each additional 10 mm

Hg pC02 increment will lower the pH by 0.08 units (Eisen berg, 1987). hus, in a mixed respiratory-metabolic acidemia, the benign respiratory component can be calculated. As an example, acute cord prolapse during labor prompts cesarean delivery of a neonate 20 minutes later. The umbilical artery blood gas pH was 6.95 and the pC02 was 90 mm Hg. The degree to which the cord compression and subsequent impair ment of CO2 exchange afected the pH is calculated using the relationship given earlier and shown below.

To correct pH: (40 -10) X 0.08 = 0.32; 6.95 + 0'.32 = 7.27

Therefore, the pH before cord prolapse was approximately 7.27, well within normal limits. Thus, the low pH resulted from respiratory acidosis.

The fetus begins to develop metabolic acidemia when oxygen deprivation is suiciently long and severe to require anaerobic metabolism for cellular energy needs. Low and associates (1997) defined fetal acidosis as a base deicit ::12 mmoUL, and severe fetal acidosis as a base deicit ::16 mmoUL. In the Parkland study of more than 150,000 newborns cited earlier, metabolic acidemia was defined using umbilical cord blood gas thresholds that were two standard deviations below the mean (Casey, 2001 b). Thus, metabolic acidemia was an umbilical artery blood pH <7.00 accompanied by a pC02 ;76.3 mm Hg, with higher values indicating a respiratory component; HC03-concentration ;17.7 mmoUL; and base deficit ::10.3 mEq/L. From the standpoint of possible neurological injury, the American College of Obstetricians and Gynecologists (2014) defines metabolic acidosis as umbilical arterial pH <7.0 and a base deficit ::12 mmoUL.

Metabolic acidemia is associated with a high rate of multiorgan dysfunction. In rare cases, such hypoxia-induced metabolic logical impairment-hypoxic-ischemic encephalopathy (Chap.

33, p. 621). In fact, a fetus without such acidemia cannot by definition have sufered recent hypoxic-induced injury. hat said, severe metabolic acidosis is poorly predictive of subse quent neurological impairment in the term neonate (King, 1998; Socol, 1994). In very-Iow-birthweight neonates, that is, those < 1000 g, newborn acid-base status may be more closely linked to intraventricular hemorrhage and possibly long-term neurological outcome (Lavrijsen, 2005; Salhab, 2005; Victory, 2003).

Casey and coworkers (2001 b) described the association between metabolic acidemia, low Apgar scores, and neonatal death in term and preterm newborns. Regarding term neonates, the risk of neonatal death was more than 3200-fold greater in term neonates with metabolic acidemia and 5-minute scores ;3 compared with those with a 5-minute Apgar score ::7.

In some centers, cord gas analysis is performed in all neonates at birth (Casey, 2001 b; Sabol, 2016). Cost-efectiveness analysis potential cost savings (White, 2010, 2016). It seems reasonable of cesarean delivery for fetal compromise, abnormal fetal heart rate tracing, fever, and low 5-minute Apgar score. Multifetal gestation and severely growth-restricted fetuses are others.

are poorly predictive of either immediate or long-term adverse neurological outcome, they provide the most objective evidence of the fetal metabolic status at birth.

Ophthalmia neonatorum is mucopurulent conjunctivitis of newborns. Some form of conjunctivitis afects 1 to 12 percent of all neonates, and gonococcal and chlamydial infections are among the most common (Zuppa, 201r1).

Neisseria gonorrhoeae infection acquired at birth was a common cause of childhood blindness in the past. However, the practice of instilling a I-percent ophthalmic solution of silver nitrate largely eliminated this. Various other antimicrobial agents have also proven efective, and gonococcal prophylaxis is now mandatory for all neonates in most states (American Academy ofPediatrics, 20 17b). Forprophyxis soon ater delivery, recommendations include a single application of either I-percent silver nitrate solution or 0.5-percent erythromycin ointment. In North America, a previously used I-percent tetracycline ophthalmic ointment is no longer available (Mabry-Hernandez, 2010; Moore, 2015).

For a neonate born to a mother with untreated gonorrhea, treatment of presumptive neonatal gonococcal conjunctivitis is a single ceftriaxone dose, 100 mg/kg, given either intramuscularly or intravenously. Before treatment, testing for both gonococcal and chlamydia infections should be obtained.

With chamydial conjunctivitis, adequate neonatal prophylaxis is complex. Ideally, prenatal screening and treatment for Chamydia trachomatis obviates conjunctival infection (Hammerschlag, 2011). In neonates delivered vaginally of mothers with an active chlamydial infection, 12 to 25 percent will develop conjunctivitis up to 20 weeks ater birth (Teoh, 2003). Prophyactic topical eye treatments do not reliaby reduce the incidence of chlamydial conjunctivitis. In a study from Kenya, 2.5-percent povidone-iodine solution was reported to be superior to either I-percent silver nitrate solution or 0.5-percent erythromycin ointment in preventing chlamydial conjunctivitis (Isenberg, 1995). In another study from Iran, povidone-iodine eye drops were twice as efective in preventing clinical conjunctivitis as erythromycin drops-9 versus 18 percent failure rate, respectively (Ali, 2007).

Conjunctivitis in a newborn up to age 3 months should prompt consideration for chlamydial infection (Moore, 2015). Treatment for pediatric chlamydial infection is with oral azithromycin for 5 days or oral erythromycin for 14 days.

Routine immunization with thimerosal-free vaccine against hepatitis B before hospital discharge is standard practice for all medically stable newborns with birthweights greater than 2000 g (merican Academy of Pediatrics, 20 17b). If the mother is seropositive for hepatitis B surface antigen, then the neonate is also passively immunized with hepatitis B immune globulin. As discussed in Chapter 55 (p. 1064), some advocate treatment of high-risk or even all seropositive women with antiviral nucleoside or nucleotide analogues during pregnancy to minimize fetal transmission (Dusheiko, 2012; Tran, 2012).

his virus is primarily spread by mosquito bites. Infection is asymptomatic in most people but can cause severe birth defects (Chap. 64, p. 1219). Screening begins with an interrogation for recent travel to endemic areas. For women at risk, serological screening is then completed. All newborns of mothers who have laboratory evidence of Zika virus infection during pregnancy should receive a comprehensive examination, a neurological assessment, postnatal head ultrasound, standard newborn hearing screen before hospital discharge, and Zika virus laboratory testing (Reynolds, 2017).

Supplemental vitamin K injection will prevent vitamin K-dependent hemorrhagic disease of the newborn (Chap. 33, p. 626). A single intramuscular dose of vitamin K, 0.5 to 1 mg, is given within 1 hour of birth (American Academy of Pediatrics, 2017b).

Numerous mass-screening tests are now available for 29 newborn conditions. Shown in Table 32-4, many are mandated by various state laws (American College of Obstetricians and Gynecologists, 2017 c). lost states require that all tests in the core panel be performed. Supplemental conditions-secondary targets-are also listed on the Maternal and Child Health Bureau website. Some states require some of these in addition to their mandated core panel. Each practitioner should be familiar with their individual state requirements, which are available at http:// genes-r-us.uthscsa.edu/resources/consumer/statemap.htm.

Newborn gestational age can be estimated very soon after delivery. The relationship between gestational age and birthweight can identiy neonates at risk for complications. For example, (cobalamin A, B) Propionic 3-Ketothiolase aDetermined by tandem mass spectrometry. bAdded after 2006.

From Centers for Disease Control and Prevention, 20r12; Watson, 2006.

The Newborn 61 5 neonates who are either small or large for gestational age are at greater risk for hypoglycemia and polycythemia, and measurements of blood glucose and hematocrit are indicated.

• Care of Skin and Umbilical Cord

All excess vernix, blood, and meconium is gently wiped of after delivery while keeping the newborn warm. Any remaining ver nix is readily absorbed and disappears within 24 hours. he first bath is postponed until the neonate's temperature is stable.

Aseptic precautions are observed in the immediate care of the cord. The American Academy of Pediatrics has concluded that keeping the cord dry is suicient care (Stewart, 2016). he umbilical cord begins to lose water from Wharton jelly shortly after birth. Within 24 hours, the cord stump loses its characteristic bluish-white, moist appearance and soon becomes dry and black. Within several days to weeks, the stump sloughs and leaves a small, granulating wound, which after healing forms the umbilicus. Separation usually takes place within the irst 2 weeks. The range is 3 to 45 days (Novack, 1988). he umbilical cord dries more quickly and separates more readily when exposed to air. Thus, a dressing is not recommended.

In resource-poor countries, local antimicrobial prophylaxis is reasonable (Salam, 2014). Triple-dye applied to the cord was reported to be superior to soap and water care in preventing colonization and exudate formation Qanssen, 2003). In a Nepalese study, cleaning the cord stump with 4-percent chlorhexidine reduced severe infection by 75 percent compared with soap and water (Mullany, 2006). Likewise, O.l-percent chlorhexidine powder was superior to dry cord care (Kapellen, 2009). he World Health Organization (2014) recommends cleansing with chlorhexidine.

Despite precautions, a serious umbilical infection-omphaLitis-sometimes develops. In a German study of more than 750 newborns with aseptic cord care, 1.3 percent sufered such infections (Kapellen, 2009). he most likely ofending organisms are StaphyLococcus aureus, Escherichia coLi, and group B streptococcus. Typical signs of cellulitis and stump discharge usually aid diagnosis. Mild erythema and some bleeding at the stump site with cord detachment is also common, but some cases present with no outward signs.

In 2016, 81 percent of U.S. newborns were initially breastfed, 52 percent were still breastfed at 6 months, and 31 percent at 1 year (Centers for Disease Control and Prevention, 2016). According to the American College of Obstetricians and Gynecologists (2017 e), exclusive breastfeeding is preferred until 6 months. In many hospitals, breastfeeding begins in the delivery room. Most term newborns thrive best when fed 8 to 12 times daily for approximately 15 minutes each episode. Preterm or growth-restricted newborns require feedings at shorter intervals. Breastfeeding is discussed further in Chapter 36 (p. 656).

Because most neonates actually receive little nutriment for the first 3 or 4 days of life, they progressively lose weight until the flow of maternal milk is established or other feeding is instituted. Preterm neonates lose relatively more weight and regain their birthweight more slowly. Conversely, growth-restricted but otherwise healthy newborns regain their initial weight more quickly than those born preterm. With proper nourishment, birthweight of term newborns usually is regained by 10 days.

For the irst 2 or 3 days after birth, the colon contains sot, brown-green meconium. his consists of desquamated epithelial cells from the intestinal tract, mucus, epidermal cells, and lanugo (fetal hair) that have been swallowed along with amnionic luid.

The characteristic color results from bile pigments. During fetal life and for a few hours after birth, the intestinal contents are sterile, but bacteria quickly colonize the bowel contents.

Meconium stooling is seen in 90 percent of newborns within the irst 24 hours, and most of the rest within 36 hours. Usually, newborns irst void shortly ater birth but may not until the second day. Meconium and urine passage indicates patency of the gastro intestinal and urinary tracts, respectively. Failure of the newborn to stool or urinate ater these times suggests a congenital defect, such as Hirschsprung disease, imperforate anus, or posterior urethral valve. Ater the third or fourth day, as a result of milk ingestion, meconium is replaced by light-yellow, soter, homogenous feces.

Between the second and fifth day of life approximately one third of all neonates develop physiological jaundice of the newborn. It has special significance considering most hospitals have policies for early discharge. Guidelines regarding standard phototherapy equipment and monitoring, as well as treatment recommendations per gestational age, hour of life, and risk factors are used (Bhutani, 2011; Maisels, 2009). Hyperbilirubinemia is discussed further in Chapter 33 (p. 626).

Neonatal circumcision of male infants has been a controversial topic in the United States for at least 30 years. Even so, scientific evidence supports several medical beneits that include prevention of phimosis, paraphimosis, and balanoposthitis. Circumcision also lowers the incidence of penile cancer and of cervical cancer among their sexual partners. Previously, the American Academy of Pediatrics Task Force on Circumcision (1999) concluded that existing evidence was insuicient to recommend routine neonatal circumcision. It seems that this policy has had only a negligible efect on practices in this country. Speciically, the Centers for Disease Control and Prevention (2011) estimated that the newborn male circumcision rate declined during a 12-year period from approximately 60 percent in 1999 to only 55 percent in 2010.

Other studies have endorsed health beneits of circumcision.

In large randomized trials from regions of Africa with a high prevalence of human immunodeiciency virus (HIV), male circumcision was found to lower the risk of HIV acquisition in the adult by half (Bailey, 2007; Gray, 2007). And, male circumcision was also reported to decrease adult incidences of HIV, HPV, and herpes infections (Tobian, 2009). In its subsequent policy statement, the American Academy of Pediatrics Task Force on Circumcision (2012) concluded that health beneits of newborn male circumcision outweigh the risks. hus, access to the procedure is justified for families who choose it. The Task Force stopped short of recommending circumcision for all newborns.

Circumcision is performed only in a healthy neonate. Other contraindications include any genital abnormalities such as hypospadias and a family history of a bleeding disorder, unless excluded in the newborn.

The Task Force (2012) recommends procedural analgesia.

Various pain relief techniques include lidocaine-prilocaine topical cream, local analgesia iniltration, dorsal penile nerve block, or ring block (Arnett, 1990; Stang, 1988). The dorsal penile nerve block or the ring block is superior to topical analgesia (Hardwick-Smith, 1998; Lander, 1997; Taddio, 1997). he use of a paciier dipped in sucrose is a useful adjunct to these methods (Kaufman, 2002).

After appropriate penile cleansing, the ring block places a wheal of I-percent lidocaine at the base of the penis and then advances the needle in a 180-degree arc around the base of the penis. The needle is advanced first to one side and then to the other to achieve a circumferential ring of analgesia. he maximum dose of lidocaine is 1.0 mL. No vasoactive compounds such as epinephrine should ever be added to a local analgesic agent or circumcision.

The most commonly used instruments are shown in Figure 32-5 and are Gomco and Mogen clamps and the Plastibell device. Compared with the Gomco procedure, Kaufman and colleagues (2002) reported that the Mogen technique required

FIGURE 32-5 Three different tools used for circumcision.

A.Mogen clamp. The arms of the clamp open to a 3-mm maximum width. B. Gomco clamp, assembled. C. Plastibell device.

less time to perform and was associated with less apparent discomfort for the newborn. Regardless of the method used, the goal is to remove enough shaft skin and inner preputial epithelium so that the glans is exposed suiciently to prevent phimosis. In all techniques: (1) the amount of external skin to be removed must be accurately estimated, (2) the preputial oriice must be dilated to visualize the glans and ensure that it is normal, (3) the inner preputial epithelium must be freed from the glans epithelium, and (4) the circumcision device must be left in place long enough to produce hemostasis before amputating the prepuce (Lerman, 2001).

The risks for bleeding, infection, and hematoma formation are low (Christakis, 2000). Unusual complications include distal glans amputation, acquisition of HIV infection or other sexually transmitted disease, meatal stenosis, penile denudation, penile destruction with electrosurgical coagulation, subsequent epidermal inclusion cyst and urethrocutaneous fistula, and ischemia following the inappropriate use of lidocaine with epinephrine (Amukele, 2003; Neulander, 1996; Nicoll, 1997; Pippi-Salle, 2013; Upadhyay, 1998).

Hospital rooming in places newborns in their mothers' rooms instead of central nurseries. This practice attempts to make all phases of childbearing as natural as possible and to foster early mother-child relationships. By 24 hours, the mother is generally fully ambulatory. hereafter, with rooming-in, she can usually provide routine care for herself and her newborn. n obvious advantage of this is her ability to assume full care when she arrives home.

Traditionally, the newborn is discharged with its mother, and in most cases, maternal stay has determined that of the neonate. From 1970 to the mid-1990s, average maternal postpartum length of stay declined steadily, and many mothers were discharged before 48 hours. The World Health Organization (2014) cites a minimal stay of only 24 hours. Although it is clear that most newborns can be safely discharged within 48 hours, this is not uniformly true. For example, in more than 2.1 million neonates in Canada, Liu and associates (2000) examined readmission rates following initial neonatal discharge. As the length of hospital stay dropped from 4.2 days in 1990 to 2.7 days in 1997, the readmission rate rose from 27 to 38 per 1000. Dehydration and jaundice accounted for most of these readmissions. Using Washington state data, Malkin and coworkers (2000) found that the 28-day mortality rate was increased fourfold in newborns discharged within 30 hours of birth, and the I-year mortality rate grew twofold. Safe discharge for latepreterm newborns has special concerns (Whyte, 2012).

Because of the increased scrutiny regarding short hospital stays, federal legislation-he Newbons' and Mothers' Health Protection Act of 199-was enacted to prohibit insurers from restricting hospital stays for mothers and newborns to less than 2 days for vaginal delivery or 4 days for cesarean delivery. In an analysis of more than 662,000 births in California, Datar and Sood (2006) found that readmission rates declined by 9, 12, and 20 percent, respectively, at 1, 2, and 3 years after the legislation was implemented.

li A, Khadije D, Elahe A, et al: Prophylaxis of ophthalmia neonatorum comparison of Betadine, erythromycin and no prophylaxis. J Trop Pediatr 53(6):388, 2007

American Academy of Pediatrics: Delayed umbilical cord clamping after birth.

Pediatrics 139(6), 2017a

American Academy of Pediatrics, American College of Obstetricians and Gynecologists: Care of the newborn. In Guidelines for Perinatal Care, 8th ed. Elk Grove Village, AAP, 2017b

American Academy of Pediatrics Task Force on Circumcision: Circumcision policy statement. Pediatrics 103:686, 1999

American Academy of Pediatrics Task Force on CircumCIsIOn: CircumCIsion policy statement. Pediatrics 130(3):585,t2012

American College of Obstetricians and Gynecologists: Executive summary: neonatal encephalopathy and neurologic outcome, second edition. Report of the American College of Obstetricians and Gynecologists' Task Force on Neonatal Encephalopathy. Obstet Gynecol 123(4):896,t2014

American College of Obstetricans and Gynecologists: Delayed umbilical cord clamping after birth. Committee Opinion No. 684, January 2017a

American College of Obstetricians and Gynecologists: Delivery of a newbor� with meconium-stained amniotic fluid. Committee Opinion No. 689, Apnl 2017b

American College of Obstetricians and Gynecologists: Newborn screening and the role of the obstetrician-gynecologist. Committee Opinion No. 616, January 2015, Reairmed 2017c

American College of Obstetricians and Gynecologists: Planned home birth.

Committee Opinion No. 697, Aprilt2017d

American College of Obstetricians and Gynecologists: Optimizing support for breastfeeding as part of obstetric practice. Committee Opinion No. 658, February 2016, Reairmed 2017 e

American College of Obstetricians and Gynecologists. American Academy of Pediatrics: The Apgar score. Committee Opinion No. 644, October 2015, Reairmed 2017f

Amukele SA, Lee GW, Stock JA, et al: 20-year experience with iatrogenic penile injury. J Urolt170:1691, 2003 .

Apgar V: A proposal for a new method of evaluation of the newborn mfant.

Curr Res Anesth Analg 32:260, 1953

Armstrong L, Stenson BJ: Use of umbilical cord blood gas analysis in the assessment of the newborn. Arch Dis Child Fetal Neonatal Ed 92:430, 2007

Arnett M, Jones JS, Horger EO III: Efectiveness of 1% lidocaine dorsal penile nerve block in infant circumcision. Am J Obstet Gynecol 163:1074, 1990

Bailey RC, Moses S, Parker CB, et al: Male circumcision for HIV prevention in young men in Kismu, Kenya: a randomized controlled trial. Lancet 369:643, 2007

Bhatt S, Alison BJ, Wallace EM, et al: Delaying cord clamping until ventilation onset improves cardiovascular function at birth in preterm lambs. J Physiol 591(8):2113,t2013

Bhutani K,Committee on Fetus and Newborn, American Academy ofPediatrics: Phototherapy to prevent severe neonatal hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 128(4):el046, 2011

Blickstein 1, Green T: Umbilical cord blood gases. Clin Perinatol 34(3):451, 2007

Carrasco M, Martell M, Estol PC: Oronasopharyngeal suction at birth: efects on arterial oxygen saturation. J Pediatr 130(5):832, 1997 .

Casey BM, Goldaber KG, Mcintire DD, et al: Outcomes among term mfants when two-hour postnatal pH is compared with pH at delivery. Am J Obstet Gynecol 184:447, 2001a

Casey BM, Mcintire DD, Leveno KJ: he continuing value of the Apgar score for the assessment of newborn infants. N Engl J Med 344:467, 2001b

Centers for Disease Control and Prevention: Breastfeeding report card: progressing toward national breastfeeding goals-United States 2016. Available at: http://www.cdc.gov/breastfeeding/data/reportcard2.htm. Accessed June 2017

Centers for Disease Control and Prevention: CDC grand rounds: newborn screening and improved outcomes. MMWR 61(21)390,t2012 Centers for Disease Control and Prevention: Trends in in-hospital newborn male circumcision-United States, 1999-2010. MMWR 60(34):1167, 2011

Chauhan SP, Cowan BD, Meydrech EF, et al: Determination of fetal acidemia at birth from a remote umbilical arterial blood gas analysis. Am J Obstet Gynecol 170: 1705, 1994

Christakis DA, Harvey E, Zerr DM, et al: A trade-of analysis of routine newborn circumcision. Pediatrics 105:246,t2000

Datar A, Sood N: Impact of postpartum hospital-stay legislation on newborn length of stay, readmission, and mortality in California. Pediatrics 118:63, 2006

The Newborn 617

Dickinson JE, Eriksen NL, Meyer BA, et al: The efect of preterm birth on umbilical cord blood gases. Obstet Gynecol 79:575, 1992

Dusheiko G: Interruption of mother-to-infant transmission of hepatitis B: time to include selective antiviral prophylaxis? Lancet 379(9830):2019, 2012 Eisenberg MS, Cummins RO, Ho MT: Code Blue: Cardiac Arrest and Resus citation. Philadelphia, Saunders, 1987

Ersdal HL, Mduma E, Svensen E, et al: Early initiation of basic resuscitation interventions including face mask ventilation may reduce birth asphyxia related mortality in low-income countries: a prospective descriptive observa tional study. Resuscitation 83(7):869, 2012 . .

Freeman JM, Nelson KB: Intrapartum asphyxia and cerebral palsy. Pediatrics 82:240, 1988

Gilstrap LC III, Leveno KJ, Burris J, et al: Diagnosis of birth asph�ia on the basis of fetal pH, Apgar score, and newborn cerebral dysfunction. Am J Obstet Gynecol 161:825, 1989

Goldaber KG, Gilstrap LC III, Leveno KJ, et al: Pathologic fetal acidemia.

Obstet Gynecol 78:1103, 1991

Gray RH, Kigozi G, Serwadda D, et al: Male circumcision for HIV prevention in Rakai, Uganda: a randomized trial. Lancet 369:657,t2007

Gungor S, Kurt E, Teksoz E, et al: Oronasopharyn�eal suction vers�s no suction in normal and term infants delivered by elective cesarean section: a prospective randomized controlled trial. Gynecol Obstet Invest 61 (1):9, 200?

Hammerschlag MR: Chlamydial and gonococcal infections in infants and children. Clin Infect Dis 53(3):S99, 2011

Hardwick-Smith S, Mastrobattista JM, Wallace PA, et al: Ring block for neonatal circumcision. Obstet Gynecol 91 :930, 1998

Hooper SB, Kitchen MJ, Wallace MJ, et al: Imaging lung aeration and lung liquid clearance at birth. FASEB J 21(12):3329, 2007

Hooper SB, te Pas AB, Kitchen MJ: Respiratory transition in the newborn: a three-phase process. Arch Dis Child Fetal Neonatal Ed 101(3):F266, 201?

Hooper SB, te Pas AB, Lang J, et al: Cardiovascular transition at birth: a phySIological sequence. Pediatr Res 77(5):608, 2015

Isenberg SJ, Apt L, Wood M: A controlled trial of povidone-iodine as prophy laxis against ophthalmia neonatorum. N Engl J Med 332:562, 1995 .

Janssen PA, Selwood BL, Dobson SR, et al: To dye or not to dye: a rando�lIzed clinical trial of a triple dye/alcohol regime versus dry cord care. PedJatflcs 111:15, 2003

Kapadia V, Wyckof MH: Chest compressions for bradycardia or asystole in neonates. Clin Perinatol 39(4):833, 2012

Kapadia VS, Wyckof MH: Epinephrine use during newborn resuscitation.

Front Pediatr 5:97, 2017

Kapellen TM, Gebauer CM, Brosteanu 0, et al: Higher rate of cord-related adverse events in neonates with dry umbilical cord care compared to chlorhexidine powder. Results of a randomized controlled study to compare eicacy and safely of chlorhexidine powder versus dry care in umbilical cord care of the newborn. Neonatology 96(1): 13, 2009

Karlberg P, Adams FH, Geubelle F, et al: Alteration of the infant's thorax dur ing vaginal delivery. Acta Obstet Gynecol Scand 41 :223, 1962 .

Katheria AC, Lakshminrusimha S, Rabe H, et al: Placental transfUSIOn: a review. J Perinatol 37(2): 105, 2017

Kattwinkel J: Textbook of Neonatal Resuscitation, 6th ed. Elk Grove Village, American Academy of Pediatrics and American Heart Association, 2010

Kaufman GE, Cimo S, Miller L W, et al: An evaluation of the efects of sucrose on neonatal pain with 2 commonly used circumcision methods. Am J Obstet Gynecol 186:564, 2002

King TA, Jackson GL, Josey AS, et al: The efect of profound umbil�cal artery acidemia in term neonates admitted to a newborn nursery. J Pedlatr 132(4):624, 1998

Kotaska K, Urinovska R, Klapkova E, et al: Re-evaluation of cord blood arterial and venous reference ranges for pH, pOz, pCOz, according to spontaneous or cesarean delivery. J Clin Lab Anal 24(5):300, 2010

Lander J, Brady-Fryer B, Metcalfe JB, et al: Comparison of ring block, dorsal penile nerve block, and topical anesthesia for neonatal circumcision: a randomized controlled trial. JAMA 278:2157, 1997

Lavrijsen SW, Uiterwaal CS, Stigter RH, et al: Severe umbilical co:d acidemia and neurological outcome in preterm and full-term neonates. BIOI Neonate 88(1):27, 2005

Lerman SE, Liao JC: Neonatal circumcision. Pediatr Clin North Am 48: 1539, 200t1

Lines A, Hooper SB, Harding R: Lung liquid production rates and v?lunes do not decrease before labor in healthy fetal sheep. J Appl PhyslOl (1985)82(3):927, 1997

Liu S, Wen SW, McMillan D, et al: Increased neonatal readmission rate associated with decreased length of hospital stay at birth in Canada. Can J Public Health 91 :46, 2000

Low JA, Lindsay BG, Derrick EJ: Threshold of metabolic acidosis associated with newborn complications. Am J Obstet GynecoIt177:1391, 1997

Lowt]A, Panagiotopoulos C, Derrick E]: Newborn complications after intrapartum asphyxia with metabolic acidosis in the term fetus. Am ] Obstet Gynecol 170: 1081, 1994

Lynn A, Beeby P: Cord and placenta arterial gas analysis: the accuracy of delayed sampling. Arch Dis Child Fetal Neonatal Ed 92(4):F281, 2007

Mabry-Henandez I, Oliverio-Hofman R: Ocular prophylaxis for gonococcal ophthalmia neonatorum: evidence update for the u.s. Preventive Services Task Force reairmation recommendation statement. AHRQ Publication No. 10-05146. Rockville, Agency for Healthcare Research and Quality, 2010

Maisels M], Bhutani VK, Bogen D, et al: hyperbilirubinemia in the newborn infant ::35 weeks' gestation: an update with clariications. Pediatrics 124(4):1193,t2009

Malkin ]D, Garber 5, Broder MS, et a1: Infant mortality and early postpartum discharge. Obstet Gynecol 96: 183, 2000

Martin ]A, Hamilton BE, Ventura 5], et al: Births: inal data for 2010. Natl Vital Stat Rep 61(1), 2012

Mokarami P, Wiberg N, Olofsson P: An overlooked aspect on metabolic acidosis at birth: blood gas analyzers calculate base deicit diferently. Acta Obstet Gynecol Scand 91(5):5 4,2012

Moore DL, MacDonald NE, Canadian Paediatric Society Infectious Disease and Immunization Committee: Preventing ophthalmia neonatorum. Paediatr Child Health 20(2):93, 2015

Mullany LC, Darmstadt GL, Khatry SK, et al: Topical applications of chlorhexidine to the umbilical cord for prevention of omphalitis and neonatal mortality in southern Nepal: a community-based, cluster randomized trial. Lancet 367:910,t2006

Neulander E, Walisch 5, Kaneti ]: Amputation of distal penile glans during neonatal ritual circumcision-a rare complication. Br] Urol 77:924, 1996 Nicoll A: Routine male neonatal circumcision and risk of infection with HIV-l and other sexually transmitted diseases. Arch Dis Child 77:t194,t1997 Novack AH, Mueller B, Ochs H: Umbilical cord separation in the normal newborn. Amt] Dis Child 142:220, 1988

O'Brodovich H, Hannam V, Seear M, et al: Amiloride impairs lung water clearance in newborn guinea pigs.t] Appl Physiol (1985)68(4): 1758, 1990

Perlman ]M, Wyllie], Kattwinkel], et al: Part 7: neonatal resuscitation: 2015 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. Pediatrics 136 Suppl 2:5120, 2015

Pippi-Salle ]L, Jesus LE, Lorenzo A], et a1: Glans amputation during routine neonatal circumcision: mechanism of injuty and strategy for prevention. ] Pediatr Urol 9:763, 2013 Ramin SM, Gilstrap LC, Leveno K], et a1: Umbilical artery acid-base status in the preterm infant. Obstet Gynecol 74:256, 1989

Reynolds MR, Jones AM, Petersen EE, et al: Vital signs: update on Zika virus-associated birth defects and evaluation of all U.S. infants with congenital Zika virus exposure-U.S. Zika Pregnancy Registry, 2017 MMWR 66(13):366,t2017 Riley R], Johnson ]W: Collecting and analyzing cord blood gases. Clin Obstet Gynecol 36: 13, 1993

Rudolph M: Fetal and neonatal pulmonary circulation. Annu Rev Physiol 41 :383, 1979

Sabol BA, Caughey AB: Acidemia in neonates with a 5-minute Apgar score of7 or greater-what are the outcomes? Am] Obstet GynecoI215(4):486 e481, 2016

Salam A, Mansoor T, Mallick D, et a1: Essential childbirth and postnatal interventions for improved maternal and neonatal health. Reprod Health 11 Suppl 1:53,t2014

Salhab WA, Perlman ]M: Severe fetal acidemia and subsequent neonatal encephalopathy in the larger premature infant. Pediatr Neurol 32(1):25, 2005

Saunders A, Milner AD: Pulmonary pressure/volume relationships during the last phase of delivery and the irst postnatal breaths in human subjects. J Pediatr 93:667, 1978

Schmolzer GM, Dawson ]A, Kamlin CO, et a1: Airway obstruction and gas leak during mask ventilation of preterm infants in the delivery room. Arch Dis Child Fetal Neonatal Ed 96(4):F254, 2011

Siew ML, te Pas AB, Wallace M], et al: Positive end-expiratory pressure enhances development of a functional residual capacity in preterm rabbits ventilated from birth.] Appl Physiol (1985)106(5):1487, 2009a

Siew ML, Wallace M], Kitchen M], et al: Inspiration regulates the rate and temporal pattern of lung liquid clearance and lung aeration at birth. ] Appl Physiol (1985)106(6):1888, 2009b

Siggaard-Anderson 0: Blood acid-base alignment nomogram. Scand ] Clin Lab Invest 15:211, 1963

Socol ML, Garcia PM, Riter 5: Depressed Apgar scores, acid-base status, and neurologic outcome. Am] Obstet Gynecol 170:991, 1994

Stang H], Gunnar MR, Snellman L, et al: Local anesthesia for neonatal circumcision: efects on distress and cortisol response. ]AMA 259: 1507, 1)88

Stewart D, Benitz W, AAP Committee on Fetus and Newborn: Umbilical cord care in the newborn infant. Pediatrics 138(3):e20162149, 2016

Taddio A, Stevens B, Craig K, et al: Eicacy and safety of lidocaineprilocaine cream for pain during circumcision. N Engl ] Med 336: 1197, 1997

Teoh D, Reynolds 5: Diagnosis and management of pediatric conjunctivitis.

Pediatr Emerg Care 19:48,t2003 te Pas AB, Davis PG, Hooper SB, et a1: From liquid to air: breathing after birth.] Pediatr 152(5):607,t2008

Thongren-]eneck K, Herbst A: Low 5-minute Apgar score: a populationbased register study of 1 million term births. Obstet Gynecol 98:65, 200t1 horp ]A, Dildy GA, Yeomans ER, et a1: Umbilical cord blood gas analysis at delivery. Am] Obstet Gynecolt175(3 Pt 1):517,t1996

Tobian A, Serwadda D, Quinn TC, et al: Male circumcision for the prevention of HSV-2 and HPV infections and syphilis. N Engl ] Med 360(13): 1298, 2009

Tran TT: Hepatitis B: treatment to prevent perinatal transmission. Clin Obstet Gynecol 55(2):541, 2012 Upadhyay V, Hammodat HM, Pease PW: Post circumcision meatal stenosis: 12 years' experience. N Z Medt] Ill:57, 1998

Victory R, Penava D, da Silva 0, et a1: Umbilical cord pH and base excess values in relation to neonatal morbidity for infants delivered preterm. Am ] Obstet Gynecol 189(3):803,t2003

Vyas H, Milner AD, Hopkins IE: Intrathoracic pressure and volume changes during the spontaneous onset of respiration in babies born by cesarean section and by vaginal delivery.t] Pediatr 99(5):787, 1981

Watson MS, Mann MY, Lloyd-Puryear MA, et a1: Newborn screening: towards a uniform screening panel and system. Executive summary. Genet Med 8(Suppl 5):15, 2006

Weiner GM: Textbook of Neonatal Resuscitation. 7th ed. Elk Grove Village, American Academy of Pediatrics, 2016

White CR, Doherty DA, Cannon ]W, et a1: Cost efectiveness of universal umbilical cord blood gas and lactate analysis in a tertiary level matenity unit.] Perinat Med 44(5):573,t2016

White CR, Doherty DA, Henderson J], et a1: Beneits of introducing universal umbilical cord blood gas and lactate analysis into an obstetric unit. Aust N Z J Obstet Gynaecol 50(4):318, 2010

Whyte RK: Neonatal management and safe discharge of late and moderate preterm infants. Semin Fetal Neonatal Med 17(3):153,t2012

World Health Organization: Postnatal care of the mother and newborn, 2013.

Geneva, WHO, 2014

Wyckof MH, Aziz K, Escobedo MB, et al: Part 13: neonatal resuscitation: 20t15 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Pediatrics 136 Suppl 2:5196,t2015

Yeh P, Emary K, Impey L: The relationship between umbilical cord arterial pH and serious adverse neonatal outcome: analysis of 51,519 consecutive validated samples. B]OG 119(7):824,t2012

Zuppa A, D'Andrea V, Catenazzi P, et al: Ophthalmia neonatorum: what time of prophylaxis? ] Matern Fetal Neonatal Med 24(6):769, 2011

Diseases and Injuries of the Term Newborn

In a small number of cases tactures of the skul are met with. his accident usualy olows violent attempts at delivey, though occasionaly it may occur spontaneousy.

-]. Whitridge Williams (1903)

In the irst edition of this book, Williams wrote very little of the disorders of the term newborn. That said, it is well known that these neonates are susceptible to a wide variey of illnesses and injuries. In many instances, clinical manifestations of these disorders are extensions of pathological efects already incurred by the fetus. A common example is the newborn who is depressed and acidotic because of intrapartum septicemia. Because many of these disorders manifest diferently, those more common in term newborns are considered here. hose more frequent in preterm neonates are discussed in Chapter 34. Speciic disorders that are the direct consequence of maternal diseases are discussed in pertinent chapters.

At the time of delivery, the newborn must convert rapidly to air breathing as described in Chapter 32 (p. 606). With inspiration, there is alveolar expansion, fluid clearance, and surfactant secretion by type II pneumocytes to prevent alveolar collapse. Interference with these functions can create respiratory insuiciency with hypoxemia and compensatory tachypnea, nasal flaring, retractions, and grunting (Reuter, 2014). In preterm infants, this is caused by lung immaturity and insuicient surfactantrespiratory distress syndrome (DS}-and variants may be seen in severely ill older children and adults (Chap. 47, p. 918). All of these have some element of surfactant deiciency because the inciting agent damages alveolar epithelium. As fetuses approach term, surfactant deiciency as a cause of respiratory distress diminishes. he leading causes in term newborns are transient tachypnea of the newborn, RDS, meconium aspiration syndrome, pneumonia, persistent pulmonaY hypertension, and hypoxic-ischemic encephalopathy (Lin, 2015).

In a report from Beijing that described 125 term infants with RDS, the most frequent causes were perinatal infection with sepsis syndrome in 50 percent, elective cesarean delivery in 27 percent, severe asphyxia in 10 percent, and meconium aspiration in 7 percent (Liu, 2010). Notably, even with a low incidence in term infants, RDS from surfactant deiciency is not rare (Berthelot-Ricou, 2012). Chorioamnionitis, male gender, and white race are independent risks (Anadkat, 2012; Higgins, 2016). lso, mutations of genes that encode for surfactant protein synthesis may augment the deiciency (Wambach, 2012). Regardless of etiology, when surfactant secretion is diminished, the pulmonary pathophysiology, clinical course, and management are similar to that for preterm infants. Treatment includes mechanical ventilation and replacement of surfactant (Chap. 34, p. 637). Evidence now supports that antenatal maternal corticosteroid treatment will enhance surfactant synthesis in late-preterm fetuses, that is, those 34 to 37 weeks' gestation (Gyami-Bannerman, 2016). At Parland Hospital, corticosteroids are not given for this indication in the late-preterm period. Neonatal hypoglycemia is a concern with such treatment, and long-term efects are unknown. However, data indicate that hypoglycemia, if promptly treated, creates no adverse sequelae (McKinlay, 2015). he prognosis in term newborns with RDS largely depends on the cause, severity, and response to treatment.

The physiology of meconium passage and amnionic luid contamination is considered in Chapter 24 (p. 474). In some instances, inhalation of meconium-stained fluid at or near delivery causes acute airway obstruction, chemical pneumonitis, surfactant dysfunction or inactivation, and pulmonary hypertension (Lee, 2016; Lindenskov, 2015). If severe, hypoxemia may lead to neonatal death or long-term neurological sequelae in survivors.

Given the high incidence-10 to 20 percent-of meconium-stained amnionic fluid in laboring women at term, one may reasonably assume that meconium aspiration must be relatively common. Fortunately, severe aspiration leading to overt respiratory failure is much less frequent. And although the exact incidence of meconium aspiration syndrome is unknown, Singh and associates (2009) reported it to complicate 1.8 percent of all deliveries. In a French study of nearly 133,000 term newborns, the prevalence of severe aspiration syndrome was 0.07 percent, and this rose progressively from 37 to 43 weeks' gestation (Fischer, 2012). Mortality rates depend on severity.

Fetal morbidity is more often associated with thicker meconium content. Presumably, in most cases, amnionic luid is ample to dilute the meconium to permit prompt clearance by normal fetal physiological mechanisms. Meconium aspiration syndrome still occasionally develops with light staining. Many newborns are afected after a normal labor and uncomplicated delivery. However, some associated obstetrical factors include postterm pregnancy and fetal-growth restriction. hese fetuses are at highest risk because diminished amnionic fluid and labor with cord compression or utero placental insuiciency are often comorbid. These can enhance the likelihood of meconium passage that is thick and undiluted (Leveno, 1984).

Previously, aspiration was thought to be stimulated by fetal hypoxic episodes, and fetal heart rate tracing abnormalities were used to identiy fetuses at greatest risk during labor. Unfortunately, this was found to be an unreliable predictor (Dooley, 1985). As another potential prevention, oropharyngeal suctioning was standard care for a time. However, this was abandoned when evidence failed to support a reduction in syndrome incidence or severity (Davis, 1985; Wiswell, 1990). At the same time, reports described that pulmonary hypertension caused by aspirated meconium was characterized by abnormal arterial muscularization beginning well before birth. These findings led some to conclude that only chronically asphyxiated fetuses developed meconium aspiration syndrome (Katz, 1992). But, correlation was not found between meconium aspiration and markers of acute asphyxia-for example, umbilical artery acidosis (Bloom, 1996; Richey, 1995). Others, however, have reported that thick meconium is an independent risk factor for neonatal acidosis (Maisonneuve, 201r1).

In response to conlicting results regarding suctioning, an II-center randomized trial was designed to compare suctioning with no suctioning (Vain, 2004). There was an identical 4-percent incidence of meconium aspiration syndrome in both groups. Subsequently, a committee that represented the American Heart Association updated its guidelines (Wyckof, 2015) . Adopted by the American College of Obstetricians and Gynecologists (2017c) and the World Health Organization (2012), these recommend against routine intrapartum oro-and nasopharyngeal suctioning at delivery. For vigorous newborns, no treatment is required. For depressed newborns, management includes intervention to support ventilation and oxygenation, and intubation is used as indicated (Chap. 32, p. 609).

Intrapartum amnioinusion has been used successully in laboring women with diminished amnionic fluid volume and frequent variable fetal heart rate decelerations (Chap. 24, p. 475). Earlier, it was studied as a preventive measure in labors complicated by meconium staining. This practice failed to lower meconium aspiration syndrome rates because fetuses usually inhaled meconium before labor (Bryne, 1987; Wenstrom, 1995). To urther settle this issue, a trial was conducted with almost 2000 women at 36 weeks' gestation or later and in whom labor was complicated by thick meconium (Fraser, 2005). he perinatal death rate with and without amnioinusion was 0.05 percent in both groups. Rates of moderate or severe meconium aspiration were also not significantly diferent-4.4 percent with and 3.1 percent without amnioinusion. Finally, cesarean delivery rates were similar-32 versus 29 percent, respectively. Currently, the American College of Obstetrics and Gynecologists (2016a) does not recommend amnioinusion to reduce meconium aspiration syndrome.

Ventilatory support and intubation are carried out as needed (Wyckof, 2015). Because some aspects of meconium aspiration syndrome are caused by surfactant deficiency, replacement therapy is beneficial (N atarajan, 20 16a). Also, inhaled corticosteroids may ameliorate the severity (Garg, 2016). Extracorporeal membrane oxygenation-ECMO-therapy is reserved for neonates who remain poorly oxygenated despite maximal ventilatory assistance (Hirakawa, 2017). In their review of randomized trials, EI Shahed and colleagues (2014) found that surfactant replacement may reduce the need for ECMO but did not lower the mortality rate. he proportion that requires ECMO treatment varies. In a report by Singh and coworkers (2009),r1.4 percent of7518 term newborns with the syndrome required such treatment, and these had a 5-percent mortality rate. Ramachandrappa and associates (2011) reported a higher mortality rate in late-preterm neonates with meconium aspiration compared with afected term newborns. Finally, pulmonary lavage with surfactant is being evaluated (Choi, 2012).

Few events evoke more apprehension in parents and obstetricians than the specter of "brain injury," which immediately

Diseases and Injuries of the Term Newborn 621 prompts concerns for disabling cerebral palsy and intellectual disability. Although most brain disorders or injuries are less profound, history has helped to perpetuate the more dismal outlook. In his irst edition of this textbook, Williams (1903) limited discussions of brain injury to those sustained from birth trauma. When later editions introduced the concept that asphyxia neonatorum was another cause of cerebral palsy, this too was linked to traumatic birth. Even as brain damage caused by traumatic delivery became uncommon during the ensuing decades, the belief-albeit erroneous-was that intrapartum events caused most neurological disability. his was a major reason for the escalating cesarean delivery rate beginning in the 1970s. Unfortunately, because in most cases the genesis of cerebral palsy occurs long before labor, this did little to mitigate risks for cerebral palsy (O'Callaghan, 2013).

These realizations stimulated scientiic investigations to determine the etiopathogenesis of fetal brain disorders, including those leading to cerebral palsy. Seminal observations include those of Nelson and Ellenberg (1984, 1985, 1986a), discussed subsequently. hese investigators are appropriately credited with proving that these neurological disorders are due to complex multifactorial processes caused by a combination of genetic, physiological, environmental, and obstetrical factors. Importantly, these studies showed that few neurological disorders were associated with peripartum events. Continuing international interest was garnered to codiy the potential role of intrapartum events. In 2000, a task force of the American College ofObstetricians and Gynecologists was appointed to study the �icissitudes of neonatal encephalopathy and cerebral palsy. he multispecialty coalition reviewed contemporaneous data and provided criteria to deine various neonatal brain disorders. heir indings were promulgated by the American Academy of Pediatrics and American College of Obstetricians and Gynecologists (2003).

Ten years later, a second task force of these organizations updated the indings (American College of Obstetricians and Gynecologists, 2014c). he 2014 Task Force findings are more circumspect in contrast to the earlier ones. Speciically, more limitations are cited in identiying cause(s) of peripartum hypoxic-ischemic encephalopathy (HIE) compared with other etiologies of neonatal encephalopathy. he 2014 Task Force recommends multidimensional assessment of each afected infant.

hey add the caveat that no one strategy is infallible, and thus, no single strategy will achieve 100-percent certainty in attributing a cause to neonatal encephalopathy.

he 20 14 Task Force defined neonatal encephalopathy as a syndrome of neurological dysfunction identiied in the earliest days of life in neonates born at :35 weeks' gestation. It is manifested by subnormal levels of consciousness or seizures and oten accompanied by diiculty with initiating and maintaining respiration and by depressed tone and relexes. he incidence of encephalopathy has been cited to be 0.27 to 1.1 per 1000 term liveborn neonates, and it is much more frequent in preterm newborns (Ensing, 2013; Plevani, 2013; Takenouchi, 2012; Wu, 2011). Although the 2014 Task Force concluded that there are many causes of encephalopathy and cerebral palsy, it focused on HIE and those that were thought to be incurred intrapartum. To identiy afected infants, a thorough evaluation is necessary and includes maternal history, obstetrical antecedents, intrapartum factors, placental pathology, and newborn course. hese are complemented by laboratory and neuroimaging indings.

There are three clinically deined levels. Mild encephalopathy is characterized by hyperalertness, irritability, jitteriness, and hypertonia and hypotonia. Moderate encephalopathy is manifest by lethargy, severe hypertonia, and occasional seizures. Severe encephalopathy is manifest by coma, multiple seizures, and recurrent apnea.

The 20 14 Task Force also concluded that of the several forms of cerebral palsy, only the spastic quadriplegic type can result from acute peripartum ischemia. Other forms-hemiparetic or hemiplegic cerebral palsy, spastic diplegia, and ataxia-are unlikely to result from an intrapartum event. Purely dyskinetic or ataxic cerebral palsy, especially when accompanied by a learning disorder, usually has a genetic origin (Nelson, 1998).

he 2014 Task Force radically revised its 2003 criteria used to deine an acute peripartum event that is consistent with an HIE and neonatal encephalopathy. hese are outlined in Table 33-1 and are considered with the following caveats.

TABLE 33-1 . Findings Consistent with an Acute Peripartum or Intrapartum Event Leading to Hypoxic-Ischemic Encephalopathy

Apgar score: <5 at 5 and 10 minutes

Umbilical arterial acidemia: pH <7.0 and/or base deficit :12 mmol/L

Neuroimaging evidence of acute brain injury: MR imaging or MRS consistent with HIE Multisystem involvement consistent with HIE

Type and Timing of Contributing Factors

Fetal heart rate monitor patterns consistent with an acute peripartum or intrapartum event

HIE = hypoxic ischemic encephalopathy; MR = magnetic resonance; MRS = magnetic resonance spectroscopy.

Summarized from the American College of Obstetricians and Gynecologists, 2014b.

First, Apgar Scores that are low at 5 and 10 minutes are associated with greater risk for neurological impairment. Low scores stem from many causes, and most of these infants will not develop cerebral palsy. With a 5-minute Apgarr? 7, it is unlikely that peripartum HIE caused cerebral palsy.

Acid-base study results deine a second HIE criterion. Low pH and base deficit levels raise the likelihood that neonatal encephalopathy was caused by HIE. Decreasing levels form a continuum of increasing risk, but most acidemic neonates will be neurologically normal (Wayock, 2013). A cord artery pH ?7.2 is very unlikely to be associated with HIE.

Magnetic resonance (MR) imaging or MR spectroscopy (MRS) is the best modality with which to visualize findings consistent with HIE. The 2014 Task Force concludes that cranial sonography and computed tomography (CT) lack sensitivity in the term newborn. Normal imaging indings after the first 24 hours of life, however, efectively exclude a hypoxic-ischemic cause of encephalopathy. MR imaging between 24 and 96 hours may be more sensitive for the timing of peripartum cerebral injury, and MR imaging at 7 to 21 days following birth is the best technique to delineate the full extent of cerebral injury.

Last, multisystem involvement of injury is consistent with HIE. hese include renal, gastrointestinal, hepatic, or cardiac injury; hematological abnormalities; or combinations of these. The severity of neurological injury does not necessarily correlate with injuries to these other systems.

The 20 14 Task Force also found that certain contributing factors may be consistent with an acute peripartum event. Of these, sentinel events are considered adverse obstetrical events that may lead to catastrophic clinical outcomes. Examples include ruptured uterus, severe placental abruption, cord prolapse, and amnionic fluid embolism. Ivfartinez-Biarge and associates (2012) studied almost 58,000 deliveries and identified 192 cases with one of these sentinel events. Of these 192 fetus/ newborns, 6 percent died intrapartum or in the early neonatal period, and 10 percent developed neonatal encephalopathy. Other risk factors for neonatal acidosis include prior or emergent cesarean delivery, maternal age ?35 years, thick meconium, chorioamnionitis, and general anesthesia (Ahlin, 2016; Johnson, 2014; Nelson, 2014).

Diferentiating an abnormal etal heart rate (FHR) tracing on presentation versus one that develops subsequently was also emphasized by the 20 14 Task Force. A category 1 or 2 FHR tracing associated with Apgar scores ?7 at 5 minutes, normal cord gases (± 1 SD), or both are not consistent with an acute HIE event (Graham, 2014). An FHR pattern at the time of presentation with persistently minimal or absent variability and lacking accelerations, with duration ?60 minutes, and even without decelerations is suggestive of an already compromised fetus (Chap. 24, p. 462). The 2014 Task Force further recommended that if fetal well-being cannot be established with these findings present, the woman should be evaluated for the method and timing of delivery.

Most prophylactic measures for neonatal encephalopathy have been evaluated in preterm infants (Chap. 42, p. 824). One of these-postnatally induced hypothermia-may prevent death and mitigate moderate to severe neurological disability in term newborns (Garfinkle, 2015; Nelson, 2014; Shankaran, 2012). MR imaging studies have demonstrated a slowing of difusional abnormalities and fewer infarctions with hypothermia (Bednarek, 2012; Natarajan, 2016b). Most randomized trials have shown improved outcomes with induced hypothermia in those born at 36 weeks' gestation or older (Azzopardi, 2014; Guillet, 2012; Jacobs, 2011). In a metaanalysis of more than 1200 newborns, Tagin and colleagues (2012) concluded that hypothermia improves survival rates and neurodevelopment. Clinical trials to evaluate concomitant neonatal erythropoietin therapy for neuroprophylaxis have reported conlicting results (Fauchere, 2015; Ivf all a, 2017). Preliminary data from one multicenter trial of maternal alopurinol therapy indicate some mitigation of cerebral damage caused by hypoxia and ischemia (Kaandorp,r2013).

This term refers to a group of nonprogressive disorders of movement or posture caused by abnormal development or damage to brain centers for motor control. Cerebral palsy is further classiied by the type of neurological dysfunction-spastic, dyskinetic, or ataxic-and by the number and distribution of limbs involved-quadriplegia, diplegia, hemiplegia, or monoplegia. Together, the major types are spastic quadriplegia-the most common-which has a strong association with mental retardation and seizure disorders; diplegia, which is common in preterm or low-birthweight infants; hemiplegia; choreoathetoid ypes; and mixed varieties. Although epilepsy and mental retardation frequently accompany cerebral palsy, these two disorders seldom are associated with perinatal asphyxia in the absence of cerebral palsy.

According to Nelson and coworkers (2015), the prevalence of cerebral palsy in the United States averages 2 of every 1000 children. t is crucial to emphasize that this rate is derived rom al children-including those born preterm. Because of the remarkably greater survival rates of the latter currently, and despite the elevated cesarean delivery rate, the overall rate of cerebral palsy has remained essentially unchanged (Fig. 33-1). For example, follow-up studies of more than 900,000 Norwegian nonanomalo us term infants cite an incidence of 1 per 1000, but the incidence was 91 per 1000 for those born at 23 to 27 weeks (Moster, 2008). Similar indings have been reported for Australian births (Smithers-Sheedy, 2016). In absolute numbers, term newborns comprise half of cerebral palsy cases because there are proportionately far fewer preterm births. It is again emphasized that most studies of cerebral palsy rates have not made distinctions between term and preterm infants.

As noted earlier, Nelson and Ellenberg (1984, 1985, 1986a) made many fundamental observations concerning cerebral palsy. Their initial studies emanated from data from the Collaborative Perinatal Project. This included children from almost 54,000 pregnancies who were followed until age 7. hey found that the most frequently associated risk factors for cerebral palsy were: (1) evidence of genetic abnormalities

Diseases and Injuries of the Term Newborn 623 20 2003 Task Force applied these criteria to more -18 contemporaneous outcomes and determined ) that only 1.6 cases of cerebral palsy per 10,000 ) deliveries are attributable solely to intrapartum hypoxia. This finding is supported by a study ) ) U.

1975 to 1980 (Stanley, 1991). Other stud :)0 (Phelan, 1996; Strijbis, 2006).

Year of birth Despite persistent attempts to validate con

Elective and emergency cesarean deliveries and live births with cerebral palsy. (Reproduced with permission from Nelson KB, Blair E: Prenatal factors in singletons ing as efective to prevent adverse perinatal with cerebral palsy born at or near term, N Engl J Med. 201o5 Sep 3;373(10):946-953.) outcomes, evidence does not support its ability to predict or reduce cerebral palsy risk such as maternal mental retardation or fetal congenital malformations; (2) birthweight <2000 g; (3) birth before 32 weeks; and (4) perinatal infection. hey also found that obstetrical complications were not strongly predictive, and only a fifth of afected children had markers of perinatal asphyxia. For the irst time, there was solid evidence that the cause of most cases of cerebral palsy was unknown, and importanty, ony a small proportion was caused by neonatal HI. Equally importantly, there was no foreseeable single intervention that would likely prevent a large proportion of cases.

Numerous studies have since confirmed many of these findings and identiied an imposing list of other risk factors that are shown in Table 33-2. As expected, preterm birth continues to be the single most important risk factor (Nelson, 2015; (Clark, 2003; hacker, 1995). Importantly, no speciic fetal heart rate patterns predict cerebral palsy. Further, no relationship has been found between the clinician's response to abnormal patterns and neurological outcome. And, eforts using assisted computer analysis of fetal

TABLE 33-2. Perinatal Risk Factors Reported to Be Increased in Children with Cerebral Palsy

Hydramnios 6.9 1n.0-49.3

Placental abruption 7.6 2.7-21.1

Interval between pregnancies 3.7 1.0-4.4 1.7-6.7

Thorngren-Jerneck, 2006). Small-for-gestational-age neonates Spontaneous preterm labor are also at higher risk. Stoknes and associates (2012) showed that in more than 90 percent of growth-restricted newborns, cerebral palsy was due to antepartum factors. Many other placental and neonatal risk factors have been correlated with neurodevelopmental abnormalities (Ahlin, 20 l3; Avagliano, 2010; Blair, 2011; Redline, 2008). Some placental factors are discussed further in Chapter 6 (p. 114). One example is the substantively greater risk from chorioamnionitis (Gilbert, 2010; Shatrov, 2010). An example of a neonatal cause is arterial ischemic stroke, which may be associated with inherited fetal thrombophilias (Harteman, 2013; Kirton, 2011). Also, newborns with isolated congenital heart lesions have an elevated risk for microcephaly, possibly due to chronic fetal hypoxemia (Barbu, 2009). Other miscellaneous etiologies of cerebral palsy include fetal anemia, twin-twin transfusion syndrome, intrauterine transfusions, and fetal alcohol syndrome (Dejong, 2012; Lindenburg, 2013; O'Leary, 2012; Rossi, 2011; Spruijt, 20r12).

Apart from these causes, intrapartum hypoxemia was linked to only a minority of cerebral palsy cases by the National Collaborative Perinatal Project. However, because the study was carried out in the 1960s, there were inconsistent criteria to accurately assign cause. The contribution of HIE to subsequent neurological disorders is discussed in detail on page 621. The

Preterm delivery at 23-27 weeks 78.9 56.5-110

Breech or face presentation, 3.8 1.6-9.1

Severe birth defect 5.6 8.1n-30.0

Nonsevere birth defect 6.1 3.1-11.8

Time to cry >5 minutes 9.0 4.3-18.8 Obesity 1.2-2 1.1-2.8

Low placental weight 3.6 1.5-8.4

Placental infarction 2.5 1n.2-5.3

Clinical 2.4 1.5-3.8

Histological 1.8 1.2-2.9 alncludes respiratory distress syndrome, meconium aspiration, emergent cesarean or operative vaginal delivery, hypoglycemia, gestational hypertension, hypotension, advanced maternal age, genetic factors, twins, thrombotic states, nighttime delivery, seizures, fetal-growth restriction, male gender, and nulliparity.

CI = confidence interval.

From Ahlin, 2013; Blair, 2011; Mcintyre, 2013; Moster, 2008; Nelson, 2015; O'Callaghan, 2011; Shatrov, 2010; Takenouchi, 2012; Torfs, 1990; Villamor, 2017; Wu, 2012.

heart tracings have not enhanced predictability (Alirevic, 2017; INFANT Collaborative Group, 2017). Indeed, an abnormal heart rate pattern in fetuses that ultimately develop cerebral palsy may reflect a preexisting neurological abnormality (Phelan, 1994). Because of these studies, the American College of Obstetricians and Gynecologists (20r17 a,d) has concluded that electronic fetal monitoring does not reduce the incidence of long-term neurological impairment. his is discussed further in Chapter 24 (p. 477).

In general, 1-and 5-minute Apgar scores are poor predictors of long-term neurological impairment (American College of Obstetricians and Gynecologists, 2017e). When the 5-minute Apgar score is $3, however, neonatal death or the risk of neurological sequelae rises substantially (Dijxhoorn, 1986; Nelson, 1984). In a Swedish study, 5 percent of such children subsequently required special schooling (Stuart, 2011). In a Norwegian study, the incidence of these low Apgar scores was 0.1 percent in more than 235,000 newborns. lmost a fourth of those with such scores died, and 10 percent of survivors devel oped cerebral palsy (Moster, 2001).

Persistence past 5 minutes of these extremely low scores correlates strongly with a higher risk for neurological morbidity and death (Grtinebaum, 2013). his of course is not absolute, and the 2003 Task Force cited a 10-percent risk for cerebral palsy for infants with 10-minute scores of 0 to 3. For 15-minute scores $2, there is a 53-percent mortality rate and a 36-percent cerebral palsy rate. For 20-minute scores $2, mortality rate is 60 percent, and a cerebral palsy rate is 57 percent. Some outcomes in the Norwegian Study of infants with these low 5-minute Apgar scores are shown in

Table33-3. Survivors who had Apgar scores of 0 at 10 minutes have even worse outcomes. In a review of 94 such newborns, 78 died, and al survivors assessed had long-term disabilities (Harrington, 2007).

TABLE 33-3. Comparison of Mortality and Morbidity in Norwegian Infants Weighing >2500 g According to 5-Minute Apgar Scores

Number 292 233,n500

Neonatal 16.5 0.05 386 (270-552)

Infant 19.2 0.3 76 (56-103) 1-8 yr 3 0.2 18 (8-39)

Cerebral palsy 6.8 0.09 81 (48-128)

Menta I reta rdation 1.3 0.1 9 (3-29)

Other neurological 4.2 0.5 9 (5-17)

As outlined on page 621, objective evidence for metabolic acidosis-cord arterial blood pH <7.0 and base deicit � 12 mmollL-is a risk factor for encephalopathy and for cerebral palsy. he risk accrues as acidosis worsens. From their review of 51 studies, Malin and coworkers (2010) found that low cord arterial pH correlates with greater risk for neonatal encephalopathy and cerebral palsy. When used alone, however, these determinations are not accurate in predicting long-term neurological sequelae (Dijxhoorn, 1986; Yeh, 2012).

Data from several studies corroborate that a pH <7.0 is the threshold for clinically signiicant acidemia (Gilstrap, 1989; Goldaber, 1991). he likelihood of neonatal death grows as the cord artery pH falls to 7.0 or less. Casey and colleagues (2001) reported that when the pH was $6.8, the neonatal mortality rate rose 1400-fold. When the cord pH was $7.0 and the 5-minute Apgar score was 0 to 3, the risk of neonatal death was increased 3200-fold.

In the study from Oxford, adverse neurological outcomes were 0.36 percent with pH <7.1 and 3 percent with pH <7.0 (Yeh, 2012). As mentioned, newborn complication rates rise coincident with increasing severity of acidemia at birth. In a Swedish study, researchers observed that cord blood lactate levels may prove to be superior to base deicit for prognostication of neurological disorders (Wiberg, 2010).

Both immature red cells and lymphocytes enter the circulation of term newborns in response to hypoxia or hemorrhage. During the past two decades, quantification of these cells has been proposed as a measure of hypoxia, but most studies do not support this premise (Boskabadi, 2017; Silva, 2006; Walsh, 2011, 2013).

Various neuroimaging techniques have provided important insight into the etiology and evolution of perinatal HIE and later cerebral palsy (p. 621). Importantly, indings are highly dependent on fetal age. he preterm neonatal brain responds quite diferently to an ischemic episode compared with that of a term newborn. Other factors include insult severity and duration as well as restoration of cerebrovascular hypoperfusion. hus, precise timing of an injuy with neuroimaging studies is not a realistic goal. Moreover, the grade of neonatal encephalopathy, that is, mild, moderate, or severe, does not correlate with MR imaging indings (Walsh, 2017).

Regarding early use, the 2014 Task Force concluded that these imaging techniques provide the following information: 1. Sonographic studies are generally normal on the day of birth.

With injury, increasing echogenicity in the thalami and basal 2.0 2 (0.8-5.5) ganglia is seen beginning at approximately 24 hours. This progresses over 2 to 3 days and persists for 5 to 7 days.

CI = confidence interval.

2. Computed tomography scans are usually normal the first

Data from Moster, 2001 .

day in term infants. With injury, decreased density in the

Diseases and Injuries of the Term Newborn 625 thalami or basal ganglia is seen beginning at about 24 hours and persists for 5 to 7 days.

3. Magnetic resonance imaging will detect some abnormalities on the irst da. Within 24 hours, MR imaging may show restricted water difusion that peaks at approximately 5 days and disappears within 2 weeks. Acquisitions with Tl-and T2-weighted images show variable abnormalities, which have an onset from less than 24 hours to several days. In a study of 175 term neonates with acute encephalopathy, it was reported that MR imaging showing basal ganglia lesions accurately predicted motor impairment at 2 years of age (Martinez-Biarge, 2012).

he 2014 Task Force concluded that for term newborns, imaging studies are helpful in timing an injury, but they provide only a window in time that is imprecise. In one study, the optimal range was 3 to 10 days (Lee, 2017).

Neuroimaging in Older Children with Cerebral Palsy

Imaging studies performed in children diagnosed with cerebral palsy frequently show abnormal indings. Wu and associates (2006) used CT or MR imaging to study 273 children who were born after 36 weeks' gestation and who were diagnosed later in childhood with cerebral palsy. lthough a third of these studies were normal, focal arterial infarction was seen in 22 percent; brain malformations in 14 percent; and periventricular white-matter injuries in 12 percent. In another study of 351 children with cerebral palsy-approximately half were born near term-MR imaging indings were abnormal in 88 percent (Bax, 2006). Similar findings were reported in an Australian study (Robinson, 2008).

CT and v1R imaging techniques have also been used in older children to help deine the timing of fetal or perinatal cerebral injury. Wiklund and coworkers (l991a,b) studied 83 children between ages 5 and 16 years who were born at term and who developed hemiplegic cerebral palsy. Nearly 75 percent had abnormal CT indings, and these investigators concluded that more than half had CT changes that suggested a prenatal injury. Approximately 20 percent were attributed to a perinatal injury. In a similar study, Robinson and associates (2008) used MR imaging. hey reported pathological indings in 84 percent of children with spastic quadriplegia. Remember, this is the neurological lesion that the 20 14 Task Force concluded correlated with neonatal encephalopathy.

The term intellectual disabiliy describes a spectrum of disabilities and seizure disorders that frequently accompany cerebral palsy. But, when either of these manifests alone, they are seldom caused by perinatal hypoxia (Nelson, 1984, 1986a,b). Severe mental disability has a prevalence of 3 per 1000 children, and its most frequent causes are chromosomal, gene mutation, and other congenital malformations. Finally, preterm birth is a common association for these (Moster, 2008).

he major predictors of seizure disorders are fetal malformations-cerebral and noncerebral; family history of seizures; and neonatal seizures (Nelson, 1986b). Neonatal encephalopathy causes a small proportion of seizure disorders. Reports from the Neonatal Research Network and other studies concluded that increasing severity of encephalopathy correlates best with seizures (Glass, 2011; Kwon, 201l).

According to the Centers for Disease Control and Prevention, the frequency of autism spectrum disorders is 14.6 per 1000 in 8-year-old children (Christensen, 2016). Although these may be associated with maternal metabolic conditions, none has been linked convincingly to peripartum events (Krakowiak, 2012).

his is a drug-withdrawal syndrome that most commonly fol lows in utero exposure to maternal opioids. It also may com plicate exposure to ethanol or benzodiazepines. The syndrome is characterized by hypertonia, autonomic instability, irritabil ity, poor sucking relex, and seizures (Finnegan, 1975). he incidence of abstinence syndrome has risen six-to sevenfold during the past decade, coincidental with the growing opioid use described in Chapter 1 (p. 9). For example, Tolia and col leagues (2015) reported that 4 percent of all neonatal intensive care unit (NICU) days in 2013 were attributed to care of these afected newborns.

Afected neonates undergo close observation, and pharmacotherapy is usually given. In addition to morphine and methadone, other treatment may include phenobarbital, benzodiazepines, and clonidine (Tolia, 2015). More recently, buprenorphine compared with morphine was reported to result in shorter lengths of stay (Kraft, 2017). Consensus is lacking regarding the most efective regimen. he American College of Obstetricians and Gynecologists and the American Society of Addiction Medicine (2017f) have taken the lead in screening, intervention, and treatment of opioid use disorders in pregnant women (Chap. 12, p. 248).

here are a few neonatal disorders of erythrocytes, platelets, and coagulation with which the obstetrician should be familiar. As is the case for most other conditions manifest by the newborn shortly after birth, many of these hematological problems were manifest by the fetus and persist in the newborn.

fter 35 weeks' gestation, the mean cord hemoglobin concentration approximates 17 g/dL, and values below 14 g/dL are considered abnormal. he American College of Obstetricians and Gynecologists (20 17b) now recommends a 30-to 60-second delay in cord clamping in all healthy newborns. A review of nearly 4000 deliveries found that this delayed cord clamping was associated with a mean neonatal hemoglobin rise of 1.5 g/dL (McDonald, 2013). At the same time, this practice almost doubled the incidence of hyperbilirubinemia requiring phototherapy.

Fetal anemia results from many causes (Colombatti, 2016; Yaish, 2017). .Many of these are discussed in more detail in Chapter 15 (p. 300). Acute anemia with hypovolemia is seen with deliveries in which the placenta is cut or torn, if a fetal vessel is perforated or lacerated, if there is recent fetal-maternal hemorrhage, or if the newborn is held well above the level of the placenta for some time before cord clamping. Intracranial or extracranial injury or trauma to fetal intraabdominal organs can also cause hemorrhage with acute anemia (kin, 2011; McAdams, 2017).

Neonatal polycythemia with hyperviscosity can be associated with chronic hypoxia in utero, twin-twin transusion syndrome, placental-and fetal-growth restriction, fetal macrosomia from maternal diabetes, and transusion at delivery. When the hematocrit rises above 65, blood viscosity markedly increases and may cause neonatal plethora, cyanosis, or neurologicl aberrations. Because of the shorter life span of macrocytic fetal erythrocytes, hyperbilirubinemia commonly accompanies polycythemia. Other findings include thrombocytopenia, fragmented erythrocytes, and hypoglycemia. Cui and associates (2017) reported a case of unilateral macular hemorrhage in a newborn with polycythemia and platelets of 1 million/IlL Partial exchange transusion may be necessary in some neonates.

Even in term fetuses, hepatic maturation is not complete, and thus some unconjugated bilirubin-either albumin bound or free-is cleared by placental transfer to be conjugated in the maternal liver (Chap. 7, p. 135). Fetal protection from unconjugated bilirubin is lost after delivery if not cleared rapidly. Because clearance is totally dependent on neonatal hepatic function, varying degrees of neonatal hyperbilirubinemia result. Even in the mature newborn, serum bilirubin levels usually rise for 3 to 4 days to reach up to 10 mg/ dL. After this, concentrations usually fall rapidly. In one large study, 1 to 2 percent of neonates delivered at 35 weeks' gestation or later had a maximum serum bilirubin level >20 mg/ dL (Eggert, 2006). Concomitant glucose-6-phosphate deiciency worsens hyperbilirubinemia (Chang, 2017). In approximately 15 percent of term newborns, bilirubin levels cause clinically visible skin yellowing termed physiological jaundice (Burke, 2009). As expected, in preterm neonates, the bilirubin elevation is greater and more prolonged.

Excessive serum bilirubin levels can be neurotoxic for newborns (Dijk, 2012; Watchko, 2013). he pathogenesis is complex, and toxicity has two forms. Acute bilirubin encephalopathy is encountered in the irst days of life and is characterized by hypotonia, poor feeding, lethargy, and abnormal auditory-evoked responses (Kaplan, 2011). Immediate recognition and treatment'will usually mitigate progressive neurotoxicity. he chronic form is termed kernicterus. With this, neurotoxicity follows bilirubin deposition and staining of the basal ganglia and hippocampus and is further characterized by profound neuronal degeneration. Survivors have spasticity, muscular incoordination, and varying degrees of mental deiciencies (Frank, 2017). Although there is a positive correlation between kernicterus and unconjugated bilirubin levels above 18 to 20 mg/dL, it can develop at much lower concentrations, especially in very preterm neonates (Sgro, 2011). Continuing hemolysis is a risk factor for kernicterus (EI Houchi, 2017; Vandborg, 2012).

Various forms of phototherapy are used to prevent and treat neonatal hyperbilirubinemia (Ree, 2017). These «bili-lights" emit a spectrum of 460 to 490 nm, which augments bilirubin oxidation to enhance its renal clearance and lower serum levels. Sunlight iltered to remove ultraviolet light has been used in resource-poor countries (Slusher, 2015). Light that penetrates the skin also increases peripheral blood low, which further enhances photo-oxidation. It is problematic that available devices are not standardized (Bhutani, 2011). Another advantage is that exchange transfusions are seldom required with phototherapy. Studies in both preterm and term newborns attest to phototherapy eicacy (Watchko, 2013). A Neonatal Research Network study reported that aggressive phototherapy in low-birthweight neonates reduced rates of neurodevelopmental impairment (Newman, 2006). Similar reductions were reported from Canada after implementation of 2007 guidelines (Sgro, 2016).

For term newborns, the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017) stress early detection and prompt phototherapy to prevent bilirubin encephalopathy. Despite these measures, bilirubin encephalopathy persists, and this is somewhat related to early hospital discharges (Gazzin, 2011; Kaplan, 2011; Sgro, 2011). According to Burke and coworkers (2009), hospitalizations for kernicterus in term newborns were 5.1 per 100,000 in 1988. Since then, however, this rate has dropped to 0.4 to 2.7 cases per 100,000 births (Watchko, 2013). This may be due in part to legislation, discussed in Chapter 36 (p. 662), to minimize brief postpartum hospital stays.

• Hemorrhagic Disease of the Newborn his disorder is characterized by spontaneous internal or external bleeding beginning any time after birth. Most hemorrhagic disease results from abnormally low levels of the vitamin K-dependent clotting factors-V, VII, IX, X, prothrombin, and proteins C and S (Zipursky, 1999). Newborns whose mothers took anticonvulsant drugs are at higher risk because these suppress maternal hepatic synthesis of some of these factors. Classic hemorrhagic disease is usually apparent 2 to 5 days after birth in neonates not given vitamin K prophylaxis at delivery (Busield, 2013). Delayed hemorrhage may occur at 2 to 12 weeks in exclusively breastfed infants because breast milk contains little vitamin K. Other causes of neonatal hemorrhage not related to vitamin K include hemophilia, congenital syphilis, sepsis, thrombocytopenia purpura, erythroblastosis, and intracranial hemorrhage.

The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017) recommend routine prophylaxis for hemorrhagic disease with a 0.5-to 1-mg dose of vitamin K\ (phytonadione) given intramuscularly. Oral administration is not efective, and maternal vitamin K administration results in very little transport to the fetus (Sankar, 2016).

Abnormally low platelet concentrations in term newborns may be due to various etiologies such as immune disorders, infections, drugs, or inherited platelet defects, or they may be part of a congenital syndrome (American College of Obstetricians and Gynecologists, 20 16b). In many, thrombocytopenia is an extension of a fetal disorder such as infection with B 19 parvovirus, cytomegalovirus, toxoplasmosis, and others discussed in Chapters 64 and 65. Neonatal thrombocytopenia has been reported with maternal antiretroviral therapy for human immunodeiciency virus (HIV) infection (Smith, 2016) . Term newborns admitted to NICUs, especially those with sepsis, have accelerated platelet consumption (Eissa, 2013).

In women with an autoimmune disorder such as systemic lupus erythematosus or immunological thrombocytopenia, maternal antiplatelet IgG is transferred to the fetus and can cause accelerated platelet destruction. Most cases are mild, and platelet levels usually reach a nadir at 48 to 72 hours. Maternal corticosteroid therapy generally has no efect on fetal platelets. Fetal blood sampling for platelet determination is seldom necessary, and platelets are usually adequate to prevent fetal hemorrhage during delivery (Chap. 56, p. 1086).

Alloimmune thrombocytopenia (AIT) or neonatal alloimmune thrombocytopenia (NAIT) is caused by maternal-fetal platelet antigen disparity. If maternal alloimmunization is stimulated, then transplacental antiplatelet IgG antibodies cause severe fetal thrombocytopenia and severe bleeding (Winkelhorst, 2017). his is considered in detail in Chapter 15 (p. 307).

Maternal platelet function and destruction can be severely afected in women with severe preeclampsia. That said, fetal or neonatal thrombocytopenia is rarely caused by the preeclampsia syndrome even when the mother has severe thrombocytopenia. Findings from the large study of mother-infant pairs delivered at Parland Hospital dispelled earlier reports of an association of neonatal thrombocytopenia with preeclampsia (Pritchard, 1987). Instead, neonatal thrombocytopenia was found to be associated with preterm delivery and its numerous complications (Chap. 34, p. 636).

Birth injuries can potentially complicate any delivery. hus, although some are more likely associated with operative delivery by forceps or vacuum, others are seen with otherwise uncomplicated vaginal or cesarean delivery. In this section, some injuries are discussed in general, but specific injuries are

Diseases and Injuries of the Term Newborn 627

TABLE 33-4. Incidence of Major and Minor Birth Trauma-Nova Scotia, 1988-2001

Type of Delivery Birth Trauma

Spontaneous (14) 88,324 1.2

Vacuum (71) 3175 3.7 67

Forceps (58) 10,478 5.2 53

Vacuum (1n05) 609 8.3 100

Forceps (56) 714 7.0 50

Cesarean (8.6) 16,132 OJ 8.3

Labor (12) 10)31 0.4 11.9

No labor (1.2) 5401 0.2 1.1

All (19.5) 119,432 1.6 18 aMajor trauma = depressed skull fracture, intracranial hemorrhage, brachial plexopathy, or combination.

bMinor trauma = linear skull fracture, other fractures, facial palsy, cephalohematoma, or combination.

Data from Baskett, 2007.

described elsewhere in connection with their associated obstetrical complications.

In three population studies that included more than 8 million term newborns, the overall incidence of birth trauma was 20 to 26 per 1000 deliveries (Baskett, 2007; Linder, 2012; Moczygemba, 2010). Data from Nova Scotia show an overall trauma risk of 19.5 per 1000 deliveries (Table 33-4). Only 1.6 cases of major trauma per 1000 were found, and these rates were highest with failed forceps or vacuum delivery and lowest with cesarean delivery without labor. hus, most traumatic injuries were minor, and these had an incidence of 18 per 1000 deliveries.

Trauma associated with cesarean delivery from a vIaternalFetal Medicine Units Network study was described by Alexander and coworkers (2006). There were 400 injuries identiied from a total of 37,100 operations-a rate of 11 per 1000 cesarean deliveries. Although skin lacerations predominated-7 per 1000-more serious injuries in these 400 infants included 88 cephalohematomas, 11 clavicular fractures, 11 facial nerve palsies, nine brachial plexopathies, and six skull fractures.

Traumatic head injuries that are associated with labor or delivery can be external and obvious, such as a skull or mandibular fracture; they can be intracranial; and in some, they are covert. The fetal head has considerable plasticity and can undergo appreciable molding. Rarely, severe molding can result in tearing of veins. hese may be the bridging cortical veins that empty into the sagittal sinus, the internal cerebral veins, the vein of Galen, or those of the tentorium itself. As a result, intracranial, subdural, and even epidural hemorrhage can be seen after an apparently uneventful vaginal delivery (Scheibl, 2012). Bleeding may also be asymptomatic. Conversely, subgaleal hemorrhages associated with forceps of vacuum delivery can be life threatening (Doumouchtsis, 2008; Swanson, 2012). In rare severe head trauma cases, fetal brain tissue can embolize to the heart or lungs (Cox, 2009).

Most aspects of neonatal intracranial hemorrhage are related to gestational age. Speciically, most hemorrhage in the preterm neonate results from hypoxia and ischemia. However, in term newborns, trauma is the most frequent cause. Some varieties are shown in Table 33-5. Importanty, in some newborns, a putative cause is not ound. Intracranial hemorrhage is asymptomatic in many cases. The reported incidence varies, but it is highest with operative deliveries-both vaginal and cesarean deliveries. In the study by Moczygemba and colleagues (2010), for more than 8 million singleton deliveries, the overall intracranial hemorrhage rate approximated 0.2 per 1000 births. In another study, Werner and associates (201rl) cited a combined incidence in more than 120,000 nulliparous singleton operative deliveries of 0.12 percent, or about 1 in 750 procedures. he rates of intracranial hemorrhage were 1 :385 with vacuum delive)a; 1: 515 with forceps, and 1: 1210 with cesarean delivery. In another study, its incidence was nearly 1 percent following vacuum-assisted deliveries (Simonson, 2007).

According to the American College of Obstetricians and Gynecologists (2015), the incidence of intracranial hemorrhage from birth trauma has been substantively lowered by elimination of diicult instrumented vaginal deliveries. This was veriied in a report of carefully conducted Kielland forceps deliveries (Burke, 2012).

The prognosis after hemorrhage depends on its location and extent (see Table 33-5). For example, subdural and subarachnoid hemorrhage seldom results in neurological abnormalities, whereas large hematomas are serious. Any bleeding into the parenchyma from intraventricular or intracerebellar hemorrhage often causes serious permanent damage or death. Periventricular hemorrhage rarely causes the type of sequelae that are common in those born preterm (Chap. 34, p. 639).

Newborns who have traumatic subdural or infratentorial hemorrhage tears will have neurological abnormalities from the time of birth (Volpe, 1995). Those most severely afected have stupor or coma, nuchal rigidity, and opisthotonos that worsen over minutes to hours. Some newborns who are born depressed appear to improve until about 12 hours of age, when drowsiness, apathy, feeble cry, pallor, failure to nurse, dyspnea, cyanosis, vomiting, and convulsions become evident.

Spontaneous intracranial hemorrhage has also been documented in healthy term neonates (Rutherford, 2012; Shah, 2016). In a prospective MR imaging study, Whitby and coworkers (2004) found that 6 percent of those delivered spontaneously and 28 percent of those delivered by forceps had a subdural hemorrhage. None of these had clinical indings, and hematomas resolved by 4 weeks in all infants.

These blood collections accumulate outside the calvarium and are categorized as a cephalohematoma or subgaleal hemorrhage (Fig. 33-2). From its most superficial surface inward, the scalp is composed of skin, subcutaneous tissue, galea aponeurotica, subgaleal space, and calvarium periosteum. The galea aponeurotica is dense fibrous tissue, whereas the subgaleal space contains

TABLE 33-5. Major Types of Neonatal Intracranial Hemorrhage

Trauma-tentorial, falx, or venous (sinus) laceration Uncommon but potentially serious; symptom causing hematoma onset is variable depending on hematoma expansion, but usually <24 hours: irritability, lethargy, and brainstem compression

Possibly due to trauma or hypoxia-excludes SAH Common but almost always benign associated with subdural, intraventricular, intracerebral (AVM, aneurysm), or intracerebellar hemorrhage

Trauma and perhaps hypoxia-most cases in preterm Uncommon but serious infants Trauma and hypoxia (no discernible cause in Uncommon but serious; symptoms as for 25 percent)-hemorrhage usually from choroid plexus subdural hemorrhage Trauma with epidural or intracerebral hemorrhage Depends on cause Hemorrhagic infarction-embolism or thrombosis in

AVM = arteriovenous malformation; SAH = subarachnoid hemorrhage. Data from Volpe, 1995.

FIGURE 33-2 Schematic of extracranialolesions in the neonate that include caput succedaneum, subgaleal hemorrhage, and cephalohematoma.

loose, ibroareolar tissue. Traversing across the subgaleal space are large, valveless emissay veins, which connect the dural sinuses inside the skull with supericial scalp veins. Both the galea aponeurotica and subgaleal space span across the occipital, parietal, and frontal bones. In contrast, periosteum invests each individual skull bone and does not cross suture lines.

Cephalohematomas are cranial subperiosteal hematomas.

These develop from shearing forces during labor and delivery that lacerate the emissary or diploic veins. Fortunately, the densely adhered periosteum impedes rapid enlargement and limits inal hematoma size. Hemorrhage can be over one or both parietal bones, but palpable edges can be appreciated as the blood reaches the limits of the periosteum. These hematomas must be diferentiated from caput succedaneum, also shown in Figure 33-2. A cephalohematoma may not be apparent until hours after delivery, when bleeding suicient to raise the periosteum has occurred. After it is identiied, it often grows larger and persists for weeks or even months, and bleeding may be suicient to cause anemia as discussed on page 625. By contrast, with caput succedaneum, swelling of the scalp is from soft-tissue edema that overlies the periosteum. The caput is maximal at birth, rapidly grows smaller, and usually disappears within hours or a few days. Occasionally it becomes infected, and an abscess may form (Kersten, 2008).

Cephalohematomas are common, and in the study from Nova Scotia shown in Table 33-3, these accounted for 80 percent of traumatic injuries with an incidence of 16 per 1000 (Baskett, 2007). They rarely develop in the absence of birth trauma, and an II-percent incidence was reported in 913 term

Diseases and Injuries of the Term Newborn 629 newborns delivered by vacuum extraction (Simonson, 2007). In the Network study of cesarean delivery outcomes cited above, the incidence of cephalohematoma was 2.4 per 1000 operations (Alexander, 2006). Others have reported lower incidences, although cephalohematoma is more common with vacuum compared with forceps deliveries-0.8 versus 2.7 per 1000 operative deliveries (Werner, 2011).

Subgaleal hemorrhage results from laceration of one of the emissary veins, with bleeding between the galea aponeurotica and the skull periosteum (Shah, 2016). Although most common with operative deliveries, cases with spontaneous vaginal delivery have been described (Uu, 2017). Because of its loose areolar tissue and large surface area, significant blood volumes can collect in this potential space and can extend from the neck to the orbits and laterally to the temporal fascia above the ears (Modanlou, 2016). Resulting hypotension can lead to signiicant morbidity, and cited mortality rates range from 12 to 18 percent (Chang, 2007; Kilani, 2006).

These are rare but are especially worrisome because of their association with the serious intracranial hemorrhages. Volpe (1995) considers three types of skull injuries to be fractures-linear and depressed fractures and occipital osteodiastasis. In a French study of nearly 2 million deliveries from 1990 to 2000, the incidence of skull fractures was reported to be 3.7 per 100,000 births, and 75 percent were associated with instrumented vaginal deliveries (Dupuis, 2005). These are occasionally seen with spontaneous or cesarean delivery (Fig. 33-3). These latter fractures are more common when the head is tightly wedged in the pelvis. In such cases, there are at least three possible causes. A fracture may result from skull compression against the sacral promontory, by hand pressure used to lift the head at cesarean delivery, or from transvaginally applied upward hand pressure by an assistant. Fractures are managed with surgical decompression, although spontaneous resolution can follow (Basaldella, 2011).

FIGURE 33-3 Depressed skull fracture evident immediately after cesarean delivery. Labor had progressed, and the head was deep in the pelvis. Dislodgment of the head from the birth canal was performed by an assistant using manual pressure upward through the vagina. (Used with permission from Dr. Kimberly M Spoonts.)

Overstretching of the spinal cord and associated hemorrhage and edema are rare. They are usually caused by excessive longitudinal or lateral traction of the spine or by torsion during delivery. In some cases, vertebrae are fractured or dislocated. Menticoglou and associates (1995) described 15 neonates with this type of high cervical spinal cord injury and found that all of the injuries were associated with forceps rotations. Spinal cord injury also can occur during breech delivery. Ross and coworkers (2006) described C5-6 vertebral dislocation associated with a Zavanelli maneuver done because of shoulder dystocia (Chap. 27, p. 523).

Traumatic injuries to nerves can be serious and distressing, especially if permanent. Injury can involve a single nerve, or it can afect a nerve root, plexus, or trunk (Volpe, 1995).

Injuries to the brachial plexus are relatively common. hey are identiied in 1 to 3 per 1000 term births (Baskett, 2007; Lindqvist, 2012; Wall, 2014). In the study reported by Moczygemba and colleagues (2010), the incidence of brachial nerve injury was 1.5 per 1000 vaginal deliveries and 0.17 per 1000 cesarean deliveries. he incidence among 366,408 neonates born at Parkland Hospital was 3.5 per 1000 births (Wall, 2014). Breech delivery and shoulder dystocia are risks for this trauma. However, severe plexopathy may also occur without risk factors (Torki, 2012).

With plexopathy, the injury damages the nerve roots that supply the brachial plexus-C5_8 and T ,. With hemorrhage and edema, axonal function may be temporarily impaired, but the recovery chances are good. However, with avulsion, the prognosis is poor. In 90 percent of cases, damage to the C5-6 nerve roots causes Erb or Duchenne paraysis (Volpe, 1995). Injuries with breech delivery are normally of this type, whereas the more extensive lesions follow diicult cephalic deliveries (Ubachs, 1995). The C5-6 roots join to form the upper trunk of the plexus, and injury leads to paralysis of the deltoid, infraspinatus, and lexor muscles of the forearm. he afected arm is held straight and internally rotated, the elbow is extended, and the wrist and ingers lexed. Finger function usually is retained. Because lateral traction on the fetal head is frequently employed to efect delivery of the shoulders in normal vertex presentations, most cases of Erb paralysis follow deliveries that do not appear diicult.

Damage to the C8-T, roots supplying the lower plexus results in Klumpke paraysis, in which the hand is laccid. Total involvement of all brachial plexus nerve roots results in laccidity of the arm and hand, and with severe damage, there may also be Horner syndrome.

Because of its importance, the American College of Obstetricians and Gynecologists (2014a) convened a task force to review extant studies. his Task Force concluded that shoulder dystocia cannot be accurately predicted, but in most cases, axonal death does not occur and the prognosis is good. Lindqvist and associates (2012) reported complete recovery in 86 percent of children with C5-6 trauma, which was the most common injury, and in 38 percent of those with C5-7 damage. However, those with global C5-8-T, inj uries always had permanent disability. Associated clavicular fracture is somewhat protective (Wall, 2014). Surgical exploration and possible repair may improve function if there is persistent paralysis (Malessy, 2009).

FIGURE 33-4 Left facial nerve injury. This was almost completely resolved two days after delivery.

Trauma to the facial nerve commonly occurs as it emerges from the stylomastoid foramen, and this can cause facial paralysis (Fig. 33-4). The incidence, which ranges from 0.2 to 7.5 per 1000 term births, is likely inluenced by the vigor with which the diagnosis is sought (Al Tawil, 2010; Moczygemba, 2010). Facial paralysis may be apparent at delivery or may develop shortly after birth. It most frequently is associated with uncomplicated vaginal delivery. However, in one series, a fourth of cases followed cesarean delivery (Alexander, 2006; Al Tawil, 2010). Facial nerve damage is likely more common with low forceps (Levine, 1984). It is possible that damage is caused by pressure exerted by the posterior blade when forceps have been placed obliquely on the fetal head. In these cases, forceps marks indicate the cause of injury. Spontaneous recovery within a few days is the rule, however, permanent paralysis has been described (Al Tawil, 2010).

Most long-bone fractures follow diicult deliveries, however, this is not always the case. At minimum, palpation of the clavicles and long bones is indicated for all newborns after a diicult delivery. Crepitation or unusual irregularity should prompt radiographic examination.

Clavicular ractures are common, unpredictable, and unavoidable complications of normal birth. heir incidence averages 5 to 10 per 1000 live births (Linder, 2012; Moczygemba, 2010). Other than female gender, no speciic risk factorsincluding birthweight and mode of delivery-have been identiied. Clavicular fractures protect against brachial plexopathy when there is shoulder dystocia (Wall, 2014).

ion No. 11, August 2017f r� haudharitBt, eased risk for respira-

HumeraL ractures are infrequent, and 70 percent follow an uneventful birth (T urpenny, 1993). Others are associated with diicult delivery of the shoulders in cephalic deliveries and of an extended arm in breech deliveries. Radiographically, they are often of the greenstick type, although complete fractures and distal humeral epiphyseal fractures can occur (harakan, 2016).

FemoraL ractures are rare and usually are associated with vag inal breech delivery. hey occasionally follow cesarean delivery, and in one report, they were bilateral (Cebesoy, 2009). Because most breech-presenting fetuses now undergo cesarean delivery, most of these fractures are associated with this mode (Alexan der, 2006; Cebesoy, 2009).

MandibuLar .ractures have been reported, are rare, and have been reviewed by Vasconcelos and coworkers (2009). he rare cases of cervicaL vertebraL disLocation in fetuses delivered as breech or after the Zavanelli maneuver were discussed earlier (Ross, 2006). Finally, rib ractures are occasionally encountered (Khan, 2016).

Sternocleidomastoid muscle injury in the past was usually seen with vaginal breech delivery. Hematomas of the muscle or the fascial sheath may resolve slowly with cicatricial contraction. With normal neck growth, the less-elastic damaged muscle does not elongate appropriately. As a result, the head is gradually turned toward the side of the injuy-torticoLis.

Conceivably, any fetal organ or part could be injured with either vaginal or cesarean delivery. Some of these include subcapsular hepatic hematomas that presented as inguinal and scrotal hematoma. In such cases, ecchymoses of the inguinal region are termed StabLer sign, and those of the scrotum are termed Bryant sign (Heyman, 2011; Saroha, 2015). hymic gland traumatic hemorrhage in those with underlying hyperplasia or cyst has been described before, during, and after delivery (EHinger, 2007; Saksenberg, 2001). Inj uries to the sixth cranial nerve with resultant lateral rectus ocular muscle paralysis have also been reported (Galbraith, 1994).

before delivery. One is the amnionic band syndrome caused when a free strip of amnion forms a focal ring around an extremity or digit. Eventually, deformation or amputation may the uterus. he genesis of such bands is debated and discussed in Chapter 6 (p. 116). A similar anomaly is a Limb-reduction deect associated with chorionic villus sampling performed before 9 weeks' gestation (Chap. 14, p. 294).

mechanical factors. Examples of the latter include chronic oli gohydramnios, as well as restricted fetal movement imposed by an abnormally shaped or small uterine cavity or by the presence of additional fetuses. Some mechanical deformations include

Diseases and Injuries of the Term Newborn 631 talipes equinovarus (clubfoot), scoliosis, and hip dislocation (Miller, 1981). Talipes and other positional foot abnormalities are associated with membrane rupture from early amniocentesis between 11 and 13 weeks' gestation (Chap. 14, p. 293).

hlin K, Himmelmann K, Hagberg G, et al: Cerebral palsy and perinatal infection in children born at term. Obstet Gynecol 122:41, 2013

Ahlin K, Himmelmann K, Nisson S, et al: Antecedents of cerebral palsy according to severity of motor impairment. Acta Obstet Gynecol Scand 95(7):793,t2016 kin MA, Coban D, Doganay S, et al: Intrahepatic and adrenal hemorrhage as a rare cause of neonatal anemia. J Perinat Med 39(3):353,2011

Al Tawil K, Saleem N, Kadri H, et al: Traumatic facial nerve palsy in newborns: is it always iatrogenic? Am J Perinatol 27:71t1, 2010

Alexander JM, Leveno KJ, Hauth J, et al: Fetal injury associated with cesarean delivery. Obstet Gynecol 108:885,t2006

Alfirevic Z, Devane D, Gyte GM, et al: Continuous cardiotocography (CTG) as a form of electronic fetal monitoring (EFM) for fetal assessment during labour. Cochrane Database System Rev 2:CD006066, 2017

American Academy of Pediatrics, American College of Obstetricians and Gyne cologists: Guidelines for perinatal care, 8th ed. Elk Grove Village, MP, 2017

American Academy of Pediatrics, American College of Obstetricians and Gynecologists: Neonatal encephalopathy and cerebral palsy. Defining the pathogenesis and pathophysiology. Elk Gtove Village, MP, 2003

American College of Obstetricians and Gynecologists: Neonatal brachial plexus palsy. Report of the American College of Obstetricians and Gynecologists' Task Force on Neonatal Brachial Plexus Palsy. Obstet Gynecolt123(4):902, 2014a

American College of Obstetricians and Gynecologists: Neonatal encephalopathy and neurologic outcome, second edition. Repon of the American College of Obstetricians and Gynecologists' Task Force on Neonatal Encephalopathy. Obstet GynecoIt123(4):896, 2014b

American College of Obstetricians and Gynecologists: Operative vaginal delivery. Practice Bulletin No. 154, November 2015

American College of Obstetricians and Gynecologists: Amnioinfusion does not prevent meconium aspiration syndrome. Committee Opinion No. 346, October 2006, Reairmed 2016a

American College of Obstetricians and Gynecologists: hrombocytopenia in pregnancy. Practice Bulletin No. 166, September 2016b

American College of Obstetricians and Gynecologists: Approaches to limit intervention during labor and birth. Committee Opinion No. 687, February 2017a

American College of Obstetricians and Gynecologists: Delayed cord clamping after birth. Committee Opinion No. 684, January 2017b

American College of Obstetricians and Gynecologists: Delivery of a newborn with meconium-stained amniotic fluid. Committee Opinion No. 689, March 2017c

American College of Obstetricians and Gynecologists: Intrapartum fetal hean rate monitoring: nomenclature, interpretation, and general management principles. Practice Bulletin No. 106, July 2009, Reairmed 2017d

American College of Obstetricians and Gynecologists, American Academy of

Pediatrics: Neonatal Encephalopathy and Neurologic Outcome, 2nd ed.

Washington, ACOG, 2014c

American College of Obstetricians and Gynecologists, American Academy of Pediatrics: The Apgar score. Committee Opinion No. 644, October 2017e

American College of Obstetricians and Gynecologists, American Society of Addiction Medicine: Opioid use disorder in pregnancy. Committee Opin tory distress among white, male, late preterm and term infants. J Perinatol 32(10):750,t2012

Avagliano L, Marconi AM, Candiani \1, et al: Thrombosis of the umbilical vessels revisited. An observational study of 317 consecutive autopsies at a single institution. Hum PathoIt41:971, 2010

Azzopardi D, Strohm B, Marlow N, et al: Efects of hypothermia for perinatal asphyxia on childhood outcomes. N Engl J Med 371(2):140, 2014

Barbu D, Men 1, Kruger M, et al: Evidence of fetal central nervous system injury in isolated congenital hean defects: microcephaly at birth. Am J

Obstet Gynecol 201(1):43.e1, 2009

Basaldella L, Marton E, Bekelis K, et al: Spontaneous resolution of atraumatic intrauterine ping-pong fractures in newborns delivered by cesarean section.

J Child Neurol 26:1149, 2011 Baskett TF, Allen VM, O'Connell CM, et al: Fetal trauma in term pregnancy.

Am) Obstet Gynecol 197:499.e1, 2007

Bax M, Tydeman C, Flodmark 0: Clinical and MRl correlates of cerebral palsy: the European cerebral palsy study. )A 296: 1602, 2006

Bednarek N, Mathur A, Inder T, et al: Impact of therapeutic hypothermia on MRl difusion changes in neonatal encephalopathy. Neurology 78:1420, 2012

Berthelot-Ricou A, Lacroze V, Courbiere B, et al: Respiratory distress syndrome after elective caesarean section in near term infants: a 5-year cohort study.) Matern Fetal Neonatal Med 26(2):1 6,2012

Bhutani K, Committee on Fetus and Newborn, American Academy of Pediatrics: Phototherapy to prevent severe neonatal hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 128(4):e1046, 2011

Blair E, de Groot )H, Nelson KD: Placental infarction identified by macroscopic examination and risk of cerebral palsy in infants at 35 weeks of gestational age and over. Am) Obstet GynecoI205(2):124.el, 2011

Bloom S, Ramin S, Neyman S, et al: Meconium stained amniotic fluid: is it associated with elevated erythropoietin levels? Am ) Obstet Gynecol 174:360,t1996 Boskabadi H, Zakerihamid M, Sadeghian MH, et al: Nucleated red blood cells count as a prognostic biomarker in predicting the complications of asphyxia in neonates.t) Matern Fetal Neonatal Med 30(21):2551, 2017

Bryne DL, Gau G: In utero meconium aspiration: an unpreventable cause of neonatal death. B)OG 94:813, 1987

Burke BL, Robbins )M, Bird TM, et al: Trends in hospitalizations for neonatal jaundice and kernicterus in the United States, 1988-2005. Pediatrics 123(2):524, 2009

Burke N, Field K, Mujahid F, et al: Use and safery of Kielland's forceps in current obstetric practice. Obstet Gynecol 120(4):766,t2012

Busield A, Samuel R, McNinch A, et al: Vitamin K deiciency bleeding after NICE guidance and withdrawal of Konakion Neonatal: British Paediatric Surveillance Unit study, 2006-2008. Arch Dis Child 98:41, 2013

Casey BM, McIntire DD, Leveno K): The continuing value of the Apgar score for the assessment of newborn infants. N Engl) Med 344:467,t2001 Cebesoy FB, Cebesoy 0, Incebiyik A: Bilateral femur fracture in a newborn: an extreme complication of cesarean delivery. Arch Gynecol Obstet 279:73, 2009

Chang HY, Peng CC, Kao HA, et al: Neonatal subgaleal hemorrhage: clinical presentation, treatment, and predictors of poor prognosis. Pediatr Int 49(6):903, 2007

Chang PW, Newman TB, Maisels M): Update on predicting severe hyperbilirubinemia and bilirubin neurotoxicity risks in neonates. Curr Pediatr Rev January 23,t2017 [Epub ahead oftprintl

Choi H), Hahn S, Leet), et al: Surfactant lavage therapy for meconium aspiration syndrome: a systematic review and meta-analysis. Neonatology 101:183,t2012

Christensen DL, Baiot), Van Naarden Braun K, et al: Prevalence and characteristics of autism spectrum disorder among children 8 years-Autism and Developmental Disabilities Monitoring Network, 11 sites, United States, 2012. MMWR 65(3):1,t2016

Clark SL, Hankins GD: Temporal and demographic trends in cerebral palsyfact and iction. Am) Obstet Gynecol 188:628, 2003

Colombatti R, Sainati L, Trevisanuto D: Anemia and transfusion in the neonate. Semin Fetal Neonatal Med 21(1):2,t2016

Cox P, Silvestri E, Lazda E, et al: Embolism of brain tissue in intrapartum and early neonatal deaths: report of9 cases. Pediatr Dev Pathol 12(6):464, 2009

Cui Z, Zhang Y, Liang L, et al: Macular hemorrhages associated with neonatal polycythemia and thrombocytopenia: a case report. Arch Pediatr 24(2): 140, 2017 Davis RO, Phillips)B III, Harris BA)r, et al: Fatal meconium aspiration syndrome occurring despite airway management considered appropriate. Am ) Obstet GynecoIt141:731, 1985 De)ong EP, Lindenburg IT, van Klink )M, et al: Intrauterine transfusion for parvovirus B 19 infection: long term neurodevelopmental outcome. Am ) Obstet GynecoIt206(3):204.e1, 2012 Dijk PH, Hulzebos C: An evidence-based view on hyperbilirubinaemia. Acta Paediatr Suppl 101(464):3,t2012 Dijxhoorn v!), Visser GHA, Fidler J, et al: Apgar score, meconium and acidemia at birth in relation to neonatal neurological morbidity in term infants. B)OG 86:217, 1986

Dooley SL, Pesavento D), Depp R, et al: l!econium below the vocal cords at delivery: correlation with intrapartum events. Am ) Obstet Gynecol 153:767, 1985 Doumouchtsis SK, Arulkumaran S: Head trauma after instrumental births. Clin Perinatol 35:69, 2008

Dupuis 0, Silveira R, Dupont C, et al: Comparison of "instrument-associated" and "spontaneous" obstetric depressed skull fractures in a cohort of 68 neonates. Am) Obstet Gynecol 192:165,t2005

Eggert LD, Wiedmeier SE, Wilson), et al: The efect of instituting a prehospital-discharge newborn bilirubin screening program in an 18-hospital health system. Pediatrics 117:e855, 2006

Eiinger F, Ernestus K, Benz-Bohm G, et al: True thymic hyperplasia associated with severe thymic cyst bleeding in a newborn: a case report and review of the literature. Ann Diagn Pathol 11 :358, 2007

Eissa OS, EI-Farrash A: New insights into thrombopoiesis in neonatal sepsis.

Platelets 24(2):122, 2013

EI Houchi SZ, Iskander I, Gamaleldin R, et al: Prediction of 3-to 5-month outcomes from signs of acute bilirubin toxicity in newborn infants. ) Pediatr 183:51, 2017

EI Shahed AI, Dargaville PA, Ohlsson A, et al: Surfactant for meconium aspiration syndrome in term and late preterm infants. Cochrane Database Syst Rev 12:CD002054, 2014 Ensing S, Abu-Hanna A, Schaaf )M, et al: Trends in birth asphyxia, obstetric interventions and perinatal mortality among term singletons: a nationwide cohort study. ) Matern Fetal Neonatal Med 28(6):632, 2015 Faucheret)C, Koller BM, Tschopp A, et al: Safety of early high-dose recombinant erythropoietin for neuroprotection in very preterm infants. ) Pediatr 167(1):52, 2015 Finnegan LP, Connaughton )F )r, Kron E, et al: Neonatal abstinence syndrome: assessment and management. Addict Dis 2: 141, 1975 Fischer C, Rybakowski C, Ferdynus C, et al: A population-based study of meconium aspiration syndrome in neonates born between 37 and 43 weeks of gestation. 1nt) Pediatr 2012:321545,t2012 Frank R, Garinkle), Oskoui M, et al: Clinical proile of children with cerebral palsy born term compared with late-and post-term: a retrospective cohort study. B)OG 124(11):1738,t2017 Fraser WD, Hofmeyr ), Lede R, et al: Amnioinfusion for the prevention of the meconium aspiration syndrome. Amnioinfusion Trial Group. N Engl ) Med 353:909, 2005 Galbraith RS: Incidence of sixth nerve palsy in relation to mode of delivery. Am ) Obstet GynecoIt170:ll58, 1994

Garinkle ), Wintermark P, Shevell MI, et al: Cerebral palsy after neonatal encephalopathy: how much is preventable? ) Pediatr 167(1):58,t2015

Garg N, Choudhary M, Sharma 0, et al: he role of early inhaled budesonide therapy in meconium aspiration in term newborns: a randomized control study.t) Matern Fetal Neonatal Med 29(1):36, 2016

Gazzin S, Tiribelli C: Bilirubin-induced neurological damage. J Matern Fetal Neonatal Med 24:154, 2011

Gilbert WM, Jacoby BN, Xing G: Adverse obstetric events are associated with signiicant risk of cerebral palsy. Am ) Obstet Gynecol 203:328, 2010

Gilstrap LC III, Leveno KJ, Burris), et al: Diagnosis of asphyxia on the basis of fetal pH, Apgar score, and newborn cerebral dysfunction. Am J Obstet Gynecol 161:825, 1989

Glass HG, Hong K), Rogers EE, et al: Risk factors for epilepsy in children with neonatal encephalopathy. Pediatr Res 70(5):535, 2011

Goldaber KG, Gilstrap LC III, Leveno J, et al: Pathologic fetal acidemia.

Obstet Gynecol 78: 1103, 1991

Graham EM, Adami RR, McKenney SL, et al: Diagnostic accuracy of fetal heart rate monitoring in the identiication of neonatal encephalopathy. Obstet Gynecol 124(3):507,t2014

Griinebaum A, McCullough LB, Sapra KJ, et al: Apgar score ofO at 5 minutes and neonatal seizures or serious neurologic dysfunction in relation to birth setting. Am) Obstet GynecoI200:323.e1, 2013

Guillet R, Edwards AD, Thoresen M, et al: Seven-to-eight year follow-up of the Cool Cap trial of head cooling for neonatal encephalopathy. Pediatr Res 71(12):205,t2012

Gyami-Bannerman C, Blackwell TS, Tita AT, et al: Antenatal betamethasone for women at risk for late preterm delivery. N Englt) Med 374(14):1311, 2016 Harrington DJ, Redman CW, Moulden M, et al: Long-term outcome in surviving infants with Apgar zero at 10 minutes: a systematic review of the literature and hospital-based cohort. m J Obstet Gynecol 196:463, 2007

Harteman J, Groenendaal F, Benders M, et al: Role of thrombophilic factors in full-term infants with neonatal encephalopathy. Pediatr Res 73(1):80, 2013 Heyman S, Vervloessem 0: Bryant's and Stabler's signs after a diicult delivery. N Engl) Med 365:1824,t2011 Higgins RD, Saade G, Polin A, et al: Evaluation and management of women and newborns with a maternal diagnosis of chorioamnionitis. Obstet Gynecol (3):426,t2016

Hirakawa E, Ibara 5, Tokuhisa T, et al: Extracorporeal membrane oxygenation in 61 neonates: Single-center experience. Pediatr Int 59(4):438, 2017

INFANT Collaborative Group: Computerised interpretation of fetal heart rate during labour (INFANT): a randomised controlled trial. Lancet 389(10080):1719,t2017

Jacobs SE, Morley q, Inder TE, et al: Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med 165(8):692,t2011

Johnson C, Burd I, Northington F, et al: Clinical chorioamnionitis is associated with a more severe metabolic acidosis in neonates with suspected hypoxic-ischemic encephalopathy. Am J Obstet Gynecol 210:5205, 2014

Kaandorp ]], Benders MJ, Schuit E, et al: Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial. Arch Dis Child Fetal Neonatal Ed 100(3):F216, 2015

Kaplan M, Bromiker R, Hammerman C: Severe neonatal hyperbilirubinemia and kernicterus: are these still problems in the third millennium? Neonatology 100(4):354,t2011

Katz VL, Bowes W A J r: Meconium aspiration syndrome: relections on a murky subject. Am J Obstet Gynecol 166(1 Pt 1): 171, 1992

Kersten CM, Moellering CM, Mato 5: Spontaneous drainage of neonatal cephalohematoma: a delayed complication of scalp abscess. Clin Pediatr 47(2): 183, 2008

Khan NA, Lam V, Rickett A, et al: Unforeseen rib fracture indings in infant chest radiographs: evidence of non-accidental injury or simply a case of birth trauma? BMJ Case Rep June 30, 2016

Kilani A, Wetmore J: Neonatal subgaleal hematoma: presentation and outcome-radiological indings and factors associated with mortaliry. Am J Perinatol 23(1):41, 2006

Kirton A, Armstrong-Wells J, Chang T, et al: Symptomatic neonatal arterial ischemic stroke: the International Pediatric Stroke Study. Pediatrics 128(6):e1402,t201t1

Kraft WK, Adeniyl-Jones SC, Chervoneva I, et al: Buprenorphine for the treatment of the neonatal abstinence syndrome. N Engl J Med 376(24):2341, 2017

Krakowiak P, Walker CK, Bremer A, et al: Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. Pediatrics 129(5):1,t2012

Kwon JM, Guillet R, Shankaran 5, et al: Clinical seizures in neonatal hypoxicischemic encephalopathy have no independent impact on neurodevelopmental outcome: secondary analyses of data from the Neonatal Research Network hypothermia trial. J Child Neurol 26:322, 2011

Lee J, Romero R, Lee A, et al: Meconium aspiration syndrome: a role for fetal systemic inlammation. Am J Obstet GynecoI214(3):366.e1, 2016

Lee K, Penn A, Patel M, et al: Hypothermia-treated neonates with hypoxicischemic encephalopathy: oprimal timing of quantitative ADC measurement to predict disease severity. Neuroradiol J 30(1):28, 2017

Leveno KJ, Quirk JG Jr, Cunningham FG, et al: Prolonged pregnancy. 1.

Observations concerning the causes of fetal distress. Am J Obstet Gynecol 150:465, 1984

Levine MG, Holroyde J, Woods JR, et al: Birth trauma: incidence and predisposing factors. Obstet Gynecol 63:792, 1984

Lin Y, Ebb DH, Boepple PA, et al: Case 12-2015. A newborn boy with respiratory distress, lethargy, and hypernatremia. N Engl J Med 372(16):1550, 2015

Lindenburg IT, van Klink JM, Smits-Wintjens EH, et al: Long-term neurodevelopmental and cardiovascular outcome after intrauterine transfusions for fetal anaemia: a review. Prenat Oiagn 33:815, 2013

Lindenskov PH, Castellheim A, Saugstad 00, et al: Meconium aspiration syndrome: possible pathophysiological mechanisms and future potetial therapies. Neonatology 107(3):225,t2015

Linder I, Melamed N, Kogan A, et al: Gender and birth trauma in full-term infants. J Matern Fetal Neonatal Med 25(9):1603,t2012

Lindqvist PG, Erichs K, Molnar C, et al: Characteristics and outcome of brachial plexus birth palsy in neonates. Acta Paediatr 101(6):579,t2012

Liu J, Shi Y, Dong JY, et al: Clinical characteristics, diagnosis and management of respiratory distress syndrome in full-term neonates. Clin Med J (Engl) 123:2640,t2010

Liu LY, Antaya RJ: Neonatal subgaleal hematoma from trauma during vaginal delivery without instrument use. Pediatr Dermatol 34(1):e40, 2017 Maisonneuve E, Audibert F, Guilbaud L, et al: Risk factors for severe neonatal acidosis. Obstet Gynecol 118(4):818,t2011 Malessy MJ, Pondaag W: Obstetric brachial plexus injuries. Neurosurg Clin North Am 20(1):1, 2009

Malin GL, Morris RK, Khan KS: Strength of association between umbilical cord pH and perinatal and long term outcomes: systematic review and metaanalysis. BMJ 340:cl471, 2010

Diseases and Injuries of the Term Newborn 633

MalIa R, Asimi R, T eli ..1A, et al: Erythropoietin monotherapy in perinatal asphyxia with moderate to severe encephalopathy: a randomized placebocontrolled trial. J Perinatol 37(5):596, 2017

Martinez-Biarge M, Madero R, Gonzalez A, et al: Perinatal morbidity and risk of hypoxic-ischemic encephalopathy associated with intrapartum sentinel events. Am J Obstet Gynecol 206(2): 148,t2012

McAdams M, Chabra 5: Umbilical cord haematoma and adrenal haemorrhage in a macrosomic neonate with anaemia. BMJ Case Rep February 3,2016

McDonald SJ, Middleton P, Dowswell T, et al: Efect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes. Cochrane Database Syst Rev 7:CD004074, 2013

McIntyre 5, Blair E, Badawi N, et al: Antecedents of cerebral palsy and perinatal death in term and late preterm singletons. Obstet Gynecol 122:869, 2013

McKinlay q, Alsweiler JM, Ansell JM, et al: Neonatal glycemia and neurodevelopmental outcomes at 2 years. N Engl J Med 373(16):1507, 2015

Menticoglou SM, Perlman M, Manning FA: High cervical spinal cord injury in neonates delivered with forceps: report of 15 cases. Obstet Gynecol 86:589, 1995

Miller ME, Graham J f Jr, Higginbottom MC, et al: Compression-related defects from early amnion rupture: evidence for mechanical teratogenesis. J Pediatr 98:292, 1981

Moczygemba CK, Paramsothy P, Meikle 5, et al: Route of delivery and neonatal birth trauma. Am J Obstet Gynecol 202(4) :361.e 1, 2010

Modanlou H, Hutson 5, Merritt AT: Early blood transfusion and resolution of disseminated intravascular coagulation associated with massive subgaleal hemorrhage. Neonatal Netw 35(1):37,t2016

Moster D, Lie RT, Irgens LM: The association of the Apgar score with subsequent death and cerebral palsy: a population-based study in term infants. J Pediatr 138(6):798, 2001

Moster D, Lie RT, Markestad T: Long-term medical and social consequences of preterm birth. N Engl J Med 359:262, 2008

Natarajan CK, Sankar MJ, Jain K, et al: Surfactant therapy and antibiotics in neonates with meconium aspiration syndrome: a systematic review and meta-analysis. J Perinatol 36(Suppl 1):549 2016a

Natarajan G, Pappas A, Shankaran 5: Outcomes in childhood following therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy (HIE). Semin Perinatol 40(8):549, 2016b

Nelson DB, Lucke M, McIntire DD, et al: Obstetric antecedents to body cooling treatment of the newborn infant. Am J Obstet Gynecol 211: 115, 20t14

Nelson KB, Blair E: Prenatal factors in singletons with cerebral palsy born at or near term. N Engl J Med 373(10):946,t2015

Nelson KB, Ellenberg JH: Antecedents of cerebral palsy: multivariate analysis of risk. N Engl J Med 315:81, 1986a

Nelson KB, Ellenberg JH: Antecedents of cerebral palsy: univariate analysis of risks. Am J Dis Child 139:1031, 1985

Nelson KB, Ellenberg JH: Antecedents of seizure disorders in early childhood.

Am J Dis Child 140:1053, 1986b

Nelson KB, Ellenberg JH: Obstetric complications as risk factors for cerebral palsy or seizure disorders. JAMA 25t1:1843, 1984

Nelson KB, Grether JK: Potentially asphyxiating conditions and spastic cerebral palsy in infants of normal birth weight. Am J Obstet GynecoIt179:507, 1998

Newman TB, Liljestrand P, Jeremy Rj, et al: Outcomes among newborns with total serum bilirubin levels of 25 mg per deciliter or more. N Engl J Med 354: 1889, 2006

O'Callaghan M, MacLennan A: Cesarean delivery and cerebral palsy: a systematic review and meta-analysis. Obstet Gynecol 122: 11t69, 2013 O'Callaghan ME, MacLennan AH, Gibson CS, et al: Epidemiologic associations with cerebral palsy. Obstet GynecoIt118(3):576, 2011

O'Leary CM, Watson L, O'Antoine H, et al: Heavy maternal alcohol consumption and cerebral palsy in the ofspring. Dec Med Child Neurol 54:224,t2012

Phelan JP, Ahn MO: Perinatal observations in forty-eight neurologically impaired term infants. Am J Obstet Gynecol 171 :424, 1994

Phelan JP, Ahn MO, Korst L, et al: Is intrapartum fetal brain injury in the term fetus preventable? Am J Obstet Gynecol 174:318, 1996

Plevani C, Pozzi I, Locatelli A, et al: Risk factors of neurological damage in infants with asphyxia. Abstract No. 414, Am J Obstet Gynecol 208 (1 Suppl):SI82, 2013

Pritchard JA, Cunningham FG, Pritchard SA, et al: How often does maternal preeclampsia-eclampsia incite thrombocytopenia in the fetus? Obstet Gynecol 69:292, 1987

Ramachandrappa A, Rosenberg ES, Wagoner 5, et al: Morbidity and mortality in late preterm infants with severe hypoxic respiratory failure on extracorporeal membrane oxygenation. J Pediatr 159(2): 192,t2011

Redline RW: Placental pathology: a systematic approach with clinical correlations. Placenta 22:S86, 2008

Ree 1M, Smits-Wintjens E, van der Bon ]G, et al: Neonatal management and outcome in alloimmune hemolytic disease. Expert Rev Hematol 10(7):607,t2017

Reuter S, Moser C, Baack M: Respiratory distress in the newborn. Pediatr Rev 35(10):417,t2014

Richey S, Ramin SM, Bawdon E, et al: Markers of acute and chronic asphyxia in infants with meconium-stained amniotic fluid. Am ] Obstet Gynecol 172:1212,t1995

Robinson MN, Peake L], Ditchield MR, et al: Magnetic resonance imaging indings in a population-based cohort of children with cerebral palsy. Dev Med Child Neurol 51(1):39, 2008

Ross MG, Beall MH: Cervical neck dislocation associated with the Zavanelli maneuver. Obstet Gynecol 108:737,t2006

Rossi AC, Vanderbilt 0, Chmait RH: Neurodevelopmental outcomes after laser therapy for twin-twin transfusion syndrome: a systematic review and meta-analysis. Obstet Gynecol 118(5):1145,t2011

Rutherford vlA, Ramenghi A, Cowan FM: Neonatal stroke. Arch Dis Child Fetal Neonatal Ed 97(5):F377, 2012

Saksenberg V, Bauch B, Reznik S: Massive acute thymic haemorrhage and cerebral haemorrhage in an intrauterine fetal death. ] Clin Pathol 54:796, 2001

Sankar M], Chandrasekaran A, Kumar P, et al: Vitamin K prophylaxis for prevenrion of vitamin K deficiency bleeding: a systematic review. ] Perinatol 36 (Suppl 1):S29, 2016

Saroha M, Batra P, Dewan P, et al: Genital injuries in neonates following breech presentation.] Neonatal Perinatal Med 8(4):421, 2015

Scheibl A, Calderon EM, Borau M], et al: Epidural hematoma.t] Pediatr Surg 47(2):el9,t2012

Sgro M, Campbell 0, Barozzino T, et al: Acute neurological indings in a national cohort of neonates with severe neonatal hyperbilirubinemia. ] PerinatoI31(6):392,t2011 Sgro M, Kandasamy S, Shah V, et al: Severe neonatal hyperbilirubinemia decreased after the 2007 Canadian guidelines.t] Pediatr 171:43,t2016

Shah NA, Wusthof C]: Intracranial hemorrhage in the neonate. Neonatal Netw ,2016

Shankaran S, Branes PO, Hintz SR, et al: Brain injury following trial of hypothermia for neonatal hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 97(6):F398, 2012

Shatrov ]G, Birch Sc, Lam FT, et al: Chorioamnionitis and cerebral palsy: a meta-analysis. Obstet Gynecol 116:387,t2010

Silva M, Smith RN, Lehmann CU, et al: Neonatal nucleated red blood cells and the prediction of cerebral white matter injury in preterm infants. Obstet Gynecol 107:550, 2006

Simonson C, Barlow P, Dehennin N, et al: Neonatal complications of vacuumassisted delivery. Obstet Gynecol 110: 189, 2007 Singh BS, Clark RH, Powers RJ, et al: Meconium aspiration syndrome remains a significant problem in the NICU: outcomes and treatment patterns in term neonates admitted for intensive care during a ten-year period. ] Perinatol 29(7):497, 2009 Slusher TM, Olusanya BO, Vreman H], et al: A randomized trial of phototherapy with filtered sunlight in Mrican neonates. N Engl] Med 373(12): 1115, 2015 Smith C, Weinberg A, Forster ]E, et al: Maternallopinavir-ritonavir is associated with fewer adverse events in infants than nelfinavir or atazanavir. Infect Dis Obstet Gynecol 2016:9848041, 2016 Smithers-Sheedy H, McInryre S, Gibson C, et al: A special supplement: indings from the Australian Cerebral Palsy Register, birth years 1993 to 2006. Dev Med Child Neurol 58(Suppl 2):5, 2016 Spruijt M, Steggerda S, Rath M, et al: Cerebral injury in twin-twin transfusion syndrome treated with fetoscopic laser surgery. Obstet Gynecol 120(1):15, 2012 Stanley F], Blair E: Why have we failed to reduce the frequency of cerebral palsy? Med ] Aust 154:623, 1991 Stoknes M, Andersen GL, Dahlseng MO, et al: Cerebral palsy and neonatal death in term singletons born small for gestational age. Pediatrics 130(6):el629,t2012 Strijbis EM, Oudman I, van Essen P, et al: Cerebral palsy and the application of the inrernational criteria for acute intrapartum hypoxia. Obstet Gynecol 107:t1t357,t2006 Stuart A, Olausson PO, Kallen K: Apgar scores at 5 minutes after birth in relation to school performance at 16 years of age. Obstet Gynecol 11t8 (2 Pt 1):201, 2011 Swanson AE, Veldman A, Wallace EM, et al: Subgaleal hemorrhage: risk factors and outcomes. Acta Obstet Gynecol Scand 91 (2):260, 2012

Tagin A, Woolcott CG, Vincer M], et al: Hypothermia for neonatal hypoxic ischemic encephalopathy: an updated systematic review and meta-analysis. Arch Pediatr Adolesc vIed 166(6):558,t2012

Takenouchi T, KasdorfE, Engel M, et al: Changing pattern of perinatal brain injury in term infants in recent years. Pediatr Neurol 46(2): 106, 2012 hacker SB, Stroup OF, Peterson HB: Eicacy and safety of intrapartum electronic fetal monitoring: an update. Obstet Gynecol 86:613, 1995 harakan S], Lee R], White M, et al: Distal humeral epiphyseal separation in a newborn. Orthopedics 39(4):e764, 2016 horngren-]erneck K, Herbst A: Perinatal factors associated with cerebral palsy in children born in Sweden. Obstet Gynecolt108:1499, 2006

Tolia VN, Patrick SW, Bennett MM, et al: Increasing incidence of the neonatal abstinence syndrome in U.S. neonatal ICUs. N Engl] Med 372(22):2118, 2015

Torfs CP, van den Berg B, Oechsli FW, et al: Prenatal and perinatal factors in the etiology of cerebral palsy. ] Pediatr 116:615, 1990

Torki M, Barton L, Miller 0, et al: Severe brachial plexus palsy in women without shoulder dystocia. Obstet Gynecol 120(3):539,t2012

Turpenny PO, Nimmo A: Fractured clavicle of the newborn in a population with a high prevalence of grand-multiparity: analysis of78 consecutive cases. B]OG 100:338, 1993

Ubachs ]M, Sloof AC, Peeters LL: Obstetric antecedents of surgically treated obstetric brachial plexus injuries. B]OG 102:813, 1995

Vain NE, Szyld EG, Prudent LM, et al: Oropharyngeal and nasopharyngeal suctioning of meconium-stained neonates before delivery of their shoulders: multicentre, randomized controlled trial. Lancet 364:597, 2004

Vandborg PK, Hansen BM, Greisen G, et al: Follow-up of neonates with total serum bilirubin levels �25 mg/dL: a Danish population-based study. Pediatrics 130(1):61,t2012

Vasconcelos BC, Lago CA, Nogueira RV, et al: Mandibular fracture in a premature infant: a case report and review of the literature. ] Oral Maxillofac Surg 67(1):218,t2009

Villamor E, Tedrof K, Peterson M, et al: Association between matenal body mass index in early pregnancy and incidence of cerebral palsy. ]AMA 317(9):925,t2017

Volpe JJ: Neurology of the Newborn, 3rd ed. Philadelphia, Saunders, 1995

Wall LB, Mills ]K, Leveno K], et al: Incidence and prognosis of neonatal brachial plexus palsy with and without clavicle fractures. Obstet Gynecol 123(6):1288,t2014

Walsh B, Boylan G, Dempsey E, et al: Association of nucleated red blood cells and severity of encephalopathy in normothermic and hypothermic infants. Acta Paediatr 102(2):e64, 2013

Walsh BH, Bovian GB, Murray OM: Nucleated red blood cells and early EEG: predicting Sarnat stage and two year outcome. Early Hum Dev 87(5):335, 201t1 Walsh BH, Neil], Morey], et al: he frequency and severity of magnetic resonance imaging abnormalities in infants with mild neonatal encephalopathy. ] Pediatr 187:26, 2017

Wambach ]A, Wegner 0], Depass K, et al: Single ABCA3 mutations increase risk for neonatal respiratory distress syndrome. Pediatrics 130(6):e 15 75, 2012 Watchko ]F, Tiribelli C: Bilirubin-induced neurologic damage-mechanisms and management approaches. N Englt] Med 369:21,t2013

Wayock CP, Meserole RL, Saria S, et al: Perinatal risk factors for severe injury in neonates treated with whole-body hypothermia for encephalopathy. Am ] Obstet GynecoIt21t1(1):41.el, 2014

Wenstrom KD, Andrews W, Maher ]E: Amnioinfusion survey: prevalence, protocols, and complications. Obstet Gynecol 86:572, 1995

Wener EF, ]anevic TM, Illuzzi], et al: Mode of delivery in nulliparous women and neonatal intracranial injury. Obstet Gynecol 118(6): 1239,t201t1

Whitby EH, Griiths PO, Rutter S, et al: Frequency and natural history of subdural haemorrhages in babies and relation to obstetrical factors. Lancet 363:846, 2004

Wiberg N, Kallen K, Herbst A, et al: Relation between umbilical cord blood pH, base deicit, lactate, 5-minute Apgar score and development of hypoxic ischemic encephalopathy. Acta Obstet Gynecol Scand 89: 1263, 2010

Wiklund LM, Uvebrant P, Flodmark 0: Computed tomography as an adjunct in etiological analysis of hemiplegic cerebral palsy, 1. Children born preterm. Neuropediatrics 22:50, 1991 a

Wiklund LM, Uvebrant P, Flodmark 0: Computed tomography as an adjunct in etiological analysis of hemiplegic cerebral palsy, 2. Children born at term. Neuropediatrics 22: 121) 1991 b

Williams ]W: Obstetrics: a Text-book for the Use of Students and Practitioners. New York, Appleton, 1903

Winkelhorst 0, Murphy MF, Greinacher A, et al: Antenatal managemet in fetal and neonatal alloimmune thrombocytopenia: a systematic review. Blood 129(11):1538,t2017

Wiswell TE, Tuggle JM, Turner BS: Meconium aspiration syndrome: have we made a diference? Pediatrics 85:715, 1990

World Health Organization: Guidelines on Basic Newborn Resuscitation.

Geneva, World Health Organization, 2012

Wu YW, Bauer A, Ballard A, et al: Erythropoietin for neuroprotection in neonatal encephalopathy: safety and pharmacokinetics. Pediatrics 130(4):683,t2012

Wu W, Croen A, Shah SJ, et al: Cerebral palsy in a term population: risk factors and neuroimaging findings. Pediatrics 1t18:691,t2006

Wu W, Plum TN, Danielsen B, et al: Nighttime delivery and risk of neonatal encephalopathy. Am J Obstet GynecoI204(l):37.e1, 2011

Diseases and Injuries of the Term Newborn 635

Wyckof MH, Aziz K, Escobedo MB, et al: Part 13: Neonatal resuscitation: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Pediatrics 136 (Suppl 2):

SI96,t2015

Yaish HM, Christensen RD, Lemmons RS: Neonatal nonimmune hemolytic anemia. Curr Opin Pediatr 29(1): 12,t2017

Yeh P, Emary K, Impey L: The relationship between umbilical cord arterial pH and serious adverse neonatal ourcome: analysis of 51,519 consecurive validated samples. BlOG 119(7):824,t2012

Zipursky A: Prevention of vitamin K deficiency bleeding in newborns. Br J Haematol 104:430, 1999

CHAPTER 34 .

The Preterm Newborn

RESPIRATORY DISTRESS SYNDROME. .. .. ... 636

NECROTIZING ENTEROCOLITIS . .... ... 638

RETINOPATHY OF PREMATURITY ..639

BRAIN DISORDERS .. ........ . 639

INTRACRANIAL .......... 639

CEREBRAL PALSY . .... ............. 640 !he prognosis or the child depends, of course, upon the degree of development, as wel as the pathological condition or which premature delivery is undertaken. Generaly speaking, in the case of children born bore the thiry-second week, the chances of surviving are vey small.

-]. Whitridge Williams (1903)

At the time of this textbook's irst edition, preterm delivery of a living newborn was frequently followed by neonatal death. Contrast this with today's technological advances that have advanced the threshold of viability to 22 to 24 weeks' gestation. Even so, the preterm newborn is susceptible to various serious medical complications both early and later in life (Table 34-1). A less commonly cited cause of morbidity and mortality is congenital malformations, which are much more prevalent in preterm births.

These complications of prematurity can be placed in perspective in terms of overall neonatal outcomes. In 2009, two thirds of all infant deaths in the United States were in the 12 percent born before 37 weeks (Mathews, 2013). Fortunately, during the past decade, rates of preterm birth have declined from approximately 12 percent in 2007 to 10 percent in 2014. This is in part due to a decline in births to teen mothers (Ferre, 2016).

The seminal complication of the preterm newborn is respiratory distress syndrome (DS). This results from immature lungs that are unable to sustain necessary oxygenation. Resulting hypoxia is an underlying associated cause of neurological damage such as cerebral palsy. In addition, hyperoxia, a side efect of DS treatmentacontributes to morbidities such as bronchopulmonary dysplasia, pulmonary hypertension, necrotizing enterocolitis, periventricular leukomalacia, and retinopathy of prematurity.

To provide blood gas exchange immediately following delivery, the lungs must rapidly fill with air while being cleared of fluid. Concurrently, pulmonary arterial blood low must rise remarkably. Although some of the luid is expressed as the chest is compressed during vaginal delivery, most is absorbed through the

TABLE 34-1. Complications of Prematurity

Retinopathy of prematurity (ROP)

The Preterm Newborn 637

Chapter 32 (p. 606). Suicient surfactant, synthesized by type II pneumocytes, is essential to stabilize the air-expanded alveoli. It expiration (Chap. 7, p. 133). If surfactant is inadequate, hyaline membranes form in the distal bronchioles and alveoli, and RDS develops. Although respiratory distress syndrome is generally a disease of preterm neonates, it does develop in term newborns, especially with sepsis or meconium aspiration. In these cases, of meconium (Chap. 33, p. 619).

With inadequate surfactant, alveoli are unstable, and low pressures cause collapse at end expiration. Pneumocyte nutrition is compromised by hypoxia and systemic hypotension. Partial persistence of the fetal circulation may lead to pulmonary hypertension and a relative right-to-Ieft shunt. Eventually, alveolar cells undergo ischemic necrosis. When oxygen therapy is initiated, the pulmonary vascular bed dilates, and the shunt reverses. Protein-filled fluid leaks into the alveolar ducts, and the cells lining the ducts slough. Hyaline membranes composed of ibrin-rich protein and cellular debris line the dilated alveoli and terminal bronchioles. he epithelium underlying the membrane becomes necrotic. At autopsy, with hematoxylin-eosin staining of lung tissue, these membranes appear amorphous and eosinophilic, like hyaline cartilage. Because of this, respiratory distress syndrome is also termed hyaline membrane disease.

In typical RDS, tachypnea develops, the chest wall retracts, and expiration is accompanied by nostril flaring and by gruntingin an attempt to provide a positive end-expiratory pressure to prevent lung collapse. Shunting of blood through nonventilated lung contributes to hypoxemia and to metabolic and respiratory acidosis. Poor peripheral circulation and systemic hypotension may be evident. The chest radiograph shows a difuse reticulogranular infiltrate and an air-illed tracheobronchial tree-air bronchogram.

As discussed further in Chapter 33 (p. 619), respiratory insuiciency can also be caused by sepsis, pneumonia, meconium aspiration, pneumothorax, persistent fetal circulation, heart failure, and malformations involving thoracic structures, such as diaphragmatic hernia. Common mutations in surfactant protein production and the phospholipid transporter (ABCA3) contribute to RDS (Beers, 2017; Tredano, 2003; Wert, 2009).

An important factor inluencing survival is neonatal intensive care. Although hypoxemia prompts supplemental oxygen, excess oxygen can damage the pulmonary epithelium, retina, and other immature tissues. Despite this, advances in mechanical ventilation technology have improved neonatal survival rates. For example, continuous positive airway pressure (CPAP) prevents the collapse of unstable alveoli. This allows high inspired-oxygen concentrations to be reduced, thereby minimizing its toxicity. In an attempt to minimize the need for tracheal intubation and intermittent positive-pressure ventilation, CPAP has been studied in well-designed multicenter trials (Morley, 2008; SUPPORT Study Group, 2010b). An initial

CPAP strategy with subsequent selective surfactant use is a beneficial alternative to immediate intubation and surfactant for many neonates of extremely early gestational age (American

Academy of Pediatrics, 2014).

rates but is an important factor in the genesis of chronic lung dis ease of prematurity-bronchopulmonary dypasia (BPD). Namely, and volutrauma. Moreover, hyperoxia can create reactive oxy gen species that trigger inflammation. Infection can also be con tributory. In afected newborns, alveolar and pulmonary vascular development is disrupted and leads to hypoxia, hypercarbia, and chronic oxygen dependence (Davidson, 2017; Kair, 2012).

As prevention, hightequency oscilatory ventilation has been evaluated. However, beneits and risks varied considerably between studies (Cools, 2015).

Treatment of the ventilator-dependent neonate with gluco corticoids was also used previously to prevent BPD. he Ameri can Academy of Pediatrics now recommends against routine steroid use because of limited beneits and greater rates of in exposed neonates (Doyle, 20a14a,b; Watterberg, 2010).

In other eforts for BPD prevention, early animal studies demonstrated significant improvements in lung function with weeks of inhaled nitric oxide (McCurnin, 2005). Despite initial enthusiasm, clinical trials failed to demonstrate a consistent benefit. A National Institutes of Health (NIH) consensus statement and the American Academy of Pediatrics (2014) concluded that the available data do not support its use to prevent or treat BPD (Cole, 2011).

Caeine has been used widely to treat apnea of prematurity, but it also has bronchodilatory efects. One large randomized trial of cafeine versus placebo showed lower BPD rates, improved neurodevelopmental outcomes during early childhood, and good evidence of safety up to 11 years (Schmidt, 2006, 2012, 2017). This therapy is now widely used for newborns weighing ; 1250 g.

The antioxidant vitamin A is necessary for normal lung growth and the integrity of respiratory tract epithelial cells. Preterm newborns have low vitamin A levels at birth, and this has been associated with a greater risk of developing BPD. Randomized trials support the use of vitamin A to achieve a modest reduction in BPD rates for very-Iow-birthweight neonates weighing <1500 g (Darlow, 2016) .

Exogenous surfactant products are delivered via endotracheal tube to help prevent RDS. They contain biological or animal surfactants such as bovine-Survanta, calf-Inasu,or porcine-Curosuf Synthetic surfactants such as irst-generation Exosuf and second-generation Suaxin R are equivalent but not superior to animal-derived surfactant (Moya, 2007). In a Cochrane review, Ardell and coworkers (2015) found that animal-derived surfactants led to better outcomes than synthetic surfactants, which do not contain important surfactant proteins. here are currently no synthetic surfactants available.

Surfactant replacement was established decades ago as an efective and safe therapy for RDS. Treatment reduces rates of mortality and pneumothorax and improves survival without BPD (Polin, 2014). It has been used for prophyxis of preterm, at-risk newborns and for rescue of those with established disease. Given together, antenatal corticosteroids and surfactant result in an even greater reduction in the overall death rate. However, randomized trials indicate that in populations with high use of antenatal steroids and routine use of CP P in the delivery room, prophylactant surfactant is no longer beneficial and is associated with more risk of death or BPD (Rojas-Reyes, 2012; Sardesai, 2017). Exploration of diferent, less invasive ways to deliver rescue surfactant to spontaneously breathing preterm neonates is currently underway. Potential routes include surfactant application into the pharynx, surfactant nebulization, or application via laryngeal mask or via a thin catheter placed in the trachea (Kribs, 2016).

The NIH (1994, 2000) has concluded that a single course of antenatal corticosteroid therapy reduces RDS and intraventricular hemorrhage rates in preterm neonates born between 24 and 34 weeks' gestation (p. 640). he American College of Obstetricians and Gynecologists (2016a) considers all women at risk for preterm birth in this gestational-age range to be potential candidates for therapy. It also may be considered for pregnant women starting at 23 weeks' gestation who are at risk of preterm delivery within 7 days. his is discussed further is Chapter 42 (p. 823). More recently, administration of antenatal corticosteroids to women at risk for late-preterm delivery (34 to 36 weeks' gestation) was found to significantly reduce the rate of neonatal respiratory complications (Gyami-Bannerman, 2016).

Amniocentesis to Assess Fetal Lung Maturity

In some instances, when gestational age is uncertain, knowledge of fetal lung maturity may inluence plans for delivery. One example is the woman with a prior classical cesarean delivery in whom repeat operation is planned and gestational age cannot be confirmed. Several tests are used to ensure fetal pulmonary maturity by analysis of amnionic fluid obtained by sonographically guided amniocentesis. At Parkland Hospital, we still find an occasional indication for such testing, however, the American College of Obstetricians and Gynecologists (2017 a, b) counsels against its use in most of these cases. Instead the College recommends late-term delivery at "41 weeks' gestation" using the best clinical estimate of gestational age (Chap. 10, p. 183).

If amniocentesis is elected, luid acquisition is similar to that described for second-trimester amniocentesis (Chap. 14, p. 292). Complications requiring urgent delivery are rare (Zalud, 2008). Following analysis, the probability of RDS developing in a given newborn depends on the test used and fetal gestational age. Importantly, administration of corticosteroids to induce pulmonary maturation has variable efects on some of these tests. Varner and colleagues (2013) have provided a review of testing options.

Of biochemical tests, the labor-intensive lecithin-sphingomyelin (LIS) ratio for many years was the gold-standard test.

2•..J• .-E c.o .-8 8c .0ll,� 2

FIGURE 34-1 Changes in mean concentrations of lecithin and sphingomyelin in amnionic fluid during gestation in normal pregnancy. (Modified with permission from Gluck L, Kulovich MV:

Lecithin-sphingomyelin ratios in amniotic fluid in normal and abnormal pregnancy, Am J Obstet Gynecol. 1973 Feb 15;115(4):539-546.)

Dipalmitoylphosphatidylcholine (DPPC), that is, lecithin, and phingomyelin are surfactant components. Before 34 weeks, both are present in amnionic fluid in similar concentrations. At 32 to 34 weeks, the concentration of lecithin relative to sphingomyelin begins to rise (Fig. 34-1). The risk of neonatal RDS is slight whenever the concentration of lecithin is at least twice that of sphingomyelin-LIS ratio >2 (Gluck, 1971). Previously, RDS was thought to develop despite an LIS ratio > 2 in newborns of women with diabetes. Some recommend that phosphatidygycerol, another surfactant phospholipid, be documented in amnionic fluid of these women. Based on current evidence, it is unclear if either diabetes, per se, or its level of control causes false-positive phospholipid test results for fetal lung maturity (De Luca, 2009).

Of biophysical tests, the luorescence poariation test is an automated assay that measures the surfactant-to-albumin ratio in uncentriuged amnionic luid and gives results in less than an hour. Investigators found the TDx-FLM to be equal or superior to the LIS ratio, foam stability index, or phosphatidylglycerol assessment. his included testing in diabetic pregnancies (Karcher, 2005; Varner, 2013). he modified TDx-FLM Ilis used by many hospitals as their primary test of pulmonary maturity. Thresholds vary by gestational age (Bennasar, 2009). he oam stabiliy or shake test relies on the ability of surfactant in amnionic luid, when mixed appropriately with ethanol, to generate stable foam at the air-liquid interface (Clements, 1972). Problems include errors caused by slight contamination and frequent false-negative test results. Of other tests, the Lumadex-FSI test, luorescent poariation (microviscomery), and amnionic luid absorbance at 650-nm waveength have all been used with variable success.

The lamelar body count is a rapid, simple, and accurate method of assessing fetal lung maturity and is comparable to TDx-FLM and LIS ratio accuracy (Karcher, 2005; Varner, 2013).

This newborn bowel disorder has clinical findings that include abdominal distention, emesis, ileus, bilious gastric aspirates,

The Preterm Newborn 639 and bloody stools. here is often radiological evidence of bacteria. Other classic imaging findings include hepatobiliary gas and pneumoperitoneum. Bowel perforation may prompt resection. Necrotizing enterocolitis (NEC) is seen primarily in low-birthweight newborns but occasionally is encountered in mature neonates. Various hypothesized causes include peri natal hypotension, hypoxia, sepsis, umbilical catheterization, exchange transfusions, blood transfusions, and the feeding of cow milk and hypertonic solutions (Neu, 2010). he patho physiology is thought to be multifactorial, and genetic disposi tion, intestinal immaturity, imbalance in microvascular tone, abnormal microbial colonization in the intestine, exposure to enteral feeds, and highly immunoreactive intestinal mucosa play potential roles (Caplan, 2017; Neu, 2010).

Medical treatment includes abdominal decompression, bowel rest, broad-spectrum antibiotics, and parenteral nutrition. Surgery is reserved for neonates with intestinal perforation or deteriorating clinical or biochemical status. Possible surgical procedures include drain placement, exploratory laparotomy with resection of diseased bowel, or enterostomy with creation of a stoma (Neu, 2010).

By 1950, this condition, formerly known as retrolental ibroplasia, became the largest single cause of blindness in this country. Mter the discovery that the disease resulted from hyperoxemia, its frequency declined but began to rise again with the increasing survival rates of extremely pre term newborns.

Normally, the fetal retina vascularizes centrifugally from the optic nerve starting at approximately the fourth month and continues until shortly after birth. During vascularization, excessive oxygen induces severe retinal vasoconstriction with endothelial damage and vessel obliteration. his is followed by subsequent aberrant neovascularization, in which the new vessels penetrate the retina and extend into the vitreous. Here, they are prone to leak proteins or burst with subsequent hemorrhage. Adhesions can form to detach the retina. Vascular endothelial growth factor (VEGF) plays an important role in normal angiogenesis and is up regulated during retinopathy of prematurity (ROP) development (Sharma, 2017). his understanding has opened new avenues of treatment with anti-VEGF therapies.

Precise levels of hyperoxemia that can be sustained without causing ROP are unknown. Mter birth, there is a "relative" hyperoxia compared with in utero oxygen content, even in newborns not exposed to higher inspired oxygen concentrations. To better understand the oxygen saturation threshold necessary to minimize ROP without raising rates of other adverse outcomes, the Neonatal Research Network performed a randomized trial of oxygenation in 1316 neonates born between 24 and 27 weeks' gestation (SUPPORT Study Group, 2010a). he two target ranges of oxygen saturation were 85 to 89 percent in one arm and 91 to 95 percent in the other arm. hese targets were both commonly employed in neonatal intensive care units. Death before discharge occurred signiicantly more frequently in the lower-oxygen saturation group-20 versus 16 percent. However, severe ROP among survivors developed signiicantly less often in the lower-oxygen saturation group 8.6 versus 17.9 percent.

roanatomical sequelae in preterm newborns compared with those at term (Chap. 33, p. 621). In preterm neonates, cerebral orrhage, cerebellar hemorrhage, periventricular hemorrhagic infarction, cystic periventricular leukomalacia, and difuse white matter injury. All of these are strongly associated with adverse neurodevelopmental outcomes (Kwon, 2014).

Cranial sonography remains the preferred approach for events. It is readily available and reliable for detecting common abnormalities and monitoring brain growth. Because cystic inju ries may take 2 to 5 weeks to evolve, serial scans are obtained dur ing this time. In those whose findings are transient and resolve in the neonatal period, prognosis is improved compared with infants whose lesions remain and evolve. At the same time, how ever, between 4 and 10 percent of prematurely born children may develop cerebral palsy (CP) in the absence of lesions. Put another way, 90 to 96 percent of preterm newborns with CP have cerebral lesions that are detectable using cranial sonography.

here are ive major categories of intracranial hemorrhage in the neonate (Volpe, 2008). Primay subarachnoid hemorrhage is more common in those born preterm and is frequently benign. Cerebelar hemorrhage is also more frequent in preterm neonates and is increasingly recognized as a cause of serious sequelae. Intraventricular hemorrhage IVH) is almost exclusively seen in preterm newborns, is relatively common, and can have serious efects. Subdural hemorrhages are more frequent in term newborns and can be serious. Miscelaneous intraparenchymal hemorrhage is also more frequent in those born at term and is of variable concern.

In preterm infants, the germinal matrix capillary network is fragile for several reasons. First, the subependymal germinal matrix provides poor support for the vessels coursing through it. Second, venous anatomy in this region causes stasis and congestion, which makes vessels susceptible to bursting if intravascular pressure rises. Third, vascular autoregulation is impaired in the preterm neonate (Matsuda, 2006; Verhagen, 2014).

If fragile capillaries in the germinal matrix rupture, blood escapes into surrounding tissues and may extend into the ventricular system and brain parenchyma. This type of hemorrhage is common in preterm neonates, especially those born before 32 weeks. However, it can also develop at later gestational ages and even in term neonates. Most hemorrhages develop within 72 hours of birth, but they have been observed as late as 24 days (Whitelaw, 20ll). Because IVH usually is recognized within 3 days of delivery, its genesis is often erroneously attributed to birth events. It is important to realize that prelabor IVH can also occur (Achiron, 1993; Nores, 1996).

The pathogenesis of IVH is multifactorial and includes hypoxic-ischemic events, carbon dioxide elevations, anatomical factors, blood pressure instability, coagulopathy, genetic factors, and many others (McCrea, 2008; Ment, 2016). Moreover, preterm birth is frequently associated with infection, which further predisposes to endothelial activation, platelet adherence, and thrombi (Redline, 2008). Respiratory distress and mechanical ventilation are commonly associated factors (Sarkar, 2009).

lmost half of hemorrhages are clinically silent. Most small germinal matrix hemorrhages and those confined to the cerebral ventricles resolve without impairment. But, nearly half do show some sign of neurological impairment (Patra, 2006). Survivors of extensive periventricularlintraventricular hemorrhage can have major neurodevelopmental handicaps (Mukerji, 2015). Large lesions can result in hydrocephalus or in degenerated cystic areas termed periventricular leukomalacia (PVL), discussed below. Importantly, the extent ofPVL correlates with CP risk (Bassan, 2006).

Ventricular hemorrhage incidences depends on gestational age at birth. From the Neonatal Research Network, approximately 65 percent of all neonates born before 28 weeks' gestation demonstrated some evidence of hemorrhage or PVL (Stoll, 2010). he incidence ranged from 60 percent in those born at 23 weeks to only 23 percent in those at 28 weeks. Importantly, grade IV intraventricular hemorrhage was documented in 21 percent of 23-week-old neonates but in only 3 percent of those at 28 weeks.

The severity of IVH can be assessed by neuroimaging studies.

Papile and coworkers (1978) devised the mostwidelyused grading scheme to quantiY the extent ofa lesion and estimate prognosis:

Grade I-hemorrhage limited to the germinal matrix

Grade Ill-hemorrhage with ventricular dilation

Grade IV-parenchymal extension of hemorrhage.

If given at least 24 hours before delivery, corticosteroids prevent or reduce the incidence and severity ofIVH (Wei, 2016). A Consensus Development Conference of the NIH (1994) concluded that such therapy reduced rates of mortality, RDS, and IVH in preterm neonates born between 24 and 32 weeks' gestation. A second consensus statement by the NIH (2000) recommended that repeated courses of corticosteroids not be given (Chap. 42, p. 823).

Subsequently, the Maternal-Fetal Medicine Units Network reported that repeated corticosteroid courses were associated with some improved preterm neonatal outcomes, but also with reduced birthweight and increased risk for fetal-growth restriction (Wapner, 2006). Surveillance of this cohort through age 2 to 3 years found that children exposed to repeated versus singledose steroid courses did not difer signiicantly in physical or neurocognitive measures (Wapner, 2007). It was worrisome, however, that there was a nonsignificant 5.7-fold relative risk of CP in infants exposed to multiple steroid courses.

At the same time, the 2-year follow-up ofthe Australian CollaborativeTrialwas reported byCrowtherand coworkers (2007). In more than 1100 newborns, the incidence of CP was almost identical4.2 versus 4.8 percent-in those given repeated versus single-course steroids, respectively. More recently, it was reported that for those born before 28 weeks' gestation, if 10 days or more had passed since betamethasone administration, the incidence of severe IVH was higher (Liebowitz, 2016).

he most recent recommendations from the American College of0bstetricians and Gynecologists (2016a) are for a single course of corticosteroids for pregnant women between 24°/ weeks and 336/ weeks' gestation who are at risk for preterm delivery. They further note that those given their initial course more than 14 days prior and who have imminent risk of preterm delivery may receive a second "rescue" course. Antenatal corticosteroids are "considered" for 23°/ to 236/7 weeks and not recommended for pregnancies <23 weeks (American College of Obstetricians and Gynecologists, 2017c).

Although antenatal magnesium suate for those at risk for preterm delivery does not reduce the incidence ofIVH, it does ofer protection from neurodevelopmental impairment (Crowther, 2007; Doyle, 2009). The American College of Obstetricians and Gynecologists (2016b) recommends its use for this indication, as discussed further in Chapter 42 (p. 824). he eicacy of antenatal vitamin K and phenobarbital, as well as postnatal phenobarbital, have not been shown to consistently reduce the incidence ofIVH (Crowther, 2010a,b; Smit, 2013). Although vitamin E reduced IVH rates, the associated risk for sepsis was increased (Brion, 2003). One metaanalysis of the many randomized trials ofpostnatal indomethacin showed a reduction in IVH rates, but no improvement in rates of death or neurodevelopmental impairment (Fowlie, 2010).

he beneits of cesarean delivery compared with vaginal birth to lower IVH rates remains controversial. One metaanalysis reported that cesarean delivery for very-Iow-birthweight neonates had no efect on rates of severe IVH but did reduce overall IVH rates (Barzilay, 2016). Delayed cord clamping compared with immediate cord clamping has been reported to reduce the risk for IVH in preterm newborns (Rabe, 2012).

This pathological description refers to cystic areas deep in brain white matter that develop after hemorrhagic or ischemic infarction. Tissue ischemia leads to regional necrosis. Because brain tissue does not regenerate and the preterm neonate has minimal gliosis, these irreversibly damaged areas appear as echolucent cysts in neuroimaging studies. Generally, they require at least 2 weeks to form but may develop as long as 4 months after the initial insult. hus, their presence at birth may help to determine the timing of an inciting event.

This term refers to a group of conditions that are characterized by chronic movement or posture abnormalities that are cerebral in onglll, arise early in life, and are nonprogressive (Nelson, 2003). Epilepsy and mental retardation frequently accom pany CP. Its cause(s) are diferent in preterm and term infants (Chap. 33, p. 622).

CP is commonly classified by the type of neurological dys function-spastic, dyskinetic, or ataxic-as well as the num ber and distribution of limbs involved-quadriplegia, diplegia, hemiplegia, or monoplegia. The major types and their frequen their associates:

Spastic quadrplegia, which has a strong association with developmental retardation and seizure disorders-20 percent

Diplegia, which is common in preterm or low-birthweight

Mixed varieties.

According to the Centers for Disease Control and Prevention (2016), the prevalence of CP in the United States approximates 3 in 1000 children. In some countries, the incidence has risen because advances in care of very preterm newborns have improved their survival but not their neurological prognosis (O'Callaghan, 2011). For example, Moster and coworkers (2008) presented long-term follow-up of more than 900,000 births in Norway. he CP rate was 0.1 percent in nonanomalous term newborns but was 9.1 percent in those born at 23 to 27 weeks.

Various clinical and pathological data link CP with associated severe IVH (grade III or IV) and resulting PVL. In one study of nearly 1500 neonates born before ;28 weeks, the rate of CP was fivefold greater in those who had grade III or IV hemorrhage compared with those who sufered no IVH (Bolisetty, 2014).

Preterm newborns are most susceptible to brain ischemia and PVL. Before 32 weeks' gestation, the vascular anatomy of the brain is composed of two systems. One penetrates into the cortex-the ventrieulopedal system. The other reaches down to the ventricles, but then curves to flow outward-the ventrieulofugal system (Weindling, 1995). There are no vascular anastomoses connecting these two systems. As a result, the area between these systems, through which the pyramidal tracts pass near the lateral cerebral ventricles, is a watershed area vulnerable to ischemia. Vascular insuiciency before 32 weeks leading to ischemia would afect this watershed area first. Resulting damage of the pyramidal tracts may cause spastic diplegia. After 32 weeks, vascular flow shifts toward the cortex, and hypoxic injury after this time primarily damages the cortical region.

The Preterm Newborn 641

PL is associated with infection and inflammation. Zupan and colleagues (1996) studied 753 infants born between 24 and 32 weeks, 9 percent of whom developed PVL. Those born before 28 weeks, those who had inflammatory events during the last days to weeks before delivery, and those who had both were at highest risk. In another study, PVL was strongly associated with prolonged membrane rupture, chorioamnionitis, and neonatal hypotension (Perlman, 1996). Bailis and coworkers (2008) reported that chronic-and not acute-placental inlammation was associated with PVL.

Fetal infection may be a key element in the pathway between preterm birth and CP (Burd, 2012; Leviton, 2010). As discussed in Chapter 42 (p. 810), chorioamnionitis is a major cause of spontaneous preterm delivery. In the pathway proposed in Figure 34-2, antenatal reproductive tract infection evokes the production of cytokines such as tumor necrosis factor and interleukins-1, -6, and -8. hese in turn stimulate prostaglandin production and preterm labor. Preterm fetal intracranial blood vessels are susceptible to rupture and damage, and the cytokines that stimulate preterm labor also have direct toxic efects on oligodendrocytes and myelin. Vessel rupture, tissue hypoxia, and cytokine-mediated damage result in massive neuronal cell death. Glutamate is released, stimulating membrane receptors to allow excess calcium to enter the neurons. High intracellular calcium levels are toxic to white matter, and glutamate may be directly toxic to oligodendrocytes (hwaja, 2008).

Many studies have shown that infection and cytokines can directly damage the immature brain (Chau, 2014; Yoon, 1997a). Tumor necrosis factor and interleukin-6 were more frequently found in the brains of infants who died with PVL (Yoon, 1997b). Cytokines are strongly linked to white matter lesions even when organisms cannot be demonstrated (Y oon, 2000).

FIGURE 34-2 Schematic representation of the hypothesized pathway between maternal or intrauterine infection and preterm birth or periventricular leukomalacia. Both potentially lead to cerebral palsy. LPS = lipopolysaccharide; PG = prostaglandin.

Andrews and colleagues (2008) provided data that raise questions regarding a higher incidence of adverse neurodevelopmental outcomes related to exposure to chorioamnionitis. In a cohort born between 23 and 32 weeks, they studied several surrogate indicators and direct markers of in utero inflammation. These included clinical findings, cytokine levels, histological findings, and microbial culture results. Infants undergoing comprehensive psychoneurological testing had similar incidences of CP, intelligence quotient (IQ) scores <70, or both, regardless of these markers. The researchers interpreted their findings to support current practices that employ eforts to delay delivery with preterm pregnancies in the absence of overt intrauterine infection. Importantly, this does not apply to preterm pregnancy in which clinical chorioamnionitis is diagnosed. Of 3094 singletons born before 33 weeks' gestation, 15 percent had evidence of clinical chorioamnionitis (Soraisham, 2009). Compared with noninfected infants, cases complicated by infection had significantly higher rates of early-onset sepsis-4.8 versus 0.9 percent-and ofaIH-22 versus 12 percent.

The beneits of antenatal magnesium sulfate and corticosteroids have already been described. Few specific treatments have been identified to reduce or prevent brain injury in the vulnerable preterm newborn. One potential neuroprotective therapy is with erythropoiesis stimulating agents (ESAs) such as erythropoietin and darbepoetin. In addition to stimulating erythropoiesis, ESAs are protective in the developing brain in animal models (Wassink, 2017). Preliminary clinical studies are encouraging, and large trials are now underway (Beirer, 2014).

Achiron R, Pinchas OH, Reichman B, et al: Fetal intracranial haemorrhage: clinical significance of in-utero ultrasonic diagnosis. BJOG 100:995, 1993 American Academy of Pediatrics: Respiratory support in preterm infants at birth. Pediatrics 133:171,t2014

American College of Obstetricians and Gynecologists, Society for MaternalFetal Medicine: Antenatal corticosteroid therapy for fetal maturation. Committee Opinion No. 677, October 2016a

American College of Obstetricians and Gynecologists, Society for MaternalFetal Medicine: Magnesium sulfate before anticipated preterm birth for neuroprotection. Committee Opinion No. 455, March 2010, Reairmed 2016b

American College of Obstetricians and Gynecologists: Medically indicated late-preterm and early-term deliveries. Committee Opinion No. 560, April 2013, Reairmed 2017a

American College of Obstetricians and Gynecologists, Society for MaternalFetal Medicine: Management of suboptimally dated pregnancies. Committee Opinion No. 688, March 2017b

American College of Obstetricians and Gynecologists: With the Society for Maternal-Fetal Medicine: Peri viable birth. Obstetric Care Consensus No. 6, October 2017 c

Andrews W, Cliver SP, Biasini F, et al: Early preterm birth: association between in utero exposure to acute inlammation and severe neurodevelopmental disability at 6 years of age. Am J Obstet Gynecol 198:466, 2008

Ardell S, Pister RH, Soli R: Animal derived surfactant extract versus protein free synthetic surfactant for the prevention and treatment of respiratory distress syndrome. Cochrane Database Syst Rev (5):CD000144, 2015

Bailis A, Maleki Z, Askin F, et al: Histopathological placental features associated with development of periventricular leukomalacia in preterm infants. Am J Obstet Gynecol 199(6):S43, 2008

Barzilay E, Gadot Y, Koren G. Safety of vaginal delivery in very low birthweight vertex singletons: a meta-analysis. J Matern Fetal Neonatal Med 29(22):3724,t2016

Bassan H, Venson CB, Limperopoulos C, et al: Ultrasonographic features and severity scoring of periventricular hemorrhagic infarction in relation to risk factors and outcome. Pediatrics 117:2111, 2006

Beers MF, Mulugeta S: he biology of the ABCA3 lipid transporter in lung health and disease. Cell Tissue Res 367(3):481, 2017

Beirer R, Peceny MC, Hartenberger CH, et al: Erythropoietin concentrations and neurodevelopmental outcome in preterm infants. Pediatrics 118:635, 2006

Bennasar M, Figueras F, Palacio M et al: Gestational age-specific cutof levels ofTDx-FLM II for the prediction of neonatal respiratory distress syndrome. Fetal Diagn Ther 25:392, 2009

Bolisetty S, Dhawan A, Abdel-Latif M, et al: Intraventricular hemorrhage and neurodevelopmental outcomes in extreme preterm infants. Pediatrics 133(1):55,t2014

Brion LP, Bell EF, Raghuveer TS: Vitamin E supplementation for prevention of morbidity and mortality in preterm infants. Cochrane Database Syst Rev 4:CD003665, 2003

Burd I, Balakrishnan B, Kannan S: Models of fetal brain injury, intrauterine inlammation, and preterm birth. Am J Reprod Immunol 67(4):287, 2012 Caplan MS, Fanarof A. Necrotizing enterocolitis: a historical perspective.

Semin PerinatoIt41(lt):2, 201

Centers for Disease Control and Prevention: Data and statistics for cerebral palsy. 2016. Available at: https:llwww.cdc.gov/ncbddd/cp/data.html. October 23, 2017

Chau V, McFadden DE, Poskitt KJ, et al: Chorioamnionitis in the pathogenesis of brain injury in preterm infants. Clin PerinatoIt41(1):83, 2014

Clements JA, Platzker ACG, Tierney OF, et al: Assessment of the risk of respiratory distress syndrome by a rapid test for surfactant in amniotic fluid. N Engl J Med 286: 1 07 , 1972

Cole FS, Alleyne C, Barks JD et al: NIH Consensus Development Conference statement: inhaled nitric-oxide therapy for premature infants. Pediatrics 127:363,t201t1

Cools F, Ofringa M, Askie LM: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants. Cochrane Database Syst Rev 3:CDOOO 1 04, 2015

Crowther CA, Crosby DO, Henderson-Smart OJ: Phenobarbital prior to preterm birth for preventing neonatal periventricular haemorrhage. Cochrane Database Syst Rev 1 :CDOOO 164, 201 Oa

Crowther CA, Crosby DO, Henderson-Smart OJ: Vitamin K prior to preteI'm birth for preventing neonatal peri ventricular haemorrhage. Cochrane Database Syst Rev 1:CD000229, 2010b

Crowther CA, Doyle L W, Haslam RR, et al: Outcomes at 2 years of age after repeat doses of antenatal corticosteroids. N Engl J Med 357: 9, 2007

Darlow BA, Graham PJ, Rojas-Reyes MX: Vitamin A supplementation to prevent mortality and short-and long-term morbidity in very low birth weight infants. Cochrane Database Syst Rev 8:CD00050 1, 2016

Davidson LM, Berkelhamer SK: Bronchopulmonary dysplasia: chronic lung disease of infancy and long-term pulmonary outcomes. J Clin Med 6(1), 2017

De Luca AK, Nakazawa CY, Azevedo BC, et al: Influence of glycemic control on fetal lung maturity in gestations afected by diabetes or mild hyperglycemia. Acta Obstet Gynecol Scand 88(9):1036, 2009

Doyle LW, Crowther CA, Middleton P, et al: Antenatal magnesium sulfate and neurologic outcome in preterm infants: a systematic review. Obstet Gynecol 113: 1327, 2009

Doyle L W, Ehrenkranz A, Halliday HL: Early « 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 5:CDOOI146, 2014a Doyle L W, Ehrenkranz A, Halliday HL: Late (> days) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database Syst Rev 5:CDOOI145, 2014b Ferre C, Callaghan W, Olson C et al: Efects of maternal age and age-speciic preterm birth rates on overall preterm birth rates-United States, 2007 and 2014. MMWR 65:1t181,t2016

Fowlie PW, Davis PG, McGuire W: Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev 7:CD000174, 2010

Freeman JM, Nelson KB: Intrapartum asphyxia and cerebral palsy. Pediatrics 82:240, 1988

Gluck L, Kulovich MV: Lecithin-sphingomyelin ratios in amniotic fluid in normal and abnormal pregnancy. Am J Obstet Gynecol 115:539, 1973

Gluck L, Kulovich MV, Borer RC J r, et al: Diagnosis of the respiratory distress syndrome by amniocentesis. Am J Obstet Gynecol 109:440, 1971

The Preterm Newborn 643

Gyami-Bannerman C, Thon EA, Blackwell Sc, et al: Antenatal betamethasone for women at risk for late preterm delivery. N Engl J Med 3 4(14):1311, 2016

Kair LR, Leonard DT, Anderson JM: Bronchopulmonary dysplasia. Pediatr Rev 33(6):255,t2012

Karcher R, Sykes E, Batton D, et al: Gestational age-speciic predicted risk of neonatal respiratory distress syndrome using lamellar body count and surfactant-to-albumin ratio in amniotic fluid. Am J Obstet Gynecol 193:1680, 2005

Khwaja 0, Volpe JJ: Pathogenesis of cerebral white matter injury of prematurity. Arch Dis Child Fetal Neonatal Ed 93(2):F153, 2008

Kribs A: Minimally invasive surfactant therapy and noninvasive respiratory support. Clin Perinatol 55,t2016

Kwon SH, Vasung L, Ment LR et al: The role of neuroimaging in predicting neurodevelopmental outcomes of preterm neonates. Clin Perinatol 41(1):257,t2014

Leviton A, Allred EN, Kuban KC, et al: Microbiologic and histologic characteristics of the extremely preterm infant's placenta predict white matter damage and later cerebral palsy. The ELGAN study. Pediatr Res 67:95, 2010

Liebowitz M, Clyman R: Antenatal betamethasone: a prolonged time interval from administration to delivery is associated with an increased incidence of intraventricular hemorrhage before 28 weeks gestation. J Pediatr 177: 114,2016

Mathews TJ, MacDorman MF: Infant mortality statistics from the 2009 period linked birth/infant death data set. Natl Vital Stat Rep 61(8):1, 2013

Matsuda T, Okuyama K, Cho K, et al: Cerebral hemodynamics during the induction of antenatal periventricular leukomalacia by hemorrhagic hypotension in chronically instrumented fetal sheep. Am J Obstet Gynecol 194:1057,t2006

McCrea HJ, Ment LR: he diagnosis, management, and postnatal preven tion of intravetricular hemorrhage in the preterm neonate. Clin Perinatol 7,t2008

McCurnin DC, Pierce A, Chang LY, et al: Inhaled NO improves early pulmonary function and modifies lung growth and elastin deposition in a baboon model of neonatal chronic lung disease. Am J Physiol Lung Cell Mol Physiol 288:L540, 2005

Ment LR, Aden U, Bauer CR, et al: Genes and environment in neonatal intraventricular hemorrhage. Semin PerinatoI39(8):592, 2016

Morley J, Davis PG, Doyle LW et al: Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med 358:700, 2008

Moster D, Lie RT, Markestad T: Long-term medical and social consequences of preterm birth. N Engl J Med 359:262, 2008

Moya F, Sinha S, Gadzinowski j, et al: One year follow-up of very preterm infants who received lucinactat for prevention of respiratory distress syndrome: results from 2 multicenter randomized controlled trials. Pediatrics 119(6):e1361,t2007

Mukerji A, Shah V, Shah PS: Periventricularlintraventricular hemorrhage and neurodevelopmental ourcomes: a meta-analysis. Pediatrics 136(6):1132,t2015 National Institutes of Health: Antenatal corticosteroids revisited: repeat courses. NIH Consensus Statement 17(2):1, 2000 National Institutes of Health: The efects of corticosteroids for fetal maturation on perinatal outcomes. NIH Consensus Statement 12(2): 1, 1994 Nelson KB: Can we prevent cerebral palsy? N Engl J Med 349: 1765, 2003 Neu j, Walker WA: Necrotizing enterocolitis. N Engl j Med 364:255,t2010

Nores j, Roberts A, Carr S: Prenatal diagnosis and management of fetuses with intracranial hemorrhage. Am j Obstet Gynecol 174:424, 1996 O'Caliaghan ME, MacLennan AH, Gibson CS, et al: Epidemiologic associations with cerebral palsy. Obstet Gynecol 118:576,2011

Papile LA, Burstein J, Burstein R, et al: Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1500 gm. J Pediatr 92:529,

Patra K, Wilson-Costello D, Taylor HG, et al: Grades I-II intraventricular hemorrhage in extremely low birth weight infants: efects on neurodevelopment. J Pediatr 149: 169,t2006

Perlman ]M, Risser R, Broyles RS: Bilateral cystic leukomalacia in the premature infant: associated risk factors. Pediatrics 97:822, 1996

Polin A, Carlo WA, Committee on Fetus and Newborn of the American Academy of Pediatrics: Surfactant replacement therapy for preterm and term neonates with respiratory distress. Pediatrics 133(1):156,t2014

Rabe H, Diaz-Rossello JL, Duley L, et al: Efect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes. Cochrane Database Syst Rev 8:CD003248,t2012

Redline RW: Placental pathology: a systematic approach with clinical correlations. Placenta 22:S86, 2008

Rojas-Reyes MX, Morley CJ, Soli R: Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preteI'm infants. Cochrane Database Syst Rev 3:CD00051 0, 2012

Rosen MG, Dickinson JC: he incidence of cerebral palsy. Am J Obstet Gynecol 167:417, 1992

Sardesai S, Biniwale M, Wertheimer F, et al: Evolution of surfactant therapy for respiratory distress syndrome: past, present, and future. Pediatr Res 81(1-2):240,t2017

Sarkar S, Bhagat I, Dechert R, et al: Severe intraventricular hemorrhage in preterm infants: comparison of risk factors and short-term neonatal morbidities between grade 3 and grade 4 intraventricular hemorrhage. Am J Perinatol 26:419,t2009

Schmidt B, Anderson Pj, Doyle LW, et al: Survival without disability to age 5 years after neonatal cafeine therapy for apnea of prematurity. JAMA 307(3):275,t2012

Schmidt B, Roberts RS, Anderson PJ, et al: Academic performance, motor function, and behavior 11 years after neonatal cafeine citrate therapy for apnea of prematuri ty: an I I-year follow-up of the CAP Randomized Clinical Trial. JAMA Pediatr 1(6):564,t2017

Schmidt B, Roberts RS, Davis P, et al: Cafeine therapy for apnea of prematurity. N Engl J Med 354(20):21t12,t2006

Sharma M, VanderVeen D: Identiication and treatment of retinopathy of prematurity: update 2017. New Reviews 18(2):e85, 2017

Smit E, Odd D, Whitelaw A: Postnatal phenobarbital for the prevention of intraventricular haemorrhage in preteI'm infants. Cochrane Database SYSt Rev 8:CDOOI691, 2013

Soraisham AS, Singhal Nalini, McMillan DD, et al: A multicenter study on the clinical outcome of chorioamnionitis in preterm infants. Am j Obstet 2.e1,t2009

Stoll Bj, Hansen NI, Bell EF et al: Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 126(3):443,t2010

SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Carlo WA, Finer NN, et al: Target ranges of oxygen saturation in extremely preterm infants. N Engl j Med 362(21):1959, 2010a

SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Finer NN, Carlo WA, et al: Early CPAP versus surfactant in extremely preterm infants. N Engl j Med 362(21):1970, 2010b

Tredano M, Griese M, De Blic J, et al: Analysis of 40 sporadic or familial neonatal and pediatric cases with severe unexplained respiratory distress: relationship to SFTPB. Am J Med Genet A 119:324, 2003

Varner S, Sherman C, Lewis D et al: Amniocentesis for fetal lung maturity: will it become obsolete? Rev Obstet Gynecol 6(3/4): 126, 2013

Verhagen EA, Hummel LA, Bos AF, et al: Near-infrared spectroscopy to detect absence of cerebrovascular autoregulation in preteI'm infants. Clin Neurophysiol 125(1):47,t2014

Volpe JJ: Neurology of the Newborn, 5th ed. Philadelphia, Saunders, 2008 Wapner Rj, Sorokin Y, Mele L, et al: Long-term outcomes after repeated doses of antenatal corticosteroids. N Engl J Med 357: 1190, 2007

Wapner RJ, Sorokin Y, Thom EA, et al: Single versus weekly courses of antenatal corticosteroids: evaluation of safety and eicacy. Am J Obstet Gynecol 195:633,t2006

Wassink G, Davidson jO, Dhillon SK, et al: Partial white and grey matter protection with prolonged infusion of recombinant human erythropoietin after asphyxia in preterm fetal sheep. J Cereb Blood Flow Metab 37(3):1080, 201

Watterberg KL, American Academy of Pediatrics Committee on Fetus and Newborn: Policy statement-postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia. Pediatrics 126(4):800,t2010

Wei JC, Catalano R, Proit J, et al: Impact of antenatal steroids on intraventricular hemorrhage in very-low-birth weight infants. j Perinatol 36(5):352, 2016 Weindling M: Periventricular haemorrhage and periventricular leukomalacia.

BJOG 102(4):278, 1995

Wert SE, Whitsett JA, Nogee LM: Genetic disorders of surfactant dysfunction.

Pediatr Dev Pathol 12(4):253, 2009

Whitelaw A: Core concepts: intraventricular hemorrhage. NeoReviews 12(2):e94,t2011

Yoon BH, Kim Cj, Romero R, et al: Experimentally induced intrauterine infection causes fetal brain white matter lesions in rabbits. Am j Obstet Gynecol 177:797, 1997a

Yoon BH, Romero R, Kim CJ, et al: High expression of tumor necrosis factoralpha and interleukin-6 in periventricular leukomalacia. Am J Obstet Gynecol 177:406, 1997b

Yoon BH, Romero R, Park JS, et al: Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol 182:6 5,t2000

Zalud I, Janas S: Risks of third trimester amniocentesis. J Reptod Med 53(1):45, 2008

Zupan V, Gonzalez P, Lacaze-Masmonteil T, et al: Periventricular leukomalacia: risk factors revisited. Dev Med Child NeuroIt38:1061, 1996

DEFINITION OF FETAL MORTALITY ................. 645

CAUSES OF FETAL DEATH ......................... 645

RISK FACTORS ....................................... 646

EVALUATION OF THE STILLBORN FETUS .............. 646

PSYCHOLOGICAL ASPECTS. . . . . . . . . . . . . . . . . . . . . . . 648

PRIOR STILLBIRTH .............................. 648

CHANGES IN STILLBIRTH RATES ................... 649

In the latter months of pregnancy, the disappearance of oetal movements usualy directs the attention of the patient to the possibiliy of oetal death. The diagnosis of this condition, however, can be considered absolute ony after repeated examinations, when one has ailed to hear the oetal heart or perceive the movements of the child.

-J. Whitridge Williams (1903)

In Williams' time, absolute documentation of fetal death was frustrating for both patient and obstetrician. Now, sonography provides prompt conirmation, which allows expedient induction of labor and delivery. However, epidemiologically, defining and reporting fetal deaths was-and continues to be-a challenge. In response, eforts to standardize the deinition of stillbirth and analyze varying reports for application into clinical practice and public health policy are now being emphasized. Moreover, stillbirth research and prevention within the United States and abroad has expanded. Global public health eforts were stimulated in part by a six-part series in The Lancet.

his compilation was considered a call to action after the recognition that an estimated 2.65 million stillbirths occur each year and that 98 percent of stillborn fetuses are from low-and middle-income countries (The Lancei s Stillbirth Series Steering Committee, 201 la-). Unfortunately, progress in improving these rates has been slow, as outlined in The Lancet's subsequent five-part progress report, which emphasized the need for dedicated leadership, measured efects of interventions, and investigation into knowledge gaps (The Lancets Ending Preventable Stillbirths Series Study Group, 20 l6a-e).

In the United States, an estimated 1 million fetal losses are reported each year, and most occur before 20 weeks' gestation. Fetal mortality data from the National Vital Statistics system are usually presented for fetal deaths after the 20-week threshold (MacDorman, 2015). Using this definition, numbers of fetal deaths in the United States in 2013 slightly surpassed numbers of infant deaths (Fig. 35-1). As shown in Figure 35-2, 24.9% Undereage 28days 33.8% 16.1%

FIGURE 35-1 Percent distribution of fetal deaths at 20 weeks' gestation or more and of infant deaths: United States, 2013. (Data from MacDorman MF, Reddy UM, Silver RM: Trends in stillbirth by gestational age in the United States, 2006-201o2, Obstet Gynecol. 2015 Dec;126(6):1146-1150.) 0.7 0.6 0.5 ) 0.4�: 0.3 0.2 0.1 0.0 weeks of gestation: United States, 2013. (Redrawn from MacDorman

MF, Reddy UM, Silver RM: Trends in stillbirth by gestational age in the United States, 2006-2012, Obstet Gynecol. 2015 Dec;126(6): 1146-1o150.) fetal death rates are highest at the earliest and latest gestational ages, which suggests etiological diferences.

he current definition of fetal death adopted by the Centers for Disease Control and Prevention National Center for Health Statistics is based on a deinition recommended by the World Health Organization (MacDorman, 2015). It states that "Fetal death means death prior to complete expulsion or extraction .rom the mother of a product of human conception irrespective of the duration of pregnancy and which is not an induced termination of pregnancy. The death is indicated by the act that after such expulsion or extraction, the etus does not breathe or show any other evidence of lie such as beating of the heart, pulsation of the umbilical cor, or deinite movement of voluntary muscles. Heartbeats are to be distinguished rom transient cardiac contractions; respirations are to be distinguished .rom fleeting respiratory eorts or gasps."

Reporting requirements for fetal deaths in the United States are determined by each state, and thus, criteria difer signiicantly (Chap. 1, p. 3). Most states mandate reporting of deaths of fetuses that are 20 weeks' gestation or older or have a minimum birthweight of 350 g (roughly equivalent to 20 weeks) or some combination of these two. However, several states require reporting of fetal deaths at all periods of gestation, and one sets the threshold at 16 weeks. lternatively, two states require reporting of deaths for fetuses with birthweights of 500 g, which approximates that at 22 weeks. here is substantial evidence that not all fetal deaths for which reporting is required are actually recorded (MacDorman, 2015). This is most likely for those at earlier gestational ages.

Comparisons of rates among countries are limited by incomplete fetal death data. Namely, internationally, less than 5 percent of neonatal deaths have formalized documentation (The Lancet's Ending Preventable Stillbirths Series Study Group, 2016d). Further, comparative analyses using birthweight versus gestational age among countries do not provide equivalent results. For example, in the United States, if stillbirth would be deined by a birthweight �500 g, the stillbirth rate would be reduced by 40 percent compared with

FIGURE 35-3 Fetal mortality rates by period of gestation: United States, 2000-2013. (Data from MacDorman MF, Reddy UM, Silver RM: Trends in stillbirth by gestational age in the United States, 2006-2012, Obstet Gynecol. 2015 Dec;126(6):1146-1150.) a 22-week-age deined cohort (Blencowe, 2016). To address nomenclature diferences, some have called for changes to the current deini tion a oseph, 2015).

Overall, fetal mortality rates in the United States have remained relatively unchanged since 2006. However, the infant mortality rate has declined 11 percent, and both rates are now essentially equal (MacDorman, 2015). Three fetal mortality epochs are generally described: early (less than 20 completed weeks' gestation); intermediate (20 to 27 weeks); and late (28 weeks or more). The fetal mortality rate at 20 to 27 weeks in 2013 declined 3 percent from the prior year. Between 2006 and 2012, rates were essentially unchanged in this age group. The late fetal mortality rate has been relatively unchanged since 2006 35-3).

The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) created the Stillbirth Collaborative Research Network to ascertain stillbirth causes in racially and geographically diverse populations in the United States. From this, the Stillbirth Collaborative Research Network Writing Group (201a1b) examined reasons for death at 20 weeks' gestation or later between 2006 and 2008 in 59 tertiary care and community hospitals in ive states. Standardized evaluations included autopsy, placental histology, and testing of maternal or fetal bloodltissues, including fetal karyotyping. Evaluations were performed in 500 women with 512 stillbirths. Of these losses, 83 percent were before labor. Causes of stillbirth were divided into eight categories shown in Table hese categories were then classified as probable, possible, or unknown. As an example, diabetes was considered a probable cause if the fetus had diabetic embryopathy with lethal anomalies or the mother had diabetic ketoacidosis. It was a possible cause if the mother had poor glycemic control and the fetus had abnormal growth. Overal, a probable or possible source was identiied in 76 percent of cases.

This Network study is unprecedented in the United States for several reasons. It was a population-based cohort of

TABLE 35-1. Causes of 512 Stillbirths in the Stillbirth Collaborative Research Network Study

Percentages are rounded and total more than 100 percent because some stillbirths had more than one cause. Overall, a cause was identified in 76 percent of stillbirths.

Data from Stillbirth Research Network Writing Group, 201n1 b.

stillbirths, in which all underwent systematic and thorough evaluation. Each assigned cause of fetal death is reasonably straightforward and comprehensible except for "placental abnormalities." This category contains "uteroplacental insufficiency" and a few other less clearly defined placental entities. his aside, the leading reasons for fetal death were obstetrical and primarily included abruption, multifetal gestation complications, and spontaneous labor or ruptured membranes before viability. Importantly, this study illustrated that systematic evaluation may identiy a likely cause in approximately three fourths of stillbirths. his rate is considerably higher than those in most prior analyses and serves to emphasize the importance of careful examination.

Many factors are associated with an increased risk of stillbirth. Among others, these include advanced maternal age; AfricanAmerican race; smoking; illicit drug use; maternal medical diseases-such as overt. diabetes or chronic hypertension; assisted reproductive technology; nulliparity; obesity; and prior adverse pregnancy outcomes-such as prior preterm birth or growth-restricted newborn (Reddy, 2010; Varner, 2014).

Two major studies have assessed whether stillbirth risk factors could be identiied either before or shortly after pregnancy confirmation. In the first, Reddy and colleagues (2010) analyzed data from the NICHD Consortium on Safe Labor. Briely, the pregnancy outcomes of 206,969 women delivered between 2002 and 2008 at 19 hospitals in the United States were analyzed. When the distribution of stillbirths according to gestational age was studied, the tragedy of stillbirth occurred primarily in term pregnancies. hese investigators concluded that their results did not support routine antenatal surveillance for any demographic risk factors.

The second analysis of stillbirth risk factors was included in the Stillbirth Collaborative Research Network study described earlier. he validity of stillbirth prediction was assessed based on risks identified in early pregnancy. They found that pregnancy factors known at the start of pregnancy accounted for only a small proportion of stillbirth risk. Except for prior stillbirth or pregnancy loss from causes such as preterm birth or fetal-growth restriction, other risks had limited predictive value (Stillbirth Collaborative Research Network Writing Group, 2011a). he importance of prior stillbirth as a risk for recurrence has been emphasized by Sharma and associates (2006). Specifically, the stillbirth risk was ivefold higher in women with a prior stillbirth. From another report, prior preterm birth, fetal-growth restriction, preeclampsia, and placental abruption were strongly associated with subsequent stillbirth (Rasmussen, 2009). Table 35-2 lists estimates of stillbirth risk according to maternal factors.

Determining the cause of fetal death aids maternal coping, helps assuage any perceived guilt, permits more accurate counseling regarding recurrence risk, and may prompt therapy or intervention to prevent a similar outcome in subsequent pregnancies (American College of Obstetricians and Gynecologists, 20 16a). Identification of inherited syndromes also provides useful information for other family members.

Important tests in stillbirth evaluation are neonatal autopsy, chromosomal analysis, and examination of the placenta, cord, and chorioamnionic membranes (Pinar, 2014). Page and coworkers (2017) found placental pathology and fetal autopsy to be the most useful. One algorithm from the American College of Obstetricians and Gynecologists (2016a) is shown in

Figure 35-4. Findings are documented in the medical record, and relevant prenatal events are delineated. Photographs are taken whenever possible, and a full radiograph of the fetusa etogram-may be performed. Postnatal magnetic resonance (MR) imaging or sonography may be especially important in providing anatomical information if parents decline a full autopsy (McPherson, 2017; Shruthi, 2017).

If autopsy and chromosomal studies are performed, up to 35 percent of stillborn fetuses are discovered to have major

TABLE 35-2. Estimated Maternal Risk Factors and Risk

Inspect fetus and placenta:

Weight, head circumference, and length of fetus Weight of placenta Photographs of fetus and placenta

Frontal and profile photographs of whole body, face, extremities, palms, and any abnormalities Document finding and abnormalities

Obtain consent from parents for cytologic specimens:

Obtain cytologic specimens with sterile techniques and instruments -Amniotic fluid obtained by amniocentesis at time of prenatal diagnosis of demise: paticularly valuable if delivery is not expected imminently -Placental block (1 x 1) cm taken from below the cord insertion site on the unfixed placenta -Umbilical cord segment (1e.5 cm) -Internal fetal tissue specimen, such as costochondral junction or patella; skin is not recommended

Place specimens in a sterile tissue culture medium of lactated Ringer's solution and keep at room temperature when transported to cytology laboratory

Fetal autopsy and placental If no consent is given for pathology (may include autopsy, send placenta fetal whole-body X-ray) alone for pathology (Chap. 13, p. 271). CMA does not require dividing cells and is reported to be more useful in the evaluation of fetal death. his is especially true because the culturing of macerated fetal tissue is frequently unsuccessful (Reddy, 2012). Both the American College of Obstetricians and Gynecologists (2016c) and the Society for Maternal-Fetal Medicine (2016) now endorse the use of CMA for stillborn fetuses.

Appropriate consent must be obtained to take fetal samples, including tissue or luid obtained postmortem by needle aspiration. As recently outlined by the American College of Obstetricians and Gynecologists (2016c), any type of fetal or placental tissue or amnionic fluid can be submitted for genetic testing by CMA. Contamination with maternal tissue or blood is ideally avoided. If fetal blood cannot be obtained from the umbilical cord or by cardiac puncture, the American College of Obstetricians and Gynecologists (20a16a) recommends at least one of the following samples: (1) a placental block measuring about 1 X 1 cm taken below the cord insertion site in the unfixed specimen; (2) umbilical cord segment approximately 1.5 cm long; or (3) internal fetal tissue specimen such as costochondral junction or patella. Tissue is washed with sterile saline before

Cholestasis of pregnancy

BMI 25-29.9 kg/m2 ::12 yr) ::40 yr 6.4 4.0-5.5 1n.0 0.86 1.5-2.7 1n.2-4.0 1n.8-4.4 1n.2-2.2 1.7-7.0 2.2-30 2.2-3.0 2.8-5.0 1n.8-4.4 1n.7-3.0 1n.9-2.7 2.1n-2.8 1.6-2.0 2-4.6 1.4-3.2 1.8-2.2 1n.8-3.3 2.0-2.2

Twins Triplets Maternal age 12 1n.0-2.8 34 2.8-3.7

FIGURE 35-4 Flow chart for fetal and placental evaluation. (Modified with permission from ACOG Practice Bulletin No.o1 02: management of stillbirth, Obstet Gynecol. 2009 Mar;1o13(3):748-761o.) aOdds ratio of the factor being present compared with the risk factor being absent.

BMI = body mass index; IUGR = intrauterine growth restriction; PIH = pregnancy-induced hypertension; SLE = systemic lupus erythematosus.

Adapted from Fretts, 2005.

structural anomalies (Faye-Petersen, 1999). Approximately 20 percent have dysmorphic features or skeletal anomalies, and 8 percent have chromosomal abnormalities (Pauli, 1994; Saller, 1995). In the absence of anatomic dysmorphology, up to 5 percent of stillborn fetuses will have a chromosomal abnormality (Korteweg, 2008). Although the American College of Obstetricians and Gynecologists (20a1a6a) previously recommended karyotyping all stillborn fetuses, technological advancements of high-resolution, whole-genome sequencing-such as with chromosomal microarray anaysis ()-are now replacing standard karyotyping for chromosomal analysis of stillborn fetuses being placed in lactated Ringer solution or sterile cytogenetic medium. Notably, placement in formalin or alcohol kills viable cells. If conventional karyotyping is the only test available and the timing of death is recent, amnionic luid can be obtained by amniocentesis, as those cells obtained in a sterile fashion provide a greater likelihood of cell growth and eventual result compared with tissue obtained after delivery. Maternal blood is obtained for Kleihauer-Betke staining; for anti phospholipid antibody and lupus anticoagulant testing if indicated; and for serum glucose measutement to exclude overt diabetes (Silver, 20al3).

In cases with significant growth restriction, with a family or personal history of thrombosis, or with severe placental pathology, testing for factor V Leiden mutation, prothrombin mutation, antithrombin level, and protein C and S activity may provide some information that could afect future pregnancy management (American College of Obstetricians and Gynecologists, 2016a). Our interpretation of relevant placental pathology includes derangements that stem from maternal vessel obstruction, which are described in Chapter 6. Although some have recommended routine evaluation of heritable thrombophilias, no evidence supports the clinical or financial eiciency of screening in an unselected population. Silver and colleagues (2016), with data from the Stillbirth Collaborative Research Network, found that most maternal and fetal thrombophilias were not associated with stillbirth and recommended against routine testing.

Parents are ofered and encouraged to allow a full autopsy. That said, valuable information can still be obtained from limited studies. Pinar and coworkers (2012) described the autopsy protocol used by the Stillbirth Collaborative Research Network. As an alternative, gross external examination combined with photography, radiography, MR imaging, bacterial cultures, and selective use of chromosomal and histopathological studies often aids determination.

A complete autopsy is more likely to yield valuable data. An analysis of 400 consecutive fetal deaths in Wales showed that autopsy altered the presumed cause of death in 13 percent and provided new information in another 26 percent (Cartlidge, 1995). Other investigators have found that autopsy results changed the recurrence risk estimates and parental counseling in 25 to 50 percent of cases (Faye-Petersen, 1999; Silver, 2007). For example, Miller and associates (2016) recently demonstrated that placental examination with autopsy altered future medical management in 45 percent of cases.

According to the survey by Goldenberg and coworkers (2013), most hospitals do not audit stillbirths. In other centers, however, maternal records and autopsy findings are reviewed on a monthly basis by a stillbirth committee composed of obstetricians, maternal-fetal medicine specialists, neonatologists, clinical geneticists, and perinatal pathologists. If possible, the cause of death is assigned based on available evidence. Most importantly, parents are then contacted and ofered counseling regarding the reason for the death, the potential recurrence risk, and possible strategies to avoid recurrence.

Fetal death is psychologically traumatic for a woman and her family. Further stressors are an interval of more than 24 hours between the diagnosis of fetal death and labor induction, not seeing her infant for as long as she desires, having no tokens of remembrance, and poor communication (Radestad, 1996; Siassakos, 2017). The importance of seeing and holding a stillborn fetus for parental psychological well-being was recently summarized by Kingdon and colleagues (2015). As discussed in Chapter 61 (p. 1176), a woman experiencing a stillbirth or early miscarriage is at increased risk for depression and should be closely monitored (Nelson, 2013).

Nuzum and coworkers (2014) reported that few obstetrical providers receive formal training in perinatal bereavement care. At Parkland Hospital, this care includes time with the infant, keepsake items, photographs, chaplaincy consultation, and bereavement support information. Care is coordinated through a dedicated nursing team ailiated with labor and delivery.

Table 35-3 lists an outlined approach for women with prior stillbirth. Importantly, these recommendations are based primarily on limited or inconsistent scientiic evidence or on expert opinions. Unfortunately, few studies address management of afected women. Those with modiiable risk factors for stillbirth, such as hypertension or diabetes, warrant speciic prevention strategies. Given that obesity has been identiied as a risk factor for stillbirth and other obstetrical complications, preconceptional weight loss would seem prudent. Logically, women with a prior fetal death due to placental vascular events, that is, placental insuiciency, are also at increased risk for subsequent adverse perinatal outcomes (Monari, 2016). According to Reddy (2007), because almost half of fetal deaths are associated with growth restriction, fetal sonographic anatomical assessment beginning at midpregnancy is recommended. his is followed by serial growth studies beginning at 28 weeks. Supplementation with vitamin C or E in pregnancy has not been demonstrated to reduce the risk of fetal death (Rumbold, 2015a,b).

Weeks and associates (1995) evaluated fetal biophysical testing in 300 women whose only indication was prior stillbirth. There was one subsequent stillbirth, and only three fetuses had abnormal testing results before 32 weeks. Notably, no relationship was found between the gestational age of the previous stillborn fetus and the incidence or timing of abnormal test results or fetal jeopardy in the subsequent pregnancy. These investigators concluded that antepartum surveillance should begin at 32 weeks or later in the otherwise healthy woman with a history of stillbirth. This recommendation is supported by the American College of Obstetricians and Gynecologists (2016a) with the caveat that it increases the iatrogenic preterm delivery rate. Although fetal movement counting strategies are routinely employed as described in Chapter 17 (p. 332), few data guide its use in clinical practice for those with a prior stillbirth (Mangesi, 2015).

Delivery at 39 weeks' gestation is recommended. Labor induction is suitable, and cesarean delivery is elected for those with a contraindication to induction. his timing minimizes

TABLE 35-3. Management of Subsequent Pregnancy after Stillbirth

Review evaluation of prior stillbirth

Determination of recurrence risk

Discuss recurrence of comorbid obstetric complications

Thrombophilia screen: antiphospholipid antibodies

First-trimester screen: pregnancy-associated plasma protein A, human chorionic gonadotropin, and nuchal

Sonographic screening for fetal-growth restriction,

Delivery before 39 weeks only with documented fetal aprovides risk modification but does not alter management. Modified from Reddy, 2007.

fetal mortality rates, although the degree of risk reduction may be greater for older women (Page, 2013).

Following declines between 2000 and 2006, the United States fetal mortality rate has been relatively unchanged since 2006 (MacDorman, 2015). Interpretation of these fetal mortality rates in the context of changing national healthcare strategies has spawned considerable debate. One example is the efort to prevent non-medically indicated deliveries before 39 weeks and its subsequent efect on term stillbirth rates. he value of this practice for neonatal outcome is described in Chapter 26 (p. 504). To analyze whether implementation of this "39week rule" has altered the term stillbirth rate, Nicholson and coworkers (2016) examined data from 45 states and the District of Columbia during a 7 -year period. The proportion of births before 39 weeks progressively declined from 2007 and 2013, but the term stillbirth rate rose. his suggested that the 39-week rule may cause unintended harm. MacDorman and associates (2015) also evaluated trends in stillbirth rates by gestational ages in the United States between 2006 and 2012. They used a "traditional stillbirth rate," which was calculated using a denominator composed of the live-birth number plus the stillbirth number at a given gestational age. They found increased rates at 24 to 27, 34 to 36, and 38 weeks' gestation. Alternatively, no diferences were found in "prospective stillbirth rates." These rates were calculated using a denominator composed of the number of women who are pregnant at a given gestational age for weeks 21 through 42. he discrepancies in stillbirth rates appear to be primarily due to the decline in the number of births in the preterm and early-term gestational ages.

To summarize, implementation of the 39-week rule has reduced the number of elective births before 39 weeks' gestation, although an unintended consequence may be an increase in term stillbirths-especially among women with medical complications. he importance of induction at less than 39 weeks in pregnant women with complications to prevent stillbirth is underscored by Little and colleagues (2015). These authors performed a retrospective multistate analysis of earlyterm deliveries (37°/7 to 386/7 weeks) from 2005 to 2011a. They noted a decline in the number of early-term deliveries during this time but not a signiicant change in the term stillbirth rates. There was, however, a 25-percent rise in the rate of term, singleton stillbirths among women with diabetes, and this was attributed to clinicians misapplying early-term delivery policies to high-risk women. Undoubtedly, continued surveillance of stillbirth rates is warranted for both high-and low-risk pregnancies at a state and national level.

American College of Obstetricians and Gynecologists: Management of still birth. Practice Bulletin No. 102, March 2009, Reairmed 2016a American College of Obstetricians and Gynecologists: Microarrays and next-generation sequencing technology: the use of advanced genetic diagnostic tools in obstetrics and gynecology. Committee Opinion No. 682, December 2016b American College of Obstetricians and Gynecologists: Prenatal diagnostic test ing for genetic disorders. Practice Bulletin No. 162, May 2016c Blencowe H, Cousens 5, Bianchi JF, et al: National, regional, and worldwide estimates of stillbirth rates in 2015, wi th trends from 2000: a systematic analysis. Lancet Glob Health 4(2):e98, 2016 Cartlidge PH, Stewart JH: Efect of changing the stillbirth deinition on evalu ation of perinatal mortality rates. Lancet 346:486, 1995 Faye-Petersen OM, Guinn DA, Wenstrom KD: Value of perinatal autopsy.

Obstet Gynecol 94(6):915, 1999 FrettS RC: Etiology and prevention of stillbirth. Am J Obstet Gynecol 193(6):1923,t2005 Goldenberg L, Farrow V, McClure EM, et l: Stillbirth: knowledge and practice among U.S. obstetrician-gynecologists. Am J Perinatol30(l 0):813, 2013

Joseph KS, Kinniburgh B, Hutcheon JA, et al: Rationalizing deinitions and stillbirth. Obstet GynecoIt125(4):784, 2015

Kingdon C, Givens JL, O'Donnell E, et al: Seeing and holding Baby: systematic review of clinical management and parental outcomes ater stillbirth. Birth 42(3):206,t2015

Korteweg FJ, Bouman K, Erwich J,et al: Cytogenetic analysis after evaluation of 750 fetal deaths. Obstet Gynecol 111 :865, 2008

Little SE, Zera CA, Clapp A, et al: A multi-state analysis of early-term delivery trends and the association with term stillbirth. Obstet Gynecol 126(6):1138,t2015

MacDorman MF, Gregory EC: Fetal and perinatal mortaliry, United States, 2013. Natl Vital Stat Rep 64(8):1, 2015

MacDorman MF, Reddy UM, Silver M: Trends in stillbirth by gestational age in the United States, 2006-2012. Obstet GynecoIt126(6):1146, 2015 Mangesi L, Hofmeyr GJ, Smith V, et al: Fetal movement counting for assess ment offetal wellbeing. Cochrane Database Syst Rev 1O:CD004909, 2015

McPherson E, Nestoridi E, Heinke D, et al: Alternatives to autopsy for fetl and early neonatal (perinatal) deaths: insights from the Wisconsin stillbirth service program. Birth Defects Res September 12, 2017 [Epub ahead of print]

Miller ES, Minturn L, Linn R, et al: Stillbirth evaluation: a stepwise assessment of placental pathology and autopsy. Am J Obstet Gynecol 214: 115, 2016

Monari F, Pedrielli G, Vergani P, et al: Adverse perinatal outcome in subsequent pregnancy after stillbirth by placental vascular disorders. PLoS One 11(5):e0155761,t2016

Nelson DB, Freeman MP, Johnson NL, et al: A prospective study of postpartum depression in 17,648 parturients. J Matern Fetal Neonatal Med 26(12):1155,t2013

Nicholson JM, Kellar LC, Ahmad S, et al: US term stillbirth rates and the 39-week rule: a cause for concern? Am J Obstet Gynecol 214:621, 2016 Nuzum D, Meaney S, O'Donoghue K: he impact of stillbirth on consultant obstetrician gynaecologists: a qualitative study. BJOG 121:1020,t2014

Page JM, Christiansen-Lindquist L, horsten V, et al: Diagnostic Tests for Evaluation of Stillbirth: Results From the Stillbirth Collaborative Research Network. Obstet Gynecolt129(4):699, 2017

Page JM, Snowden JM, Cheng W, et al: he risk of stillbirth and infant death by each additional week of expectant management stratiied by maternal age. Am J Obstet GynecoI209(4):375.e1, 2013

Pauli M, Reiser CA: Wisconsin Stillbirth Service Program: II. Analysis of diagnoses and diagnostic categories in the irst 1,000 referrals. Am J Med Genet 50: 135, 1994

Pinar H, Goldenberg L, Koch MA, et al: Placental indings in singleton stillbirths. Obstet Gynecol 123:325,t2014

Pinar H, Koch A, Hawkins H, et al: The stillbirth collaborative research network postmortem examination protocol. Am J Perinatol 29:187, 2012

Radestad I, Steineck G, Nordin C, et al: Psychological complications after stillbirth-influence of memories and immediate management: population based study. BMJ 312:1505, 1996

Rasmussen S, Irgens LM, Skjaerven R, et al: Prior adverse pregnancy outcome and the risk of stillbirth. Obstet Gynecol 114(6): 1259, 2009

Reddy UM: Prediction and prevention of recurrent stillbirth. Obstet Gynecol 110:1151,t2007

Reddy UM, Laughon SK, Sun L, et al: Prepregnancy risk factors for antepartum stillbirth in the United States. Obstet Gynecol 116:11t19,t2010

Reddy UM, Page GP, Saade GR, et al: Karyotype versus microarray testing for genetic abnormalities after stillbirth. N Engl J Med 367(23):2185,t2012 Rumbold A, Ota E, Hori H, et al: Vitamin E supplementation in pregnancy.

Cochrane Database Syst Rev 9:CD004069, 2015a Rumbold A, Ota E, Nagata C, et al: Vitamin C supplementation in pregnancy.

Cochrane Database Syst Rev 9:CD004072, 2015b

Saller DN Jr, Lesser KB, Harrel U, et al: he clinical utility of the perinatal autopsy. JAMA 273:663, 1995

Sharma PP, Salihu HM, Oyelese Y, et al: Is race a determinant of stillbirth recurrence? Obstet Gynecol 107(2 Pt 1):391,2006

Shruthi M, Gupta N, Jana M, et al: Comparative study of conventional and virtual autopsy using postmortem MRI in the phenotypic characterization of stillbirths and malformed fetuses. Ultrasound Obstet Gynecol March 13, 2017 [Epub ahead of print]

Siassakos D, Jackson S, Gleeson K, et al: ll bereaved parents are entitled to good care after stillbirth: a mixed-methods multicentre study (INSIGHT). B JOG July 31, 2017 [Epub ahead of print]

Silver M:Fetal death. Obstet Gynecol 109: 153, 2007

Silver RM, Parker CB, Reddy UM, et al: Antiphospholipid antibodies in stillbirth. Obstet GynecoIt122(3):641, 2013

Silver RM, Saade GR, Thorsten V, et al: Factor V Leiden prothrombin G20210A, and methylene tetrahydrofolate reductase mutations and stillbirth: the Stillbirth Collaborative Research Network. Am J Obstet Gynecol 215:468,t2016

Society for Maternal-Fetal Medicine: he use of chromosomal micro array for prenatal diagnosis. Sociery for Maternal-Fetal Medicine (SMFM) Consult Series No. 41, October 2016

Stillbirth Collaborative Research Network Writing Group: Association between stillbirth and risk factors known at pregnancy conirmation. JAMA 306(22):2469,t2011a

Stillbirth Collaborative Research Network Writing Group: Causes of death among stillbirths. JAMA 306(22):2459, 2011b

The Lancet's Ending Preventable Stillbirths Series Study Group: Stillbirths: economic and psychosocial consequences. Lancet 387:604, 2016a

The Lancet's Ending Preventable Stillbirths Series Study Group: Stillbirths: ending preventable deaths by 2030. Lancet 387:703, 2016b

The Lancet's Ending Preventable Stillbirths Series Study Group: Stillbirths: progress and uninished business. Lancet 387:574, 2016c

The Lancet's Ending Preventable Stillbirths Series Study Group: Stillbirths: rates, risk factors, and acceleration towards 2030. Lancet 387:587, 2016d The Lance's Ending Preventable Stillbirths Series Study Group: Stillbirths: recall to action in high-income countries. Lancet 387: 691, 2016e

The Lancet's Stillbirths Series Steering Committee: Stillbirths: how can health systems deliver for mothers and babies? Lancet 377:1610, 20lla

The Lancet's Stillbirths Series Steering Committee: Stillbirths: the vision for 2020. Lancet 3 7:1798,2011b

The Lancet's Stillbirths Series Steering Committee: Stillbirths: the way forward in high-income countries. Lancet 7:1703,t2011c

The Lancet's Stillbirths Series Steering Committee: Stillbirths: what diference can we make and at what cost? Lancet :1523, 2011d

The Lancet's Stillbirths Series Steering Committee: Stillbirths: where? When? Why? How to make the data count? Lancet 377: 1448, 2011e

The Lancet's Stillbirths Series Steering Committee: Stillbirths: why they matter.

Lancet 377:1353, 2011f

Varner JW, Silver M, Rowland Hogue CJ, et al: Association between stillbirth and illicit drug use and smoking during pregnancy. Obstet Gynecol 123:113,t2014

Weeks JW, Asrat T, Morgan MA, et al: Antepartum surveillance for a history of stillbirth: when to begin? Am J Obstet Gynecol 172:486, 1995

The Puerperi um

REPRODUCTIVE TRACT INVOLUTION ................ 652

PLACENTAL SITE INVOLUTION.. . . . . . . . . . . . . . . . .. 654 URINARY TRACT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 654

PERITONEUM AND ABDOMINAL WALL ............. 655

BLOOD AND BLOOD VOLUME .........0............ 655

LACTATION AND BREASTFEEDING ................ 656

HOSPITAL CARE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659

HOME CARE ................................... 663

Although the changes occurring during the puerperium are considered as physiological, they border vey closey upon the pathological, in as much as under no other circumstances does such marked and rapid tissue metabolism occur without a departure rom a condition of health.

-J. Whitridge Williams (1903)

The word puerperium is derived from Latin-puer, child + parus, bringing forth. Currently, it defines the time following delivery during which pregnancy-induced maternal anatomical and physiological changes return to the nonpregnant state. Its duration is understandably inexact, but is considered to be between 4 and 6 weeks. Although much less complex compared with pregnancy, the puerperium has appreciable changes as stated above by Williams (1903), and some of these may be either bothersome or worrisome for the new mother. Kanotra and colleagues (2007) analyzed challenges that women faced from 2 to 9 months following delivery. The Pregnancy Risk Assessment Surveillance System-PRAMS-of the Centers for Disease Control and Prevention (2016) listed concerns of new mothers that are shown in Table 36-1. At least a third of these women felt the need for social support, and 25 percent had concerns with breastfeeding.

Return of the tissues in the birth canal to the nonpregnant state begins soon ater delivery. he vagina and its outlet gradually diminish in size but rarely regain their nulliparous dimensions. Rugae begin to reappear by the third week but are less prominent than before. he hymen is represented by several small tags of tissue, which scar to form the mytom caunces. The vaginal epithelium reflects the hypoestrogenic state, and it does not begin to proliferate until 4 to 6 weeks. This timing is usually coincidental with resumed ovarian estrogen production. Lacerations or stretching of the perineum during delivery can lead to vaginal outlet relaxation. Some damage to the pelvic loor may be inevitable, and parturition predisposes to urinary incontinence and pelvic organ prolapse.

The massively increased uterine blood flow necessary to maintain pregnancy is made possible by signiicant hypertrophy and remodeling of pelvic vessels. After delivery, their caliber gradually diminishes to approximately that of the prep regnant state. Within the puerperal uterus, larger blood vessels become obliterated by hyaline changes. They are gradually resorbed and replaced by smaller ones. Minor vestiges of the larger vessels, however, may persist for years.

During labor, the margin of the dilated cervix, which corresponds to the external os, may be lacerated. The cervical opening contracts slowly, and for a few days immediately after

The Puerperium 653

TABLE 36-1 . Pregnancy Risk Assessment Surveillance System-PRAMSa Concerns Raised by Women in the First 2-9 Months Postpartum

Help with postpartum depression 10 aCenters for Disease Control and Prevention, 201n6. Data from Kanotra 5, D'Angelo 0, Phares TM, et al: Challenges faced by new mothers in the early postpartum period: an analysis of comment data from the 2000 Pregnancy Risk Assessment Monitoring System (PRAMS) survey. Matern Child Health J 11 (6):549,n2007.

labor, it readily admits two ingers. By the end of the first week, this opening narrows, the cervix thickens, and the endocervical canal re-forms. The external os does not completely resume its pregravid appearance. It remains somewhat wider, and typically, ectocervical depressions at the site of lacerations become permanent. These changes are characteristic of a parous cervix (Fig. 36-1). Cervical epithelium also undergoes considerable remodeling. This actually may be salutary because almost half of women have regression of high-grade dysplasia following delivery (Ahdoot, 1998; Kaneshiro, 2005).

Ater delivery, the fundus of the contracted uterus lies slightly below the umbilicus. It consists mostly of myometrium covered by serosa and internally lined by decidua. The markedly attenuated lower uterine segment contracts and retracts, but not as forceully as the uterine corpus. During the next few weeks, the lower segment is converted from a clearly distinct substructure large enough to accommodate the fetal head to a barely discernible uterine isthmus located between the corpus and internal cervical os. Immediately postpartum, the anterior and posterior walls, which lie in close apposition, are each 4 to 5 cm thick (Buhimschi, 2003). At this time, the uterus weighs approximately 1000 g.

Myometrial involution is a truly remarkable feat of destruction or deconstruction that begins as soon as 2 days ater delivery (Williams, 1931). The total number of myocytes does not decrease appreciably-rather, their size decreases markedly. As emphasized by Hytten (1995), the quality of studies that describe the degree of decreasing uterine weight postpartum are (8) cervices.

12.8 12.4 10 9 Cavity length 7.6 6.7 AP diameter 6.4

E) 10 12 ;:) 8 6

FIGURE 36-2 Sonographic measurements of uterine involution during the first 9 days postpartum. AP = anteroposterior. (Data from Hytten F: The Clinical Physiology of the Puerperium. London, Farrand Press, 1995.) poor. Best estimates show that the uterus weighs approximately 500 g by 1 week postpartum, about 300 g by 2 weeks, and at 4 weeks, involution is complete and the uterus weighs approximately 100 g. Ater each successive delivery, the uterus is usually slightly larger than before the most recent pregnancy.

Uterine involution and rapid dissipation of size progresses in the first week (Fig. 36-2). Sonographically, the uterus and endometrium return to pregravid size by 8 weeks postpartum (Bae, 2012; Steinkeler, 2012). In a study of 42 normal puerperas, Tekay and Jouppila (1993) identiied fluid in the endometrial cavity in 78 percent of women at 2 weeks, 52 percent at 3 weeks, 30 percent at 4 weeks, and 10 percent at 5 weeks. Belachew and coworkers (2012) used three-dimensional sonography and visualized intracavitary tissue matter in a third on day 1, in 95 percent on day 7, in 87 percent on day 14, and in 28 percent on day 28. By day 56, the small cavity was empty. Sohn and associates (l9��) described Doppler ultrasound results showing continuously increasing uterine artery vascular resistance during the first 5 days postpartum. Weintraub and colleagues (2013) posited that uterine involution may be diferent in preeclamptic women because they more likely had early diastolic notches seen on uterine artery velocimetry.

Because separation of the placenta and membranes involves the spongy layer, the decidua basalis is not sloughed. The in situ decidua varies markedly in thickness, it has an irregular jagged border, and it is infiltrated with blood, especially at the placental site. Within 2 or 3 days ater delivery, the remaining decidua becomes diferentiated into two layers. he superficial layer becomes necrotic and is sloughed in the lochia. The basal layer adjacent to the myometrium remains intact and is the source of new endometrium.

Endometrial regeneration is rapid, except at the placental site. Within a week or so, the free surface becomes covered by epithelium, and Sharman (1953) identified ully restored endometrium in all biopsy specimens obtained from the 16th day onward. Histological endometritis is part of the normal reparative process.

vforeover, microscopic inflammatory changes characteristic of acute salpingitis are seen in almost half of women between 5 and 15 days, however, these findings are not thought to reflect infection (Andrews, 1951).

Afterpains. Several clinical findings arise with uterine involution. In primiparas, the uterus tends to remain tonically contracted following delivery. In multiparas, it often contracts vigorously at intervals and gives rise to aterpains, which are similar to but milder than labor contractions. hese are more pronounced as parity increases and worsen when the newborn suckles, likely because of oxytocin release (Holdcroft, 2003). Usually, afterpains decrease in intensity and become mild by the third day. We have encountered unusually severe and persistent afterpains in women with postpartum uterine infections.

Lochia. Early in the puerperium, sloughing of decidual tissue results in a vaginal discharge of variable quantity. he discharge is termed lochia and contains erythrocytes, shredded decidua, epithelial cells, and bacteria. For the irst few days ater delivery, there is blood suicient to color it red-lochia rubra. Ater 3 or 4 days, lochia becomes progressively pale in color-lochia serosa. ter approximately the 10th day, because of an admixture of leukocytes and reduced fluid content, lochia assumes a white or yellow-white color-lochia alba. he average duration of lochial discharge ranges from 24 to 36 days (Fletcher, 2012). Because of this expected leukocyte component, saline preparations of lochia for microscopic evaluation in cases of suspected puerperal metritis are typically uninformative and not recommended.

Complete extrusion of the placental site takes up to 6 weeks. Immediately after delivery, the placental site is approximately palm-sized. Within hours of delivery, it normally contains many thrombosed vessels that ultimately undergo organization. By the end of the second week, it is 3 to 4 cm in diameter.

Placental site involution is an exfoliation process, which is prompted in great part by undermining of the implantation site by new endometrial proliferation (Williams, 1931). Thus, involution is not simply absorption in situ. Exfoliation consists of both extension and "downgrowth" of endometrium from the margins of the placental site, as well as development of endometrial tissue from the glands and stroma left deep in the decidua basalis after placental separation. Anderson and Davis (1968) concluded that placental site exfoliation results from sloughing of infarcted and necrotic supericial tissues followed by a remodeling process.

In some cases, uterine involution is hindered because of infection, retained placental fragments, or other causes. Such subinvolution is accompanied by varied intervals of prolonged lochia as well as irregular or excessive uterine bleeding. During bimanual examination, the uterus is larger and soter than would be expected. With bleeding, pelvic sonography may help exclude retained placenta or, less-commonly, vascular malformations as the source (lraha, 2017). Methylergonovine (Methergine), 0.2 mg orally every 3 to 4 hours for 24 to 48 hours, is recommended by many, but its eicacy is questionable. If there is infection, antimicrobial therapy usually leads to a good response. In an earlier study, Wager and coworkers (1980) reported that a third of these late cases of postpartum metritis are caused by Chamydia trachomatis. For mild infection, empirical therapy with azithromycin or doxycycline usually prompts resolution regardless of bacterial etiology. At our institution, common oral options taken for 7 to 10 days include doxycycline, 100 mg twice daily; azithromycin, 500 mg twice daily; or ampicillin-clavulanate (Augmentin), 875 mg twice daily. Serious metritis is treated with intravenous broad-spectrum antibiotics listed in Table 37-2.

Another cause of subinvolution is incompletely remodeled uteroplacental arteries (Andrew, 1989; Kavalar, 2012). hese noninvoluted vessels are illed with thromboses and lack an endothelial lining. Perivascular trophoblasts are also identiied in the vessel walls, which suggests an aberrant interaction between uterine cells and trophoblasts.

Seconday pospartum hemorrhage is deined as bleeding 24 hours to 12 weeks ater delivery. Clinically worrisome uterine hemorrhage develops within 1 to 2 weeks in perhaps 1 percent of women. Such bleeding most oten is the result of abnormal involution of the placental site. It occasionally is caused by retention of a placental fragment or by a uterine artery pseudoaneurysm. Usually, retained products undergo necrosis with ibrin deposi tion and may eventually form a so-called placental poyp. As the eschar of the polyp detaches from the myometrium, hemorrhage may be brisk. As discussed in Chapter 56 (p. 1090), delayed postpartum hemorrhage may also be caused by von Willebrand disease or other inherited coagulopathies (Lipe, 2011).

In our experiences, few women with delayed hemorrhage are found to have retained placental fragments. hus, we and others do not routinely perform curettage (Lee, 1981). Another concern is that curettage may worsen bleeding by avulsing part of the implantation site. Thus, in a stable patient, if sonographic examination shows an empty cavity, then oxytocin, methylergonovine, or a prostaglandin analogue is given. Suitable dosing is found in Table 20-2 (p. 392). Antimicrobials are added if uterine infection is suspected. If large clots are seen in the uterine cavity with sonography, then gentle suction curettage is considered. Otherwise curettage is carried out only if appreciable bleeding persists or recurs after medical management.

Normal pregnancy-induced glomerular hyperiltration persists during the puerperium but returns to prepregnancy baseline by 2 weeks (Hladunewich, 2004). Dilated ureters and renal pelves return to their prep regnant state by 2 to 8 weeks postpartum. Because of this dilated collecting system, coupled with residual urine and bacteriuria in a traumatized bladder, symptomatic urinary tract infection remains a concern in the puerperium.

Funnell and colleagues (1954) used cystoscopy immediately postpartum and described varying degrees of submucosal hemorrhage and edema. Bladder trauma is associated most

The Puerperium 655 closely with labor length and thus to some degree is a normal accompaniment of vaginal delivery. Postpartum, the bladder has an increased capacity and a relative insensitivity to intravesical pressure. hus, overdistention, incomplete emptying, and excessive residual urine are frequent (Buchanan, 2014; Mulder, 2014). Acute urinary retention is also more common with narcotic analgesia (Kandadai, 2014). heir management is discussed on page 660.

It is unusual for urinary incontinence to manifest during the puerperium. hat said, much attention has been given to the potential for subsequent development of urinary incontinence and other pelvic loor disorders in the years following delivery. A more detailed discussion is found in Chapter 30 (p. 568).

The broad and round ligaments require considerable time to recover from stretching and loosening during pregnancy. As a result of ruptured elastic ibers in the skin and prolonged distention by the pregnant uterus, the abdominal wall remains soft and laccid. If the abdomen is unusually labby or pendulous, an ordinary girdle is often satisfactory. n abdominal binder is another temporary measure. Several weeks are required for these structures to return to normal, and recovery is aided by exercise. hese may be started anytime following vaginal delivery. Ater cesarean delivery, a 6-week interval to allow fascia to heal and abdominal soreness to diminish is reasonable. Silvery abdominal striae commonly develop as striae graviarum (Chap. 4, p. 53). Except for these, the abdominal wall usually resumes its prep regnancy appearance. When muscles remain atonic, however, the abdominal wall also remains lax. Marked separation of the rectus abdominis muscles-diastasis recti-may result.

Marked leukocytosis and thrombocytosis may occur during and after labor. The white blood cell count sometimes reaches 30,000/�L, with the increase predominantly due to granulocytes. There is a relative lymphopenia and an absolute eosinopenia. Normally, during the irst few postpartum days, hemoglobin concentration and hematocrit luctuate moderately. We routinely check these on the irst postpartum day or earlier if indicated. If they fall much below the levels present just before labor, a considerable amount of blood has been lost.

By the end of pregnancy, laboratory values that assess coagulation are altered (Kenny, 2014). These changes are discussed in Chapter 4 (p. 59) and listed in the Appendix (p. 1256). Many persist variably in the puerperium. For example, a markedly increased plasma ibrinogen level is maintained at least through the irst week and hence so is an elevated sedimentation rate. Hypercoagulability appears to be greater and is relected by the likelihood of deep-vein thrombosis and pulmonary embolism in the 12 weeks following childbirth (Kamel, 2014). his is depicted in Figure 36-3 and is discussed further in Chapter 52 (p. 1004).

FIGURE 36-3 Risk of deep-vein thrombosis or pulmonary embolism following childbirth. (Data from Kamel H, Navi S, Sriram N, et al: Risk of a Thrombotic Event after the 6-week postpartum period. N Engl J Med 370:1307,o2014.)

When the amount of blood attained by normal pregnancy hypervolemia is lost as postpartum hemorrhage, the woman almost immediately regains her nonpregnant blood volume (Chap. 41, p. 756). If less has been lost at delivery, blood volume generally nearly returns to its nonpregnant level by 1 week after delivery. Cardiac output usually remains elevated for 24 to 48 hours postpartum and declines to nonpregnant values by 10 days (Robson, 1987). Heart rate changes follow this pattern, and blood pressure similarly returns to nonpregnant values (Fig. 36-4). Correspondingly, systemic vascular resistance remains in the lower range characteristic of pregnancy for 2 days postpartum and then begins to steadily increase to normal nonpregnant values (Hibbard, 2014). Despite this, Morris and coworkers (2015) found that reduced arterial stifness persists following pregnancy. They suggest a signiicant favorable

FIGURE 36-4 During the early puerperium, blood pressure normally rises toward nonpregnant values. MAP = mean arterial pressure.

efect of pregnancy on maternal cardiovascular remodeling, which may represent a mechanism by which preeclampsia risk is reduced in subsequent pregnancies.

Normal pregnancy is associated with an appreciable increase in extracellular sodium and water retention, and postpartum diuresis is a physiological reversal of this process. Chesley and coworkers (1959) demonstrated a decrease in sodium space of approximately 2 L during the first week postpartum. his also corresponds with loss of residual pregnancy hypervolemia. In preeclampsia, pathological retention of luid antepartum and its diuresis postpartum may be prodigious (Chap. 40, p. 744).

Postpartum diuresis results in relatively rapid weight loss of 2 to 3 kg, which is additive to the 5 to 6 kg incurred by delivery and normal blood loss. Weight loss from pregnancy itself is likely to be maximal by the end of the second week postpartum. It follows that any residual increased weight compared with prepregnancy values probably represents fat stores that will persist. According to Schauberger and associates (1992), women approach their self-reported prepregnancy weight 6 months after delivery but still retain an average surplus of 1.4 kg (3 Ib).

Each mature mammary gland or breast is composed of 15 to 25 lobes. hey are arranged radially and are separated from one another by varying amounts of fat. Each lobe consists of several lobules, which in turn are composed of numerous alveoli. Each alveolus is provided with a small duct that joins others to form a single larger duct for each lobe as shown in Figure 36-5. These lacterous ducts open separately on the nipple, where they may be distinguished as minute but distinct orifices. he alveolar secretory epithelium synthesizes the various milk constituents.

After delivery, the breasts begin to secrete colostrum, which is a deep lemon-yellow liquid. It usually can be expressed from the nipples by the second postpartum day. Compared with mature milk, colostrum is rich in immunological components and contains more minerals and amino acids (Ballard, 2013). It also has more protein, much of which is globulin, but less sugar and fat. Secretion persists for 5 days to 2 weeks, with gradual conversion from "transitional" to mature milk by 4 to 6 weeks. The colostrum content of immunoglobulin A (IgA) ofers the newborn protection against enteric pathogens. Other host resistance factors found in colostrum and milk include complement, macrophages, lymphocytes, lactoferrin, lactoperoxidase, and lysozymes.

Mature milk is a complex and dynamic biological luid that includes fat, proteins, carbohydrates, bioactive factors, minerals, vitamins, hormones, and many cellular products (Table 36-2). The concentrations and contents of human milk change even during a single feed and are inluenced by maternal diet and by newborn age, health, and needs. A nursing mother easily produces 600 mL of milk daily, and maternal gestational

FIGURE 36-5 Schematic of the alveolar and ductal system during lactation. Note the myoepithelial fibers (M) that surround the outside of the uppermost alveolus. The secretions from the glandular elements are extruded into the lumen of the alveoli (A) and ejected by the myoepithelial cells into the ductal system (0), which empties through the nipple. Arterial blood supply to the alveolus is identified by the upper right arrow and venous drainage by the arrow beneath.

PUFA = Polyunsaturated fatty acids. The Puerperium 657 weight gain has little impact on its quantity or quality. Milk is isotonic with plasma, and lactose accounts for half of the osmotic pressure. Essential amino acids are derived from blood, and nonessential amino acids are derived in part from blood or synthesized in the mammary gland. Most milk proteins are unique and include alpha-lactalbumin, beta-lactoglobulin, and casein. Fatty acids are synthesized in the alveoli from glucose and are secreted by an apocrine-like process. Most vitamins are found in human milk, but in variable amounts. Vitamin K is virtually absent, and thus, an intramuscular dose is given to the newborn (Chap. 33, p. 626). Vitamin D content is low 22 IU/mL, and newborn supplementation is also recommended by the American Academy of Pediatrics (Wagner, 2008).

Whey is milk serum and has been shown to contain large amounts of interleukin-6 (Saito, 1991). Human milk has a whey-to-casein ratio of 60:40, considered ideal for absorption.

Prolactin appears to be actively secreted into breast milk.

Epidermal growth octor (EGF) has been identiied, and because it is not destroyed by gastric proteolytic enzymes, it may be absorbed to promote growth and maturation of newborn intes tinal mucosa (McCleary, 1991). Other critical components in human milk include lactoferrin, melatonin, oligosaccharides, and essential fatty acids.

• Endocrinology of Lactation

The precise humoral and neural mechanisms involved in lactation are complex. Progesterone, estrogen, and placental lactogen, as well as prolactin, cortisol, and insulin, appear to act in concert to stimulate the growth and development of the milksecreting apparatus (Stuebe, 2014). With delivery, the maternal serum levels of progesterone and estrogen decline abruptly and profoundly. This drop removes the inhibitory inluence of progesterone on alpha-lactalbumin production and stimulates lactose synthase to increase milk lactose. Progesterone withdrawal also allows prolactin to act unopposed in its stimulation of alpha-lactalbumin production. Activation of calcium-sensing receptors (CaSR) in mammary epithelial cells downregulates parathyroid hormone-related protein (PTHrP) and increases calcium transport into milk (Vanhouten, 2013). Serotonin is also produced in mammary epithelial cells and has a role in maintaining milk production (Collier, 2012).

The intensity and duration of subsequent lactation are controlled, in large part, by the repetitive stimulus of nursing and emptying of milk from the breast. Prolactin is essential for lactation, and women with extensive pituitary necrosisSheehan syndrome�o not lactate (Chap. 58, p. 1133). Although plasma prolactin levels fall after delivery to levels lower than during pregnancy, each act of suckling triggers a rise in levels (Pang, 2007). Presumably a stimulus from the breast curtails the release of dopamine, also known as prolactin-inhibiting octor, from the hypothalamus. In turn, this transiently induces increased prolactin secretion.

The posterior pituitary secretes oxytocin in pulsatile fashion. This stimulates milk expression from a lactating breast by causing contraction of myoepithelial cells in the alveoli and small milk ducts (see Fig. 36-5). Milk ejection, or letting down, is a relex initiated especially by suckling, which stimulates the posterior pituitary to liberate oxytocin. he reflex may even be provoked by an infant cry and can be inhibited by maternal fright or stress (Stuebe, 2014).

Human milk contains several protective immunological substances, including secretory IgA and growth factors. The antibodies in human milk are speciically directed against maternal environmental antigens such as Escherichia coli (Iyengar, 2012). According to the Centers for Disease Control and Prevention (Perrine, 2015), breastfeeding decreases the incidence of ear, respiratory, and gastrointestinal infections; necrotizing enterocolitis; and sudden infant death syndrome.

Much attention has been directed to the role of maternal breast milk lymphocytes in neonatal immunological processes. Milk contains both T and B lymphocytes, but the T lymphocytes appear to difer from those found in blood. Speciically, milk T lymphocytes are almost exclusively composed of cells that exhibit speciic membrane antigens. These memory T cells appear to be an avenue for the neonate to beneit from the maternal immunological experience.

Human milk is ideal food for newborns in that it provides agespeciic nutrients, immunological factors, and antibacterial substances. Milk also contains factors that act as biological signals for promoting cellular growth and diferentiation. A list of the advantages of breastfeeding is shown in Table 36-3. For both mother and infant, the beneits of breastfeeding are long-term. For example, women who breastfeed have a lower risk of breast and reproductive cancer, and their children have increased adult intelligence independent of a wide range of possible confounding factors (J ong, 2012; Kramer, 2008). Breastfeeding is associated with decreased postpartum weight retention (Baker, 2008). In addition, rates of sudden-infant-death syndrome are signiicantly lower among breastfed infants. Bartek and colleagues (2013) estimate that a 90-percent breastfeeding rate for 12 months would save more than $3 billion annually in excess infant and maternal morbidity costs. For all these reasons, the

TABLE 36-3. Advantages of Breastfeeding

Data from American Academy of Pediatrics and the American College of Obstetricians and Gynecologists:

Guidelines for Perinatal Care, 8th ed, Elk Grove Village, AAP, 2017.

TABLE 36-4. Ten Steps to Successful Breastfeeding 1n. Have a written breastfeeding policy that is regularly communicated to all health-care staff 2.

Train all staf in skills necessary to implement this policy 3.

Inform all pregnant about the beneits and management of breastfeeding 4.

Help mothers initiate breastfTeding within an hour of birth 5.

Show mothers how to breastfeed and how to sustain lactation, even if they should be separated from their infants 6.

Feed newborns nothing but breast milk, unless medi cally indicated, and under no circumstances provide breast milk substitutes, feeding bottles, or paCiiers free of charge or at low cost 7.

Practice rooming-in, which allows mothers and newborns to remain together 24 hours a day 8.

9.

Give no artiicial paCiiers to breastfeeding newborns 10.

Help start breastfeeding support groups and refer mothers to them

Adapted with permission from World Health Organization:

Protecting, promoting and supporting breast-feeding: the special role of maternity services. Geneva, World Health Organization, 1989.

American Academy of Pediatrics (2017) and American College of Obstetricians and Gynecologists (2016a, 20 17b) supports the World Health Organization (201r1) recommendations of exclusive breastfeeding for up to 6 months.

The Surgeon General of the u.S. Department of Health and Human Services (2011) lists some barriers to breastfeeding and suggests practical means of overcoming them. Educational initiatives that include father and peer counseling may improve these rates (Pisacane, 2005; Wolfberg, 2004). The Baby Friendy Hospital Initiative is an international program to increase rates of exclusive breastfeeding and to extend its duration. It is based on the World Health Organization (1989) Ten Steps to Successul Breaseeding (Table 36-4). Worldwide, almost 20,000 hospitals are designated as "baby-friendly," however, only 10 to 15 percent of hospitals in the United States are so designated (Centers for Disease Control and Prevention, 2014; Perrine, 2015). Forrester-Knauss and coworkers (2013) described successul trends toward exclusive breastfeeding in Switzerland during 9 years in which a Baby-Friendly Hospital Initiative was implemented. In a large population-based study done in the United States, fewer than two thirds of term neonates were exclusively breastfed at the time of discharge (McDonald, 2012).

Various individual resources available are available for breastfeeding mothers that include online information from the American Academy of Pediatrics (http://www.aap.org) and La Leche League International (http://ww.llli.org).

• Care of Breasts

The nipples require little attention other than cleanliness and attention to skin issures. Fissured nipples render nursing painful, and they may have a deleterious influence on milk production. These cracks also provide a portal of entry for pyogenic bacteria. Because dried milk is likely to accumulate and irritate the nipples, washing the areola with water and mild soap is helpful before and ater nursing. When the nipples are irritated or fissured, some recommend topical lanolin and a nipple shield for 24 hours or longer. Although specific evidence supporting this practice is lacking, nipple pain usually subsides by 10 days (Dennis, 2014). If issuring is severe, the newborn should not be permitted to nurse on the afected side. Instead, the breast is emptied regularly with a pump until the lesions are healed. Poor latching of the neonate to the breast can create such issures. For example, the newborn may take into its mouth only the nipple, which is then is forced against the hard palate during suckling. Ideally, the nipple and areola are both taken in to evenly distribute suckling forces. Moreover, the force of the hard palate against the lactiferous sinuses aids their eicient emptying, while the nipple is thereby positioned closer to the soft palate.

• Contraindications to Breastfeeding

Nursing is contraindicated in women who take street drugs or do not control their alcohol use; have an infant with galactosemia; have human immunodeiciency virus (HIV) infection; have active, untreated tuberculosis; take certain medications; or are undergoing breast cancer treatment (American Academy of Pediatrics, 2017; Faupel-Badger, 2013). Breastfeeding has been recognized for some time as a mode of HIV transmission and is proscribed in developed countries in which adequate nutrition is otherwise available. Other viral infections do not contraindicate breastfeeding. For example, with maternal cytomegalovirus infection, both virus and antibodies are present in breast milk. And, although hepatitis B virus is excreted in milk, breastfeeding is not contraindicated if hepatitis B immune globulin is given to the newborns of afected mothers. Maternal hepatitis C infection is not a contraindication because breastfeeding has not been shown to transmit infection (Society for MaternalFetal Medicine, 2017).Women with active herpes simplex virus may sucle their infants if there are no breast lesions and if particular care is directed to hand washing before nursing.

Most drugs given to the mother are secreted in breast milk, although the amount ingested by the infant typically is small. Many factors influence drug excretion and include plasma concentration, degree of protein binding, plasma and milk pH, degree of ionization, lipid solubility, and molecular weight (Rowe, 2013). The ratio of drug concentration in breast milk to that in maternal plasma is the milk-to-plasma drug-concentration ratio. Ideally, to minimize infant exposure, medication selection should favor drugs with a shorter halflife, poorer oral absorption, and lower lipid solubility. If multiple daily drug doses are required, then each is taken by the mother ater the closest feed. Single daily-dosed drugs may be taken just before the longest infant sleep interval-usually at bedtime (Spencer, 2002).

Only a few drugs are absolutely contraindicated while breastfeeding (Berlin, 2013; Bertino, 2012). Cytotoxic drugs may interfere with cellular metabolism and potentially cause immune suppression or neutropenia, afect growth, and at least theoretically, increase the risk of childhood cancer. Examples include cyclophosphamide, cyclosporine, doxorubicin, metho trexate, and mycophenolate. If a medication presents a con cern, then the importance of therapy should be ascertained.

It should be determined whether there is a safer alternative or whether neonatal exposure can be minimized if the medication dose is taken immediately after each breastfeeding (American

Academy of Pediatrics, 2017). Finally, recreational drugs such of Obstetricians and Gynecologists, 2017 a). Data on individual drugs are available through the National Institutes of Health website, LactMed, which can be found at toxnet.nlm.nih.gov.

Radioactive isotopes of copper, gallium, indium, iodine, sodium, and technetium rapidly appear in breast milk. Con sultation with a nuclear medicine specialist is recommended before performing a diagnostic study with these isotopes (Chap. 46, p. 908). he goal is to use a radionuclide with the shortest excretion time in breast milk. The mother should pump her breasts before the study and store enough milk in a freezer to feed the infant. After the study, she should pump her breasts to maintain milk low but discard all milk produced during the time that radioactivity is present. his ranges from 15 hours to 2 weeks, depending on the isotope used. Importantly, radioactive iodine concentrates and persists in the thyroid. Its special considerations are discussed in Chapter 63 (p. 1201).

his is common in women who do not breastfeed. It is typified by milk leakage and breast pain, which peak 3 to 5 days after delivery (Spitz, 1998). Up to half of afected women require analgesia for breast pain relief, and as many as 10 percent report severe pain for up to 14 days.

Evidence is insuicient to irmly support any speciic treatment (Mangesi, 2016). hat said, breasts can be supported with a well-itting brassiere, breast binder, or sports bra. Cool packs and oral analgesics for 12 to 24 hours aid discomfort. Pharmacological or hormonal agents are in general not recommended to suppress lactation.

Fever caused by breast engorgement was common before the renaissance of breastfeeding. In one study, Almeida and Kitay (1986) reported that 13 percent of puerperas had fever from engorgement that ranged from 37.8 to 39°C. Fever seldom persists for longer than 4 to 16 hours. The incidence and severity of engorgement and of the fever associated with it are much lower if women breastfeed. Other causes of fever, especially those due to infection, must be excluded. Of these, mastitis is infection of the mammary parenchyma. I t is relatively common in lactating women and is discussed in Chapter 37 (p. 675).

• Other Issues with Lactation

With inverted nipples, lactiferous ducts open directly into a depression at the center of the areola. With these depressed nipples, nursing is diicult. If the depression is not deep, milk sometimes can be drawn out by a breast pump. If instead the

The Puerperium 659 nipple is greatly inverted, daily attempts are made during the last few months of pregnancy to draw or "tease" the nipple out with the fingers.

Extra breasts-poymastia, or extra nipples-poythelia, may develop along the former embryonic mammary ridge.

Also termed the milk line, this line extends from the axilla to the groin bilaterally. In some women, rests of accessory breast tissue can be found in the mons pubis or vulva (Wagner, 2013). In the general population, the incidence of accessory breast tissue ranges from 0.22 to 6 percent (Loukas, 2007).

hese breasts may be so small as to be mistaken for pigmented moles, or if without a nipple, for lymphadenopathy or lipoma.

Polymastia has no obstetrical significance, although occasion ally enlargement of these accessory breasts during pregnancy and anxiety.

Galactocele is a milk duct that becomes obstructed by inspis sated secretions. The amount is ordinarily limited, but an excess pressure symptoms and have the appearance of an abscess. It may resolve spontaneously or require aspiration.

Among individuals, the volume of milk secreted varies markedly. This depends not on general maternal health but on breast glandular development. Rarely, there is complete lack of mammary secretion-agalactia. Occasionally, mammary secretion is excessive-poygalactia.

For 2 hours after delivery, blood pressure and pulse are taken every 15 minutes, or more frequently if indicated. Temperature is assessed every 4 hours for the first 8 hours and then at least every 8 hours subsequently (American Academy of Pediatrics, 2017). The amount of vaginal bleeding is monitored, and the fundus palpated to ensure that it is well contracted. If relaxation is detected, the uterus should be massaged through the abdominal wall until it remains contracted. U terotonics are also sometimes required. Blood can accumulate within the uterus without external bleeding. his may be detected early by uterine enlargement during fundal palpation in the irst postdelivery hours. Because the likelihood of signiicant hemorrhage is greatest immediately postpartum, even in normal births, the uterus is closely monitored for at least 1 hour after delivery. Postpartum hemorrhage is discussed in Chapter 41 (p. 758). If regional analgesia or general anesthesia was used for labor or delivery, the mother should be observed in an appropriately equipped and stafed recovery area.

Women are out of bed within a few hours after delivery. n attendant should be present for at least the irst time, in case the woman becomes syncopal. he many conirmed advantages of early ambulation include fewer bladder complications, less frequent constipation, and reduced rates of puerperal venous thromboembolism. As discussed on page 655, deep-vein thrombosis and pulmonary embolism are common in the puerperium (see Fig. 36-3). In an audit of puerperal women at Parkland Hospital, the frequency of venous thromboembolism was found to be 0.008 percent after a vaginal birth and 0.04 percent following cesarean delivery. We attribute this low incidence to early ambulation. Risk factors and other measures to diminish the frequency of thromboembolism are discussed in Chapter 52 (p. 1004).

here are no dietary restrictions for women who have been delivered vaginally. Two hours after uncomplicated vaginal delivery, a woman is allowed to eat. With breastfeeding, the level of calories and protein consumed during pregnancy are increased slightly as recommended by the Food and Nutrition Board of the National Research Council (Chap. 9, p. 167). If the mother does not breastfeed, dietary requirements are the same as for a nonpregnant woman. We recommend oral iron supplementation for at least 3 months after delivery and hematocrit evaluation at the first postpartum visit.

As noted earlier, profound drops in estrogen levels follow removal of the placenta. Reminiscent of the menopause, postpartum women may experience hot lushes, especially at night. Importantly, the patientr's temperature is assessed to diferentiate these physiological vasomotor events from infection.

In women with migraines, dramatic hypoestrogenism may trigger headaches. Importantly, severe headaches should be differentiated from spinal headache or hypertensive complications. Care varies depending on migraine severity. Mild headaches may respond to analgesics such as ibuprofen or acetaminophen. lternatively, Midrin combines isometheptene mucate, which is a sympathomimetic agent; dichloralphenazone, which is a mild sedative; and acetaminophen and is compatible with breastfeeding. For more severe headaches, oral or systemic narcotics can be used. Instead of Midrin, a triptan, such as sumatriptan (Imitrex), can efectively relieve headaches by causing intracranial vasoconstriction.

he woman is instructed to clean the vulva from anterior to posterior-the vulva toward the anus. A cool pack applied to the perineum may help reduce edema and discomfort during the irst 24 hours if there is a perineal laceration or an episiotomy. Most women also appear to obtain a measure of relief from the periodic application of a local anesthetic spray. Severe perineal vaginal, or rectal pain always warrants carul inspection and papation. Severe discomfort usually indicates a problem, such as a hematoma within the irst day or so and infection ater the third or fourth day (Chap. 37, p. 674 and Chap. 41, p. 764). Beginning approximately 24 hours after delivery, moist heat as provided by warm sitz baths can be used to reduce local discomfort. Tub bathing after uncomplicated delivery is allowed. The episiotomy incision normally is firmly healed and nearly asymptomatic by the third week.

Rarely, the cervix, and occasionally a portion of the uterine body, may protrude from the vulva following delivery. his is accompanied by variable degrees of anterior and posterior vaginal wall prolapse. Symptoms include a palpable mass at or past the introitus, voiding diiculties, or pressure. Puerperal procidentia typically improves with time as the weight of the uterus lessens with involution. As a temporizing measure in those with pronounced prolapse, the uterus can be replaced and held in position with a suitable pessary.

Hemorrhoidal veins are often congested at term. Thrombosis is common and may be promoted by second-stage pushing. Treatment includes topically applied anesthetics, warm soaks, and stool-softening agents. Nonprescription topical preparations containing corticosteroids, astringents, or phenylephrine are often used, but no randomized studies support their eicacy compared with conservative management.

In most delivery units, intravenous luids are inused during labor and for an hour or so ater delivery. Oxytocin, in doses that have an antidiuretic efect, is typically inused postpartum, and rapid bladder filling is common. Moreover, both bladder sensation and capability to empty spontaneously may be diminished by local or conduction analgesia, by trauma to the bladder, by episiotomy or lacerations, or by operative vaginal delivery. Thus, urinary retention and bladder overdistention is common in the early puerperium. he incidence in more than 5500 women studied with a bladder scanner was 5.1 percent (Buchanan, 2014). In another study, Musselwhite and coworkers (2007) reported retention in 4.7 percent of women who had labor epidural analgesia. Risk factors that increased the likelihood of retention were primiparity, cesarean delivery, perineal laceration, oxytocin-induced or augmented labor, operative vaginal delivery, catheterization during labor, and labor durationr> 10 hours.

Prevention of bladder overdistention demands observation ater delivery to ensure that the bladder does not overill and that it empties adequately with each voiding. he enlarged bladder can be palpated suprapubically, or it is evident abdominally indirectly as it elevates the fundus above the umbilicus. he use of an automated bladder scanner sonography system has been studied to detect high bladder volumes and thus postpartum urinary retention (Buchanan, 2014; Van Os, 2006).

If a woman has not voided within 4 hours ater delivery, it is likely that she cannot. If she has trouble voiding initially, she also is likely to have further trouble. n examination for perineal and genital-tract hematomas is completed. With an overdistended bladder, an indwelling catheter should be left in place until the factors causing retention have abated. Even without a demonstrable cause, it usually is best to leave the catheter in place for at least 24 hours. his prevents recurrence and allows recovery of normal bladder tone and sensation.

When the catheter is removed, a voiding trial is completed to demonstrate an ability to void appropriately. If a woman cannot void after 4 hours, she should be catheterized and the urine volume measured. If more than 200 mL, the bladder is not functioning appropriately, and the catheter is left for another 24 hours. Although rare, if retention persists after a second voiding trial, an indwelling catheter and leg bag can be elected, and the patient returns in 1 week for an outpatient voiding trial. Intermittent sel-catheterization is another option (Mulder, 2017).

During a voiding trial, if less than 200 mL of urine is obtained, the catheter can be removed and the bladder subsequently monitored clinically as described earlier. Harris and coworkers (1977) reported that 40 percent of such women develop bacteriuria, and thus a single dose or short course of antimicrobial therapy against uropathogens is reasonable after the catheter is removed.

• Pain, Mood, and Cognition

Discomfort and its causes following cesarean delivery are con sidered in Chapter 30 (p. 585). During the irst few days after vaginal delivery, the mother may be uncomfortable because of afterpains, episiotomy and lacerations, breast engorgement, and at times, postdural puncture headache. Mild analgesics contain ing codeine, aspirin, or acetaminophen, preferably in combina tions, are given as frequently as every 4 hours during the irst few days.

It is important to screen the postpartum woman for depression (American College of Obstetricians and Gynecologists, 2016b). It is fairly common for a mother to exhibit some degree of depressed mood a few days after delivery. Termed pospartum blues, this likely is the consequence of several factors. hese include emotional letdown that follows the excitement and fears experienced during pregnancy and delivery, discomforts of the early puerperium, fatigue from sleep deprivation, anxiety over the ability to provide appropriate newborn care, and body image concerns. In most women, efective treatment includes anticipation, recognition, and reassurance. This disorder is usually mild and self-limited to 2 to 3 days, although it sometimes lasts for up to 10 days. Should these moods persist or worsen, an evaluation for symptoms of major depression is done (Chap. 61, p. 1176). Suicidal or infanticidal ideation is dealt with emergently. Because major postpartum depression recurs in at least a fourth of women in subsequent pregnancies, some recommend pharmacological prophylaxis beginning in late pregnancy or immediately postpartum.

Last, postpartum hormonal changes in some women may afect brain function. Bannbers and colleagues (2013) compared a measure of executive function in postpartum women and controls and observed a functional decline in postpartum subjects.

Pressure on branches of the lumbosacral nerve plexus during labor may manifest as complaints of intense neuralgia or cramplike pains extending down one or both legs as soon as the head descends into the pelvis. If the nerve is injured, pain may continue after delivery, and variable degrees of sensory loss or muscle paralysis can result. In some cases, there is footdrop, which can be secondary to injury at the level of the lumbosacral plexus, sciatic nerve, or common fibular (peroneal) nerve (Bunch, 2014). Components of the lumbosacral plexus cross the pelvic brim and can be compressed by the fetal head or by forceps. The common ibular nerves may be externally compressed when the legs are positioned in stirrups, especially during prolonged second-stage labor.

Obstetrical neuropathy is relatively infrequent. Wong and associates (2003) evaluated more than 6000 puerperas and found that approximately 1 percent had a conirmed nerve injury. Lateral femoral cutaneous neuropathies were the most

The Puerperium 661 common (24 percent), followed by femoral neuropathies (14 percent). A motor deicit accompanied a third of injuries. Nul liparity, prolonged second-stage labor, and pushing for a long duration in the semi-Fowler position were risk factors. The median duration of symptoms was 2 months, and the range was 2 weeks to 18 months.

Nerve injuries with cesarean delivery include the iliohypo gastric and ilioinguinal nerves (Rahn, 2010). These are dis cussed further in Chapter 2 (p. 15).

Pain in the pelvic girdle, hips, or lower extremities may follow stretching or tearing injuries sustained at normal or diicult delivery. Magnetic resonance (MR) imaging is often informative (Miller, 2015). One example is the piriformis muscle hematoma shown in Figure 36-6. Most injuries resolve with antiinlammatory agents and physical therapy. Rarely, there may be septic pyomyositis such as with iliopsoas muscle abscess (Nelson, 2010; Young, 2010).

Separation of the symphysis pubis or one of the sacroiliac synchondroses during labor leads to pain and marked interference with locomotion (Fig. 36-7). Estimates of the frequency of this event vary widely from 1 in 600 to 1 in 30,000 deliveries (Reis, 1932; Taylor, 1986). In our experiences, symptomatic separations are uncommon. heir onset of pain is often acute during delivery, but symptoms may manifest either antepartum or up to 48 hours postpartum (Snow, 1997). In suspected cases, radiography is typically selected. The normal distance of the symphyseal joint is 0.4 to 0.5 cm, and symphyseal separation > 1 cm is diagnostic for diastasis. Treatment is generally conservative, with rest in a lateral decubitus position and an appropriately itted pelvic binder (Lasbleiz, 2017). Surgery is occasionally necessary in some symphyseal separations of more than 4 cm (Kharrazi, 1997). The recurrence risk is high in subsequent pregnancy, and Culligan and coworkers (2002) recommend consideration for cesarean delivery.

FIGURE 36-6 Inhomogeneous mass of the right piriformis muscle consistent with a hematoma (yellow cursor measurements) is compared with the normal-appearing left piriformis muscle (yellow arrow), postpartum day following vaginal delivery of a 2840-g newborn. The patient had pain over the pubic bone and pain with ambulation. A shuffling gait was noted, and she had difficulty with leg elevation when supine. The patient was treated with physical therapy and analgesics. A pelvic binder was applied, and a rolling walker was provided. She improved quickly and was discharged home on postoperative day S.

In rare cases, fractures of the sacrum or pubic ramus are caused by even uncomplicated deliveries (Alonso-Burgos, 2007; Speziali, 2015). As discussed in Chapter 58 (p. 1129), the latter are more likely with osteoporosis associated with heparin or corticosteroid therapy (Cunningham, 2005). In rare bur serious cases, bacterial osteomyelitis-osteitis pubis-can be devastating. Lawford and coworkers (2010) reported such a case that caused massive vulvar edema.

he D-negative woman who is not isoimmunized and whose newborn is D-positive is given 300 -1g of anti-D immune globulin shortly after delivery (Chap. IS, p. 305). Women who are not already immune to rubella or varicella are excellent candidates for vaccination before discharge (Swamy, 2015). hose who have not received a tetanus/diphtheria or inluenza vaccine should be given these (American College of Obstetricians and Gynecologists, 2017 c). Morgan and colleagues (2015) reported that implementation of a best-practices alert in the electronic medical record was associated with a tetanus/diphtheria immunization rate of 97 percent at Parkland Hospital. Vaccination is also discussed in Chapter 9 (p. 171).

Following uncomplicated vaginal delivery, hospitalization is seldom warranted for more than 48 hours. A woman should receive instructions concerning anticipated normal physiological puerperal changes, including lochia patterns, weight loss from diuresis, and milk let-down. She also should receive instructions concerning fever, excessive vaginal bleeding, or leg pain, swelling, or tenderness. Persistent headaches, shortness of breath, or chest pain warrant immediate concern.

Hospital-stay length following labor and delivery is now regulated by federal law (Chap. 32, p. 616). Currently, the norms are hospital stays up to 48 hours following uncomplicated vaginal delivery and up to 96 hours following uncomplicated cesarean delivery (American Academy of Pediatrics, 2017; Blumenfield, 2015). Earlier hospital discharge is acceptable for appropriately selected women if they desire it .

During the hospital stay, a concerted efort is made to provide family planning education. Various forms of contraception are discussed throughout Chapter 38 and sterilization procedures in Chapter 39.

Women not breastfeeding have return of menses usually within 6 to 8 weeks. At times, however, it is diicult clinically to assign a speciic date to the first menstrual period after delivery. A minority of women bleed small to moderate amounts intermittently, starting soon after delivery. Ovulation occurs at a mean of 7 weeks, but ranges from 5 to 11 weeks (Perez, 1972). hat said, ovulation before 28 days has been described (Hytten, 1995). hus, conception is possible during the artiicially deined 6-week puerperium. Women who become sexualy active during the puerperium, and who do not desire to conceive, should initiate contraception. Kelly and associates (2005) reported that by the third month postpartum, 58 percent of adolescents had resumed sexual intercourse, but only 80 percent of these were using contraception. Because of this, many recommend long-acting reversible contraceptives-LARC (Baldwin, 2013).

Women who breastfeed ovulate much less frequently compared with those who do not, but variation is great. Timing of ovulation depends on individual biological variation and the intensity of breastfeeding. Lactating women may first menstruate as early as the second or as late as the 18th month after delivery. Campbell and Gray (1993) analyzed daily urine specimens to determine the time of ovulation in 92 lactating women. As shown in Figure 36-8, breastfeeding in general delays resumption of ovulation, although as already empha 8..) 50

FIGURE 36-8 Cumulative proportion of breastfeeding women who ovulated during the first 70 weeks following delivery. (Data from Campbell OM, Gray RH: Characteristics and determinants of postpartum ovarian function in women in the United States. Am J Obstet Gynecol 169:5S, 1993.) sized, it does not invariably forestall it. Other findings in their study included the following: 1.

Resumption of ovulation was frequently marked by return of normal menstrual bleeding.

2.

Breastfeeding episodes lasting 15 minutes seven times daily delayed ovulation resumption.

3.

Ovulation can occur without bleeding.

4.

Bleeding can be anovulatory.

5.

The risk of pregnancy in breastfeeding women was approximately 4 percent per year.

For the breastfeeding woman, progestin-only contraceptives, such as progestin pills, depot medroxyprogesterone, or progestin implants, do not afect the quality or quantity of milk. Success with the progesterone-releasing vaginal ring has also been described (Carr, 2016). hese may be initiated any time during the puerperium. Estrogen-progestin contraceptives likely reduce the quantity of breast milk, but under the proper circumstances, they too can be used by breastfeeding women. hese hormonal methods are discussed in Chapter 38.

No evidence-based data guide resumption of coitus after delivery, and practices are individualized (Minig, 2009). After 2 weeks, coitus may be resumed based on desire and comort. Barrett and colleagues (2000) reported that almost 90 percent of 484 primiparous women resumed sexual activity by 6 months. And although 65 percent of these reported problems, only 15 percent discussed them with a health-care provider.

Intercourse too soon may be unpleasant, if not frankly painful, and this may be related to episiotomy incisions or severe lacerations. In a study of women without an episiotomy, only 0.4 percent of those with a first-or second-degree tear had dyspareunia (Ventolini, 2014). Conversely, in primiparas with an episiotomy, 67 percent had sexual dysfunction at 3 months, 31 percent at 6 months, and 15 percent at 12 months (Chayachinda, 2015). Dyspareunia was also common following cesarean delivery (McDonald, 2015).

Postpartum, the vulvovaginal epithelium is thin, and very little lubrication follows sexual stimulation. his stems from the hypoestrogenic state following delivery, which lasts until ovulation resumes. It may be particularly problematic in breastfeeding women who are hypoestrogenic for many months postpartum (Palmer, 2003). For treatment, small amounts of topical estrogen cream can be applied daily for several weeks to vulvar tissues. Additionally, vaginal lubricants may be used with coitus.

This same thinning of the vulvovaginal epithelium can lead to dysuria. Topical estrogen can again be ofered once cystitis is excl uded.

Taken together, major and minor maternal morbidity are surprisingly common in the months following childbirth. In a survey of 1249 British mothers followed for up to 18 months,

The Puerperium 663

Gin 87 percent of all women, at least one symptom was reported.

Data from Glazener CM, Abdalla M, Stroud P, et al:

Postnatal maternal morbidity: extent, causes, prevention and treatment. BJOG 102:282, 1995.

3 percent required hospital readmission within 8 weeks (Glazener, 1995; hompson, 2002). Milder health problems during the first 8 weeks were reported by 87 percent (Table 36-5). Moreover, almost three fourths continued to have various problems for up to 18 months. Practitioners should be aware of these potential issues in their convalescing patients.

By discharge, women who had an uncomplicated vaginal delivery can resume most activities, including bathing, driving, and household functions. Jimenez and Newton (1979) tabulated cross-cultural information on 202 societies from various international geographical regions. Following childbirth, most societies did not restrict work activity, and approximately half expected a return to full duties within 2 weeks. Wallace and coworkers (20 l3) reported that 80 percent of women who worked during pregnancy resume work by 1 year ater delivery. Despite this, Tulman and Fawcett (1988) reported that only half of mothers regained their usual level of energy by 6 weeks. Women who delivered vaginally were twice as likely to have normal energy levels at this time compared with those with a cesarean delivery. Ideally, the care and nurturing of the infant should be provided by the mother with ample help from the father.

The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017) recommend a postpartum visit between 4 and 6 weeks. his has proven quite satisfactory to identiy abnormalities beyond the immediate puerperium and to initiate contraceptive practices.

Ahdoot 0, Van Nostrand M, Nguyen NJ, et al: he efect of route of deliv ery on regression of abnormal cervical cytologic indings in the postpartum period. Am J Obstet Gynecol 178: 1116, 1998 Almeida 00 Jr, Kitay DZ: Lactation suppression and puerperal fever. m J

Obstet Gynecol 154:940, 1986 Alonso-Burgos A, Royo P, Diaz L, et al: Labor-related sacral and pubic frac tures. J Bone Joint Surg 89:396, 2007

TABLE 36-5. Puerperal Morbidity Reported by 8 Weeks Morbidity PercentQ

American Academy of Pediatrics: Breastfeeding and the use of human milk. Pediatrics 129(3):e827, 2012

American Academy of Pediatrics, American College of Obstetricians and Gynecologists: Guidelines for Perinatal Care, 8th ed. Elk Grove Village, AAP, 2017

American College of Obstetricians and Gynecologists: Breastfeeding in underserved women: increasing initiation and continuation of breastfeeding. Committee Opinion No. 570, August 2013, Reairmed 2016a

American College of Obstetricians and Gynecologists: Screening for perinatal depression. Committee Opinion No. 630, May 2015, Reairmed 2016b American College of Obstetricians and Gynecologists: Marijuana use during pregnancy and lactation. Committee Opinion No. 722, October 2017a

American College of Obstetricians and Gynecologists: Optimizing support for breastfeeding as part of obstetric practice. Committee Opinion No. 658, February 2016, Reairmed 2017b

American College of Obstetricians and Gynecologists: Update on immunizationand pregnancy: tetanus, diphtheria, and pertussis vaccination. Committee Opinion No. 718, September 2017c

Anderson R, Davis J: Placental site involution. Am J Obstet Gynecol 102:23, 1968 Andrew AC, Bulmer IN, Wells M, et al: Subinvolution of the uteroplacental arteries in the human placental bed. Histopathology 15:395, 1989 Andrews MC: Epithelial changes in the puerperal fallopian tube. Am J Obstet Gyneco1 62:28, 1951

Bae HS, m KH, Oh MJ, et al: Postpartum uterine involution: sonographic changes in the endometrium between 2 and 6 weeks postpartum related to delivery mode and gestational age at delivery. Ultrasound Obstet Gynecol 39(6):727, 2012

Baker JL, Gamborg M, Heitmann BL, et al: Breastfeeding reduces postpartum weight retention. Am J Clin Nutr 88(6):1543, 2008

Baldwin MK, Edelman AB: he efect of long-acting reversible contraception on rapid repeat pregnancy in adolescents: a review. J Adolesc Health 52(4 Suppl):S47, 2013

Ballard 0, Morrow L: Human milk composition: nutrients and bioactive factors. Pediatr Clin North Am 60(1):49, 2013

Bannbers E, Gingnell M, Engman J, et al: Prefrontal activity during response inhibition decreases over time in the postpartum period. Behav Brain Res 241:132, 2013

Barrett G, Pendry E, Peacock J, et al: Women's sexual health after childbirth.

BJOG 107:186, 2000

Bartek MC, Stuebe M, Schwarz EB, et al: Cost analysis of maternal disease associated with suboptimal breastfeeding. Obstet Gynecol 122:111, 2013

Belachew J, Axelsson 0, Mulic-Lutvica A, et al: Longitudinal study of the uterine body and cavity with three-dimensional ultrasonography in the puerperium. Acta Obstet Gynecol Scand 91(10):1184, 2012

Berlin CM Jr, van den Anker IN: Safety during breastfeeding: drugs, foods, environmental chemicals, and maternal infections. Semin Fetal Neonatal Med 18(1):13, 2013

Bertino E, Varalda A, Di Nicola P, et al: Drugs and breastfeeding: instructions for use. J Matern Fetal Neonatal Med 25(Supp1 4):78, 2012 Blumenfield J, El-sayed Y, Lyell DJ, et al: Risk factors for prolonged postpartum length of stay following cesarean delivery. Am J Perinatol 32:825, 2015 Buchanan J, Beckmann M: Postpartum voiding dysfunction: identiying the risk factors. Aust N Z J Obstet Gynaecol 54(1):41, 2014

Buhimschi CS, Buhimschi A, Malinow M, et al: Myometrial thickness during human labor and immediately postpartum. Am J Obstet Gynecol 188:553, 2003

Bunch K, Hope E: An uncommon case of bilateral peroneal nerve palsy following delivery: a case report and review of the literature. Case Rep Obstet Gyneco1 2014:746480, 2014

Campbell OM, Gray RH: Characteristics and determinants of postpartum ovarian function in women in the United States. Am J Obstet Gynecol 169:55, 1993

Carr SL, Gaield ME, Dragoman MV, et al: Safety of the progesterone-releasing vaginal ring (PVR) among lactating women. Contraception 94(3):253, 2016

Centers for Disease Control and Prevention: Breastfeeding Report CardUnited States, 2014. Available at: http://ww.cdc.gov/breastfeeding/data/ reportcard.htm. Accessed March 27, 2016

Centers for Disease Control and Prevention: PRAMS, the Pregnancy Risk Assessment Monitoring System. 2016. Available at: http://ww.cdc.gov/ PRAMS/index.htm. Accessed March 27, 2016

Chayachinda C, Titapant V, UngkanungdechaA: Dyspareunia and sexual dysfunction ater vaginal delivery in hai primiparous women with episiotomy. J Sex Med 12(5):1275, 2015

Chesley LC, Valenti C, Uichano L: Alterations in body fluid compartments and exchangeable sodium in early puerperium. Am J Obstet Gynecol 77: 1054, 1959

Collier RJ, Hernandez LL, Horseman ND: Serotonin as a homeostatic regulator of lactation. Domest Anim Endocrino1 43(2):161, 2012

Culligan P, Hill S, Heit M: Rupture of the symphysis pubis during vaginal delivery followed by two subsequent uneventful pregnancies. Obstet Gynecol 100:1114, 2002

Cunningham FG: Screening for osteoporosis. N Engl J Med 353(18):1975, 2005

Dennis CL, Jackson K, Watson J: Interventions for treating painful nipples among breastfeeding women. Cochrane Database Syst Rev 12:CD007366, 2014 Faupel-Badger JM, Arcaro F, Balkam J], et al: Postpartum remodeling, lactation, and breast cancer risk: summary of a National Cancer Institute-sponsored workshop. J Nat! Cancer Inst 105(3):166, 2013 Fletcher S, Grotegut CA, James AH: Lochia patterns among normal women: a systematic review. J Womens Health (Larchmt) 21(12):1290, 2012 Forrester-Knauss C, Merten S, Weiss C, et al: The Baby-Friendly Hospital Initiative in Switzerland: trends over a 9-year period. J Hum Lact 29(4):510, 2013 Funnell JW, Klawans AH, Cottrell TL: he postpartum bladder. Am J Obstet Gyneco1 67:1249, 1954 Glazener CM, Abdalla M, Stroud P, et al: Postnatal maternal morbidity: extent, causes, prevention and treatment. BJOG 102:282, 1995 Harris E, homas L, Hui GW: Postpartum suveillance for urinary tract infection: patients at risk of developing pyelonephritis after catheterization. South MedJ 70:1273, 1977 Hibbard JU, Schrof SG, Cunningham FG: Cardiovascular alterations in normal and preeclamptic pregnancy. In Taylor N, Roberts JM, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 2014 Hladunewich A, Lafayette A, Derby GC, et al: The dynamics of glomerular iltration in the puerperium. Am J Physiol Renal Physiol 286:F496, 2004 Holdcrot A, Snidvongs S, Cason A, et al: Pain and uterine contractions during breast feeding in the immediate post-partum period increase with parity. Pain 104:589, 2003 Hytten F: he Clinical Physiology of the Puerperium. London, Farrand Press, 1995 Iraha Y, Okada M, Toguchi M, et al: Multimodality imaging in secondary postpartum or postabortion hemorrhage: retained products of conception and related conditions. Jpn J Radiol October 19, 2017 [Epub ahead of print]

Iyengar SR, Walker WA: Immune factors in breast milk and the development of atopic disease. J Pediatr Gastroenterol Nutr 55(6):641, 2012

Jimenez MH, Newton N: Activity and work during pregnancy and the postpartum period: a cross-cultural study of 202 societies. Am J Obstet Gynecol 135:171, 1979

Jong DE, Kikkert HR, Fidler V, et al: Efects of long-chain polyunsaturated fatty acid supplementation of infant formula on cognition and behavior at 9 years of age. Dev Med Child Neurol 54(12):1102, 2012 Kamel H, Navi B, Sriram N, et al: Risk of a thrombotic event after the 6-week postpartum period. N Engl J Med 370: 1307, 2014 Kandadai P, Kandadai V, Saini J, et al: Acute urinary retention after cesarean delivery: a case-control study. Female Pelvic Med Reconstr Surg 20(5):276, 2014 Kaneshiro BE, Acoba JD, Holzman J, et al: Efect of delivery route on natural history of cervical dysplasia. Am J Obstet Gynecol 192(5): 1452, 2005 Kanotra S, D'Angelo 0, Phares TM, et al: Challenges faced by new mothers in the early postpartum period: an analysis of comment data from the 2000 Pregnancy Risk Assessment Monitoring System (PRAMS) survey. Matern Child Health J 11 (6):549, 2007 Kavalar R, Arko D, Fokter Dovnik N, et al: Subinvolution of placental bed vessels: case report and review of the literature. Wien Klin Wochenschr 124(19-20):725, 2012 Kelly LS, Sheeder J, Stevens-Simon C: Why lightning strikes twice: postpartum resumption of sexual activity during adolescence. J Pediatr Adolesc Gynecol 18:327, 2005 Kenny LC, McCrae R, Cunningham FG: Platelets, coagulation, and the liver. In Taylor N, Roberts JM, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 2014 Kharrazi FD, Rodgers B, Kennedy JG, et al: Parturition-induced pelvic dislocation: a report oHour cases. J Orthop Trauma 11:277, 1997 Kramer MS, Aboud F, Mironova E, et al: Breastfeeding and child cognitive development: new evidence from a large randomized trial. Arch Gen Psychiatry 65(5):578, 2008 Lasbleiz J, Sevestre FX, Moquet PY: Using an elastic band device after a severe obstetric pubic symphyseal separation: clinical and imaging evaluation. Obstet Gynecol 130(3):625, 2017 Lawford M, Scott K, Lust K: A case of massive vulvar oedema due to septic pubic symphysitis complicating pregnancy. Aust N Z J Obstet Gynaecol 50(6):576, 2010

Lee CY, Madrazo B, Drukker BH: Ultrasonic evaluation of the postpartum uterus in the management of postpartum bleeding. Obstet Gynecol 58:227, 1981

Lipe BC, Dumas MA, Ornstein DL: Von Willebrand disease in pregnancy.

Hematol Oncol Clin North Am 25(2):335, 201n1

Loukas M, Clarke P, Tubbs RS: Accessory breasts: a historical and current perspective. Am Surg 73(5):525, 2007

Mangesi L, Zakarija-Grkovic I: Treatments for breast engorgement during lactation. Cochrane Database Syst Rev 6:CD006946, 2016

McCleary MJ: Epidermal growth factor: an important constituent of human milk. J Hum Lact 7:123,n1991

McDonald EA, Gartland D, Small R, et al: Dyspareunia and childbirth: a ptospective cohort study. BJOG 122:672,n2015

McDonald SD, Pullenayegum E, Chapman B, et al: Prevalence and predictors of exclusive breastfeeding at hospital discharge. Obstet Gynecol 119(6):1171, 2012

Miller JM, Low LK, Zielinski R, et al: Evaluating maternal recovery from labor and delivery: bone and levator ani injuries. Am J Obstet Gynecol 213:188e1,2015

Minig L, Trimble EL, Sarsotti C, et al: Building the evidence base for postoperative and postpartum advice. Obstet Gynecol 114(4):892, 2009

Morgan JL, Baggari SR, Chung W, et al: Association of a Best-Practice Alert and prenatal administration with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccination rates. Obstet Gynecol 126(2):333, 2015

Morris EA, Hale SA, Badger GJ, et al: Pregnancy induces persistent changes in vascular compliance in primiparous women. Am J Obstet Gynecol 212(5):633.e1,n2015

Mulder FE, Hakvoort A, de Bruin JP, et al: Comparison of clean intermittent and transurethral indwelling catheterization for the treatment of overt urinary retention after vaginal delivery: a multicentre randomized controlled clinical trial. Int Urogynecol J August 30, 2017 [Epub ahead of print]

Mulder FE, Hakvoort A, Schofelmeer MA, et al: Postpartum urinary retention: a systematic review of adverse efects and management. Int Urogynecol J 25(12):1605, 2014

Musselwhite KL, Faris P, Moore K, et al: Use of epidural anesthesia and the risk of acute postpartum urinary retention. Am J Obstet Gynecol 196:472, 2007

Nelson DB, Manders DB, Shivvers SA: Primary iliopsoas abscess and pregnancy. Obstet Gynecol 116(2 Pt 2):479, 2010

Palmer AR, Likis FE: Lactational atrophic vaginitis. J Midwifery Womens Health 48:282, 2003

Pang W, Hartmann PE Initiation of human lactation: secretory diferentiation and secretory activation. J Mammary Gland Bioi Neoplasia 12:21n1, 2007

Perez A, Vela P, Masnick GS, et al: First ovulation after childbirth: the efect of breast feeding. Am J Obstet Gynecol 114:1041, 2 Perrine CG, Galuska DA, Dohack JL, et al: Vital signs: improvements in maternity care policies and practices that support breastfeeding-United States, 2007-2013. MMWR 64:1112,n2015 Pisacane A, Continisio GI, Aldinucci M, et al: A controlled trial of the father's role in breastfeeding promotion. Pediatrics 116:e494, 2005

Rahn DO, Phelan ]N, Roshanravan SM, et al: Anterior abdominal wall nerve and vessel anatomy: clinical implications for gynecologic surgery. Am ] Obstet Gynecol 202(3):234.e1, 2010

Reis A, Baer JL, Arens A, et al: Traumatic separation of the symphysis pubis during spontaneous labor: with a clinical and x-ray study of the normal symphysis pubis during pregnancy and the puerperium. Surg Gynecol Obstet 55:336, 1932

Robson SC, Dunlop W, Hunter S: Haemodynamic changes during the early puerperium. BM] (Clin Res Ed) 294: 1065, 1987 Rowe H, Baker T, Hale W: Maternal medication, drug use and breastfeeding.

Pediatr Clin North Am 6(1):275, 2013

Saito S, Maruyama M, Kato Y, et al: Detection of IL-6 in human milk and its involvement in IgA production. J Reprod ImmunoI20:267, 1991 Schauberger CW, Rooney BL, Brimer LM: Factors that influence weight loss in the puerperium. Obstet Gynecol 79:424, 1992

Sharman A: Postpartum regeneration of the human endometrium. J Anat 87: 1, 1953

Snow RE, Neubert AG: Peripartum pubic symphysis separation: a case series and review of the literature. Obstet Gynecol Surv 52:438, 1997 ,2010

The Puerperium 665

Society for Maternal-Fetal Medicine, Hughes BL, Page CM, et al: Hepatitis C in pregnancy: screening, treatment, and management. Am J Obstet Gynecol August 4, 2017 [Epub ahead of print]

Sohn C, Fendel H, Kesternich P: Involution-induced changes in arterial uterine blood flow [German]. Z Geburtshilfe PerinatoIn192:203, 1988

Spencer JP, Gonzalez LS III, Barnhart DJ: Medications in the breast-feeding mother. Am Fam Physician 65(2): 170, 2002

Speziali A, Tei MM, Placella G, et al: Postpartum sacral stress fracture. Case Rep Orthop 2015:704393, 2015

Spitz M, Lee NC, Peterson HB: Treatment for lactation suppression: little progress in one hundred years. Am ] Obstet Gynecol 179: 1485, 1998 Steinkeler J, Coldwell BJ, Warner MA: Ultrasound of the postpartum uterus.

Ultrasound Q28(2):97, 2012

Stuebe M: Enabling women to achieve their breastfeeding goals. Obstet Gynecol 123:643,n2014

Swamy G, Heine RP: Vaccinations for pregnant women. Obstet Gynecol 125:212,n2015

Taylor RN, Sonson RD: Separation of the pubic symphysis. An underrecognized peripartum complication. J Reprod Med 31 :203, 1986

Tekay A, Jouppila P: A longitudinal Doppler ultrasonographic assessment of the alterations in peripheral vascular resistance of uterine arteries and ultrasonographic indings of the involuting uterus during the puerperium. Am J Obstet Gynecol 168(1 Pt 1): 190, 1993 hompson JF, Roberts CL, Currie M, et al: Prevalence and persistence of health problems after childbirth: associations with parity and method of birth. Birth 29:83, 2002

Tulman L, Fawcett J: Return of functional ability after childbirth. Nurs Res 37:77, 1988

U.S. Department of Health and Human Services. Executive summary: the Surgeon General's call to action to support breastfeeding. 20n11. Available at: http://ww.surgeongeneral.gov/library/calls/breastfeeding/executivesummary. pdf. Accessed March 27, 2016

Van Os AF, Van der Linden PJ: Reliability of an automatic ultrasound system in the post partum period in measuring urinary retention. Acta Obstet Gynecol Scand 85:604, 2006

Vanhouten IN, Wysolmerski JJ: he calcium-sensing receptor in the breast.

Best Prac Res Clin Endocrinol Metab 27(3)403, 2013

Ventolini G, Yaklic JL, Galloway ML, et al: Obstetric vulvar lacerations and postpartum dyspareunia. ] Reprod Med 59(11-12):560, 2014

Wager GP, Martin DH, Koutsky L, et al: Puerperal infectious morbidity: relationship to route of delivery and to antepartum Chlamydia trachomatis infection. Am J Obstet GynecoIn138:1028, 1980

Wagner CL, Greer FR, American Academy of Pediatrics Section on Breastfeeding: Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics 122(5): 1142, 2008

Wagner IJ, Damitz A, Carey E, et al: Bilateral accessory breast tissue of the vulva: a case report introducing a novel labiaplasty technique. Ann Plast Surg 70(5):549,n2013

Wallace M, Saurel-Cubizolles M], EDEN mother-child cohort study group:

Returning to work one year after childbirth: data from the mother-child cohort EDEN. Matern Child Health] 17(8): 1432,n2013

Weintraub AY, Aricha-Tamir B, Steiner N, et al: Postpartum uterine artery Doppler velocimetry among patients following a delivery complicated with preeclampsia. Hypenens Pregnancy 32(4):450,n2013

Williams JW: Obstetrics. New York, D. Appleton, 1903

Williams JW: Regeneration of the uterine mucosa after delivery with especial reference to the placental site. Am J Obstet Gynecol 22:664, 1931

Wolfberg A], Michels KB, Shields W, et al: Dads as breastfeeding advocates: results from a randomized controlled trial of an educational intervention. Am J Obstet GynecoIn191n:708, 2004

Wong CA, Scavone BM, Dugan S, et al: Incidence of postpartum lumbosacral spine and lower extremity nerve injuries. Obstet Gynecol 101:279,n2003

World Health Organization: Exclusive breastfeeding for six months best for babies everywhere. 2011. Available at: http://www.who.int/mediacentre/news/statemenrs/20111breastfeeding..,20110115/en.l Accessed March ,2016

World Health Organization: Protecting, promoting and supporting breastfeeding: the special role of maternity services. Geneva, World Health Organization, 1989

Young OM, Werner E, Sfakianaki AK: Primary psoas muscle abscess after an uncomplicated spontaneous vaginal delivery. Obstet Gynecol 116(2 Pt 2):

PUERPERAL FEVER ............................. 666 UTERINE INFECTION............................ 667 ABDOMINAL INCISIONAL INFECTIONS............. 670 ADNEXAL ABSCESSES AND PERITONITIS ........... 671

PARAMETRIAL PHLEGMON ...................... 672

SEPTIC PELVIC THROMBOPHLEBITIS............... 673

PERINEAL INFECTIONS.......................... 674 TOXIC SHOCK SYNDROME ....................... 675 BREAST INFECTIONS............................ 675

One cannot ail to be impressed with the very large proportion of patients whose troubles have originated rom ibrile aictions during the puerperium, which in many cases were cleary due to the neglect of aseptic precautions on the part of the obstetrician or midwe.

-J. Whitridge Williams (1903)

Although the woman who recently gave birth is susceptible to several potentially serious complications, pelvic infection continues to be the most important source of maternal morbidity and mortality. Other infections include mastitis and breast abscesses. hat said, puerperal complications include many of those encountered during pregnancy. For example, as discussed in Chapter 52 (p. 1004), venous thromboembolism during the short 6-week puerperium is as frequent as during all 40 antepartum weeks. Other puerperal issues and care are discussed in Chapter 36.

Traditionally, the term puerperal iniction describes any bacterial infection of the genital tract after delivery. hese infections as well as preeclampsia and obstetrical hemorrhage formed the lethal triad of maternal death causes before and during the 20th century. Fortunately, because of efective antimicrobials, maternal mortality from infection has become uncommon. Creanga and associates (2017) reported results from the Pregnancy Mortality Surveillance System, which contained 2009 pregnancy-related maternal deaths in the United States from 2011 through 2013. Infection caused 12.7 percent of pregnancy-related deaths and was the second leading cause. In a similar analysis of the North Carolina population from 1991 through 1999, Berg and colleagues (2005) reported that 40 percent of infection-related maternal deaths were preventable.

Several infective and noninfective factors can cause puerperal fever-a temperature of 38.0°C (100.4°F) or higher. Most persistent ivers ater childbirth are caused by genital tract iniction. Using this conservative deinition of fever, Filker and Monif (1979) reported that only about 20 percent of women febrile within the first 24 hours after vaginal delivery were subsequently diagnosed with pelvic infection. his was in contrast to 70 percent of those after cesarean delivery. It must be emphasized that spiking fevers of 39°C or higher that develop within the first 24 hours postpartum may be associated with virulent pelvic infection caused by group A streptococcus, discussed on page 667.

Other causes of puerperal fever include breast engorgement; infections of the urinary tract, of perineal lacerations, and of episiotomy or abdominal incisions; and respiratory complications ater cesarean delivery (Nlaharaj, 2007). Approximately 15 percent of women who do not breastfeed develop postpartum fever from breast engorgement. As discussed in Chapter 36 (p. 659), the incidence of fever is lower in breastfeeding women. "Breast fever" rarely exceeds 39°C in the irst few postpartum days and usually lasts <24 hours. Urinary inections are uncommon post partum because of the normal diuresis encountered then. Acute pyelonephritis has a variable clinical picture. The irst sign of renal infection may be fever, followed later by costovertebral angle ten derness, nausea, and vomiting. Atelectasis following abdominal delivery is caused by hypoventilation and is best prevented by gery. Fever associated with atelectasis is thought to stem from normal flora that proliferate distal to obstructing mucus plugs.

Postpartum uterine infection or puerperal sepsis has been called variously endometritis, endomyometritis, and endoparametritis. Because infection involves not only the decidua but also the myometrium and parametrial tissues, we prefer the inclusive term metritis with pelvic celulitis.

The route of delivery is the single most signiicant risk factor for the development of uterine infection (Burrows, 2004; Koroukian, 2004). In the French Confidential Enquiry on Maternal Deaths, Deneux-haraux and coworkers (2006) cited a nearly 25-fold increased infection-related mortality rate with cesarean versus vaginal delivery. Rehospitalization rates for wound complications and metritis were increased significantly in women undergoing a planned primary cesarean delivery compared with those having a planned vaginal birth (Declercq, 2007).

Women delivered vaginally at Parkland Hospital have a Ito 2-percent incidence of metritis. For women at high risk for infection because of membrane rupture, prolonged labor, and multiple cervical examinations, the frequency of metritis after vaginal delivery is 5 to 6 percent. If intrapartum chorioamnionitis is present, the risk of persistent uterine infection increases to 13 percent (Maberry, 1991). These igures are similar to those reported from a cohort of more than 11r5,000 women by the Maternal Fetal Medicine Units Network in whom the overall pelvic infection rate approximated 5 percent (Grobman, 2015).

Because of the significant morbidity following hysterotomy, single-dose perioperative antimicrobial prophylxis is recommended for all women undergoing cesarean delivery (American College of Obstetricians and Gynecologists, 2016b). Antimicrobial prophylaxis has done more to decrease the incidence and severity of postcesarean delivery infections than any other intervention in the past 30 years. Such practices decrease the puerperal pelvic infection risk by 65 to 75 percent (Smaill, 2010).

he magnitude of the risk is exemplified from earlier reports that predate antimicrobial prophylaxis. Cunningham and associates (1978) described an overall incidence of 50 percent in all women undergoing cesarean delivery at Parland Hospital. Important risk factors for infection following surgery included prolonged labor, membrane rupture, multiple cervical examinations, and internal fetal monitoring. Women with all these factors who were not given perioperative prophylaxis had a 90-percent serious postcesarean delivery pelvic infection rate (DePalma, 1982).

It is generally accepted that pelvic infection is more frequent in women of lower socioeconomic status (Maharaj, 2007).

Except in extreme cases usually not seen in this country, it is likely uncommon that anemia or poor nutrition predispose to infection. Bacterial colonization of the lower genital tract with certain microorganisms-for example, group B streptococcus,

Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma ureayticum, and Gardnerela vaginalis-has been associated with an increased postpartum infection risk (Andrews, 1995; Jacobsson, 2002; Watts, 1990). Other factors associated with an increased infection risk include general anesthesia, cesarean delivery for multifetal gestation, young maternal age and nulliparity, prolonged labor induction, obesity, and meconium-stained amnionic fluid (Acosta, 2012; Leth, 2011; Siriwachirachai, 2014; Tsai,r2011).

Most female pelvic infections are caused by bacteria indigenous to the genital tract. Over the past 25 years, there have been reports of group A 3-hemolytic streptococcus causing toxic shock-like syndrome and life-threatening infection (Castagnola, 2008; Nathan, 1994). Prematurely ruptured membranes are a prominent risk factor in these infections (Anteby, 1999). In reviews by Crum (2002) and Udagawa (1999) and their colleagues, women in whom group A streptococcal infection was manifested before, during, or within 12 hours of delivery had a maternal mortality rate of almost 90 percent and fetal mortality rater> 50 percent. In the past 10 years, skin and sot-tissue infections due to community-acquired methicillin-resistant Staphylococcus aureus (A-MRSAJ have become common (Chap. 64, p. 1223). Although this variant is not a frequent cause of puerperal metritis, it is oten implicated in abdominal incisional infections (Anderson, 2007; Patel, 2007). Rotas and coworkers (2007) reported a woman with episiotomy cellulitis from CA-MRSA and hematogenously spread necrotizing pneumonia.

Common Pathogens. Bacteria responsible for most female genital tract infections are listed in Table

Most of these infections are polymicrobial, which enhances bacterial synergy.

TABLE 37-1 . Bacteria Commonly Responsible for Female Genital Infections

Gram-positive cocci-group A, B, and D streptococci, enterococcus, Staphylococcus aureus, Staphylococcus

Gram-negative bacteria-Escherichia coll� Klebsiella,

Mycoplasma and Chlamydia, Neisseria gonorrhoeae

Cocci-Peptostreptococcus and Peptococcus species Others-Clostridium, Bacteroides, Fusobacterium,

Other factors that promote virulence are hematomas and devitalized tissue. Although the cervix and vagina routinely harbor such bacteria, the uterine cavity is usually sterile before rupture of the amnionic sac. As the consequence of labor and delivery and associated manipulations, the amnionic fluid and uterus become contaminated with anaerobic and aerobic bacteria. Intraamnionic cytokines and C-reactive protein are also markers of infection (Combs, 2013; Marchocki, 2013). In studies done before the use of antimicrobial prophylaxis, Gilstrap and Cunningham (1979) cultured amnionic fluid obtained at cesarean delivery in women in labor with membranes ruptured more than 6 hours. All had bacterial growth, and on average, each specimen contained 2.5 organisms. Anaerobic and aerobic organisms were identified in 63 percent, anaerobes alone in 30 percent, and aerobes alone in only 7 percent. Anaerobes included Peptostreptococcus and Peptococcus species in 45 percent, Bacteroides species in 9 percent, and Clostridium species in 3 percent. Aerobes included Enterococcus in 14 percent, group B streptococcus in 8 percent, and Escherichia coli in 9 percent of isolates. Sherman and coworkers (1999) later showed that bacterial isolates at cesarean delivery correlated with those taken from women with metritis at 3 days postpartum. Group B streptococci, E coli, and enterococci are some of the more common blood culture isolates with metritis (Cape, 2013; O'Higgins, 2014). Although important because of the severity of infections they cause, clostridial species rarely cause puerperal infections (Chong, 2016).

he role of other organisms in the etiology of these infections is unclear. Observations of Chaim and colleagues (2003) suggest that when cervical colonization of U ureayticum is heavy, it may contribute to the development of metritis. To add evidence to these observations, Tita and associates (2016) recently reported that azithromycin-based extended-spectrum antimicrobial prophylaxis reduced postoperative cesarean delivery infections from 12 to 6 percent compared with j-Iactam agents given alone. Chlamydial infections have been implicated in late-onset, indolent metritis (Ismail, 1985). Finally, Jacobsson and associates (2002) reported a threefold risk of puerperal infection in a group of Swedish women in whom bacterial vaginosis was identified in early pregnancy (Chap. 65, p. 1245).

Bacterial Cultures. Routine genital tract cultures obtained before treatment serve little clinical use and add significant costs. Similarly, routine blood cultures seldom modiy care. In two earlier studies done before perioperative prophylaxis was used, blood cultures were positive in 13 percent of women with postcesarean metritis at Parkland Hospital and 24 percent in those at Los Angeles County Hospital (Cunningham, 1978; DiZerega, 1979). In a later Finnish study, Kankuri and associates (2003) identified bacteremia in only 5 percent of almost 800 women with puerperal sepsis. Blood cultures might be reasonable in women with exceedingly high temperature spikes that may signiy virulent infection with group A streptococci.

Puerperal infection following vaginal delivery primarily involves the placental implantation site, decidua and adjacent myometrium, or cervicovaginal lacerations. The pathogenesis of uterine infection following cesarean delivery is that of an infected surgical incision. Bacteria that colonize the cervix and vagina gain access to amnionic fluid during labor. Postpartum, they invade devitalized uterine tissue. Parametrial cellulitis next follows with infection of the pelvic retroperitoneal fibroareolar connective tissue. With early treatment, infection is contained within the parametrial and paravaginal tissue, but it may extend deeply into the pelvis.

Fever is the most important criterion or the diagnosis of postpartum metritis. Intuitively, the degree of fever is believed proportional to the extent of infection and sepsis syndrome. Temperatures commonly are 38 to 39°C. Chills that accompany fever suggest bacteremia or endotoxemia. Women usually complain of abdominal pain, and parametrial tenderness is elicited on abdominal and bimanual examination. Leukocytosis may range from 15,000 to 30,000 cells/�L, but recall that delivery itself increases the leukocyte count (Hartmann, 2000). Although an ofensive odor may develop, many women have foul-smelling lochia without evidence for infection, and vice versa. Some other infections, notably those caused by group A j-hemolytic streptococci, may be associated with scant, odorless lochia (Anderson, 2014).

If nonsevere metritis develops following vaginal delivery, then treatment with an oral or intramuscular antimicrobial agent may be suicient (Meaney-Delman, 2015). For moderate to severe infections, however, intravenous therapy with a broad-spectrum antimicrobial regimen is indicated. Improvement follows in 48 to 72 hours in nearly 90 percent of women treated with one of several regimens discussed below. Persistent fever after this interval mandates a careful search for causes of refractory pelvic infection. hese include a parametrial phlegmon-an area of intense cellulitis; an abdominal incisional or pelvic abscess or infected hematoma; and septic pelvic thrombophlebitis. In our experience, persistent fever is seldom due to antimicrobial-resistant bacteria or due to drug side efects. he woman may be discharged home after she has been afebrile for at least 24 hours, and further oral antimicrobial therapy is not needed (French, 2004; Nlackeen, 2015).

Choice of Antimicrobials. Although therapy is empirical, ini tial treatment following cesarean delivery is directed against elements of the mixed lora shown in Table 37-1. For infections following vaginal delivery, as many as 90 percent of women respond to regimens such as ampicillin plus gentamicin. In contrast, anaerobic coverage is included for infections following cesarean delivery (Table 37-2).

In 1979, DiZerega and colleagues compared the efectiveness of clindamycin plus gentamicin with that of penicillin G plus gentamicin for treatment of pelvic infections following cesarean delivery. Women given the clindamycin-gentamicin regimen had a 95-percent response rate, and this regimen is still considered by most to be the standard by which others are measured (F rench, 2004; Mackeen, 2015). Because enterococcal cultures may be persistently positive despite this standard

TABLE 37-2. Antimicrobial Regimens for Pelvic Infections Following Cesarean Delivery

Clindamycin + gentamicin "Gold standard," 90-97% eficacy, once-daily gentamicin dosing acceptable

Ampicillin added to regimen with sepsis syndrome or suspected enterococcal infection Clindamycin + aztreonam Gentamicin substitute for renal insuficiency Extended-spectrum penicillins Piperacillin, piperacillin tazobactam, ampicillin/sulbactam, ticarcillin/clavulanate Cephalosporins Cefotetan, cefoxitin, cefotaxime

Vancomycin Added to other regimens for suspected Staphylococcus aureus infections Metronidazole + Metronidazole has excellent anaerobic coverage ampicillin + gentamicin Carbapenems Imipenemlcilastatin, meropenem, ertapenem .eserved for special indications therapy, some add ampicillin to the clindamycin-gentamicin regimen, either initially or if there is no response by 48 to 72 hours (Brumfield, 2000).

Many authorities recommend that serum gentamicin levels be periodically monitored. At Parkland Hospital, we do not routinely do so if the woman has normal renal function. Oncedaily dosing and multiple-dosing with gentamicin both provide adequate serum levels, and either method has similar cure rates (Livingston, 2003). Because of potential nephrotoxicity and ototoxicity with gentamicin in the event of diminished glomerular iltration, some have recommended a combination of clindamycin and a second-generation cephalosporin to treat such women. Others recommend a combination of clindamycin and aztreonam, which is a monobactam compound with activity similar to the aminoglycosides.

The spectra of 3-lactam antimicrobials include activity against many anaerobic pathogens. Some examples include cephalosporins such as cefoxitin, cefotetan, cefotaxime, and ceftriaxone, as well as extended-spectrum penicillins such as piperacillin, ticarcillin, and mezlocillin. 3-Lactam antimicrobials are inherently safe and, except for allergic reactions, are free of major toxicity. The 3-lactamase inhibitors clavulanic acid, sulbactam, and tazobactam have been combined with ampicillin, amoxicillin, ticarcillin, and piperacillin to extend their spectra. Metronidazole has superior in vitro activity against most anaerobes. This agent given with ampicillin and an aminoglycoside provides coverage against most organisms encountered in serious pelvic infections. Metronidazole is also used to treat Clostridium dficile colitis.

lmpenem and similar antimicrobials are in the carbapenem family. hese ofer broad-spectrum coverage against most organisms associated with metritis. Imipenem is used in combination with cilastatin, which inhibits its renal metabolism. Preliminary indings with ertapenem indicated suboptimal outcomes (Brown, 2012). It seems reasonable from both a medical and an economic standpoint to reserve these drugs for serious nonobstetrical infections.

Vancomycin is a glycopeptide antimicrobial active against gram-positive bacteria. It is used in lieu of 3-lactam therapy for a patient with a type 1 allergic reaction and given for suspected infections due to Staphylococcus aureus and to treat C diicile colitis (Chap. 54, p. 1048).

The use of periprocedural antimicrobial prophylaxis is com mon in obstetrics. Even so, no rigorous studies have evalu delivery or manual removal of the placenta (Chongsomchai, 2014; Liabsuetrakul, 2017). But, as discussed, antimicrobial prophylaxis at the time of cesarean delivery has remarkably reduced the postoperative pelvic and wound infection rates.

bials reduce the pelvic infection rate by 70 to 80 percent (Chelmow, 2001; Dinsmoor, 2009; Smaill, 2014). he observed benefit applies to both elective and nonelective incision infection rates.

Single-dose prophylaxis with a 2-g dose of ampicillin or a first-generation cephalosporin is ideal. Both equal the eicacy of broad-spectrum agents or multiple-dose regimens (American College of Obstetricians and Gynecologists, 2016b). For obese women, evidence supports a 3-g dose of cefazolin to reach optimal tissue concentrations (Swank, 2015). Extendedspectrum prophylaxis with azithromycin added to standard single-dose prophylaxis further reduced postcesarean metritis rates (Sutton, 2015; Ward, 2016). As noted earlier, Tita and colleagues (2016) reported that postoperative uterine infection was decreased from 12 to 6 percent with the addition of azithromycin to cefazolin. Women known to be colonized with MRSA are given vancomycin in addition to a cephalosporin (Chap. 64, p. 1223).

It is controversial whether the infection rate is lowered further if the antimicrobial is given before the skin incision compared with after umbilical cord clamping (Baaqeel, 2013; Macones, 2012; Sun, 2013). The American College of Obstetricians and Gynecologists (2016b) has concluded that the evidence favors predelivery administration. Abdominal preoperative skin preparation with chlorhexidine-alcohol is superior to iodine-alcohol for preventing surgical-site infections (Tuuli, 2016). Additive salutary efects may be gained by preoperative vaginal cleansing with povidone-iodine rinse or application of metronidazole gel (Haas, 2014; Reid, 2011; Yildirim, 2012).

Other Methods of Prophylaxis. Several studies have addressed the value of prenatal cervicovaginal cultures. These are obtained in the hope of identiying pathogens that might be eradicated to decrease incidences of preterm labor, chorioamnionitis, and puerperal infections. Unfortunately, treatment of asymptomatic vaginal infections has not been shown to prevent these complications. Carey and coworkers (2000) reported no beneficial efects for women treated for asymptomatic bacterial vaginosis. Klebanof and colleagues (2001) reported a similar postpartum infection rate in women treated for second-trimester asymptomatic Trichomonas vaginalis infection compared with that of placebo-treated women.

Technical maneuvers done to alter the postpartum infection rate have been studied with cesarean delivery. For example, allowing the placenta to separate spontaneously compared with removing it manually lowers the infection risk. However, changing gloves by the surgical team after placental delivery does not (Atkinson, 1996). Exteriorizing the uterus to close the hysterotomy may decrease febrile morbidity (Jacobs-Jokhan, 2004). Postdelivery mechanical lower segment and cervical dilatation has not been shown to be efective (Liabsuetrakul, 2011). No diferences were found in postoperative infection rates when single-and two-layer uterine closures were compared (Hauth, 1992). Similarly, infection rates are not appreciatively afected by closure versus nonclosure of the peritoneum (Bamigboye, 2014; Tulandi, 2003). Importantly, although closure of subcutaneous tissue in obese women does not lower the wound infection rate, it does decrease the wound separation incidence (Chelmow, 2004). Similarly, skin closure with staples versus suture has a higher incidence of noninfectious skin separation (Mackeen, 2012; Tuuli, 2011).

• Complications of Uterine and Pelvic Infections

In more than 90 percent of women, metritis responds to antimicrobial treatment within 48 to 72 hours. In some of the remainder, any of several complications may arise. These include wound infections, complex pelvic infections such as phlegmons or abscesses, and septic pelvic thrombophlebitis (Jaiyeoba, 2012). As with other aspects of puerperal infections, the incidence and severity of these complications are remarkably decreased by perioperative antimicrobial prophylaxis.

Wound infection is a common cause of persistent fever in women treated for metritis. Incisional infection risk factors include obesity, diabetes, corticosteroid therapy, immunosuppression, anemia, hypertension, and inadequate hemostasis with hematoma formation. If prophylactic antimicrobials are given, the incidence of abdominal wound infection following cesarean delivery ranges from 2 to 10 percent depending on risk factors (Andrews, 2003; Chaim, 2000). From our experiences at Parkland Hospital, the incidence is closer to 2 percent.

Incisional abscesses that develop following cesarean delivery usually cause persistent fever or fever that begins on about the fourth day. In many cases, antimicrobials had been given to treat pelvic infection, yet fever persisted. The wound is

FIGURE 37-1 Secondary abdominal wound closure technique. (Reproduced with permission from Worley KC: Postoperative complications. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds):

Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw Hill Education, 201o7.) erythematous and drains pus. Although organisms that cause wound infections are generally the same as those isolated from amnionic luid at cesarean delivery, hospital-acquired pathogens may also be causative (Owen, 1994).

Treatment includes antimicrobials and surgical drainage and debridement of devitalized tissue. his typically requires spinal analgesia or general anesthesia. The fascia is carefully inspected to document integrity. Local wound care thereafter is completed twice daily. Before each dressing change, procedural analgesia is tailored to wound size and location, and oral, intramuscular, or intravenous dosage routes are suitable. Topical lidocaine may also be added. Necrotic tissue is removed, and the wound is repacked with moist gauze. At 4 to 6 days, healthy granulation tissue is typically present, and secondary en bloc closure of the open layers can usually be accomplished (Wechter, 2005). As shown in Figure 37-1, a polypropylene or nylon suture of appropriate gauge enters 2 to 3 cm from one wound edge. It crosses the wound to incorporate the full wound thickness and emerges 3 cm from the other wound edge. hese are placed in series to close the opening. In most cases, sutures may be removed on postprocedural day 10.

his system was designed to apply negative pressure to a foamwound interface that would promote wound healing. The technique is variably referred to as vacuum-assisted closure-VAC; topical negative pressure-TNP; and negative-pressure wound therapy-NPWT. Several systems are available and widely (Echebiri, 2015; Rouse, 2015; Swift, 2015). In obstetrics, disrupted and infected abdominal wounds are a major indica tion for vacuum-assisted closure. Closure of perineal wounds resulting from infected episiotomies, hematomas, or abscesses is another (Aviki, 2015). hese devices are also used for the "open surgical abdomen," which is occasionally encountered in obstetrics. Negative-pressure wound therapy has also been used to prevent wound infections in those closed to heal by primary intention.

wound closure with conventional wound care (Semsarzadeh, 2015). Likewise, its cost efectiveness has not been thoroughly studied, although provider time is decreased substantially (Lewis, 2014). From their review, Moues and colleagues (201l) wounds because of scarce data. Other reviewers conclude that vacuum therapy is the most eicient method of temporary abdominal closure for patients with open abdominal wounds (Bruhin, 2014; Quyn, 2012).

Wound disruption or dehiscence refers to separation of the fascial layer. This is a serious complication and requires secondary closure of the incision in the operating room. McN eeley and associates (1998) reported a fascial dehiscence rate of approximately 1 per 300 operations in almost 9000 women undergoing cesarean delivery. Other than wound infection, obesity may be a risk factor (Subramaniam, 2014). Most disruptions manifested on about the fifth postoperative day and were accompanied by a serosanguinous discharge. Two thirds of 27 fascial dehiscences identified in this study were associated with concurrent fascial infection and tissue necrosis.

This uncommon, severe wound infection is associated with high mortality rates. In obstetrics, necrotizing fasciitis may involve abdominal incisions, or it may complicate episiotomy or other perineal lacerations. As the name implies, tissue necrosis is significant. Of the risk factors for fasciitis summarized by Owen and Andrews (1994), three of these-diabetes, obesity, and hypertension-are relatively common in gravidas. Like pelvic these wound complications usually are polymicrobial and are caused by organisms that make up the normal vaginal lora. In some cases, however, infection is caused by a single virulent bacterial species such as group A O-hemolytic streptococcus (Anderson, 2014; Rimawi, 2012). Occasionally, necrotizing infections are caused by rarely encountered pathogens (Chong, 2016; Swartz, 2004).

Goepfert and coworkers (1997) reviewed their experiences with necrotizing fasciitis. Nine cases complicated more than 5000 cesarean deliveries, a frequency of 1.8 per 1000. In two women, the infection was fatal. In another report, Schorge and colleagues (1998) described ive women with fasciitis following cesarean delivery. None of these women had predisposing risk factors, and none died.

FIGURE 37-2 Necrotizing fasciitis involving the abdominal wall and Pfannenstiel incision. The skin rapidly became dusky and gangrenous, and pus is seen exuding from the left angle of the incision. Extensive debridement and supportive therapy were lifesaving.

Infection may involve skin, supericial and deep subcu taneous tissues, and any of the abdominopelvic fascial layers (Fig. 37-2). In some cases, muscle is also involved-myoosciitis.

Although some virulent infections-for example, those caused tum, most of these necrotizing infections do not cause symp toms until 3 to 5 days after delivery. Clinical findings vary, and it is frequently diicult to diferentiate more innocuous superi cial wound infections from an ominous deep fascial one. A high index of suspicion, with surgical exploration if the diagnosis is uncertain, may be lifesaving (Goh, 2014). We aggressively pursue early exploration. Certainly, if myofasciitis progresses, the woman may become ill from septicemia (Chap. 47, p. 921).

Early diagnosis, surgical debridement, antimicrobials, and intensive care are paramount to successfully treat necrotizing soft-tissue infections (Gallup, 2002; Goh, 2014). Surgery includes extensive debridement of all infected tissue, leaving wide margins of healthy bleeding tissue. This may include extensive abdominal or vulvar debridement with unrooing and excision of abdominal, thigh, or buttock fascia. Death is virtually universal without surgical treatment, and rates approach 25 percent even if extensive debridement is performed. With extensive resection, synthetic mesh may ultimately be required later to close the fascial incision (Gallup, 2002; McNeeley, 1998).

An ovarian abscess rarely develops in the puerperium. These are presumably caused by bacterial invasion through a rent in the ovarian capsule (Wetchler, 1985). The abscess is usually unilateral, and women typically present 1 to 2 weeks after delivery. Rupture is common, and peritonitis may be severe.

Peritonitis is infrequent following cesarean delivery. It almost invariably is preceded by metritis, especially cases with uterine incisional necrosis and dehiscence. However, it may stem from a ruptured adnexal abscess or an inadvertent intraoperative bowel injury.

Peritonitis is rarely encountered ater vaginal delivery, and many such cases are due to virulent strains of group A 3-hemolytic streptococci or similar organisms. Importantly in postpartum women, abdominal rigidity may not be prominent with puerperal peritonitis because of physiological abdominal wall laxity from pregnancy. Pain may be severe, but frequently, the irst symptoms of peritonitis are those of adynamic ileus. Marked bowel distention may develop, which is unusual ater uncomplicated cesarean delivery. If the infection begins in an intact uterus and extends into the peritoneum, antimicrobial treatment alone usually sufices. Conversely, peritonitis caused by uterine incisional necrosis as discussed subsequently, or from bowel perforation, must be treated promptly with surgical intervention .

For some women in whom metritis develops following cesarean delivery, parametrial cellulitis is intensive and forms an area of induration-a phlemon-within the leaves of the broad ligament (Fig. 37-3). hese infections are considered when fever persists longer than 72 hours despite intravenous antimicrobial therapy (Brown, 1999; DePalma, 1982).

Phlegmons are usually unilateral, and they frequently are limited to the parametrium at the base of the broad ligament.

FIGURE 37-3 Left-sided parametrial phlegmon: cellulitis causes induration in the parametrium adjacent to the hysterotomy incision. (Reproduced with permission from Worley KC: Postoperative complications. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw Hill Education, 201o7.)

FIGURE 37-4 Pelvic computed tomography scan showing necrosis of the uterine incision with gas in the myometrium (arrows). There is also a large right-sided parametrial abscess (a).

If the inflammatory reaction is more intense, cellulitis extends along natural lines of cleavage. he most common form of extension is laterally along the broad ligament, with a tendency to extend to the pelvic sidewall. Occasionally, posterior extension may involve the rectovaginal septum, producing a firm mass posterior to the cervix. In most women with a phlegmon, clinical improvement follows continued treatment with a broad-spectrum antimicrobial regimen. Typically, fever resolves in 5 to 7 days, but in some cases, it persists longer. Absorption of the induration may require several days to weeks.

In some women, severe cellulitis of the uterine incision may ultimately lead to necrosis and separation (T reszezamsky, 201r1). Extrusion of purulent material as shown in Figure 37-4 causes intraabdominal abscess formation and peritonitis as described above. Surgery is reserved for women in whom uterine incisional necrosis is suspected because of ileus and peritonitis. For most, hysterectomy and surgical debridement are needed and are predictably diicult because the cervix and lower uterine segment are involved with an intense inflammatory process that extends to the pelvic sidewall. he adnexa are seldom involved, and one or both ovaries can usually be conserved. Blood loss is often appreciable, and transfusion is usually necessary.

Persistent puerperal infections can be evaluated using computed tomography (CT) or magnetic resonance (MR) imaging. Brown and associates (1991) used CT imaging in74 women in whom pelvic infection was refractory to antimicrobial therapy given for 5 days. hey found at least one abnormal radiological inding in 75 percent of these women, and in most, these were nonsurgical lesions. In most cases, imaging can be used to dissuade surgical exploration. Uterine incisional dehiscence such as shown in Figure 37-4 can sometimes be confirmed based on CT scanning images. hese indings must be interpreted within the clinical context because apparent uterine incisional defects thought to represent edema can be seen even after uncomplicated cesarean delivery (Twickier, 1991). Shown in 37-5 is a necrotic hysterotomy incision that leaked into the peritoneal cavity.

FIGURE 37-5 Necrotic hysterotomy infection. Severe cellulitis of the uterine incision resulted in dehiscence with subsequent leakage into the peritoneal cavity. Hysterectomy was required for sufficient debridement of necrotic tissue.

Occasionally, a parametrial phlegmon may suppurate, forming a fluctuant broad ligament mass that may point above the inguinal ligament. hese abscesses can dissect anteriorly as shown in Figure 37-4 and be amenable to CT-directed needle drainage. Occasionally they dissect posteriorly to the rectovaginal septum, where surgical drainage is easily efected by colpotomy. Apsoas abscess is rare, and despite antimicrobial therapy, percutaneous drainage may be required to efectively treat it (Shahabi, 2002; Swanson, 2008).

Suppurative thrombophlebitis was a frequent complication in the preantibiotic era, and septic embolization was common. However, with the advent of antimicrobial therapy, the mortality rate and need for surgical therapy for these infections diminished. Septic phlebitis arises as an extension along venous routes and may cause thrombosis as shown in Figure 37-6. Lymphangitis often coexists. he ovarian veins may then become involved because they drain the upper uterus and therefore the placental implantation site. The experiences of Witlin and Sibai (1995) and Brown and coworkers (1999) suggest that puerperal septic thrombophlebitis is likely to involve one or both ovarian venous plexuses. In a fourth of women, the clot extends into the inferior vena cava and occasionally to the renal vein.

The incidence of septic phlebitis has varied in several reports.

In a 5-year survey of 45,000 women who were delivered at Parkland Hospital, Brown and associates (1999) found an incidence of septic pelvic thrombophlebitis in 1 per 9000 gravidas following vaginal delivery and 1 per 800 after cesarean delivery. he overall incidence of 1 per 3000 deliveries was similar to the 1 per 2000 reported by Dunnihoo and colleagues (1991). In large studies of women with cesarean delivery, the incidence was 1 in 400 to 1 in 1000 surgeries (Dotters-Katz, 2017; Rouse 2004). Chorioamnionitis, endometritis, and wound complications were other risks.

Women with septic thrombophlebitis usually have symptomatic improvement with antimicrobial

Inferior vena cava treatment, however, they continue to have fever. Although pain occasionally is noted in one or both lower quadrants, patients are usually asymptomatic except for chills. As shown in

Common iliac vein Figure 37-7, the diagnosis can be con firmed by pelvic CT or MR imaging (Klima, 2008). Using either, Brown and colleagues (1r999) found that 20 percent of 69 women with metritis who had fever despite >5 days of appropriate antimicrobial therapy Internal iliac vein had septic pelvic thrombophlebitis.

It has been disproven that intravenous heparin causes fever to dissipate with septic phlebitis (Brown, 1986; Witlin, 1995). And although Garcia and coworkers (2006) and Klima and Snyder (2008) advocate heparin therapy, we do not recommend anticoagulation. In a randomized study of (1999), the addition of heparin to to any pelvic vessel as well as the inferior vena cava. The clot in the right common iliac vein extends from the uterine and internal iliac veins and into the inferior vena cava. The ovarian antimicrobial therapy for septic pelvein septic thrombosis extends halfway to the vena cava. vic thrombophlebitis did not hasten FIGURE 37-7 Septic ovarian vein thrombosis-contrast-enhanced computed tomography scan. A.Enlarged right ovarian vein filled with low-density thrombus (black arrow). Contrast is seen in ureter (white arrow). R = lower pole, right kidney. B. Coronal image demonstrates enlarged right ovarian vein filled with low-density thrombus (arrows). (Reproduced with permission from Worley KC: Postoperative complications. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds):

Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw Hill Education, 201o7.) recovery or improve outcome. Certainly, no evidence supports long-term anticoagulation.

Episiotomy infections are not common because the operation is performed much less frequently now than in the past (American College of Obstetricians and Gynecologists, 20 16a). Reasons for this are discussed further in Chapter 27 (p. 530). In an older study, Owen and Hauth (1990) described only 10 episiotomy infections in 20,000 women delivered vaginally.

With infection, however, dehiscence is a concern. Ramin and colleagues (1992) reported an episiotomy dehiscence rate of 0.5 percent at Parkland Hospital-80 percent of these were infected. Uygur and associates (2004) reported a I-percent dehiscence rate and attributed two thirds to infection. No data suggest that dehiscence is related to faulty repair.

When the anal sphincter is disrupted at delivery, the subsequent infection rate is higher and is likely influenced by intrapartum antimicrobial treatment (Buppasiri, 2014; Stock, 2013). Lewicky-Gaupp and colleagues (2015) reported a 20-percent infection rate. Infection of a fourth-degree laceration can be even more serious. Goldaber and coworkers (1993) described fourth-degree lacerations in 390 parturients, of whom 5.4 percent had morbidity. In these women, 2.8 percent had infection and dehiscence, 1.8 percent had only dehiscence, and 0.8 percent only infection. Although life-threatening septic shock is rare, it may still occur as a result of an infected episiotomy. Occasionally also, necrotizing fasciitis develops as discussed on page 671.

Episiotomy dehiscence is most commonly associated with infection. Other factors include coagulation disorders, smoking, and human papillomavirus infection (Ramin, 1994). Local pain and dysuria, with or without urinary retention, are frequent symptoms. Ramin and colleagues (1992), evaluating a series of 34 women with episiotomy dehiscence, reported that the most common indings were pain in 65 percent, purulent discharge in 65 percent, and fever in 44 percent. In extreme cases, the entire vulva may become edematous, ulcerated, and covered with exudate.

Vaginal lacerations may also become infected directly or by extension from the perineum. he epithelium becomes red and swollen and may then become necrotic and slough. Parametrial extension can lead to lymphangitis. Cervical lacerations are common but seldom are noticeably infected, which may manifest as metritis. Deep lacerations that extend directly into the base of the broad ligament may become infected and cause lymphangitis, parametritis, and bacteremia.

Treatment. Infected episiotomies are managed similar to other infected surgical wounds. Drainage is established, and in most cases, sutures are removed and the infected wound debrided. In women with obvious cellulitis but no purulence, close observation and broad-spectrum antimicrobial therapy alone may be appropriate. With dehiscence, local wound care is continued along with intravenous antimicrobials.

Early Repair of Infected Episiotomy. Hauth and colleagues (1986) were the irst to advocate early episiotomy repair after infection subsided, and other studies have confirmed the eicacy of this approach. Hankins and coworkers (1990) described early repair in 31 women with an average duration of 6 days from dehiscence to repair. All but two had a successful repair. Each of the two women with failures developed a pinpoint rectovaginal istula that was treated successfully with a small rectal lap. With episiotomy dehiscence due to infection, Ramin and coworkers (1992) reported successful early repair in 32 of

TABLE 37-3. Preoperative Protocol for Early Repair of Episiotomy Dehiscence

Open wound, remove sutures, begin intravenous or general anesthesia may be necessary for the first

Scrub wound twice daily with a povidone-iodine solution

Closure when afebrile and pink, healthy granulation tissue 34 women (94 percent), and Uygur and colleagues (2004) noted a similarly high percentage. Rarely, intestinal diversion may be required to allow healing (Rose, 2005).

Before performing early repair, diligent preparation is essential as outlined in Table 37-3. The surgical wound must be properly cleaned and cleared of infection. Once the surface of the episiotomy wound is free of infection and exudate and covered by pink granulation tissue, secondary repair can be accomplished. The tissue must be adequately mobilized, with special attention to identiy and mobilize the anal sphincter muscle. Secondary closure of the episiotomy is accomplished in layers, as described for primary episiotomy closure (Chap. 27, p. 531). Postoperative care includes local wound care, stool softeners, and nothing per vagina or recrum until healed.

This acute febrile illness with severe multisystem derangement has a case-fatality rate of 10 to 15 percent. Fever, headache, mental confusion, difuse macular erythematous rash, subcutaneous edema, nausea, vomiting, watery diarrhea, and marked hemoconcentration are usual findings. Renal failure followed by hepatic failure, disseminated intravascular coagulopathy, and circulatory collapse may follow in rapid sequence. During recovery, the rash-covered areas undergo desquamation. For some time, Staphylococcus aureus was recovered from almost all aHicted persons. Specifically, a staphylococcal exotoxin, termed toxic shock syndrome toxin-l (TSST-l), was found to cause the clinical manifestations by provoking profound endothelial injury. A very small amount ofTSST-1 has been shown to activate T cells to create a "cytokine storm" as described by Que (2005) and Heying (2007) and their coworkers.

During the 1990s, sporadic reports of virulent group A 3-hemolytic streptococcal infection began to appear (Anderson, 2014). Heavy colonization or infection is complicated in some cases by streptococcal toxic shock syndrome, which is produced when pyrogenic exotoxin is elaborated. Serotypes MI and M3 are particularly virulent (Beres, 2004; Okumura, 2004). Finally, almost identical indings of toxic shock were reported by Robbie and associates (2000) in women with Clos tridium sordellii colonization.

Thus, in some cases of toxic shock syndrome, infection is not apparent and colonization of a mucosal surface is the pre sumed source. At least 10 to 20 percent of pregnant women have vaginal colonization with S aureus. And Clostridium petingens and sordellii are cultured from 3 to 10 percent of asymptomatic women (Chong, 2016). Thus, it is not surprising that the disease develops in postpartum women when growth of vaginal bacteria is luxuriant (Chen, 2006; Guerinot, 1982).

Delayed diagnosis and treatment may be associated with maternal mortality (Schummer, 2002). Crum and colleagues shock syndrome. Principal therapy is supportive, while allow ing reversal of capillary endothelial injury. Ant�microbial ther apy that includes staphylococcal and streptococcal coverage is given. With evidence of pelvic infection, antimicrobial therapy must also include agents used for polymicrobial infections.

Women with these infections may require extensive wound debridement and possibly hysterectomy. Because the toxin is so potent, the mortality rate is correspondingly high (Hotch kiss, 2003).

Parenchymal infection of the mammary glands is a rare antepartum complication but is estimated to develop in up to a third of breast feeding women (Barbosa-Cesnik, 2003). Excluding breast engorgement, in our experiences, as well as that of Lee and associates (2010), the incidence of mastitis is much lower and probably approximates 3 percent. No evidence supports any of several prophylactic measures to prevent breast infection (Crepinsek, 2012). Risk factors include diiculties in nursing, cracked nipples, and oral antibiotic therapy (BranchElliman, 2012; Mediano, 2014). Symptoms of suppurative mastitis seldom appear before the end of the first week postpartum and, as a rule, not until the third or fourth week. Infection almost invariably is unilateral, and marked engorgement usually precedes inlammation. Symptoms include chills or actual rigors, which are soon followed by fever and tachycardia. Pain is severe, and the breast(s) becomes hard and red (Fig. 37-8). Approximately 10 percent of women with mastitis develop an abscess. Detection of fluctuation may be diicult, and sonography is usually diagnostic.

Staphylococcus au reus, especially MRSA, is the most commonly isolated organism in breast infections. Matheson and coworkers (1988) found it in 40 percent of women with mastitis. Other commonly isolated organisms are coagulase-negative staphylococci and viridans streptococci. The immediate source of organisms that cause mastitis is almost always the infant's nose and throat. Bacteria enter the breast through the nipple at fissures or small abrasions. he infecting organism can usually be cultured from milk. Toxic shock syndrome from mastitis caused by S aureus has been reported (Demey, 1989; Fujiwara, 2001).

FIGURE 37-8 Puerperal mastitis with breast abscess. A.Photograph shows indurated, erythematous skin overlying area of right breast infection. B. Sonographic picture of this 5-cm abscess. (Used with permission from Dr. Emily Adhikari.)

At times, suppurative mastitis reaches epidemic levels among nursing mothers. Such outbreaks most often coincide with the appearance of a new strain of antibiotic-resistant staphylococcus. A contemporaneous example is CA-MRSA, which has rapidly become the most commonly isolated staphylococcal species in some areas (Berens, 2010; Klevens, 2007). At Parkland Hospital from 2000 to 2004, Laibl and associates (2005) reported that a fourth of CA-MRSA isolates were from pregnant or postpartum women with puerperal mastitis. Hospital-acquired MRSA may cause mastitis when the newborn becomes colonized ater contact with nursery personnel who are colonized (Centers for Disease Control and Prevention, 2006). Staford and colleagues (2008) found a higher incidence of recurrent abscess in those with CA-MRSA-associated mastitis.

Provided that appropriate therapy for mastItiS is started before suppuration begins, the infection usually resolves within 48 hours. As discussed, abscess formation is more common with Saureus infection (Matheson, 1988). Most recommend that milk be expressed from the afected breast onto a swab and cultured before therapy is begun. Bacterial identification and antimicrobial sensitivities provide information mandatory for a successful program of nosocomial infection surveillance (Lee, 2010).

The most efective treatment has not been reported Oahanfar, 2013). hus, the initial antimicrobial choice is influenced by the current experience with staphylococcal infections at a given institution. Dicloxacillin, 500 mg orally four times daily, may be started empirically. Erythromycin is given to women who are penicillin sensitive. If the infection is caused by resistant, penicillinase-producing staphylococci or if resistant organisms are suspected while awaiting the culture results, then vancomycin, clindamycin, or trimethoprim-sulfamethoxazole is given (Sheield, 2013). Although clinical response may be prompt, treatment is recommended for 10 to 14 days.

Marshall and coworkers (1975) demonstrated the importance of continued breastfeeding. hey reported that of 65 women with mastitis, the only three who developed abscesses were among the 15 women who quit breastfeeding. Vigorous milk expression may be suicient treatment alone (homsen, 1984). Sometimes the infant will not nurse on the inlamed breast. his probably is not related to any changes in the milk taste but is secondary to engorgement and edema, which can make the areola harder to grip. Pumping can alleviate this. When nursing bilaterally, it is best to begin suckling on the uninvolved breast. This allows let-down to commence before moving to the tender breast.

In resource-poor countries, breastfeeding in women infected with the human immunodeficiency virus (HIV) is not contraindicated. In the setting of mastitis or breast abscess, it is recommended to stop feeding from the infected breast. his is because HIV RNA levels increase in afected breast milk. These levels return to baseline after symptoms resolve (Semrau, 2013).

In a population-based study of nearly 1.5 million Swedish women, the incidence of breast abscess was 0.1 percent (Kvist, 2005). An abscess should be suspected when defervescence does not follow within 48 to 72 hours of mastitis treatment or when a mass is palpable. Again, sonographic imaging is valuable. Breast abscesses can be large, and in one case report, 2 L of pus were released (Martic, 2012). Traditional therapy is surgical drainage, which usually requires general anesthesia. he incision ideally is placed along Langer skin lines for a cosmetic result (Stehman, 1990). In early cases, a single incision over the most dependent portion of luctuation is usually suicient. Multiple abscesses, however, require several incisions and disruption of loculations. The resulting cavity is loosely packed with gauze, which should be replaced at the end of 24 hours by a smaller pack.

A more recently used technique that is less invasive is sonographically guided needle aspiration using local analgesia. his has an 80-to 90-percent success rate (Geiss, 2014; Schwarz, 2001). In a randomized trial, Naeem and colleagues (2012) compared surgical drainage and aspiration. They found aspiration resulted in quicker healing at 8 weeks, 77 versus 93 percent, respectively.

Acosta CD, Bhattacharya S, Tufnell D, et al: Maternal sepsis: a Scottish population-based case-control study. BJOG 119(4):474,2012

American College of Obstetricians and Gynecologists: Prevention and management of obstetric lacerations at vaginal delivery. Practice Bulletin No. 165,

July 2016a . .

American College of Obstetricians and Gynecologists: Use of prophylaCtIc antibiotics in labor and delivery. Practice Bulletin No. 120, June 2011, Reafirmed 20n16b

Anderson BL: Puerperal group A streptococcal infection: beyond Semmelweis.

Obstet GynecoIn123(4):874, 2014

Anderson OJ, Sexton DJ, Kanafani ZA, et al: Severe surgical site infection in community hospitals: epidemiology, key procedures, and the changing prevalence of methicillin-resistant Staphylococcus aureus. Infect Control Hosp Epidemioln28 (9):1047,n2007

Andrews W, Hauth Jc, Cliver SP, et al: Randomized clinical trial of extended spectrum antibiotic prophylaxis with coverage for Ureapasma ureayticum to reduce post-cesarean delivery endometritis. Obstet Gynecol 101: 1183, 2003

Andrews W, Shah SR, Goldenberg L, et al: Association of post-cesarean delivery endometritis with colonization of the chorioamnion by Ureaplasma ureayticum. Obstet Gynecol 85:509, 1995

Anteby EY, Yagel S, Hanoch J, et al: Puerperal and intrapartum group A streptococcal infection. Infect Dis Obstet Gynecol 7:276, 1999

Atkinson MW, Owen J, Wren A, et al: he efect of manual removal of the placenta on post-cesarean endometritis. Obstet Gynecol :99, 1996 Aviki EM, Batalden RP, del Carmen MG, et al: Vacuum-assisted closure for episiotomy dehiscence. Obstet GynecoIn126(3):530, 20�5 ..n.

Baaqeel H, Baaqeel R: Timing of administration of prophylactic antibIOtics for caesarean section: a systematic review and meta-analysis. BJOG 120(6):661,2013 Bamigboye A, Hofmeyr GJ: Closure versus non-closure of the peritoneum at caesarean section. Cochrane Database Syst Rev 8:CDOOOI63, 2014 Barbosa-Cesnik C, Schwartz K, et al: Lactation mastitis. JAvlA 289: 1609, 2003

Berens P, Swaim L, Peterson B: Incidence of methicillin-resistant Staphylococcus aureus in postpartum breast abscesses. Breastfeed Med 5 (3): 113n201n?

Beres SB, Sylva GL, Sturdevant DE, et al: Genome-wide molecular disseCtIon of serorype M3 group A Streptococcus strains causing two epidemics of invasive infections. Proc Nat! Acad Sci USA 101:11833, 2004

Berg CJ, Harper vlA, Atkinson SM, et al: Preventability of pregnancy-related deaths: results of a state-wide review. Obstet Gynecol 106: 1228, 2005 Branch-Elliman W, Golen TH, Gold HS, et al: Risk factors for Staphylococcus aureus postpartum breast abscess. C1in Infect Dis 54(1):71, 2012

Brown CE, Dunn DH, Harrell R, et al: Computed tomography for evaluation of puerperal infection. Surg Gynecol Obstet 172:2, 1991

Brown CE, Lowe W, Cunningham FG, et al: Puerperal pelVIC thrombophlebitis: impact on diagnosiS and treatment using x-ray computed romography and magnetic resonance imaging. Obstet GynecoIn68:78?, 198�

Brown CE, Stettler RW, Twickler 0, et al: Puerperal septic pelVIC thrombophlebitis: incidence and response ro heparin therapy. Am J Obstet Gynecol 181:143,n1999

Brown KR, Williams SF, Apuzzio JJ: Ertapenem compared ro combination drug therapy for the treatment of postpartum endometritis after cesarean delivery. J Matern Fetal Neonatal Med 43,n2012

Bruhin A, Ferreira F, Chariker M, et al: Systematic review and evidence based recommendations for the use of negative pressure wound therapy in the open abdomen. Int J Surg 12(10) 1105, 2014

Brumield CG, Hauth JC, Andrews W: Puerperal infection after cesarean delivery: evaluation of a standardized protocol. Am ] Obstet Gynecol

Buppasiri P, Lumbiganon P, hinkhamrop J, et al: Antibiotic prophylaxis for third-and fourth-degree perineal tear during vaginal birth. Cochrane Data base Syst Rev 10:CD005125, 2014 .n. .

Burrows LJ, Meyn A, Weber M: Maternal morbidity assoCiated With vagll1al versus cesarean delivery. Obstet Gynecol 103:907, 2004

Cape A, Tuomala RE, Taylor C, et al: Peripartum bacteremia in the era of group B streptococcus prophylaxis. Obstet Gynecol 121(4):812,n2013

Carey Jc, Klebanof \1A, Hauth JC, et al: Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. N Engl J Med 342:534, 2000

Castagnola DE, Hofman MK, Carlson J, et al: Necrotizing cervical and uterine infection in the postpartum period caused by Group A Streptococcus. Obstet Gynecol 111 :533, 2008

Centers for Disease Control and Prevention: Community-associated methicillin-resistant Staphylococcus au reus infection among healthy newbornsChicago and Los Angeles County, 2004. MMWR 55(12):329,n2006

Chaim W, Bashiri A, Bar-David J, et al: Prevalence and clinical signiicance of postpartum endometritis and wound infection. Infect Dis Obstet Gynecol 8:77,n2000

Chaim W, Horowitz S, David JB, et al: Ureaplasma ureayticum in the development of postpartum endometritis. Eur J Obstet Reprod BioI 15: 145, 2003

Chelmow D, Rodriguez EJ, Sabatini MM: Suture closure of subcutaneous fat and wound disruption after cesarean delivery: a meta-analysis. Obstet Gynecol 103:974,n2004

Chelmow 0, Ruehli MS, Huang E: Prophylactic use of antibiotics for nonlaboring patients undergoing cesarean delivery with intact membranes: a meta-analysis. Amn] Obstet Gynecol 184:656,n2001

Chen KT, Huard RC, Della-Latta P, et al: Prevalence of methicillin-sensitive and methicillin-resistant Staphylococcus au reus in pregnant women. Obster Gynecol 108:482,n2006

Chong E, Winikof B, Charles 0, et al: Vaginal and rect�1 Clostrzdttm sordelltt and Clostridium peringens presence among women 11,the United States. Obstet GynecoIn127:360, 2016

Chongsomchai C, Lumbiganon P, Laopaiboon M: Prophylactic antibiotics for manual removal of retained placenta in vaginal birth. Cochrane Database Syst Rev 10:CD004904, 2014

Combs CA, Gravett M, Garite T, et al: Intramniotic inlammation may be more important than the presence of microbes as a determinant of perinatal outcome in preterm labor. Am J Obstet GynecoIn208(1):S44, 2013

Creanga A, Syverson C, Seed K, et al: Pregnancy-related mortality in the United States, 2011-2013. Obstet Gynecol 130:2:366,n2017

Crepinsek A, Crowe L, Michener K, et al: Interventions for preventing mastitis after childbirth. Cochrane Database Syst Rev 10:CD007239, 2012 Crum NF, Chun HM, Gaylord TG, et al: Group A streptococcal toxic shock syndrome developing in the third trimester of pregnancy. Infect Dis Obstet

Gynecol 10:209,n2002 . . .

Cunningham FG, Hauth Jc, Strong JD, et al: Infectious morbidity follow1l1g cesarean: comparison of two treatment regimens. Obstet Gynecol 52:656, 1978 Declercq E, Barger M, Cabral HJ, et al: Maternal outcomes asso�iated with planned primary cesarean births compared with planned vag1l1al bmhs. Obstet Gynecol 109:669,n2007

Demey HE, Hautekeete MI, Buytaert P, et al: Mastitis and toxic shock syndrome. A case report. Acta Obstet Gynecol Scand 68:87, 1989

Deneux-Tharaux C, Carmona E, Bouvier-Colle MH, et al: Postpartum maternal mortality and cesarean delivery. Obstet Gynecol 108:541,n2006

DePalma RT, Cunningham FG, Leveno KJ, et al: Continuing investigation of women at high risk for infection following cesarean delivery. Obstet Gynecol 60:53, 1982

Dinsmoor MJ, Gilbert S, Landon MB, et al: Perioperative antibiotic prophylaxis for nonlaboring cesarean delivery. Obstet Gynecol 52, 2009

DiZerega G, Yonekura L, Roy S, et al: A comparison of clindamycin-ge�tamicin and penicillin gentamicin in the treatment of post-cesarean section endomyometritis. Am J Obstet GynecoIn134:238, 1979

Dotters-Katz SK, Smid MC, Grace MR, et al: Risk factors for postpartum septic pelvic thrombophlebitis: a multicenter cohort. Am J Perinatol 34(11): 1148,n2017 .

Dunnihoo DR, GaliaspynJW, Wise RB, et al: Postpartum ovarian vein thrombophlebitis: a review. Obstet Gynecol Surv 46:415, 1991

Echebiri NC, McDoom MM, Aalto MM, et al: Prophylactic use of negative pressure wound therapy ater cesarean delivery. Obstet Gynecol 125 (2):299, 201n?

Filker RS, Monif GR: Postpartum septicemia due to group G streptococCi.

Obstet Gynecol 53:28S, 1979

French LM, Smaill FM: Antibiotic regimens for endometritis after delivery.

Cochrane Database Syst Rev 4:CD001067, 2004

Fujiwara Y, Endo S: A case of toxic shock syndrome secondary to mastltl � caused by methicillin-resistant Staphylococcus aureus. Kansenshogaku Zasshl 75:898,n2001

Gallup DG, Freedman \1A, Meguiar RV, et al: Necrotizing fasciitis in gynecologic and obstetric patients: a surgical emergency. Am J Obstet Gynecol 187(2)305,n2002

Garcia J, Aboujaoude R, Apuzzio J, et al: Septic pelvic thrombophlebitis: diagnosis and management. Infect Dis Obstet Gynecol 2006(15614): 1, 2006

Geiss CS, Golshan M, Flaherty K, et al: Clinical experience with aspiration of breast abscesses based on size and etiology at an academic medical center. J Clin Ultrasound 42(9):513,n2014

Gilstrap LC III, Cunningham FU: The bacterial pathogenesis of infection following cesarean section. Obstet Gynecol 53:545, 1979

Goepfert AR, Guinn DA, Andrews W, et al: Necrotizing fasciitis after cesarean section. Obstet Gynecol 89:409, 199

Goh T, Goh LG, Ang CH, et al: Early diagnosis of necrotizing fasciitis. Br J

Surg 101(1):el19, 2014 .n. .

Goldaber KG, Wendel PJ, Mcintire DO, et al: Postpartum penneal morbidity after fourth degree perineal repair. Am J Obstet Gynecol 168:489, 1993

Grobman WA, Bailit ]L, Rice MM, et al: Racial and ethnic disparities in maternal morbidity and obstetric care. Obstet GynecoIn125(6):1460, 2015 Guerinot GT, Gitomer SD, Sanko SR: Postpartum patient with toxic shock syndrome. Obstet Gynecol 59:43S, 1982

Haas DM, Morgan S, Contreras K: Vaginal preparation with antiseptic solution before cesarean section for preventing postoperative infections. Cochrane Database Syst Rev 12:CD007892, 2014

Hankins GD, Hauth ]C, Gilstrap LC, et al: Early repair of episiotomy dehiscence. Obstet Gynecol 75:48, 1990

Hartmann KE, Barrett E, Reid VC, et al: Clinical usefulness of white blood cell count after cesarean delivery. Obstet Gynecol 96:295, 2000

Hauth ]C, Gilstrap LC III, Ward SC, et al: Early repair of an external sphincter ani muscle and rectal mucosal dehiscence. Obstet Gynecol 67:806, 1986 Hauth ]C, Owen ], Davis RO: Transverse uterine incision closure: one versus two layers. Amn] Obstet GynecoIn167:n1108, 1992

Heying R, van de Gevel ], Que YA, et al: Fibronectin-binding proteins and clumping factor A in Staphylococcus aureus experimental endocarditis:

FnBPA is suicient to activate human endothelial cells. hromb Haemost 97:617,n2007

Hotchkiss RS, Karl IE: The pathophysiology and treatment of sepsis. N Engl ] Med 348:2, 2003

Ismail MA, Chandler AE, Beem ME: Chlamydial colonization of the cervix in pregnant adolescents.] Reprod Med 30:549, 1985 ]acobs-]okhan D, Hofmeyr G: Extra-abdominal versus intra-abdominal repair of the uterine incision at caesarean section. Cochrane Database Syst Rev 4:CD000085, 2004 ]acobsson B, Pernevi P, Chidekel L, et al: Bacterial vaginosis in early pregnancy may predispose for preterm birth and postpartum endometritis. Acta Obstet Gynecol Scand 81: 1006, 2002 ]ahanfar S, Ng q, Teng CL: Antibiotics for mastitis in breastfeeding women.

Cochrane Database Syst Rev 2:CD005458, 2013 ]aiyeoba 0: Postoperative infections in obstetrics and gynecology. Clin Obstet Gynecol 55(4):904, 2012

Kankuri E, Kurki T, Carlson P, et al: Incidence, treatment and outcome of peripartum sepsis. Acta Obstet Gynecol Scand 82:730, 2003

KlebanofnMA, Careyn]C, Hauth ]C, et al: Failure of metronidazole to prevent preterm delivery among pregnant women with asymptomatic Trichomonas vaginalis infection. N Engl] Med 345:487,n2001

Klevens M, Morrison MA, Nadle], et al: Invasive methicillin-resistant Staphylococcus aureus infections in the United States. ]AMA 298: 1763, 2007 Klima DA, Snyder TE: Postpartum ovarian vein thrombosis. Obstet Gynecol 111 :431, 2008

Koroukian SM: Relative risk of postpartum complications in the Ohio Medicaid population: vaginal versus cesarean delivery. Med Care Res Rev 61 :203, 2004

Kvist LJ, Rydhstroem H: Factors related to breast abscess after delivery: a population-based study. BJOG 112: 1070, 2005

Laibl VR, Sheield JS, Roberts S, et al: Clinical presentation of communityacquired methicillin-resistant Staphylococcus aureus in pregnancy. Obstet Gynecol 106:461,n2005

Lee IW, Kang L, Hsu HP, et al: Puerperal mastitis requiring hospitalization during a nine-year period. Am] Obstet Gynecol 203(4):332, 2010

Leth A, Uldbjerg N, Norgaard M, et al: Obesity, diabetes, and the risk of infections diagnosed in hospital and post-discharge infections ater cesarean section: a prospective cohort study. Acta Obstet Gynecol Scand 90(5):501, 2011

Lewis LS, Convery PA, Bolac CS, et al: Cost of care using prophylactic negative pressure wound vacuum on closed laparotomy incisions. Gynecologic Oncology 132(3):684,n2014

Liabsuetrakul T, Choobun T, Peeyananjarassri K, et al: Antibiotic prophylaxis for operative vaginal delivery. Cochrane Database Syst Rev 8:CD004455, 2017

Liabsuetrakul T, Peeyananjarassri K: Mechanical dilatation of the cervix at nonlabour caesarean section for reducing postoperative morbidity. Cochrane Database Syst Rev II :CD0080 19, 2011

Livingstonn]c, Llata E, Rinehart E, et al: Gentamicin and clindamycin therapy in postpartum endometritis: the eicacy of daily dosing versus dosing every 8 hours. Am] Obstet GynecoIn188:149, 2003

Lewicky-Gaupp C, Leader-Cramer A, Johnson LL, et al: Wound complications after obstetric anal sphincter injuries. Obstet Gynecol 125(5):1088,n2015

Maberry MC, Gilstrap LC ITI, Bawdon RE, et al: Anaerobic coverage for intraamnionic infection: matenal and perinatal impact. Am J Perinatol 8:338, 1991

Mackeen AD, Berghella V, Larsen ML: Techniques and materials for skin closure in caesarean section. Cochrane Database Syst Rev II :CD00357 ,n2012 Mackeen AD, Packard RE, Ota E, et al: Antibiotic regimens for postpartum endometritis. Cochrane Database Syst Rev 2:CDOO1067, 2015

Macones GA, Cleary L, Parry S, et al: The timing of antibiotics at cesarean: a randomized controlled trial. Am J PerinatoI29(4):273, 2012

Maharaj D: Puerperal pyrexia: a review. Part II: Obstet Gynecol Surv 62:400, 2007

Marchocki Z, O'Donoghue M, Collins K, et al: Clinical signiicance of elevated high-sensitivity C-reactive protein in amniotic fluid obtained at emergency caesarean section. Am] Obstet Gynecol 208(1)S314, 2013

Marshall BR, Hepper ]K, Zirbel CC: Sporadic puerperal mastitis-an infection that need not interrupt lactation. ]AMA 344: 13 77, 1975

Martic K, Vasilj 0: Extremely large breast abscess in a breastfeeding mother. ] Hum Lact 28(4):460,n2012

Matheson I, Aursnes I, Horgen M, et al: Bacteriological indings and clinical symptoms in relation to clinical outcome in puerperal mastitis. Acta Obstet Gynecol Scand 67:723, 1988

McNeeley SG ]r, Hendrix SL, Bennett SM, et al: Synthetic graft placement in the treatment of fascial dehiscence with necrosis and infection. Amn] Obstet Gynecol 179: 1430, 1998

Meaney-Delman D, Bartlett A, Gravett MG, et al: Oral and intramuscular treatment options for early postpartum endometritis in low-resource settings: a systematic review. Obstet GynecoIn125(4):789, 2015

Mediano P, Fernandez L, Rodriguez JM, et al: Case-control study of risk factors for infectious mastitis in Spanish breastfeeding women. BMC Pregnancy Childbirth 14: 195, 2014

Moues CM, Heule F, Hovius SE: A review of topical negative pressure therapy in wound healing: suicient evidence? Am] Surg 201(4):544,2011

Naeem M, Rahimnajjad MK, Rahimnajjad NA, et al: Comparison of incision and drainage against needle aspiration for the treatment of breast abscess. Am Surg 78(11):1224,n2012

Nathan L, Leveno K]: Group A streptococcal puerperal sepsis: historical review and 1990s resurgence. Infect Dis Obstet Gynecol 1 :252, 1994

O'Higgins AC, Egan AF, Murphy Oc, et al: A clinical review of maternal bacteremia. Int Gynaecol Obstet 124(3):226,n2014

Okumura K, Schrof R, Campbell R, et al: Group A streptococcal puerperal sepsis with retroperitoneal involvement developing in a late postpartum woman: case report. Am Surg 70:730, 2004

Owen ], Andrews W: X'ound complications after cesarean section. Clin Obstet Gynecol 27:842, 1994

Owen J, Hauth JC: Episiotomy infection and dehiscence. In Gilstrap LC III, Faro S (eds): Infections in Pregnancy. New York, Liss, 1990, p 61

Patel M, Kumar A, Stamm AM, et al: USA300 genotype community-associated methicillin-resistant Staphylococcus aureus as a cause of surgical site infection.n] Clin Microbioln45 (10):3431,n2007

Que YA, HaeAiger ]A, Piroth L, et al: Fibrinogen and ibronectin binding cooperative for valve infection and invasion in Staphylococcus aureus experimental endocarditis.n] Exp Med 201:1627,n2005

Quyn A], Johnston C, Hall D, et al: he open abdomen and temporary abdominal closure systems-historical evolution and systematic review. Colorectal Dis 14(8):e429, 2012

Ramin SM, Gilstrap LC: Episiotomy and early repair of dehiscence. Clin Obstet Gynecol 37:816, 1994

Ramin SM, Ramus R, Little B, et al: Early repair of episiotomy dehiscence associated with infection. Am J Obstet Gynecol 167: 11 04, 1992

Reid VC, Hartmann E, McMahon M, et al: Vaginal preparation with povidone iodine and postcesarean infectious morbidity: a randomized controlled trial. Obstet GynecoIn97:147, 2011

Rimawi BH, Soper DE, Eschenbach DA: Group A streptococcal infections in obstetrics and gynecology. Clin Obstet Gynecol 55(4):864,2012

Robbie A, Dummer S, Booth NA, et al: Plasminogen activator inhibitor 2 and urokinase-type plasminogen activator in plasma and leucocytes in patients with severe sepsis. Br] Haematol 109:342, 2000

Rose CH, Blessitt L, Araghizadeh F: Episiotomy dehiscence that required intestinal diversion. Am J Obstet Gynecol 193: 1759, 2005

Rotas M, McCalla S, Liu C, et al: Methicillin-resistant Staphylococcus aureus necrotizing pneumonia arising from an infected episiotomy site. Obstet Gynecol 109:533, 2007

Rouse D]: Prophylactic negative pressure wound therapy. Obstet Gynecol 125:297,n2015

Rouse DJ, Landon M, Leveno KJ, et al: The Maternal-Fetal Medicine Units cesarean registry: chorioamnionitis at term and its duration-relationship to outcomes. m] Obstet Gynecol 191 :211, 2004

Schorge JO, Granter SR, Lerner LH, et al: Postpartum and vulvar necrotizing fasciitis: early clinical diagnosis and histopathologic correlation. ] Reprod Med 43:586, 1998

Schummer W, Schummer C: Two cases of delayed diagnosis of postpartal streptococcal toxic shock syndrome. Infect Dis Obstet Gynecoln10:217, 2002 Schwarz RJ, Shrestha R: Needle aspiration of breast abscesses. Am J Surg 182:117,n2001

Semrau K, Kuhn L, Brooks DR, et al: Dynamics of breast milk HIV-1 RNA with unilateral mastitis or abscess.n] Acquir Immune Defic Syndr 62(3):348,n2013

Semsarzadeh NN, Tadisina KK, Maddox ], et al: Closed incision negativepressure therapy is associated with decreased surgical-site infections: a metaanalysis. Plast Reconstr Surg 136(3):592, 2015

Shahabi S, Klein ]P, Rinaudo PF: Primary psoas abscess complicating a normal vaginal delivery. Obstet Gynecol 99:906, 2002

Sheield ]S: Methicillin-resistant Staphylococcus aureus in obstetrics. Amn] Perinato I 30(2):125, 2013

Sherman 0, Lurie S, Betzer M, et al: Uterine flora at cesarean and its relationship to postpartum endometritis. Obstet Gynecol 94:787, 1999

Siriwachirachai T, Sangkomkamhang US, Lumbiganon P, et al: Antibiotics for meconium-stained amniotic fluid in labour for preventing matenal and neonatal infections. Cochrane Database Syst Rev 11:CD007772, 2014

Smaill FM, Grivell M: Antibiotic prophylaxis versus no prophylaxis for preventing infection after cesarean section. Cochrane Database Syst Rev 10:CD007482,n2014

Staford I, Hernandezn], Laibl V, et al: Community-acquired methicillin-resistant Staphylococcus aureus among patients with puerperal mastitis requiring hospitalization. Obstet GynecoIn112(3):533, 2008

Stehman FB: Infections and inflammations of the breast. In Hindle WH (ed):

Breast Disease for Gynecologists. Norwalk, Appleton & Lange, 1990, p 151

Stock L, Basham E, Gossett DR, et al: Factors associated with wound complications in women with obstetric and sphincter injuries (OASIS). Am ] Obstet Gynecol 208(4):327.e1, 2013

Subramaniam A, ]auk VC, Figueroa 0, et al: Risk factors for wound disruption following cesarean delivery.] Matern Fetal Neonatal Med 27(12): 1237,2014

Sun], Ding M, Liu], et al: Prophylactic administration of cefazolin prior to skin incision versus antibiotics at cord clamping in preventing postcesarean infectious morbidity: a systematic review and meta-analysis of randomized controlled trials. Gynecol Obstet Invest 75(3):175, 2013

Sutton AL, Acosta EP, Larson KB, et al: Perinatal pharmacokinetics of azithromycin for cesarean prophylaxis. Amn] Obstet GynecoIn212(6):812.el, 2015

Swank ML, Wing DA, Nicolau DP, et al: Increased 3-gram cefazolin dosing for cesarean delivety prophylaxis in obese women. Am ] Obstet Gynecol 213(3):415.e1,2015

Swanson A, Lau KK, Kornman T, et al: Primary psoas muscle abscess in pregnancy. Aust N Z] Obstet Gynaecol 48(6):607, 2008

Swartz MN: Cellulitis. N Engln] Med 350:904, 2004

Swift SH, Zimmerman MB, Hardy-Fairbanks A]: Efect of Single-use negative pressure wound therapy on postcesarean infections and wound complications for high-risk patients.] Reprod Med 60(5-6):211,n2015

Pue.peral Complications 679

Tita AT, Szychowski ]M, Boggess K, et al: Adjunctive azithromycin prophylaxis for cesarean delivery. N Engl] Med 375(13):1231,n2016

Thomsen AC, Espersen T, Maigaard S: Course and treatment of milk stasis, noninfectious inflammation of the breast, and infectious mastitis in nursing women. Am] Obstet GynecoIn149:492, 1984

Treszezamsky AD, Feldman 0, Sarabanchong VO: Concurrent postpartum uterine and abdominal wall dehiscence and Streptococcus anginosus infection. Obstet GynecoIn118(2):449, 2011

Tsai PS, Hsu CS, Fan YC: General anaesthesia is associated with increased risk of surgical site infection after cesarean delivery compared with neuraxial anaesthesia: a population-based study. Br] Anaesth 107(5):757,2011

Tulandi T, Al-]aroudi 0: Nonclosure of peritoneum: a reappraisal. Am ] Obstet Gynecol 189:609,n2003

Tuuli MG, Liu], Stout M], et al: A randomized trial comparing skin antiseptic agents at cesarean delivery. N Engl] Med 4(7):647-55,n2016

Tuuli MG, Rampersad \1, Carbone ]F, et al: Staples compared with subcuticular suture for skin closure after cesarean delivety: a systematic review and meta-analysis. Obstet Gynecol 117(3):682,n2011

Twickler OM, Setiawan AT, Harrell RS, et al: CT appearance of the pelvis after cesarean section. A]R Am ] Roentgenol 156:523, 1991

Udagawa H, Oshio Y, Shimizu Y: Serious group A streptococcal infection around delivery. Obstet Gynecol 94: 153, 1999

Uygur 0, Yesildaglar N, Kis S, et al: Early repair of episiotomy dehiscence.

Aust N Z] Obstet Gynaecol 44:244, 2004

Ward E, Duf P: A comparison of 3 antibiotic regimens for prevention of postcesarean endometritis: an historical cohort study. Amn] Obstet Gynecol 214(6):751.e1,n2016

Watts DH, Krohn A, Hillier SL, et al: Bacterial vaginosis as a risk factor for post-cesarean endometritis. Obstet Gynecol 75:52, 1990

Wechter ME, Pearlman MD, Hartmann KE: Reclosure of the disrupted laparotomy wound. A systematic review. Obstet Gynecol 106:376,n2005 Wetchler S], Dunn L]: Ovarian abscess. Report of a case and a review of the literature. Obstet Gynecol Surv 40:476, 1985

Widin AG, Sibai BM: Postpartum ovarian vein thrombosis ater vaginal delivery: a report of 11 cases. Obstet Gynecol 85:775, 1995

Worley KC: Postoperative complications. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hill Education, 2017

Yildirim G, Gungorduk K, Asicioglu 0, et al: Does vaginal preparation with povidone-iodine prior to cesarean delivery reduce the risk of endometritis? A randomized controlled trial. ] Maten Fetal Neonatal Med 25(11):2316, 2012

INTRAUTERINE DEVICES ..n........................ 681

PROGESTIN IMPLANTS .n..............n............. 685

PROGESTIN-ONLY CONTRACEPTIVES .............n. 689

HORMONAL CONTRACEPTIVES.. . . . . . . . . . . . . . . . . . . 689

BARRIER METHODS ............................. 693

FERTILITY AWARENESS-BASED METHODS .......... 695

SPERMICIDES ....n........n...........n.........n....... 695

EMERGENCY CONTRACEPTION . . . . . . . . . . . . . . . . . . . 696

PUERPERAL CONTRACEPTION.. . . . . . . . . . . . . . . . . . . . 697

From the evidence available, it appears to be toleraby satiactoriy demonstrated that in women who copulate at requent intervals the tube must be regarded as a species of receptaculum seminis, in which spermatozoa are always present and waiting or the ovum, and that ertilization usualy occurs in the tubes and ony rarey in the uterus.

-J. Whitridge Williams (1903)

Nearly half of all pregnancies each year in the United States are unintended (Finer, 2016). hese may follow contraceptive method failure or stem from lack of contraceptive use. In 2011 to 2013, 7 percent of sexually active fertile women in the United States not pursuing pregnancy did not use any birth control method (Daniels, 2015).

TABLE 38-1. Contraceptive Failure Rates During the First Year of Method Use in Women in the United States

Top Tier: Most Effective

Intrauterine devices:

Levonorgestrel system 0.2 0.2

T 380A copper 0.6 0.8

Levonorgestrel implants 0.05 0.05

Female sterilization 0.5 0.5

Male sterilization 0.1 0.1n5

Second Tier: Very Effective

DMPA 0.2 6

Third Tier: Effective

Diaphragm with spermicides 6 12 Fertility-awareness 24

Sym ptotherma I 0.4

Fourth Tier: Least Effective

For those seeking contraception, efective contraceptive No contraception methods are available and variably selected (Table 38-1). With aMethods organized according to tiers of efficacy.

these methods, estimated failure rates of perfect and typical use during the irst year difer widely. To reflect these failure

WHO = World Health Organization.

rates, the World Health Organization (WHO) has grouped

Data from Trussell, 201n1 a.

methods into eicacy tiers (see Table 38-1). Implants and intrauterine devices are found in the top tier. They efectively lower unintended pregnancy rates and are considered long-act ing reversible contraception (ARC). he American College tiers, recommends counseling on al options, and encourages highly efective LARC for appropriate candidates.

No contraceptive method is completely without side efects, but contraception usually poses less risk than pregnancy.

However, some disorders or medications can raise the risks from certain contraceptives. The World Health Organization (2015) has provided and updated evidence-based guidelines, termed Medical Eigibiliy Criteria, for the use of all highly efective reversible contraceptive methods by women with vari ous health conditions. Individual countries have subsequently modiied these guidelines. The United States Medical Eligibiliy

Criteria (US MEC) was updated in 2016 by the Centers for

Disease Control and Prevention (Curtis, 2016b). These docu ments are available at: http://ww.cdc.govlreproductivehealth/

U nin tendedPregnancy/ Contraception_ Guidance.h tm.

In the United States MEC, reversible contraceptive methods are organized into six groups by their similarity: combination hormonal contraceptives (CHCs), progestin-only pills (POPs), depot medroxyprogesterone acetate (DMPA), implants, levonorgestrel-releasing intrauterine system (LNGIUS), and copper intrauterine devices (Cu-IUDs). For a given health condition, each method is categorized 1 through 4 (Table 38-2). he score describes the safety proile for a typical woman with that condition: (1) no restriction of method use, (2) method advantages outweigh risks, (3) method risks outweigh advantages, and (4) method poses an unacceptably high health risk.

lternatively, depending on the underlying disorder or patient desire, male or female sterilization may be a preferred or recommended permanent contraceptive method (American College of Obstetricians and Gynecologists, 20 17b). hese options are fully discussed in Chapter 39.

Globally, 14 percent of reproductive-aged women use intrauterine contraception, and in the United States, 10 percent of contracepting women use this method (Buhling, 2014; Daniels, 2015). he five intrauterine devices (IUDs) currently approved for use in the United States are chemicaly active and continually elute either copper or levonorgestrel. These all have arT-shaped frame of polyethylene that is compounded with barium to render them radiopaque. Of devices, Mirena and Liletta both measure 32 X 32 mm and contain a 52-mg levonorgestrel-releasing cylinder reservoir in the stem of the T (Fig. 38-1). Two trailing strings that are tan (Mirena) or blue (Liletta) are attached to the distal stem to aid eventual device removal. Skyla-known asJaydess in some countries-contains 13.5 mg of levonorgestrel. It has smaller dimensions-28 X 30 mm-and was sized to more appropriately it a nulliparous uterus (Gemzell-Danielsson, 2012). yleena has the same dimensions but contains 19.5 mg of the same progestin. Two trailing strings of Skyla are tan, and those of yleena are blue. Skyla and yleena can be diferentiated from Mirena and

Liletta visually and sonographically by a silver ring near the junction of their stem and arms. Mirena and yleena are cur rently approved for 5 years of use following insertion, whereas

Skyla and Liletta are approved for 3 years.

he third device, the T380A IUD named ParaGar, is wound with copper, and two strings extend from the stem base. Originally blue, the strings are now white. It is currently approved for 10 years of use following insertion (T eva Wom en's Health, 2014).

In addition to these ive currently marketed IUDs, women may retain discontinued brands. A Lippes Loop has two "S" shapes stacked one on the other. he Dalkon Shield has a crab form, whereas a Copper 1 mirrors that number. Progestasert is an early T -shaped progestin-releasing IUD. Last, various metaleluting ring devices are common in Asia.

All these IUDs are efective. Failure rates are well below 1 percent and similar overall to those of tubal sterilization (Thonneau, 2008; Trussell, 2011 b). heir mechanisms have not been precisely deined, but prevention of fertilization is now favored.

With the LNG-IUS, long-term progestin release leads to endometrial atrophy, which hinders normal implantation (Silverberg, 1986). Moreover, progestins create scant viscous cervical mucus that obstructs sperm motility (Apter, 2014; Moraes, 2016). Within the uterus, an intense local endometrial inlammatory response is induced, especially by coppercontaining devices. Cellular and humoral components of this inlammation are expressed in endometrial tissue and in luid illing the uterine cavity and fallopian tubes. These lead to decreased sperm and egg viability (Ortiz, 2007). Also, in the unlikely event that fertilization does occur, the same inlammatory actions are directed against the blastocyst. Also, with the Cu-IUD speciically, copper levels rise in the cervical mucus of users and act to decrease sperm motility and viability (Jecht, 1973). he above efects are considered primary for contraception because ovulation inhibition is inconsistent with the LNG-IUS and lacking with the Cu-IUD (Nilsson, 1984).

FIGURE 38-1 Intrauterine devices (IUDs). A.ParaGard T 380A copper IUD. B. Mirena levonorgestrel-releasing intrauterine system. (Reproduced with permission from Stuart GS: Contraception and sterilization. In Hoffman BL, Schorge JO, Bradshaw KD, et al: Williams Gynecology, 3rd ed. New York, McGraw-Hili Education, 201o6.)

TABLE 38-2. Contraindications and Cautions with Specific Contraceptive Methods

In this table, a blank space indicates the method is category 1 or 2

Smoking & age ::35 yr 3/4c

Active breast cancer 4 4 4 4 4 Breast disease free ::5 yr 3 3 3 3

Systolic BP ::160 or diastolic BP ::100 4 3

Surgery with long immobilization 4

MS with immobilization 3

DM with end-organ disease 3/4d 3

Cirrhosis (severe, decompensated) 4 3 3 3 3 Liver tumors9 4 3 3 3 3 iStartlContinue (S/C).

Current r history of ISHD 4 2/3 3 2/3 2/3 Stroke 4 2/3 3 2/3

Migraine with aura 4 2/3 2/3 2/3 2/3 Unexplained vaginal bleedingl 3 3 4/2 4/2 aCombination hormone contraception (CHC) group includes pills, vaginal ring, and patch.

bAssociated risks that increase category score include: age :35, transfusion at delivery, BMI :30, postpartum hemorrhage, cesarean delivery, smoking, preeclampsia.

(Smoking : 15 cigarettes/day increases risk category to 4 in this age group.

dRisk category score is modified by associated risk factors and disease severity.

elncluding superficial thrombosis. fOral agents only. Ring and patch are category 1.

gBenign hepatic adenoma or hepatocellular cancer. Focal nodular hyperplasia compatible with hormone use.

hThese include phenytoin, barbiturates, carbamazepine, oxcarbazepine, primidone, topiramate.

lin those methods under Start/Continue columns, the first US MEC number refers to whether a method may be initiated in an afected patient. For patients who initially develop the condition while using a specific method, the second number refers to risks for continuing that method.

JPrior to evaluation.

kThose on chronic corticosteroids and at risk for bone fracture.

= antiretroviral; BP = blood pressure; BMI = body mass index; CHTN = chronic hypertension; Cu-IUD = copper intrauterine device; DM = diabetes mellitus; DMPA = depot medroxyprogesterone acetate; GC/CT = gonorrhea/chlamydial infection; GTD = gestational trophoblastic disease; ISHD = ischemic heart disease; LNG-IUS = levonorgestrel-releasing intrauterine system; MS = multiple sclerosis; PI = protease inhibitor; PID = pelvic inflammatory disease; POP = progestin-only pills; SLE = system lupus erythematosus; VTE = venous thromboembolism. Compiled from Curtis, 2016b; Merck, 2015; Teva Women's Health, 2014.

Contraindications to IUD use are few and shown in Table 38-2. In the past, IUDs were perceived to increase the risk of ectopic pregnancy, but this has since been clariied. Speciically, IUDs provide efective contraception and lower the absolute number of ectopic pregnancies by half compared with the rate in noncontracepting women (World Health Organization, 1985, 1987). But, the IUD mechanisms of action are more efective in preventing intrauterine implantation. hus, if an IUD fails, a higher proportion of pregnancies are likely to be ectopic (Backman, 2004; Furlong, 2002).

Expulsion of an IUD from the uterus is most common during the first month. hus, women are examined approximately 1 month following IUD insertion, usually after menses, to identiy the tails trailing from the cervix. Following this, a woman is instructed to palpate the strings each month after menses. Regardless of IUD type, the cumulative 3-year expulsion rate approximates 10 percent (Madden, 2014; Simonatto, 2016). This rate is higher in those :;25 years Qatlaoui, 2017).

If the tail of an IUD cannot be visualized, the device may have been expelled, may have perforated the uterus, or may be malpositioned. Alternatively, the device may be normally positioned with its tails folded within the endocervical canal or uterine cavi ty. To investigate, after excluding pregnancy, a cytological brush can be twirled within the endocervical canal to entangle the strings and bring them gently into the vagina. If unsuccessful, the uterine cavity is probed gently with a Randall stone clamp or with a specialized rod with a terminal hook to snare the strings or device.

One should not assume that a device has been expelled unless it was seen. Thus, if tails are not visible and the device is not felt by gentle probing of the uterine cavity, transvaginal sonography can be used to ascertain if the device lies within the uterus. lthough traditional sonography will document IUD position adequately in most cases, three-dimensional sonography ofers improved visualization, especially with the LNG-IUS (Moschos, 201l). If sonography is inconclusive or if no device is seen, then a plain radiograph of the abdominopelvis is taken. Computed tomography (CT) scanning or, less commonly, magnetic resonance (MR) imaging is an alternative (Boortz, 2012). It is safe to perform MR imaging at 1.5 and 3 Tesla (T) with an IUD in place (Ciet, 2015).

During uterine sounding or IUD insertion, the uterus may be perforated, which is identiied by the tool traveling farther than the expected uterine length based on initial bimanual examination. Rates approximate 1 per 1000 insertions, and risks include puerperal insertion, lactation, provider inexperience, and extremes of uterine lexion (Harrison-Woolrych, 2003; Heinemann, 2015). Although devices may migrate spontaneously into and through the uterine wall, most perforations occur, or at least begin, at the time of insertion (Ferguson, 2016).

With acute perforation, the fundus is the more common site, and bleeding is typically minimal due to myometrial contraction around the puncture hole. If no brisk or persistent bleeding is noted from the os following instrument or device removal, then patient observation alone is reasonable. Rarely, acute lateral perforations may lacerate the uterine artery, and subsequent brisk bleeding may prompt laparoscopy or laparotomy for control. Following any perforation, although this is not irmly evidence-based, a single dose of broad-spectrum antibiotic may mitigate infection.

With chronic perforation, a device can penetrate the muscular uterine wall to varying degrees. A patient may be asymptomatic but abdominal pain, uterine bleeding, or missing strings can be clues (Kaislasuo, 2013). hose with a predominantly intrauterine location are usually managed by hysteroscopic IUD removal. In contrast, devices that have nearly or completely perforated through the uterine wall are more easily removed laparoscopically. Notably, an extrauterine Cu-IUD frequently induces an intense local inlammatory reaction and adhesions (Kho, 2014). Laparotomy may be necessary, and bowel preparation is considered. Sigmoid and bladder perforations and small-bowel obstruction have been reported remote from insertion (Sano, 2017; Xu, 2015; Zeino, 2011).

Dysmenorrhea and bleeding irregularities can complicate IUD use (Aoun, 2014; Grunloh, 2013). These can be treated with some degree of success by nonsteroidal antiinlammatory drugs (NSAIDs) or tranexamic acid, which is an antiibrinolytic (Godfrey, 2013; Madden, 2012; S0rdal, 2013). Of the two IUDs, heavy bleeding more often complicates Cu-IUD use and may cause iron-deiciency anemia, for which oral iron salts are given. With the LNG-IUS, irregular spotting for up to 6 months after placement often gives way to progressive amenorrhea, which is reported by 30 percent of women after 2 years and by 60 percent after 12 years (Ronnerdag, 1999). his is frequently associated with improved dysmenorrhea.

he risk of upper genital tract device-related infection is greatest during the irst months following IUD insertion (Farley, 1992; Turok, 2016). Pathogens include Neisseria gonorrhoeae, Chlamydia trachomatis, and vaginal lora. Women at risk for sexually transmitted diseases (STDs) should be screened either before or at the time of IUD insertion (Centers for Disease Control and Prevention, 2015; Sufrin, 2012). That said, device insertion need not be delayed while awaiting sexually transmitted disease or Pap test results in asymptomatic women (Birgisson, 2015). If these bacteria are subsequently found and the patient is without symptoms, then the IUD may remain and treatment prescribed as detailed in Chapter 65 (p. 1240). Importantly, routine antimicrobial prophylaxis before insertion is not recommended (Grimes, 2012; Walsh, 1998). And the American Heart Association does not recommend bacterial endocarditis prophylaxis with insertion (Nishimura, 2014).

Mter the irst month, infection risk is not increased in IUD users who would otherwise be at low risk of sexually transmitted infections. Correspondingly, IUDs appear to cause little, if any, increase in infertility rates in these low-risk patients (H ubacher, 2001). The American College of 0bstetricians and Gynecologists (20 15c, 2016a) recommends that women at low risk for STDs, including adolescents, be considered good candidates for IUDs. he IUD is also safe and efective in women infected with human immunodeiciency virus (HIV) and may be used in others who are immunosuppressed (Centers for Disease Control and Prevention, 2015; Tepper, 2016a).

If infection does develop, it may take several forms and typically requires broad-spectrum antimicrobials. Pelvic inlammatoy disease (PID) without abscess is treated with antibiotics on an outpatient or inpatient basis, depending on infection severity. here are theoretical concerns that a coexistent IUD may worsen the infection or delay resolution. A provider may choose to remove an IUD in this setting, although some evidence supports allowing a device to remain during treatment in those hospitalized with mild or moderate PID (Centers for Disease Control and Prevention, 2015; Tepper, 2013). Ifinfection fails to improve during 48 to 72 hours of treatment, the device is removed. Tuboovarian abscess can complicate PID and is treated aggressively with intravenous broad-spectrum antibiotics and IUD removal. Last, septic abortion mandates immediate uterine evacuation and antibiotics.

Actinomyces israelii is a gram-positive, slow-growing, anaerobic indigenous vaginal bacterium that rarely causes suppurative infection. Some have found it more frequently in the vaginal lora or on the Pap smears of IUD users (Curtis, 1981; Kim, 2014). Current recommendations advise that an asymptomatic woman may retain her IUD and does not require antibiotic treatment (American College of Obstetricians and Gynecologists, 2017c; Lippes, 1999; Westhof, 2007a). However, if signs or symptoms of infection develop in a woman who harbors Actinomyces species, then the device is removed and antibiotics are given. Early indings with infection include fever, weight loss, abdominal pain, and abnormal uterine bleeding or discharge. Actinomyces species are sensitive to antibiotics with gram-positive coverage, notably the penicillins.

Pregnancy with an IUD

For women who conceive while using an IUD, ectopic pregnancy should be excluded. With intrauterine pregnancy, if the tail is seen, it should be grasped and the IUD removed by gentle outward traction. his action reduces complications such as abortion, chorioamnionitis, and preterm birth (Fulkerson Schaefer, 2017; Kim, 2010). Speciically, in one cohort, a 54-percent abortion rate and 17 -percent preterm delivery rate was noted if the device remained in situ. More favorably, rates of 25 percent and 4 percent, respectively, resulted from prompt Cu-IUD removal (Tatum, 1976). Few data guide management with the LNG-IUS, and most practice extrapolates from copper devices.

If the tail is not visible, attempts to locate and remove the device may result in abortion. Although not our practice, some case reports and small series describe sonography or hysteroscopy to assist in diicult device removals (Perez-Medina, 2014; Schiesser, 2004). Ater fetal viability is reached, it is unclear whether it is better to remove an IUD whose strings are visible and accessible or to leave it in place. Fetal malformation rates are not greater with a device let in situ (Tatum, 1976; Vessey, 1979).

Second-trimester miscarriage with an IUD in place is more likely to be infected (Vessey, 1974). Sepsis may be fulminant and fatal. Pregnant women with a device in utero who demonstrate any evidence of pelvic infection are treated with broadspectrum antibiotics and prompt uterine evacuation. Because of these risks, a woman should be given the option of early pregnancy termination if the device cannot be removed early in pregnancy. Last, in women who give birth with a device in place, appropriate steps should be taken at delivery to identiy and remove the IUD.

To reduce expulsion rates and perforation risks, IUD insertion 6 weeks after delivery. Women delivered at Parkland Hospital are seen 3 weeks postpartum, and IUDs are inserted 6 weeks postpartum or sooner if involution is complete.

Alternatively, immediately ater miscarriage, surgical abortion, or delivery, an IUD may be inserted in the absence of overt infection (Lopez, 2015a; Okusanya, 2014). Also, "immediate" insertion 1 week ater mifepristone and completed medical abortion has been described (Saav, 2012; Shimoni, 2011). The risk ofIUD expulsion is slightly higher if it is placed immediately following any of these recent pregnancies (Whitaker, 2017). However, in studies, the number of women in immediate-placement groups who ultimately receive and retain an IUD is greater than in groups scheduled for traditionally timed placement, some of whose members do not return for insertion (Bednarek, 2011; Chen, 2010).

With immediate insertion, techniques depend on uterine size. After irst-trimester evacuation, the IUD can be placed using the manufacturer's standard instructions. If the uterine cavity is larger, the IUD can be placed using ring forceps with sonographic guidance (Drey, 2009; Fox, 2011).

Immediately following vaginal or cesarean delivery, an IUD can be placed by a hand, by its inserter tube, or by ring forceps (Levi, 2015; Xu, 1996). With any of these methods, the arms of the IUD need not be folded into the inserter tube prior to insertion. During cesarean delivery placement, the hand or inserter travels through the unsutured open hysterotomy to deposit the device at the fundus. A second hand cupping the outer fundus can provide back pressure and stabilize the uterus during insertion. Strings are then gently directed toward the cervix. For instrumented insertion following vaginal delivery, the clinician resterilizes the vulva and changes gloves after placental delivery but before perineal repairs. he anterior lip of the loppy cervix is held with ring forceps. A second ring forceps grasp the IUD stem and guides it through the uterine cavity to the fundus. For manual insertion following vaginal delivery, the provider secures the IUD between the index and middle fingers to deposit the device. In either case, back pressure against the fundus by an abdominal hand can guide positioning (Stuart, 2017; The ACQUIE Project, 2008).

For placement not related to pregnancy, insertion near the end of normal menstruation, when the cervix is usually softer and somewhat more dilated, may be easier and also helps exclude early pregnancy. But, insertion is not limited to this time. For the woman who is sure she is not pregnant and does not want to be pregnant, insertion is done at any time.

Before insertion, contraindications are sought. Candidates are counseled, and written consent obtained. n oral NSAID, with or without codeine, can be used to allay cramps ater insertion (Ngo, 2015). But NSAIDs, misoprostol, or even paracervical during device placement (Bednarek, 2015; Hubacher, 2006;

Mody, 2012; Pergialiotis, 2014). Of topical lidocaine products, 2-percent gel is inefective, but a newer gel and a spray both show promise (Aksoy, 2016; Lopez, 2015b; Tornblom-Paulander, 2015). Bimanual pelvic examination delineates uterine position and size. Abnormalities are evaluated, as they may contraindi cate insertion. Mucopurulent cervicitis or signiicant vaginitis is appropriately treated and resolved before IUD insertion.

The cervical surface is cleansed with an antiseptic solution, and sterile instruments and a sterile IUD are used. A tenaculum is placed on the cervical lip, and the canal and uterine cavity are straightened by applying gentle outward traction. The cav ity is then probed by a uterine sound to identiy its direction and depth. Speciic steps of ParaGard and Mirena insertion are tive package inserts.

Following insertion, only the threads should be visible trailing from the cervix. These are trimmed to allow 3 to 4 cm to protrude into the vagina, and their length is recorded. If improper device positioning is suspected, placement should be confirmed, using sonography if necessary. If the IUD is not positioned completely within the uterus, it is removed and replaced with a new device. An expelled or partially expelled device should not be reinserted.

Contraception can be provided by thin, pliable progestincontaining cylinders that are implanted subdermally and release hormone over many years. One of these, Nepanon is a single-rod implant with 68 mg of etonogestrel covered by an ethylene vinyl acetate copolymer cover. The implant is placed subdermally on the medial surface of the upper arm 8 to 10 cm from the elbow in the biceps groove and is aligned with the long axis of the arm. It may be used as contraception for 3 years, removed, and then replaced at the same site or in the opposite arm (Merck, 2016a).

Nexplanon is radiopaque, and its inserter device is designed to assist with subdermal positioning and avert deeper placement. This device replaced Implanon, which is not radiopaque. A misplaced Implanon may be identiied with sonography using a 10-to IS-MHz linear array transducer (Shulman, 2006). In some cases, MR imaging may be required if supplemental information is needed despite sonography (Correia, 2012). Both implants are similarly shaped and pharmacologically identical. They are highly efective, and the mechanism of action for progestin-only products is described later (p. 689) (Croxatto, 1998; Mommers, 2012). Implanon is safe and still approved by

Flange 1.5cm

After slider moved back, inserter tube removed

FIGURE 38-2 Insertion of the Mirena intrauterine system. Initially, threads from behind the slider are first released to hang freely. The slider found on the handle should be positioned at the top ofthe handle nearest the device. The IUD arms are oriented horizontally. A flange on the outside ofthe inserter tube is positioned from the IUD tip to reflect the depth found with uterine sounding. A.As both free threads are pulled, the Mirena IUD is drawn into the inserter tube. The threads are then tightly fixed from below into the handle's cleft. In these depictions, the inserter tube has been foreshortened. The inserter tube is gently inserted into the uterus until the flange lies 1.5 to 2 cm from the external cervical os to allow the arms to open. B. While holding the inserter steady, the IUD arms are released by pulling the slider back to reach the raised horizontal mark on the handle, but no further. C. The inserter is then gently guided into the uterine cavity until its flange touches the cervix. D. The device is released by holding the inserter firmly in position and pulling the slider down all the way. The threads will be released automatically from the clet. The inserter may then be removed, and IUD strings trimmed. (Reproduced with permission from Stuart GS: Contraception and sterilization. In Hoffman BL, Schorge JO, Bradshaw KD, et al: Williams Gynecology, 3rd ed. New York, McGraw-Hili Education, 2016.)

Tip of IUD inserter rod Inserter tube Flange A B

FIGURE 38-3 Insertion of ParaGard T 380A. The uterus is sounded, and the IUD is loaded into its inserter tube not more than 5 minutes before insertion. A blue plastic flange on the outside of the inserter tube is positioned from the IUD tip to reflect uterine depth. The IUD arms should lie in the same plane as the flat portion of the oblong blue flange. A.The inserter tube, with the IUD loaded, is passed into the endometrial cavity. A long, solid, white inserter rod abuts the base of the IUD. When the blue flange contacts the cervix, insertion stops.

B. To release the IUD arms, the solid white rod within the inserter tube is held steady, while the inserter tube is withdrawn no more than 1 cm. C. The inserter tube, not the inserter rod, is then carefully moved upward toward the top of the uterus until slight resistance is felt. At no time during insertion is the inserter rod advanced forward. D. First, the solid white rod and then the inserter tube are withdrawn individually. At completion, only the threads should be visible protruding from the cervix. These are trimmed to allow 3 to 4 cm to extend into the vagina. (Reproduced with permission from Stuart GS: Contraception and sterilization. In Hoffman BL, Schorge JO, Bradshaw KD, et al: Williams Gynecology, 3rd ed. New York, McGraw-Hili Education, 2016.) the Food and Drug Administration (FDA), but it is no longer distributed by the manufacturer.

he irst progestin implants contained levonorgestrel (LNG), and systems are still available outside the United States. Jadelle, originally named Norplant-2, provides LNG and contraception for 5 years through two subdermally implanted Silastic rods. Ater this time, rods may be removed and if desired, new rods inserted at the same site (Bayer Group, 2015). Jadele is approved by the FDA, however, it is not marketed or distributed in the United States. Sino-implant II is a two-rod system with the same amount (150 mg) of LNG and same mechanism of action asJadele but provides 4 years of contraception. Sinoimplant II is manufactured in China and approved for use by 20 countries in Asia and Mrica (FHI 360, 2012).

Like the etonogestrel implant, these systems are placed subdermally on the inner arm approximately 8 cm from the elbow and have similar removal steps. Implants vary regarding their insertion technique, and manufacturer instructions should be consulted. Both implant systems are highly efective (Sivin, 1998; Steiner, 2010).

he forerunner of these implants was the Norpant System, which provided LNG in six Silastic rods implanted subdermally. The manufacturer stopped distributing the system in 2002.

Few data compare the LNG and etonogestrel implants. In one, eicacy and discontinuation rates by 2.5 years of use were similar (Bahamondes, 2015).

Unscheduled bleeding is common with progestin-only methods and described on page 689. Device-specific adverse efects derive mainly from malpositioning. First, branches of the medial antebrachial cutaneous nerve can be injured during implant or needle insertion that is too deep or during exploration for a lost implant. Clinically, numbness and paresthesia over the anteromedial aspect of the forearm are noted (Wechselberger, 2006).

Second, nonpalpable devices are not uncommon and require radiological imaging for localization. As an adjunct, one group adopted the hook-wire tagging method used in breast tumor surgery to allow deep-lying implants to be marked prior to extraction (Nouri, 2013). If imaging fails to locate an implant, etonogestrel blood level determination can help veriy that the implant is indeed in situ. his special assay must be coordinated with the manufacturer (1-877-467-5266).

For those not currently using hormonal contraception, the etonogestrel implant is ideally inserted within 5 days of menses onset. With LNG-releasing implants, contraception is established within 24 hours if inserted within the first 7 days of the menstrual cycle (Sivin, 1997; Steiner, 2010). For transitioning methods, an implant is placed on the day of the first placebo combination oral contraceptive (COC) pill; on the day that the next depot-medroxyprogesterone injection would be due; or within 24 hours of taking the last POP (Merck, 2016a). In women certain that they are not pregnant, insertion at other times of the cycle is followed by alternative contraception for 7 days. Related to pregnancy, an implant may be inserted before discharge following delivery or abortion (Sothornwit, 2017).

With the patient lying down, her nondominant arm, forearm, and hand are outstretched on the bed with the inner aspects of each exposed upward, and the elbow is flexed. The insertion site is marked with a sterile pen 8 to 10 cm proximal to the medial condyle of the humerus. A second mark is placed 4 cm proximally and delineates the inal path of the implant. he Nexplanon is inserted using sterile technique. The area is cleansed aseptically, and a I-percent lidocaine anesthetic track is injected beneath the sin along the planned insertion path. The implant is then placed as shown in Figure 38-4. Ater placement, both

FIGURE 38-4 Nexplanon insertion. A sterile pen marks the insertion site, which is 8 to 10 cm proximal to the medial humeral condyle. A second mark is placed 4 cm proximally along the arm's long axis. The area is cleaned aseptically, and a l-percent lidocaine anesthetic track is injected along the planned insertion path. A.The insertion device is grasped at its gripper bubbles found on either side, and the needle cap is removed outward. The device can be seen within the needle bore. The needle bevel then pierces the skin at a 30-degree angle.

B. Once the complete bevel is subcutaneous, the needle is quickly angled downward to lie horizontally. C. Importantly, the skin is tented upward by the needle as the needle is slowly advanced horizontally and subdermally. D. Once the needle is completely inserted, the lever on the top of the device is pulled backward toward the operator. This retracts the needle and thereby deposits the implant. The device is then lifted away from the skin. After placement, both patient and operator should palpate the 4-cm implant.

patient and provider should palpate and identiY both ends of the 4-cm implant. To minimize bruising at the site, a pressure ban dage is created around the arm and is removed the following day.

With implant extraction, the removal site is irst cleansed with antiseptic. he proximal end of the implant is depressed with a finger to allow the distal end to bulge up toward the skin. Ater anesthetizing the skin over this bulge, the skin is incised 2 mm toward the elbow along the long axis of the arm. he proximal butt of the implant is then pushed toward this incision. Once vis ible, the distal end of the implant is grasped with a hemostat and removed. If present, supericial adhesions surrounding an implant may be dissected away with hemostat tips placed into the incision.

Progestin-only contraceptives include the implants just described, injectables, and pills. s their primary contraceptive action, these progestins suppress luteinizing hormone (LH) and in turn block ovulation. As other efects, cervical mucus is thickened to retard sperm passage, and atrophy renders the endometrium unfavorable for implantation. Fertility is restored rapidly following cessation of progestin-only contraception. n exception is DMPA, as described on page 693 (Mansour, 201l).

For all progestin-only methods, irregular or heavy uterine bleeding is a distinct disadvantage. It is the most frequently reported adverse event leading to method discontinuation. Often, counseling and reassurance is suicient. Troublesome bleeding may be improved by one to two cycles of combination oral contraceptives, by a 1-to 3-week course of estrogen alone, or by a short course of NSAIDs combined with the established method (Abdel-Aleem, 2013). Fortunately, with prolonged use, progestins induce endometrial atrophy, which leads to sustained amenorrhea. For the well-counseled patient, this is often an advantage.

Most progestin-only contraceptive methods do not signiicantly afect lipid metabolism, glucose levels, hemostatic factors, liver function, thyroid function, or blood pressure (DorRinger, 2002). However, the increased low-density lipoprotein (LDL) cholesterol and decreased high-density lipoprotein (HDL) cholesterolrlevels seen with DMPA may be less desirable for women with cardiac or vascular disease risks (Kongsayreepong, 1993).

Progestin-only methods do not impair milk production and are an excellent choice for lactating women. here are no increased risks of genital tract, liver, or breast neoplasia (Samson, 2016; Wilailak, 2012; World Health Organization, 1991a,b, 1992). Weight gain and bone fracture are not prominent side efects of this contraceptive group, except for depot progesterone, discussed on page 693 (Lopez, 2012a, 2013a). Functional ovarian cysts develop with a greater frequency in women using progestin-only agents, although they do not usually necessitate intervention (European Society of Human Reproduction and Emblyology, 2001; Hidalgo, 2006; Nahum, 2015). Last, an association between depression and DMPA or POPs is unclear (Civic, 2000; Pagano, 2016; Svendal, 2012; Westhof, 1995). Women with depression may be prescribed these methods, but surveillance following initiation is reasonable.

These methods are ideal for most women, but contraindications and cautions are associated with a few conditions listed in Table 38-2. Current breast cancer and pregnancy are the only two absolute contraindications. In a few instances, manufacturer restrictions difer from the US MEC. First, manufacturer prescribing information lists thrombosis or thromboembolic disorders as contraindications (Merck, 2016a; Pizer, 2015a,b). However, for individuals with these disorders, US MEC considers progestin-containing methods category 2. Moreover, evidence does not link progestin-only methods with thromboembolism, stroke, or cardiovascular disease (Mantha, 2012; Tepper, 2016b; World Health Organization, 1998). Second, for many progestin products, manufacturers note prior ectopic pregnancy as a contraindication. his is secondary to progesterone's efect of slowing fallopian tube motility and thereby delaying fertilized egg transport to the endometrial cavity. hat said, efective contraception lowers pregnancy rates overall. Thus, for those with prior ectopic pregnancy, US MEC considers progestin injectables and implants category 1, and progestin-only pills are category 2.

These currently are available in forms that contain both estrogen and progestin or contain only progestin. Progestin-only injectables and pills are considered very efective, yet secondtier agents, due to the need for increased patient compliance. Similarly, products containing both estrogen and progestin, often termed combination hormonal contraception (CHC), are considered in this tier. These may be supplied as pills, transvaginal rings, or transdermal patches.

• Combination Hormonal Contraceptives Mechanism of Action

Actions of combination hormonal contraceptives are multiple, but the most important efect is suppression of hypothalamic gonadotropin-releasing factors. his in turn blocks pituitary secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and thereby inhibits ovulation. The progestin component of CHCs provides ovulation prevention by suppressing LH; it thickens cervical mucus and thereby retards sperm passage; and it renders the endometrium unfavorable for implantation. Estrogen blocks ovulation by suppressing FSH release. To promote cycle control, estrogen stabilizes the endometrium, which prevents intermenstrual bleeding-also known as breakthrough bleeding. The net efect is an extremely efective yet highly reversible method (Mansour, 2011).

hese pills are the most frequently used reversible birth control method in the United States. In a 2006 to 2010 survey, 16 percent of contracepting women in the United States were using these (Daniels, 2015). COCs are marketed in a wide variety of estrogen and progestin combinations. lvlost are available as generics, and the FDA (2016) confirms the bioequivalence of COC generics. The merican College of Obstetricians and Gynecologists (2015a) supports the use of either branded or generic preparations.

Pharmacologically, ethinyl estradiol is the most common estrogen present in COC formulations in the United States. Less frequently, mestranol or estradiol valerate is used. Unwanted efects most often attributed to the estrogen component include breast tenderness, weight gain, nausea, and headache.

COCs also contain one of several progestins that are structurally related to progesterone, testosterone, or spironolactone. hus, these progestins bind variably to progesterone, androgen, glucocorticoid, and mineralocorticoid receptors. hese ainities explain many pill-related side efects and are often used to compare one progestin with another.

Most progestins used in COCs are related to testosterone and may impart androgenic side afects such as acne and adverse HDL and LDL levels. To avoid these efects, antiandrogenic progestins have been introduced and include dienogest and nomegestroL acetate. he latter is used in a COC approved outside the United States. Despite these pharmacological differences, the true advantage of one progestin over another is less apparent clinically (Lawrie, 2011; Moreau, 2007).

Another progestin, drospirenone, is structurally similar to spironolactone. he doses in currently marketed COCs have efects similar to 25 mg of this diuretic (Seeger, 2007). Drospirenone displays antiandrogenic activity, provides an antialdosterone action to minimize water retention, and has antimineralocorticoid properties that may, in theory, cause potassium retention and hyperkalemia (Krattenmacher, 2000). hus, it is avoided in women with renal or adrenal insuiciency or with hepatic dysfunction. Moreover, serum potassium level monitoring is recommended in the first month for patients chronically treated concomitantly with any drug associated with potassium retention. hese include NSAIDs, angiotensinconverting enzyme (ACE) inhibitors, angiotensin II antagonists, heparin, aldosterone antagonists, and potassium-sparing diuretics (Bayer HealthCare Pharmaceuticals, 2015).

Since the development of COCs, their estrogen and progestin content has dropped remarkably to minimize adverse efects. Currently, the lowest acceptable dose is limited by the ability to prevent pregnancy and to avoid unacceptable breakthrough bleeding. hus, the daily estrogen content varies from 10 to 50 1g of ethinyl estradiol, and most contain 35 j.1g or less.

In a few COCs, inert placebo pills have been replaced by tablets containing iron. These have the suix Fe added to their name. In addition, Beyaz has a form of folate-levomefolate calcium-within both its active and placebo pills.

With COCs termed monophasic piLs, the progestin dose remains constant throughout the cycle. In others, the dose frequently is varied, and term biphasic, triphasic, or quadriphasic piL is used depending on the number of dose changes within the cycle. In some formulations, the estrogen dose also varies. In general, phasic pills were developed to reduce the total progestin content per cycle without sacrificing contraceptive eicacy or cycle control. he theoretical advantage of a lower total progesterone dose per cycle, however, has not been borne out clinically (Moreau, 2007). Cycle control also appears to be comparable among mono-through triphasic pills (van Vliet, 2011a,b,c).

Hormones are taken daily for a specified time (21 to 81 days) and then replaced by placebo for a speciied time (4 to 7 days), which is called the "pill-free interval." During these pill-free days, withdrawal bleeding is expected.

With the trend toward lower estrogen doses to minimize side efects, follicular development and ovulation may occur. To counter this, the active-pill duration in some formulations is extended to 24 days. In comparison, these 24/4 regimens perform similarly to higher-estrogen-dose 21/7 regimens (Anttila, 2011; Marr, 2012).

Alternatively, longer durations of active hormone, designed to minimize the number of withdrawal episodes, have similar eicacy and safety proiles as more traditional administration (Edelman, 2014). These extended-cycle products produce a 13-week cycle, that is, 12 weeks of hormone use, followed by a week for withdrawal menses. The product Amethyst provides continuous active hormone pills for 365 days each year. Such extended or continuous regimens may be especially suited for women with significant menstrual symptoms (Mendoza, 2014).

For general initiation, women ideally begin COCs on the first day of a menstrual cycle. In such cases, a supplementary contraceptive method is unnecessary. With the more traditional "Sunday start," women begin pills on the irst Sunday that follows menses onset, and an additional method is needed for 1 week to prevent conception. If menses begin on a Sunday, then pills are begun that day and no supplemental method is required. Alternatively, with the "quick start" method, COCs are started on any day, commonly the day prescribed, regardless of cycle timing. An additional method is used during the first week (Westhof, 2002, 2007b). If the woman is unknowingly already pregnant during quick start initiation, COCs are not teratogenic (Lammer, 1986; Rothman, 1978; Savolainen, 1981). However, a missed menses following COC initiation should prompt pregnancy testing. Similar same-day initiation can be implemented with the contraceptive vaginal ring or patch (Murthy, 2005; Schafer, 2006).

For maximum eiciency, pills are best taken at the same time each day. If one dose is missed, the missed pill is taken immediately; the scheduled dose for that day is taken on time; and then daily pills are continued. If two or more doses are missed, the most recent missed pill is taken immediately; the scheduled dose for that day is taken on time; and an efective barrier technique used for 7 days while daily pills are then continued (Curtis, 2016a). If withdrawal bleeding fails to occur during the pill-free interval, a woman should continue her pills but seek attention to exclude pregnancy.

With initiation of COCs, spotting or bleeding is common.

It does not relect contraceptive failure and typically resolves within one to three cycles. If unscheduled bleeding persists, those with bleeding during the first part of a pill pack may beneit from an increase in the estrogen dose, whereas those with bleeding during the second part may improve with a higher progestin dose (Nelson, 2011).

Some drugs decrease COC efectiveness, and choosing another contraceptive method is preferable. However, if a COC is selected for concurrent use in these instances, a preparation containing a minimum of 30 �g ethinyl estradiol is ideally chosen. Conversely, some COCs interfere with the actions of certain drugs (see Table 38-2).

In obese women, COCs are efective (Lopez, 2016). Some studies point to lowered hormone bioavailability, but over all eicacy remains high (Nakajima', 2016; Westhof, 2010;

Yamazaki, 2015). With the transdermal patch method, how ever, evidence is more robust that obesity may alter pharmaco kinetics and lower eicacy, as discussed on page 692.

Combination oral contraceptives alter lipid synthesis and in general raise serum levels of triglycerides and of total cholesterol, HDL, and very-low density lipoprotein (VLDL) cholesterol. Estrogen lowers LDL cholesterol concentrations. Oral contraceptives are not atherogenic, and their efect on lipids is clinically inconsequential for most women (Wallach, 2000). In women with dyslipidemias, limited data suggest that COCs increase the risk for myocardial infarction and minimally so for venous thromboembolism or stroke (Dragoman, 2016). For those with multiple additional risk factors for vascular disease, alternative contraceptive methods are recommended.

With COCs, protein metabolism is afected, and estrogens boost hepatic production of various globulins. First, fibrinogen and many of the clotting factor levels rise in direct proportion to the estrogen dose and may lead to thrombosis. Angiotensinogen production is also augmented by COCs, and its conversion by renin to angiotensin I may be associated with "pill-induced hypertension," discussed subsequently. Last, COCs elevate sex hormone-binding globulin (SHBG) levels, which in turn lower concentrations of bioavailable testosterone and lessen androgenic side efects.

Regarding carbohydrate metabolism, current low-dose formulations have minimal efects in women who do not have diabetes (Lopez, 2014). And, the risk of developing diabetes is not increased (Kim, 2002). For diabetic women, COCs may be used in nonsmokers with disease duration <20 years and without associated vascular disease, nephropathy, retinopathy, or neuropathy (Curtis, 2016b).

Of other metabolic changes, thyroid-binding globulin and thyroid-stimulating hormone (TSH) levels are elevated, but free plasma thyroxine (FT4) levels are unchanged (Raps, 2014). Studies have not supported a connection between COCs and weight gain (Gallo, 2014).

Despite increased plasma angiotensinogen (renin substrate) levels, women using low-dose COC formulations rarely develop clinically significant hypertension (Chasan-Taber, 1996). However, it is common practice for patients to return 8 to 12 weeks ater COC initiation for evaluation of blood pressure and other symptoms.

During initial contraception selection, a history of gesta tional hypertension does not preclude subsequent COC use.

Among women with well-controlled hypertension, COC use is linked to greater risks than nonusers for stroke, acute myo cardial infarction, and peripheral arterial disease, and in these women, COCs are considered US MEC category 3 (Curtis, 2016b). Severe forms of hypertension, especially those with end-organ involvement, preclude COC use.

For nonsmoking women younger than 35, the risk of stroke is extremely low (World Health Organization, 1996). COCs are associated with a small increased risk for ischemic stroke (Chan, 2004; Lidegaard, 2012). Rates increase signiicantly for women who have hypertension, who smoke, or who have migraine headaches with visual aura or other focal neurological changes and use COCs (MacClellan, 2007; Tepper, 2016c).

The evidence for stroke risk in migraineurs without aura is less clear (Etminan, 2005; Schurks, 2009). COC initiation may be considered for women with preexisting migraines without aura if they are otherwise healthy, younger, normotensive nonsmok ers. For women with prior stroke, COCs should not be consid ered due to risks for repeat events.

For women with prior myocardial infarction, COCs should not be considered. Also, in women with multiple cardiovas cular risk factors, which include smoking, hypertension, older age, and diabetes, the risk for myocardial infarction outweighs the beneits of this method. However, for those without these risks, low-dose oral contraceptives are not associated with an increased risk of myocardial infarction (Margolis, 2007; World

Health Organization, 1997).

The risks for deep-vein thrombosis and pulmonary embolism are increased in women who use COCs (Stadel, 1981). These clearly are estrogen-dose related, and rates have substantively declined with lower-dose formulations containing 10 to 35 �g of ethinyl estradiol. he general-population risk of venous thromboembolism (VTE) is 4 to 5 events per 100,000 woman-years. he incidence ofVTE with COC use increases three-to fivefold compared with nonusers (Shaw, 2013; van Hylckama Vlieg, 2009). Obesity raises the VTE risk, which is compounded by COCs (Horton, 2016; Suchon, 2016). Accordingly, in an obese woman, COCs are considered a US MEC category 2. VTEs are signiicantly increased in women older than 35 years who smoke, and COCs are not recommended. Those most at risk for VTE include women with thrombophilias (ESHRE Capri Workshop Group, 2013). Nloreover, COC use during the month before a major operative procedure appears to double the risk for postoperative VTE (Robinson, 1991). Thus, the merican College of Obstetricians and Gynecologists (2016d) recommends balancing the risks ofVTE and the degree of postoperative immobility with the risk of unintended pregnancy during the 4 to 6 weeks required to reverse the thrombogenic efects of COCs before surgery. In the early puerperium, VTE risks are also increased, and COCs are not recommended for women within the irst 4 weeks after delivery.

Certain progestins within COC are linked with greater rates of thromboembolism. A slightly higher VTE risk with drospirenone-containing COCs has been shown in two studies. In response, an assessment of benefits and VTE risks in users of these pills has been emphasized (Food and Drug Administration, 2012; Jick, 2011; Parkin, 2011). Desogestrel and gestodene are also implicated and carry similarly elevated risks (Stegeman, 2013; Vinogradova, 2015).

Most studies indicate that COCs overall are not associated with an increased risk of cancer (Cibula, 2010). In fact, a protective efect against ovarian and endometrial cancer has been shown (Collaborative Group on Epidemiological Studies of Ovarian Cancer, 2008; Tsilidis, 201r1). As an exception, the relative risk of cervical dysplasia and cervical cancer is higher in current COC users, but this declines after use is discontinued. Following 10 or more years, risk returns to that of never users (International Collaboration of Epidemiological Studies of Cervical Cancer, 2007). It is unclear whether COCs contribute to breast cancer development. Major studies show no risk or a small risk among current users, which drops with time following cessation (Collaborative Group on Hormonal Factors in Breast Cancer, 1996; Hannaford, 2007; Marchbanks, 2002).

Although COC use in the past was linked to development of hepatic ocal nodular hyperplasia and benign hepatic adenoma, large studies do not support this (Heinemann, 1998). Moreover, no evidence supports concern for greater risk of hepatocellular cancer (Maheshwari, 2007). For women with known tumors, COCs may be used in those with focal nodular hyperplasia, but avoided in those with benign hepatic adenoma and hepatocellular carcinoma (Kapp, 2009b). Rates of colorectal cancer appear to be reduced in ever users (Bosetti, 2009; Luan, 2015).

Cholestasis and cholestatic jaundice are uncommon, but they resolve when COCs are discontinued. In women who have active hepatitis, COCs should not be initiated, but these may be continued in women who experience a flare of their liver disease while already taking COCs. Use of progestin-only contraception in these women is not restricted. Moreover, there is no reason to withhold COCs from women who have recovered. Mild compensated cirrhosis does not limit the use of COCs or progestin-only methods. But in those with severe decompensated disease, all hormonal methods are avoided (Kapp, 2009a).

Chloasma, which is hyperpigmentation of the face and forehead, is more likely in women who demonstrated such a change during pregnancy (Chap. 4, p. 53). This is less common with lowdose estrogen formulations. Although previously used for treating unctional ovarian cysts, low-dose COC formulations have been shown to have no efects related to cyst resolution or prevention (European Society of Human Reproduction and Embryology, 2001; Grimes, 2014).

Many noncontraceptive beneits are associated with COC use (American College of Obstetricians and Gynecologists, 20 16c). And indeed, COCs may be used for these efects, even in those without contraceptive needs. Dysmenorrhea and heavy menstrual bleeding lessen with COC use. Another action is to improve androgenic conditions such as acne and hirsutism. For women with premenstrual dysphoric disorder (PMDD), several studies have shown symptom improvement in those who use the drospirenone-containing COC Yaz (Lopez, 2012b; Pearlstein, 2005; Yonkers, 2005).

he Ortho Evra patch contains ethinyl estradiol and the progestin norelgestromin. It has an inner layer containing an adhesive and hormone matrix, and a water-resistant outer layer. Thus, women can wear the patch in bathtubs, showers, swimming pools, saunas, and whirlpools without decreased eicacy. he patch may be applied to buttocks, upper outer arm, lower abdomen, or upper torso, but the breasts are avoided. Because the hormones are combined with the adhesive, improper skin adherence will lower hormone absorption and eicacy. herefore, if a patch is so poorly adhered that it requires reinforcement with tape, it should be replaced.

Initiation of the patch is the same as for COCs, and a new patch is applied weekly for 3 weeks, followed by a patch-free week to allow withdrawal bleeding. Although a patch is ideally worn no longer than 7 days, hormone levels remain in an efective range for up to 9 days. This afords a 2-day window for patch-change delays (Abrams, 2001).

In general, the transdermal patch and vaginal ring produce metabolic changes, side efects, and eicacy rates comparable to those with COC pills. However, the patch has been associated with a higher thromboembolism risk in some but not all studies (Cole, 2007; Jick, 2010; Lidegaard, 2011). In response, the Food and Drug Administration (2015 b) approved labeling for the patch to state that the risk for VTE may be increased compared with other COCs, and relative risk estimates range from 1.2 to 2.2. Obesity-90 kg or greater-may be associated with a higher risk for patch contraceptive failure (Janssen Pharmaceuticals, 2015; Zieman, 2002). Finally, applicationsite reaction and breast tenderness are more frequent during initial cycles in patch wearers (Urdl, 2005).

The NuvaRing is yet another form of combination hormonal contraception and is a lexible intravaginal ring. he ring is constructed of ethinyl vinyl acetate, and it measures 54 mm in diameter and 4 mm in cross section (Fig. 38-5). During

FIGURE 38-5 NuvaRing: estrogen-progestin-releasing vaginal contraceptive ring.

insertion, the ring is compressed and threaded into the vagina, but no specific final orientation within the vagina is required.

Its core releases ethinyl estradiol and the progestin etonogestrel, which are absorbed across the vaginal epithelium. Before being dispensed, the rings are refrigerated, and once dispensed, their shelflife is 4 months. he ring is placed within 5 days of menses onset and, after 3 weeks of use, is removed for 1 week to allow withdrawal bleeding. Contraception will still be aforded if a ring is left in place for a fourth week (Merck, 2016b).

Patient satisfaction is high with this method, although vagi nitis, ring-related events, and leukorrhea are more common (Lopez, 2013b; Oddsson, 2005). Despite this, no deleterious been found (Lete, 2013; Veres, 2004). A ring may be used con currently with vaginal medications or with a tampon (Haring, 2003; Verhoeven, 2004a,b). Approximately 70 percent of part ners feel the ring during intercourse (Dieben, 2002). If this is bothersome, the ring may be removed for intercourse but should be replaced within 3 hours to maintain eicacy.

Both intramuscular depot medroxyprogesterone acetate-DepoProvera (DMPA)-150 mg every 3 months, and norethisterone enanthate, 200 mg every 2 months, are injectable progestin contraceptives used worldwide. Of the two, DMPA is available in the United States. DMPA is injected into the deltoid or gluteus muscle, but massage is avoided to ensure that the drug is released slowly. lternatively, a subcutaneous version, depo-subQprovera 104, is also available and is injected into the subcutaneous tissue of the anterior thigh or abdomen every 3 months.

DMPA is efective, and as with other progestin-only methods, contraception is provided by ovulation inhibition, greater cervical mucus viscosity, and creation of an endometrium unfavorable for ovum implantation. Initial injection is given within the irst 5 days following menses onset. Serum levels suicient for contraception are observed by 24 hours. Thus, no additional contraceptive method is required for initiation within this window. Alternatively, limited data support a "quick weart," or initiation of DMPA regardless of cycle day. If so implemented, investigators recommend an initial negative pregnancy test result before injection, a supplemental contraceptive method during the 7 days following injection, and a second pregnancy test after 3 to 6 weeks to identiy an early pregnancy (Rickert, 2007; Sneed, 2005). Pregnancies conceived during DMPA use are not associated with a higher risk of fetal malformation (Katz, 1985). For women who present for intramuscular DMPA reinjection more than 13 weeks or for subcutaneous DMPA reinjection more than 14 weeks ater the prior dose, the manufacturer recommends exclusion of pregnancy before reinjection (Pfizer, 2015a,b).

Injected progestins ofer the convenience of a 3-month dosing schedule, contraceptive eicacy comparable with or better than COCs, and minimal to no lactation impairment. Irondeiciency anemia is less likely in long-term users because of amenorrhea, which develops in up to 50 percent after 1 year and in 80 percent after 5 years.

Similar to other progestin-only contraceptive, irregular menstrual bleeding is common, and a fourth of women dis continued DVIPA in the irst year because of this (Cromer, 1994). Unique to DMPA, prolonged anovulation can follow discontinuation, which results in delayed fertility resumption.

After injections are stopped, a fourth of patients do not resume regular menses for up to 1 year (Gardner, 1970). Accordingly,

DMPA may not be ideal for women who plan to use birth control only brieRy before attempting conception.

As with other progestins, DMPA has not been associ ated with cardiovascular events or stroke in otherwise healthy women. However, in those with severe hypertension, a higher risk of stroke has been found in DMPA users (World Health

Organization, 1998). Moreover, the US MEC authors express levels from DMPA in women with vascular disease or multiple risks for cardiovascular disease.

Weight gain is generally attributed to DMPA, and these increases are comparable between the two depot forms (Bahamondes, 2001; Vickery, 2013; Westhof, 2007c). In long-term users, loss of bone mineral density is also a potential problem (Petitti, 2000; Scholes, 1999). In 2004, the FDA added a black box warning to DMPA labeling, which notes that this concern is probably most relevant for adolescents, who are building bone mass, and perimenopausal women, who will soon have increased bone loss during menopause. That said, World Health Organization (1998) and American College of Obstetricians and Gynecologists (20 16b) believe that DMPA should not be restricted in those high-risk groups. And, it seems prudent to reevaluate overall risks and beneits during extended use. It is somewhat reassuring that bone loss appears to be reversible after discontinuation of therapy, although reversal is still not complete after 18 to 24 months (Clark, 2006; Scholes, 2002).

So-called mini-pils are progestin-only contraceptives that are taken daily. hese contraceptives have not achieved widespread popularity and are used by only 0.4 percent of reproductive-aged American women (Hall, 2012). Unlike COCs, they do not reliably inhibit ovulation. Rather, their efectiveness depends more on cervical mucus thickening and endometrial atrophy. Because mucus changes are not sustained longer than 24 hours, mini-pills should be taken at the same time every day to be maximally efective. If a progestin-only pill is taken even 4 hours late, a supplemental form of contraception must be used for the next 48 hours. Progestin-only pills are contraindicated in women with known breast cancer or pregnancy. Other cautions are listed in Table 38-2.

For many years, male and female condoms, vaginal diaphragms, and periodic abstinence have been used for contraception with variable success (see Table 38-2). When used properly, condoms

FIGURE 38-6 FC2 Female Condom insertion and positioning. A. diaphragm. B. The inner ring is pushed inward with an index finger.

provide considerable but not absolute protection against a broad range of sexually transmitted diseases, including HIV (Eaton, 2014). Contraceptive eicacy of the male condom is enhanced appreciably by a reservoir tip and probably by the addition of a spermicide. Such agents, as well as those used for lubrication, should be water-based because oil-based products degrade latex condoms and diaphragms.

For individuals sensitive to latex, condoms made from lamb intestines are efective, but they do not provide infection protection. Fortunately, nonallergenic condoms have been developed that are made of polyurethane or of synthetic elastomers. Polyurethane condoms are efective against STDs but have a higher breakage and slippage rate compared with latex condoms (Gallo, 2012a).

The only female condom available in the United States is marketed as the FC2 Female Condom. It is a synthetic nitrile sheath with one lexible polyurethane ring at each end. Its open ring remains outside the vagina, whereas its closed internal ring is fitted under the symphysis like a diaphragm (Fig. 38-6). The female condom can be used with both water-based and oilbased lubricants. Male condoms should not be used concurrently because simultaneous use may cause friction that leads to condom slipping, tearing, and displacement. Following use, the female condom outer ring should be twisted to seal the condom so that no semen spills. As an added value, the female condom may ofer some protection against STDs (Minnis, 2005).

The diaphragm consists of a circular latex dome of variable diameter supported by a circumferential latex-covered metal spring. It is efective when used in combination with spermicidal

The inner ring is squeezed for insertion. The sheath is inserted similarly to a jelly or cream. The spermicide is applied into the dome cup and along the device rim. The diaphragm is then positioned so that the cup faces the cervix and that the cervix, vaginal fornices, and anterior vaginal wall are partitioned efectively from the remainder of the vagina and the penis. In this fashion, the centrally placed spermicide is held against the cervix. When appropriately positioned, one rim is lodged deep in the posterior vaginal fornix, and the opposite rim its behind the inner surface of the symphysis and immediately below the urethra (Fig. 38-7). If a diaphragm is too small, it will not remain in place. If it is too large, it is uncomfortable when forced into position. A coexistent cystocele or uterine prolapse typically leads to instability and expulsion. Because size and spring flexibility must be individualized, the diaphragm is itted by

FIGURE 38-7 A diaphragm in place creates a physical barrier between the vagina and cervix.

providers and available only by prescription.

For use, the diaphragm and spermicide can be inserted hours before intercourse. If more than 6 hours elapse, the diaphragm can remain but additional spermicide is placed in the upper vagina for maximum protection. Spermicide is reapplied before each subsequent coital episode. The diaphragm is not removed for at least 6 hours after intercourse. Because toxic shock syn drome has been described following its use, it may be worth while to remove the diaphragm at 6 hours, or at least the next morning, to minimize this rare event. Diaphragm use is associ ated with a slightly greater rate of urinary infections, presumably from urethral irritation by the ring under the symphysis.

FemCap is currently the only available cervical cap in the United States. Made of silicone rubber, it has a sailor-cap shape with a dome that covers the cervix and a lared brim, which allows the cap to be held in place by the muscular walls of the upper vagina. Available in 22-, 26-, and 30-mm sizes, it is used with a spermicide applied once at insertion to both sides of the dome cup. For contraception, it should remain in place for 6 hours following coitus and may remain for up to 48 hours. Even with proper itting and correct use, pregnancy rates with this method are higher that with the diaphragm (Gallo, 2012b; Mauck, 1999).

These family planning methods attempt to identiY the fertile days each cycle and advise sexual abstinence during these days. Their major drawback is their limited eicacy, which is shown in Table 38-1r. Common forms of these fertility awarenessbased (FAB) methods include Standard Days, Temperature Rhythm, Cervical Mucus, and Symptothermal Methods. Some smartphone applications aim to assist these practices (Fehring, 2013).

he Standard Days Method counsels women to avoid unprotected intercourse during cycle days 8 through 19. For successful use, women must have regular monthly cycles of 26 to 32 days. hose who use this method can mark a calendar or can use Cycle-Beads, which is a ring of counting beads, to keep track of their days.

he Temperature Rhythm Method relies on a sustained O.4°F rise in the basal body temperature, which usually precedes ovulation. For maximum eicacy, the woman must abstain from intercourse from'the irst day of menses through the third day after the temperature increase.

he Cervical Mucus Method, also called the Two-Day Method or Billings Method, relies on awareness of vaginal "dryness" and "wetness." hese reflect changes in the amount and quality of cervical mucus at diferent times in the menstrual cycle. With the Billings Method, abstinence is required from the beginning of menses until 4 days after slippery mucus is identified. With the T wo-Day Method, intercourse is considered safe if a woman did not note mucus on the day of planned intercourse or the day prior.

he Symptothermal Method combines changes in cervical mucus-onset of fertile period; changes in basal body temperature-end of fertile period; and calculations to estimate the time of ovulation. This method is more complex to learn and apply, but it does not appreciably improve eicacy.

These contraceptives are marketed variously as creams, jellies, suppositories, films, and aerosol foam. \10st can be purchased without a prescription. They are considered a less efective method (see Table 38-1). If pregnancy does occur, they are not teratogenic (Briggs, 2015).

Typically, spermicides function by providing a physical barrier to sperm penetration and a chemical spermicidal action. The active ingredient is nonoxynol-9 or octoxynol-9. Although these are spermicidal, they do not provide STD protection. Ideally, spermicides must be deposited high in the vagina in contact with the cervix shortly before intercourse. Their duration of maximal efectiveness is usually no more than 1 hour, and thereafter, they must be reinserted before repeat intercourse. Douching is avoided for at least 6 hours after coitus.

The Today contraceptive sponge is an over-the-counter, onesize-fits-all device. The nonoxynol-9-impregnated polyurethane disc is 2.5 cm thick and 5.5 cm wide and has a dimple on one side and satin loop on the other (Fig. 38-8). The sponge can be inserted up to 24 hours prior to intercourse, and while in place, it provides contraception regardless of coital frequency. It should remain in place for 6 hours after intercourse. Pregnancy is prevented primarily by the spermicide nonoxynol-9 and to a lesser extent by covering the cervix and absorbing semen.

FIGURE 38-8 Today sponges. The sponge is moistened with tap water and gently squeezed to create light suds. It is then tioned with the dimple directly against the cervix. The fabric loop trails within the vagina and can be hooked with a finger to later extract the sponge.

TABLE 38-3. Methods Available for Use as Emergency Contraception

Pills per Number of

COC Pillsb,c aDoses taken 12 hours apart if multiple.

bOther COC brands with formulations identical to those above may also be used.

(Use of an antiemetic agent before taking the medication will lessen the risk of nausea, which is a common side effect.

COC = combination oral contraceptive; EE = ethinyl estradiol; IUD = intrauterine device; LNG = levonorgestrel; PRM = progesterone-receptor modulator.

Although the sponge is possibly more convenient than the diaphragm or condom, it is less efective than either (Kuyoh, 2013). Most common causes for method discontinuance are pregnancy, irritation, discomfort, or vaginitis (Beckman, 1989). Although toxic shock syndrome has been reported with the contraceptive sponge, it is rare, and evidence suggests that the sponge may actually limit production of the responsible staphylococcal exotoxin (Remington, 1987). Still, it is recommended that the sponge not be used during menses or the puerperium.

Following unprotected sexual intercourse, many women present for contraceptive care. Several emergency contraception (EC) regimens substantially lower the likelihood of an unwanted pregnancy when used correctly. Current methods include COCs, progestins, progesterone antagonists, and copper-containing IUDs (Table 38-3). Overall, the IUD is most efective, and ulipristal acetate is the most eicient oral regimen (American College of Obstetricians and Gynecologists, 2017a). Patients can obtain information regarding emergency contraception by calling 1-888-NOT-2-LATE or accessing The Emergency Contraception Website: http://not-2-late.com.

Except for allergy to a particular component, no conditions in the US MEC contraindicate hormonal EC methods. With progestin-only regimens, levonorgestrel is taken as a single, onetime 1.5-mg dose (Arowojolu, 2002). his is now recommended instead of two 0.75-mg doses separated by 12 or 24 hours (Ngai, 2005). Dosing begins ideally within 72 hours of unprotected coitus but may be given up to 120 hours. Notably, the singledose regimen is available over-the-counter without a prescription to all reproductive-aged women (Food and Drug Administration, 2013,r2015a).

One progesterone-receptor modulator currently available for EC is ulipristal acetate and is marketed as Ela. It is taken as a single 30-mg tablet up to 120 hours after unprotected intercourse (Brache, 2010; Watson, 2010).

Also known as the Yuzpe method, this older EC method provides a minimum of 100 jLg of ethinyl estradiol and 0.5 mg of levonorgestrel in each of two doses. As shown in Table 38-3, a suicient dose may be achieved by two or more pills. he first dose is taken ideally within 72 hours of intercourse but may be given up to 120 hours. The initial dose is followed 12 hours later by a second equivalent dose.

The major mechanism with all hormonal regimens is inhibition or delay of ovulation. Of oral methods, failure rates are lowest with ulipristal (1 to 2 percent) and greatest with the Yuzpe method (2 to 3.5 percent) (Cleland, 2014). IfEC fails to prevent pregnancy or is mistimed, no associations with major congenital malformation or pregnancy complications have been noted with these hormonal methods (Jatlaoui, 2016; Levy, 2014).

With EC administration, nausea and vomiting can be an important side efect (American College of Obstetricians and Gynecologists, 2015b; Gemzell-Danielsson, 2013). Accordingly, an oral antiemetic may be prescribed at least 1 hour before each dose (Rodriguez, 2013). If a woman vomits within 2 hours of a dose, the dose is repeated.

For women who are candidates, Cu-IUD insertion is the most efective emergency contraceptive method and provides an efective 10-year method of contraception (Cheng, 2012). If an IUD is placed up to 5 days after unprotected coitus, the failure rate approximates only 0.1 percent (Cleland, 2012; Wu, 2010).

For mothers who are nursing exclusively, ovulation during the irst 10 weeks after delivery is unlikely. Nursing, however, is not a reliable method of family planning for women whose infants are on a daytime-only feeding schedule. Moreover, waiting for first menses involves a risk of pregnancy, because ovulation usually antedates menstruation. Certainly, after the first menses, contraception is essential unless the woman desires pregnancy.

As shown in Table 38-2, all methods may be suitable for nursing mothers after the initial weeks, during which thromboembolism risks are still great. With all hormonal methods, very small quantities are excreted in breast milk, but no adverse efects on infants have been reported (Phillips, 2015; World Health Organization, 1988). Although not robust, some older studies link decreased infant weight gain or milk volume with early initiation of combination oral contraceptives before 6 weeks postpartum (Lopez, 2015c; Tepper, 2016a).

Abdel-Aleem H, d'Arcangues C, Vogelsong M, et al: Treatment of vaginal bleeding irregularities induced by progestin only contraceptives. Cochrane Database Syst Rev 10:CD003449, 2013

Abrams LS, Skee OM, Wong FA, et al: Pharmacokinetics of norelgestromin and ethinyl estradiol from two consecutive contraceptive patches. J Clin PharmacoIn41:1232,n2001

Aksoy H, Aksoy U, Ozyurt S, et al: Lidocaine 10% spray to the cervix reduces pain during intrauterine device insertion: a double-blind randomised controlled trial. J Fam Plann Reprod Health Care 42(2):83,2016

American College of Obstetricians and Gynecologists: Brand versus generic oral contraceptives. Committee Opinion No. 375, August , Reairmed 2015a American College of Obstetricians and Gynecologists: Emergency contraception. Practice Bulletin No. 152, September 2015b

American College of Obstetricians and Gynecologists: Increasing access to contraceptive implants and intrauterine devices to reduce unintended pregnancy. Committee Opinion No. 642, October 2015c

American College of Obstetricians and Gynecologists: Adolescents and long-acting reversible contraception: implants and intrauterine devices. Committee Opinion No. 539, October 2012, Reairmed 2016a

American College of Obstetricians and Gynecologists: Depot medroxyprogesterone acetate and bone efects. Committee Opinion No. 602, June 2014, Reairmed 2016b

American College of Obstetricians and Gynecologists: Noncontraceptive use of hormonal contraceptives. Practice Bulletin No. 110, January 2010, Reafirmed 2016c

American College of Obstetricians and Gynecologists: Prevention of deep vein thrombosis and pulmonary embolism. Practice

No. 84, August 2007, Reairmed 2016d

American College of Obstetricians and Gynecologists: Access to emergency contraception. Committee Opinion No. 707, July 2017a

American College of Obstetricians and Gynecologists: Beneits and risks of sterilization. Practice Bulletin No. 133, February 2013, Reairmed 2017b

American College of Obstetricians and Gynecologists: Long-acting reversible contraception: implants and intrauterine devices. Practice Bulletin No. 186, November 2017c

Anttila L, Bachmann G, Hernadi L, et a1: Contraceptive eicacy of a combined oral contraceptive containing ethinyl oestradiol 20 !lg/drospirenone 3 mg administered in a 24/4 regimen: a pooled analysis of four open-label studies. Eur J Obstet Gynecol Reprod BioI 155(2):180,n2011

Aoun J, Dines VA, Stovall OW, et al: Efects of age, parity, and device type on complications and discontinuation of intrauterine devices. Obstet Gynecol 123(3):585,n2014

Apter 0, Gemzell-Danielsson K, Hauck B, et al: Pharmacokinetics of two lowdose levonorgestrel-releasing intrauterine systems and efects on ovulation rate and cervical function: pooled analyses of phase II and III studies. Ferti! Steriln101(6):1656,n2014

Arowojolu AO, Okewole A, Adekunle AO: Comparative evaluation of the efectiveness and safety of two regimens oflevonorgestrel for emergency contraception in Nigerians. Contraception 66(4):269, 2002

Backman T, Rauramo I, Huhtala S, et al: Pregnancy during the use of levonorgesrrel intrauterine system. Am J Obstet Gynecol 190(1):50, 2004

Bahamondes L, Brache V, Meirik 0, et a1: A 3-year multicentre randomized controlled trial of etonogestrel-and levo-norgestrel-releasing contraceptive implants, with non-randomized matched copper-intrauterine device controls. Hum Reprod 30(11):2527,n2015

Bahamondes L, Del Castillo S, Tabares G: Comparison of weight increase in users of depot medroxyprogesterone acetate and copper IUD up to 5 years. Contraception 64(4):223, 2001

Bayer Group: Jadelle: data sheet. 2015. Available at: http://www.medsafe.govt. nz/profs/datasheet/jIJadelleimplant.pdf. Accessed October 11n,n2016

Bayer HealthCare Pharmaceuticals: Yaz: highlights of prescribing information. 2015. Available at: http://labeling.bayerhealthcare.com/htmllproducts/pil fhclYAZ_Pl.pdf. Accessed October 11,n2016

Beckman LJ, Murray J, Harvey SM: he contraceptive sponge: factors in initiation and discontinuation of use. Contraception 40:481, 1989

Bednarek PH, Creinin MD, Reeves MF, et a1: Immediate versus delayed IUD insertion after uterine aspiration. N Engl J Med 364(23):2208, 2011

Bednarek PH, Creinin MD, Reeves MF, et a1: Post-Aspiration IUD Randomization (PAIR) Study Trial Group. Prophylactic ibuprofen does not improve pain with IUD insertion: a randomized trial. Contraception 91(3):193, 2015

Birgisson NE, Zhao Q, Secura GM, et al: Positive testing for Neisseria gonorrhoeae and Chlamydia trachomatis and the risk of pelvic inlammatory disease in IUD users. J Womens Health 24(5):354, 2015

Boortz HE, Margolis OJ, Ragavendra N, et al: Migration of intrauterine devices: radiologic indings and implications for patient care. Radiographies 32(2):335,n2012

Bosetti C, Bravi F, Negri E, et a1: Oral contraceptives and colorectal cancer risk: a systematic review and meta-analysis. Hum Reprod Update 15(5):489,2009

Brache V, Cochon L, J esam C, et al: Immediate pre-ovulatory administration of 30 mg ulipristal acetate significantly delays follicular rupture. Hum Reprod 25(9):2256, 2010

Briggs GG, Freeman RK: Drugs in Pregnancy and Lactation, 10th ed.

Philadelphia, Wolters K1uwer, 2015

Buhling KJ, Zite NB, Lotke P, et a1: Worldwide use of intrauterine contraception: a review. Contraception 89(3):162, 2014 Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines, 2015. MMWR 64(3):1,2015

Chan WS, Ray J, Wai EK, et al: Risk of stroke in women exposed to low-dose oral contraceptives: a critical evaluation of the evidence. Arch Intern Med 164:741,n2004

Chasan-Taber L, Willett WC, Manson JE, et al: Prospective study of oral contraceptives and hypertension among women in the United States. Circulation 94:483, 1996

Chen BA, Reeves MF, Hayes JL, et al: Postplacental or delayed insertion of the levonorgestrel intrauterine device after vaginal delivery: a randomized controlled trial. Obstet Gynecol 116(5):1079,2010

Cheng L, Che Y, Gulmezoglu AM: Interventions for emergency contraception.

Cochrane Database Syst Rev 2:CDOOI324, 2012

Cibula 0, Gompel A, Mueck AO, et al: Hormonal contraception and risk of cancer. Hum Reprod Update 16(6):631,n2010 Ciet P, Litmanovich DE: MR safety issues particular to women. Magn Reson Imaging Clin N Am 23(1):59, 2015

Civic 0, Scholes 0, Ichikawa L, et al: Depressive symptoms in users and nonusers of depot medroxyprogesterone acetate. Contraception 61 (6):385,02000

Clark MK, Sowers M, Levy B, et al: Bone mineral density loss and recovery during 48 months in irst-time users of depot medroxyprogesterone acetate. Fertil Steril 86: 1466, 2006

Cleland K, Raymond EG, Westley E, et al: Emergency contraception review: evidence-based recommendations for clinicians. Clin Obstet Gynecol 57(4): 741,n2014

Cleland K, Zhu H, Goldstuck N, et al: he eicacy of intrauterine devices for emergency contraception: a systematic review of 35 years of experience. Hum Reprod 27(7):1994, 2012

Cole JA, Norman H, Doherty M, et al: Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. Obstet Gynecol 109:339,n2007

Collaborative Group on Epidemiological Studies of Ovarian Cancer, Beral V, Doll R, et al: Ovarian cancer and oral contraceptives: collaborative reanalysis of data of 45 epidemiological studies including 23,25 women with ovarian cancer and 87,303 controls. Lancet 371:303, 2008

Collaborative Group on Hormonal Factors in Breast Cancer: Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Lancet 347: 1 13, 1996

Correia L, Ramos AB, Machado AI, et al: Magnetic resonance imaging and gynecological devices. Contraception 85(6):538, 2012 Cromer BA, Smith RD, Blair JM, et al: A prospective study of adolescents who choose among levonorgestrel implant (Norplant), medroxyprogesterone acetate (Depo-Provera), or the combined oral contraceptive pill as contraception. Pediatrics 94:687, 1994

Croxatto HB, Makirainen L: he pharmacodynamics and eicacy of Implanon. An overview of the data. Contraception 58:915, 1998 Curtis EM, Pine L: Actinomyces in the vaginas of women with and without intrauterine contraceptive devices. Am J Obstet Gynecol 140:880, 1981 Curtis M,Jadaoui TC, Tepper NK, et al: U.S. selected practice recommendations for contraceptive use, 2016. MMWR 65(4):1, 2016a Curtis KM, Tepper NK, Jadaoui TC, et al: U.S. medical eligibility criteria for contraceptive use, 2016. MMWR 65(3):1, 2016b Daniels K, Daugherty J, Jones J, et al: Current contraceptive use and variation by selected characteristics among women aged 15-44: United States, 2011-2013. Nat! Health Stat Report 86:1, 2015 Dieben TO, Roumen FJ, Apter 0: Eicacy, cycle control, and user acceptability of a novel combined contraceptive vaginal ring. Obstet Gynecol 100:585,2002 Dorlinger LJ: Metabolic efects of implantable steroid contraceptives for women. Contraception 65(1):47, 2002 Dragoman M, Curtis M, Gaield ME: Combined hormonal contraceptive use among women with known dyslipidemias: a systematic review of critical safety outcomes. Contraception 94(3):280, 2016 Drey EA, Reeves MF, Ogawa DO, et al: Insertion of intrauterine contraceptives immediately following first-and second-trimester abortions. Contraception 79(5):397, 2009 Eaton EF, Hoesley CJ: Barrier methods for human immunodeiciency virus prevention. Infect Dis Clin North Am 28(4):585,n2014 Edelman A, Micks E, Gallo MF, et al: Continuous or extended cycle vs. cyclic use of combined hormonal contraceptives for contraception. Cochrane Database Syst Rev 7:CD004695, 2014 ESHRE Capri Workshop Group: Venous thromboembolism in women: a speciic reproductive health risk. Hum Reprod Update 19(5):471,n2013 Etminan M, Takkouche B, Isorna FC, et al: Risk ofischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies. BMJ 330:63, 2005 European Society of Human Reproduction and Embryology-ESHRE Capri Workshop Group: Ovarian and endometrial function during hormonal contraception. Hum Reprod 16(7):1527,n2001 Farley TM, Rosenberg MJ, Rowe PJ, et al: Intrauterine devices and pelvic inlammatory disease: an international perspective. Lancet 339: 85, 1992 Fehring RJ, Schneider M, Raviele K, et al: Randomized comparison of two internet-supported fertility-awareness-based methods of family planning. Contraception 88(1):24, 2013 Ferguson CA, Costescu 0, Jamieson MA, et al: Transmural migration and perforation of a levonorgestrel intrauterine system: a case report and review of the literature. Contraception 93(1):81, 2016 FHI 360: Sino-implant (II) project. 2012. Available at: https:llwww.urbanreproductivehealth.org/sites/mle/iles/hi360_factsheecsino-implanc5.30.2012. pd. Accessed July 1, 2016 Finer LB, Zolna MR: Declines in unintended pregnancy in the United States, 2008-2011. N Engl J Med 374(9):843, 2016 Food and Drug Administration: Citizen petition partial approval and denial response from FDA COER to state of Wisconsin (Department of Justice). 2015a. Available at: https:llwww.regulations.gov/document?D = FDA2001-P-0123-0188. Accessed October 10, 2016 Food and Drug Administration: FDA approves Plan B One-Step emergency contraceptive for use without a prescription for all women of child-bearing potential. 2013. Available at: http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm358082.htm. Accessed June 21, 2016 Food and Drug Administration: FDA Drug Safety Communication: Updated information about the risk of blood clots in women taking birth control pills containing drospirenone. 2012. Available at: http://www.fda.gov/Drugsl DrugSafety/ucm299305.htm. Accessed July 7,n2016 Food and Drug Administration: FDA MedWatch 2004 Safety Alert-DepoProvera (medroxyprogesterone acetate injectable suspension). 2004. Available at: http://www.fda.gov/Safety/MedWatch/Safetylnformation/SafetyAlertsforHumanMedicalProducts/ucm154784.htm. Accessed October 10, 2016

Food and Drug Administration: Orange book: approved drug products with therapeutic equivalence evaluations. 2016. Available at: http://www.accessdata.fda.gov/scripts/cderlob/defaulr.cfm. Accessed October 10, 2016

Food and Drug Administration: Ortho Evra (norelgestrominl ethinyl estradiol) transdermal system. 2015b. Available at: http://www.fda.gov/Safety/Med �latch/SafetyInformation/ucm211821.htm. Accessed July 7,n2016

Fox Me, Oat-Judge J, Severson K, et al: Immediate placement of intrauterine devices after irst and second trimester pregnancy termination. Contraception 83(1):34, 2011

Fulkerson Schaefer 5, Gimovsky Ae, et al: Pregnancy and delivery with an intrauterine device in situ: outcomes in the National Inpatient Sample Database. J Matern Fetal Neonatal Med October 26, 201 [Epub ahead of print]

Furlong A: Ecropic pregnancy risk when contraception fails. J Reprod Med 47:881, 2002

Gallo MF, Grimes DA, Lopez LM, et al: Non-latex versus latex male condoms for contraception. Cochrane Database Syst Rev 1 :CD003550, 2006, Reassessed 2012a

Gallo MF, Grimes DA, Schulz KF: Cervical cap versus diaphragm for contraception. Cochrane Database Syst Rev 4:CD003551, 2002, Reassessed 2012b

Gallo MF, Lopez LM, Grimes DA, et al: Combination contraceptives: efects on weight. Cochrane Database Syst Rev 1:CD003987, 2014

Gardner JM, Mishell DR Jr: Analysis of bleeding patterns and resumption of fertility following discontinuation of a long-acting injectable contraceptive. Fertil Steril 21 :286, 1970

Gemzell-Danielsson K, Rabe T, Cheng L: Emergency contraception. Gynecol Endocrinol 29 Suppl 1: 1, 2013

Gemzell-Danielsson K, Schellschmidt I, Apter 0: A randomized, phase II study describing the eicacy, bleeding proile, and safety of two low-dose levonorgestrel-releasing intrauterine contraceptive systems and Mirena. Fertil Steril 97(3):616, 2012

Godfrey EM, Folger SG, Jeng G, et al: Treatment of bleeding irregularities in women with copper-containing IUDs: a systematic review. Contraception 87(5):549,n2013

Grimes DA, Jones LB, Lopez LM, et al: Oral contraceptives for functional ovarian cysts. Cochrane Database Syst Rev 4:CD006134, 2014

Grimes DA, Schulz KF: Antibiotic prophylaxis for intrauterine contraceptive device insertion. Cochrane Database Syst Rev 2:CD001327, 2001, Reaffirmed 2012

Grunloh OS, Casner T, Secura GM, et al: Characteristics associated with discontinuation of long-acting reversible contraception within the irst 6 months of use. Obstet Gynecol 122(6):1214,n2013

Hall KS, Trussell J, Schwarz EB: Progestin-only contraceptive pill use among women in the United States. Contraception 86(6):653,n2012 Hannaford PC, Selvaraj 5, Elliott M, et al: Cancer risk among users of oral contraceptives: cohort data from the Royal College of General Practitioners' oral contraception study. BMJ 335:651, 2007 Haring T, Mulders TMT: The combined contraceptive ring NuvaRing® and spermicide co-medication. Contraception 6 :271, 2003 Harrison-Woolrych M, Ashton J, Coulter 0: Uterine perforation on intrauterine device insertion: is the incidence higher than previously reported? Contraception 67:53, 2003 Heinemann K, Reed 5, Moehner 5: Risk of uterine perforation with levonorgestrel-releasing and copper intrauterine devices in the European Active Surveillance Study on Intrauterine Devices. Contraception 91(4):274, 2015 Heinemann LA, Weimann A, Gerken G, et al: Modern oral contraceptive use and benign liver tumors: the German Benign Liver Tumor Case-Control Study. Eur J Contracept Reprod Health Care 3: 194, 1998 Hidalgo MM, Lisondo C, Juliato CT, et al: Ovarian cysts in users ofImplanon and Jadelle subdermal contraceptive implants. Contraception 73(5):532, 2006 Horron LG, Simmons KB, Curtis M: Combined hormonal contraceptive use among obese women and risk for cardiovascular events: a systematic review. Contraception 94(6):590 2016 Hubacher 0, Lara-Ricalde R, Taylor OJ, et al: Use of copper intrauterine devices and the risk of tubal infertility among nulligravid women. N Engl J Med 345:561, 2001 Hubacher 0, Reyes V, Lillo 5, et al: Pain from copper intrauterine device insertion: randomized trial of prophylactic ibuprofen. Am J Obstet Gynecol 195(5):1272,n2006 International Collaboration of Epidemiological Studies of Cervical Cancer: Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies. Lancet 370: 1609, 2007

Janssen Pharmaceuticals: ORTHO EVRA prescribing information. 2015. Available at: http://www.accessdara.fda.gov/drugsatfda_docs/labeIl20 15/ 021180s0471bl.pdf. Accessed July 7,n2016 ]arlaoui TC, Riley H, Curtis M: Safety data for levonorgestrel, ulipristal acetate and Yuzpe regimens for emergency contraception. Contraception 93(2):93,n2016 ]arlaoui TC, Riley HE, Curtis KM: The safety of intrauterine devices among young women: a systematic review. Contraception 95(1): 17, 2017 ]echt EW, Benstein GS: The inAuence of copper on the motility of human spermatozoa. Contraception 7:381, 1973 lick SS, Hagberg W, Kaye ]A: ORTHO EVRA and venous thromboembolism: an update. Contraception 81(5):452, 2010 lick SS, Hernandez RK: Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data. BM] 340:d2151, 201n1

Kaislasuo], Suhonen S, Gissler M, et al: Uterine perforation caused by intrauterine devices: clinical course and treatment. Hum Reprod 28(6): 1546, 2013 Kapp N, Curtis KM: Hormonal contraceptive use among women with liver tumors: a systematic review. Contraception 80(4):387, 2009a

Kapp N, Tilley IB, Curtis KM: The efects of hormonal contraceptive use among women with viral hepatitis or cirrhosis of the liver: a systematic review. Contraception 80(4):381, 2009b

Katz Z, Lancet M, Skornik], et al: Teratogenicity of progestogens given during the irst trimester of pregnancy. Obstet Gynecol 75, 1985

Kho A, Chamsy 0]: Perforated intraperitoneal intrauterine contraceptive devices: diagnosis, management, and clinical outcomes. J Minim Invasive Gynecol 21(4):596, 2014

Kim C, Siscovick OS, Sidney S, et al: Oral contraceptive use and association with glucose, insulin, and diabetes in young adult women: the CARDIA Study. Coronary Artery Risk Development in Young Adults. Diabetes Care 25: , 2002

Kim SK, Romero R, Kusanovic ]P, et al: he prognosis of pregnancy conceived despite the presence of an intrauterine device (IUD). J Perinat Med 38(1):45,n2010

Kim YJ, Youm], Kim JH, et al: Actinomyces-like organisms in cervical smears: the association with intrauterine device and pelvic inAammatory diseases. Obstet Gynecol Sci 57(5):393, 2014

Kongsayreepong R, Chutivongse S, George P, et al: A multicentre comparative study of serum lipids and apolipoproteins in long-term users of DMPA and a control group of IUD users. World Health Organization. Task Force on Long-Acting Systemic Agents for Fertiliry Regulation Special Programme of Research, Development and Research Training in Human Reproduction. Contraception 7, 1993

Krattenmacher R: Drospirenone: pharmacology and pharmacokinetics of a unique progestogen. Contraception 62:29, 2000

Kuyoh MA, Toroitich-Ruto C, Grimes DA, et al: Sponge versus diaphragm for contraception. Cochrane Database Syst Rev 5:CD003n172 2013

Lammer E], Cordero ]F: Exogenous sex hormone exposure and the risk for major malformations. ]AMA 255:3128, 1986

Lawrie TA, Helmerhorst F 1, Maitra NK, et al: Types of progestogens in combined oral contraception: efectiveness and side-efects. Cochrane Database Syst Rev 5:CD004861, 2011 Lcte 1, Cuesta Me, Marin ]M, et al: Vaginal health in contraceptive vaginal ring users-a review. EurJ Contracept Reprod Health Care 18(4):234,2013

Levi EE, Stuart GS, Zerden ML, et al: Intrauterine device placement during cesarean delivery and continued use 6 months postpartum: a randomized controlled trial. Obstet Gynecol 126(1):5,n2015

Levy DP, Jager M, Kapp N, et al: Ulipristal acetate for emergency contraception: postmarketing experience after use by more than 1 million women. Contraception 89(5):431, 2014

Lidegaard 0, L0kkegaard E, Jensen A, et al: Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl] Med 366(24):2257, 20n12

Lidegaard 0, Nielsen LH, Skovlund CW, et al: Risk of venous thromboembolism from use of oral contraceptives containing diferent progestogens and oestrogen doses: Danish cohort study, 2001-9. B\1] 343:d6423, 2011

Lippesn]: Pelvic actinomycosis: a review and preliminary look at prevalence. Am J Obstet Gynecol 180:265, 1999

Lopez LM, Benholc A, Chen

I, et al: Hormonal contraceptives for contraception in overweight or obese women. Cochrane Database Syst Rev 8:CD008452, 2016

Lopez LM, Bernholc A, Hubacher 0, et al: Immediate postpartum insertion of intrauterine device for contraception. Cochrane Database Syst Rev 6:CD003036,n2015a

Lopez LM, Bernholc A, Zeng Y, et al: Interventions for pain with intrauterine device insertion. Cochrane Database Syst Rev 373,n2015b

Lopez LM, Chen M, Mullins S, et al: Steroidal contraceptives and bone fractures in women: evidence from observational studies. Cochrane Database Syst Rev 8:CD009849, 2012a

Lopez LM, Edelman A, Chen M, et al: Progestin-only contraceptives: efects on weight. Cochrane Database Syst Rev 7:CD008815, 2013a

Lopez LM, Grey W, Stuebe AM, et al: Combined hormonal versus nonhormonal versus progestin-only contraception in lactation. Cochrane Database Syst Rev 3:CD003988, 2015c

Lopez LM, Grimes DA, Gallo MF, et al: Skin patch and vaginal ring versus combined oral contraceptives for contraception. Cochrane Database Syst Rev 4:CD003552, 2013b

Lopez LM, Grimes DA, Schulz KF: Steroidal contraceptives: efect on carbohydrate metabolism in women without diabetes mellitus. Cochrane Database SYSt Rev 2:CD006133, 2014

Lopez LM, Kaptein A, Helmerhorst FM: Oral contraceptives containing drospirenone for premenstrual syndrome. Cochrane Database Syst Rev 2:CD006586,n2012b

Luan NN, Wu L, Gong TT, et al: Nonlinear reduction in risk for colorectal cancer by oral contraceptive use: a meta-analysis of epidemiological studies. Cancer Causes Control 26(1):65, 2015

MacClellan LR, Giles W, Cole ], et al: Probable migraine with visual aura and risk of ischemic stroke: the Stroke Prevention in Young Women Study. Stroke 38:2438, 2007

Madden T, McNicholas C, Zhao Q, et al: Association of age and pariry with intrauterine device expulsion. Obstet Gynecol 124(4):718,n2014

Madden T, Proehl S, AIlsworth JE, et al: Naproxen or estradiol for bleeding and spotting with the levonorgestrel intraurerine system: a randomized controlled trial. Am] Obstet GynecoI206(2):129.e1, 2012

Maheshwari S, Sarraj A, Kramer ], et al: Oral contraception and the risk of hepatocellular carcinoma. ] Hepatol 47:506, 2007

Mansour 0, Gemzell-Danielsson K, Inki P, et al: Fertiliry after discontinuation of contraception: a comprehensive review of the literature. Contraception 84(5):465,n2011

Mantha S, Karp R, Raghavan V, et al: Assessing the risk of venous thromboembolic events in women taking progestin-only contraception: a meta-analysis. BM] 345:e4944, 2012

Marchbanks PA, McDonald]A, Wilson HG, et al: Oral contraceptives and the risk of breast cancer. N Engl] Med 346(26):2025, 2002

Margolis KL, Adami HO, Luo], et al: A prospective study of oral contraceptive use and risk of myocardial infarction among Swedish women. Ferril Steril 88:310, 2007

Marr ], Gerlinger C, Kunz M: A historical cycle control comparison of two drospirenone-containing combined oral contraceptives: ethinyl estradiol 30 flg/drospirenone 3 mg administered in a 2117 regimen versus ethinyl estradiol 20 pg/drospirenone 3 mg administered in a 24/4 regimen. Eurn] Obstet Gynecol Reprod Bioi 162(1):91, 2012

Mauck C, Callahan M, Weiner DH, et al: A comparative study of the safety and eicacy of FemCap, a new vaginal barrier contraceptive, and the Orrho AIIFlex diaphragm. he FemCap Investigators' Group. Contraception 60(2): 1, 1999

Mendoza N, Lobo P, Lertxundi R, et al: Extended regimens of combined hormonal contraception to reduce symptoms related to withdrawal bleeding and the hormone-free interval: a systematic review of randomised and observational studies. Eur] Contracept Reprod Health Care 19(5):321,n2014

Merck: Mirena: highlights of prescribing information. 2015. Available at: http://labeling.bayerhealthcare.com/h tmIl products/pi/Mirena_PI. pdf. Accessed October 11, 2016

Merck: Nexplanon: highlights of prescribing information. 2016a. Available at: https:llwww.merck.com/product/usa/pi_circulars/n/nexplanon/nexplanon_pi.pd. Accessed December 27,n2016

Merck: NuvaRing: prescribing information. 2016b. Available at: https:llwww. merck.com/product/usa/pi_circulars/n/nuvaring/nuvarin�pi.pdf. Accessed December 27,n2016

Minnis MI, Padian NS: Efectiveness of female controlled barrier methods in preventing sexually transmitted infections and HIV: current evidence and future research directions. Sex Transm Infect 81(3):193, 2005 \lody SK, Kileyn], Rademaker A, et al: Pain control for intrauterine device insertion: a randomized trial of 1 % lidocaine paracervical block. Contraception 86(6):704, 2012 fommers E, Blum GF, Gent TG, et al: Nexplanon, a radiopaque etonogestrel implat in combination with a next-generation applicator: 3-year results of a noncomparative multicenter trial. Am ] Obstet Gynecol 20 (5):388. el,n2012

Moraes LG, Marchi NM, Pitoli AC, et al: Assessment of the quality of cervical mucus among users of the levonorgestrel-releasing intrauterine system at diferent times of use. Eur J Contracept Reprod Health Care 7: 1, 2016

Moreau e, Trussell ], Gilbert F, et al: Oral contraceptive tolerance: does the type of pill matter? Obstet Gynecol 109: 1277, 2007

Moschos E, Twickler OM: Does the type of intrauterine device affect conspicuity on 20 and 3D ultrasound? AJR Am J Roentgenol 196(6): 1439, 2011

Murthy AS, Creinin MD, Harwood B, et al: Same-day initiation of the transdermal hormonal delivery system (contraceptive patch) versus traditional initiation methods. Contraception 72(5):333, 2005

Nahum GG, Kaunitz M, Rosen K, et al: Ovarian cysts: presence and persistence with use of a 13.5 mg levonorgestrel-releasing intrauterine system. Contraception 91(5):412, 2015

Nakajima ST, Pappadakis J, Archer OF: Body mass index does not afect the eicacy or bleeding proile during use of an ultra-low-dose combined oral contraceptive. Contraception 93(1):52, 2016

Nelson AL, Cwiak C: Combined oral contraceptives (COCs). In Hatcher A, Trussell J, Nelson AL, et al (eds): Contraceptive Technology, 20th ed. New York, Ardent Media, 2011

Ngai SW, Fan S, Li S, et al: A randomized trial to compare 24 h versus 12 h double dose regimen of levonorgestrel for emergency contraception. Hum Reprod 20:307, 2005

Ngo LL, Ward KK, Mody SK: Ketotolac for pain control with intrauterine device placement: a randomized controlled trial. Obstet Gynecol 126(1):29,n2015

Nilsson CG, ihteenmaki PL, Luukkainen T: Ovarian function in amenorrheic and menstruating users of a levonorgestrel-releasing intrauterine device. Fertil Steriln41(1):52, 1984

Nishimura A, Otto CM, Bonow RO, et al: 2014 AHA/ACC Guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 129(23):e521, 2014

Nouri K, Pinker-Domenig K, Ott J, et al: Removal of non-palpable Implanon® with the aid of a hook-wire marker. Contraception ,2013

Oddsson K, Leifels-Fischer B, Wiel-Masson 0, et al: Superior cycle control with a contraceptive vaginal ring compared with an oral contraceptive containing 30 microg ethinylestradiol and 150 microg levonorgestrel: a randomized trial. Hum Reprod 20:557, 2005

Okusanya BO, Oduwole 0, Efa EE: Immediate postabortal insertion of intrauterine devices. Cochrane Database Syst Rev 7:CDOOl777, 2014

Ortiz ME, Croxatto HB: Copper-T intrauterine device and levonorgestrel intrauterine system: biological bases of their mechanism of action. Contraception 75:S 16, 2007

Pagano HP, Zapata LB, Berry-Bibee EN, et al: Safety of hormonal contraception and intrauterine devices among women with depressive and bipolar disorders: a systematic review. Contraception 94(6):641, 2016 Parkin L, Sharples K, Hernandez RK, et al: Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: nested case-control study based on UK General Practice Research Database. BM] 340:d2139, 2011 Pearlstein TB, Bachmann GA, Zacur HA, et al: Treatment of premenstrual dysphoric disorder with a new drospirenone-containing oral contraceptive formulation. Contraception 72:414, 2005 Perez-Medina T, Sancho-Sauco J, Rios M, et al: Hysteroscopy in pregnancyrelated conditions: descriptive analysis in 273 patients. J Minim Invasive GynecoIn21(3):417,n2014 Pergialiotis V, Vlachos DG, Protopappas A, et al: Analgesic options for placement of an intrauterine contraceptive: a meta-analysis. Eur J Contracept Reprod Health Care 19(3):149,n2014 Petitti DB, Piaggio G, Mehta S, et al: Steroid hormone contraception and bone mineral density: a cross-sectional study in an international population. he WHO Study of Hormonal Contraception and Bone Health. Obstet Gynecol 95(5):736, 2000

Pfizer: Depo-Provera (medroxyprogesterone acetate) injectable suspension: highlights of prescribing information. 201n5a. Available at: http://labeling. pizer.com/ShowLabeling.aspx?id = 522. Accessed October 11,n2016 Pfizer: Depo-subQ Provera 104: physician information. 2015b. Available at: http://labeling.pizer.com/ShowLabeling.aspx?id = 549. Accessed October 11,n2016 Phillips SJ, Tepper NK, Kapp N, et al: Progestogen-only contraceptive use among breastfeeding women: a systematic review. Contraception 94(3):226, 2015 Raps M, Curvers], Helmerhorst FM, et al: hyroid function, activated protein C resistance and the risk of venous thrombosis in users of hormonal contraceptives. hromb Res 133(4):640,n2014 Remington KM, Buller RS, Kelly JR: Efect of the Today contraceptive sponge on growth and toxic shock syndrome toxin-1 production by StaphyLococcus aureus. Obstet Gynecol 69:563, 1987 Rickert VI, Tiezzi L, Lipshutz J, et al: Depo Now: preventing unintended pregnancies among adolescents and young adults.] Adolesc Health 40(1):22,2007 Robinson GE, Burren T, Mackie IJ, et al: Changes in haemostasis after stopping the combined contraceptive pill: implications for major surgely. BMJ 302:269, 1991 Rodriguez MI, Godfrey EM, Warden M, et al: Prevention and management of nausea and vomiting with emergency contraception: a systematic review. Contraception 87(5):583, 2013

Ronnerdag M, Odlind V: Health efects of long-term use of the intrauterine levonorgestrel-releasing system. Acta Obstet Gynecol Scand 78:716, 1999 Rothman KJ, Louik C: Oral contraceptives and birth defects. N Engl J Med 299:522, 1978

Saav I, Stephansson 0, Gemzell-Danielsson K: Early versus delayed insertion of intrauterine contraception ater medical abortion-a randomized controlled trial. PLoS One 7(11):e48948, 2012

Samson M, Porter N, Orekoya 0, et al: Progestin and breast cancer risk: a systematic review. Breast Cancer Res Treat 155(1):3,n2016

Sano M, Nemoto K, Miura T, et al: endoscopic treatment of intrauterine device migration into the bladder with stone formation. J Endourol Case Rep 3(1):105,n2017

Savolainen E, Saksela E, Saxen L: Teratogenic hazards of oral contraceptives analyzed in a national malformation register. Am] Obstet GynecoIn140:521, 1981

Schafer ]E, Osborne LM, Davis AR, et al: Acceptability and satisfaction using Quick Start with the contraceptive vaginal ring versus an oral contraceptive. Contraception 73(5):488, 2006

Schiesser M, Lapaire 0, Tercanli S, et al: Lost intrauterine devices during pregnancy: maternal and fetal outcome after ultrasound-guided extraction. An analysis of 82 cases. Ultrasound Obstet Gynecol 23:486, 2004

Scholes 0, LaCroix AS, Ichikawa LE, et al: Injectable hormone contraception and bone density: results from a prospective study. Epidemioloy 13:581, 2002

Scholes 0, LaCroix AS, Ott SM, et al: Bone mineral density in women using depot medroxyprogesterone acetate for contraception. Obstet Gynecol 93:233, 1999

Schurks M, Rist PM, Bigal ME, et al: Migraine and cardiovascular disease: systematic review and meta-analysis. BM] 339:b3914, 2009

Seeger JD, Loughlin ], Eng PM, et al: Risk of thromboembolism in women taking ethinylestradiolldrospirenone and other oral contraceptives. Obstet Gynecol 110:587,n2007

Shaw A, Edelman AB: Obesity and oral contraceptives: a clinician's guide.

Best Pract Res Clin Endocrinol Metab 27(1):55,n2013

Shimoni N, Davis A, Ramos ME, et al: Timing of copper intrauterine device insertion after medical abortion: a randomized controlled trial. Obstet Gynecol 118(3):623, 2011

Shulman LP, Gabriel H: Management and localization strategies for the nonpalpable Implanon rod. Contraception 73:325, 2006

Silverberg SG, Haukkamaa M, Arko H, et al: Endometrial morphology during long-term use of levonorgestrel releasing intrauterine devices. Int J Gynecol Pathol 5:235, 1986

Simonatto P, Bahamondes MV, Fernandes A, et al: Comparison of rwo cohorts of women who expulsed either a copper-intrauterine device or a levonorgestrel-releasing intrauterine system. J Obstet Gynaecol Res 42(5):554,n2016

Sivin I, Campodonico 1, Kiriwat 0, et al: The performance of levonorgestrel rod and Norplant contraceptive implants: a 5 year randomized study. Hum Reprod 1, 1998

Sivin I, Viegas 0, Campodonico I, et al: Clinical performance of a new rwo-rod levonorgestrel contraceptive implant: a three-year randomized study with Norplant implants as controls. Contraception 55(2):73, 199

Sneed R, Westhof C, Morroni C, et al: A prospective study of immediate initiation of depot medroxyprogesterone acetate contraceptive injection. Contraception 71 (2) :99, 2005

S0rdal T, Inki P, Draeby J, et al: Management of initial bleeding or spotting ater levonorgestrel-releasing intrauterine system placement: a randomized controlled trial. Obstet Gynecol 121(5):934,n2013

Sothornwit J, Werawatakul Y, Kaewrudee S, et al: Immediate versus delayed postpartum insertion of contraceptive implant for contraception. Cochrane Database Syst Rev 4:CDOl1913, 2017

Stadel BV: Oral contraceptives and cardiovascular disease. N Engl J Med 305:612, 1981

Stegeman BH, de Bastos M, Rosendaal FR, et al: Diferent combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis. BM] 347:f5298, 2013

Steiner M, Lopez M, Grimes 0, et al: Sino-implant (II)-a levonorgestrel releasing two-rod implant: systematic review of the randomized controlled trials. Contraception 81n(3)n197, 2010

Stuart GS: Contraception and sterilization. In Hofman BL, Schorge JO, Bradshaw KD, et al: Williams Gynecology, 3rd ed. New York, McGraw-Hill Education, 2016

Stuart GS: Puerperal sterilization. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hill Education, 2017

Suchon , AJ Frouh F, Henneuse A, et al: Risk factors for venous thromboembolism in women under combined oral contraceptive. The PILi Genetic Risk Monitoring (PILGRIM) Study. Thromb Haemost 115(1):13,n2016

Sufrin CB, Postlethwaite 0, Armstrong A, et al: Neisseria gonorrhea and Chlamydia trachomatis screening at intrauterine device insertion and pelvic inflammatory disease. Obstet GynecoIn120(6):1314, 2012

Svendal G, Berk M, Pasco JA, et al: The use of hormonal contraceptive agents and mood disorders in women. J Afect Disord 140(1):92,n2012

Tatum HJ, Schmidt FH, Jain AK: Management and outcome of pregnancies associated with Copper-T intrauterine contraceptive device. Am J Obstet Gynecol 126:869, 1976

Tepper NK, Curtis KM, Nanda K, et al: Safety of intrauterine devices among women with HIV: a systematic review. Contraception 94(6):713, 2016a

Tepper NK, Phillips SJ, Kapp N, et al: Combined hormonal contraceptive use among breastfeeding women: an updated systematic review. Contraception 94(3):262n2016b

Tepper NK, Steenland MW, Gaield ME, et al: Retention of intrauterine devices in women who acquire pelvic inflammatory disease: a systematic review. Contraception 87(5):655, 2013

Tepper NK, Whiteman MK, Marchbanks PA, et al: Progestin-only contraception and thromboembolism: a systematic review. Contraception 94(6):678, 2016c

Tepper NK, Whiteman MK, Zapata LB, et al: Safety of hormonal contraceptives among women with migraine: a systematic review. Contraception 94(6):630,n2016d

Teva Women's Health: ParaGard T 380A intrauterine copper contraceptive: prescribing information, 2014. Available at: http://paragard.com/Pdf/ParaGard-PLpdf. Accessed October 10, 2016 he ACQUIRE Project: The Postpartum Intrauterine Device: a Training Course for Service Providers. New York, EngenderHealth, 2008 honneau PF, Almont TE: Contraceptive eicacy of intrauterine devices. Am J Obstet GynecoIn198:248, 2008

Tornblom-Paulander S, Tingaker BK, Werner A, et al: Novel topical formulation of lidocaine provides signiicant pain relieffor intrauterine device insertion: pharmacokinetic evaluation and randomized placebo-controlled trial. Ferril Steriln103(2):422, 2015

Trussell J: Contraceptive eicacy. In Hatcher A, Trussell J, Nelson AL, et al (eds): Contraceptive Technology, 20th ed. New York, Ardent Media, 2011a Trussell J: Contraceptive failure in the United States. Contraception 70:89, 2011b

Tsilidis KK, Allen NE, Key TJ, et al: Oral contraceptive use and reproductive factors and risk of ovarian cancer in the European Prospective Investigation into Cancer and Nutrition. Br J Cancer 105(9): 1436,n2011

Turok OK, Eisenberg DL, Teal SB, et al: A prospective assessment of pelvic infection risk following same-day sexually transmitted infection testing and levonorgestrel intrauterine system placement. Am J Obstet Gynecol 215(5):599.el, 2016

Urdl W, Apter 0, Alperstein A, et al: Contraceptive eicacy, compliance and beyond: factors related to satisfaction with once-weekly transdermal compared with oral contraception. Eur J Obstet Gynecol Reprod Bioi 121n:202, 2005 van H ylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, et al: The venous thrombotic risk of oral contraceptives, efects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ 339:b2921, 2009

Van Vliet A, Grimes DA, Helmerhorsr FM, et al: Biphasic versus mono phasic oral contraceptives for contraception. Cochrane Database Syst Rev 6:CD002032, 2006, Reairmed 2011a

Van Vliet HA, Grimes DA, Lopez LM, et al: Triphasic versus monophasic oral contraceptives for contraception. Cochrane Database Syst Rev 11:CD003553,n2011b

Van Vliet HA, Raps M, Lopez LM, et al: Quadriphasic versus monophasic oral contraceptives for contraception. Cochrane Database Syst Rev 1ln:CD009038,n2011c

Veres S, Miller L, Burington B: A comparison between the vaginal ring and oral contraceptives. Obstet Gynecol 104:555, 2004 Verhoeven CH, Dieben TO: he combined contraceptive vaginal ring, NuvaRing, and tampon co-usage. Contraception 69(3): 197, 2004a

Verhoeven CH, van den Heuvel MW, Mulders TM, et al: The contraceptive vaginal ring, NuvaRing, and antimycotic co-medication. Contraception 69(2): 129, 2004b

Vessey MP, Johnson B, Doll R, et al: Outcome of pregnancy in women using intrauterine devices. Lancet 1 :495, 1974

Vessey MP, Meisler L, Flavel R, et al: Outcome of pregnancy in women using diferent methods of contraception. Br J Obstet Gynaecol 86:548, 9 Vickery Z, Madden T, Zhao Q, et al: Weight change at 12 months in users of three progestin-only contraceptive methods. Contraception 88(4):503, 2013

Vinogradova Y, Coupland C, Hippisley-Cox J: Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD data-bases. BMJ 350:h2135, 2015

Wallach M, Grimes DA (eds): Modern Oral Contraception. Updates from he Contraception Report. Totowa, Emron, 2000

Walsh T, Grimes 0, Frezieres R, et al: Randomised controlled trial of prophylactic antibiotics before insertion of intrauterine devices. IUD Study Group. Lancet 351:1005, 1998

Watson: Ella prescribing information. 2010. Available at: http://www.access data. fda.govl drugsatfda_docs/labell20 1 01022474s0001bl.pdf. Accessed

December 27,n2016

Wechselberger G, Wolfram 0, Piilzl P, et al: Nerve injury caused by removal of an implantable hormonal contraceptive. Am J Obstet Gynecol 195(1):323, 2006

Westhof C: IUDs and colonization or infection with Actinomyces. Contraception 75:S48, 2007a

WesthofC, Heartwell S, Edwards S, et al: Initiation of oral contraceptive using a quick start compared with a conventional start: a randomized controlled trial. Obstet Gynecoln109:1270, 2007b

Westhof C, Jain JK, Milson, et al: Changes in weight with depot medroxyprogesterone acetate subcutaneous injection 104 mg/0.65 mL. Contraception 75:261,n2007c

Westhof C, Kerns J, Morroni C, et al: Quick start: novel oral contraceptive initiation method. Contraception 66: 141, 2002

WesthofC, Wieland 0, Tiezzi L: Depression in users of depo-medroxyprogesterone acetate. Contraception 51(6):351,n1995

Westhof CL, T orgal AH, Mayeda ER, et al: Pharmacokinetics of a combined oral contraceptive in obese and normal-weight women. Contraception 81(6):474,n2010

Whitaker AK, Chen BA, Borgatta L: Society of Family Planning Guidelines: postplacental insertion of intrauterine devices. Contraception October 5, 20n17 [Epub ahead of print)

Wilailak S, Vipupinyo C, Suraseranivong V, et al: Depot medroxyprogesterone acetate and epithelial ovarian cancer: a multicentre case-control study. BJOG 119(6):672,2012

World Health Organization: A multinational case-control study of ectopic pregnancy. Clin Reprod Ferriln3:131, 1985

World Health Organization: Acute myocardial infarction and combined oral contraceptives: results of an international multi-center case-control study. Lancet 349:1202, 1997

World Health Organization: Cardiovascular disease and use of oral and injectable progestogen-only contraceptives and combined injectable contraceptives. Resulrs of an international, multicenter, case-control study. Contraception 57:315, 1998

World Healrh Organization: Depot-medroxyprogesterone acetate (DMPA) and risk of endometrial cancer. Int J Cancer 49: 186, 1991a

World Health Organization: Depot-medroxyprogesterone acetate (DMPA) and risk of invasive squamous cell cervical cancer. Contraception 45(4): 299, 1992

World Health Organization: Depot-medroxyprogesterone acetate (DMPA) and risk of liver cancer. Int J Cancer 49(2):182, 1991b

World Health Organization: Efects of hormonal contraceptives on breast milk composition and infant growth. Stud Fam Plann 19/361, 1988

World Health Organization: Ischaemic stroke and combined oral contraceptives: results of an international, multi-center case-control study. Lancet 348:498, 1996

World Health Organization: Mechanism of action, safety and eicacy of intrauterine devices. Technical Reporr No. 753, Geneva, Switzerland, WHO, 1987

World Health Organization: vledical Eligibility for Contraceptive Use, 5th ed.

Geneva, World Health Organization, 2015

Wu S, Godfrey EM, Wojdyla 0, et al: Copper T380A intrauterine device for emergency contraception: a prospective, multicentre, cohort clinical trial. BJOG 117(10):1205,2010

XU JX, Remedios E, Duthie A, et al: Intrauterine contraceptive device: cause of small bowel obstruction and ischaemia. ANZ J Surg May 26, 2015 [Epub ahead of print)

XU JX, Rivera R, Dunson TR, et al: A comparative study of two techniques used in immediate postplacental insertion (IPPI) of the Copper T-380A IUD in Shanghai, People's Republic of China. Contraception 54(1):33, 1996

Yamazaki M, Dwyer K, Sobhan M, et al: Efect of obesity on the efectiveness of hormonal contraceptives: an individual participant data meta-analysis. Contraception 92(5):445, 2015

Yonkers A, Brown C, Pearlstein TB, et al: Eicacy of a new low-dose oral contraceptive with drospirenone in premenstrual dysphoric disorder. Obstet Gynecol 106:492, 2005

Zeino MY, Wietfeldt ED, Advani V, et al: Laparoscopic removal of a copper intrauterine device from the sigmoid colon. JSLS 15(4):568,n2011

Zieman M, Guillebaud J, Weisberg E, et al: Contraceptive eicacy and cycle control with the Orrho Evra/Evra transdermal system: the analysis of pooled data. Fertil Steril 77:S13, 2002

PUERPERAL TUBAL STERILIZATION.................702

NON PUERPERAL TUBAL STERILIZATION............ 704

COMPLICATIONS. . . . . . . ............. 704

TRANSCERVICAL STERILIZATION................... 705

VASECTOMY....................................706

In order, therore, to render a woman permanenty sterile by an operation upon the tubes, they must be excised by wedge-shaped incisions at the cornua of the uterus and the wounds closed by sutures.

-J. Whitridge Williams (1903)

Sterilization is a popular choice of contraception for millions of men and women. Among women using contraception, one third rely on either male or female sterilization (Daniels, 2015). This procedure is indicated in those requesting sterilization and who clearly understand its permanence and its diicult and often unsuccessful reversal. All persons considering sterilization should also be counseled regarding alternative contraceptive choices (American College of Obstetricians and Gynecologists, 2017a,c).

Female sterilization is usually accomplished by occlusion, excision, or division of the fallopian tubes. Puerperal sterilization procedures follow cesarean or vaginal delivery and approximately 7 percent of all live births in the United States (Moniz, 2017). Nonpuerperal tubal sterilization is done at a time unrelated to recent pregnancy and is also termed interval sterilization.

For several days postpartum, the uterine fundus lies at the level of the umbilicus, and fallopian tubes are accessible directly beneath the abdominal wall. Moreover, abdominal laxity allows easy repositioning of the incision over each uterine cornu.

On our service, puerperal tubal ligation is performed by a surgical team dedicated to this role the morning after delivery. This timing minimizes hospital stay but lowers the likelihood that postpartum hemorrhage would complicate recovery following surgery. In addition, the status of the newborn can be better ascertained before surgery. In contrast, some prefer to perform sterilization immediately following delivery and use neuraxial analgesia already placed for labor. In this model, barriers to sterilization can be lessened by designating these postpartum surgeries as urgent, especially in high-volume labor and delivery units, which usually prioritize limited operating-room availability for intrapartum procedures (American College of Obstetricians and Gynecologists, 2016; Potter, 2013).

Various techniques are now used to disrupt tubal patency. In general, a midtubal segment of fallopian tube is excised, and the severed ends seal by fibrosis and peritoneal regrowth. Commonly used methods of puerperal sterilization include the Parkland, Pomeroy, and modiied Pomeroy techniques (American College of Obstetricians and Gynecologists, 2017a). Less often, Filshie clips are used (Madari, 2011). Irving and Uchida techniques or Kroener fimbriectomy are rarely used because of their increased required dissection or unfavorably high failure rates. Also, in the absence of uterine or other pelvic disease, hysterectomy solely for sterilization at the time of cesarean delivery, early in the puerperium, or even remote from pregnancy is diicult to justiy. It carries significantly increased surgical morbidity compared with tubal sterilization.

Evidence suggests that the fallopian tube may be the origin of pelvic serous carcinomas, especially those of the ovary. With this knowledge, the Society of Gynecologic Oncologists (2013) and American College of Obstetricians and Gynecologists (2017b) recommend consideration of salpingectomy to lower cancer risks. Speciically, for women at average risk of ovarian cancer, risk-reducing salpingectomy should be discussed and considered with patients at the time of abdominal or pelvic surgery, at hysterectomy, or in lieu of tubal ligation.

Spinal analgesia is typically selected for cases scheduled for the first postpartum day. If done more proximate to delivery, the same epidural catheter used for labor analgesia can be used for sterilization analgesia. Notably, for those with preeclampsia,

HELLP (hemolysis, �levated liver enzyme levels, low 2latelet count) syndrome, or gestational thrombocytopenia, platelet levels should be > 100,000 for spinal blockade (Chap. 25, p.

496). General anesthesia may be less desirable due to residual pregnancy-related airway vulnerabilities (Bucklin, 2003). The bladder is emptied before surgery to avoid its laceration. A full bladder can also push the fundus above the umbilicus.

A small infraumbilical incision is ideal for several reasons. As noted, the fundus in most cases lies near the umbilicus. Second, the umbilicus usually remains the thinnest portion of the anterior abdominal wall and requires less subcutaneous dissection to reach the linea alba fascia. hird, an infraumbilical incision ofers fascia with suicient integrity to provide a closure that has minimal risk for later incisional hernia. Last, incisions that follow the natural curve of the lower umbilical skin fold yield suitable cosmesis. A 2-to 4-cm transverse or vertical skin incision is usually suicient for normal-weight women. For obese women, a 4-to 6-cm incision may be needed for adequate abdominal access.

Beneath this incision, the subcutaneous tissue is bluntly separated to reach the linea alba fascia. For this, an Allis clamp can be opened and closed as downward pressure is exerted. Similarly, the blades of two army-navy retractors both pulling in downward yet opposite directions can part the subcutaneous layer. Clearing this fatty tissue away from the fascia isolates the fascia for incision and for later closure without intervening fat, which may impede wound healing.

he fascial incision may be transverse or vertical and follows the same orientation of the skin incision. For this, once the linea alba is reached, it is grasped with two Allis clamps-one placed on either side of the planned fascial incision. The purchase of tissue with each clamp should be substantial and creates a small roll of fascia to be incised. Often, the peritoneum is incorporated simultaneously and entered. If not, the peritoneum is grasped with two hemostats and sharply cut. Others may prefer to bluntly enter with a single index finger. Notably, if the initial fascial incision is too small, it can be extended with curved Mayo scissors.

Adequate exposure is critical, and army-navy or appendiceal retractors are suitable. For obese women, a slightly larger incision and narrow deeper retractors may be required. If bowel or omentum is obstructing, Trendelenburg position can help displace these cephalad. Digitally packing with a single, moist, fanned-out piece of surgical gauze can also be used, but a hemostat should always be attached to the distal end to avert

FIGURE 39-1 Parkland method. A.An avascular site in the meso salpinx adjacent to the fallopian tube is perforated with a small hemostat. The jaws are opened to separate the fallopian tube from the adjacent mesosalpinx for approximately 2.5 cm. B. The freed fallopian tube is ligated proximally and distally with O-chromic suture. The intervening segment of approximately 2 cm is excised, and the excision site is inspected for hemostasis. This method was designed to avoid the initial intimate proximity of the cut ends of the fallopian tube inherent with the Pomeroy procedure. (Reproduced with permission from Hoffman BL, Corton MM: Surgeries for benign gynecologic conditions. In Hoffman BL, Schorge JO, Bradshaw KD, et al: Williams Gynecology, 3rd ed. New York, McGraw-Hili Education, 201o6.) its retention. At times, tilting the entire table to the opposite side of the tube being exposed assists tube isolation.

he fallopian tube is identiied and grasped at its midportion with a Babcock clamp, and the distal fimbria conirmed. his prevents confusing the round ligament with the midportion of the tube. A common reason for sterilization failure is ligation of the wrong structure, typically the round ligament. Therefore, identiication and isolation of the distal tube prior to ligation is necessary. Whenever the tube is inadvertently dropped, it is mandatory to repeat this identification process. Surgical steps for ligation are outlined in Figures 39-1 and 39-2.

FIGURE 39-2 Pomeroy method. During ligation of a tubal loop, plain catgut is used to ensure prompt absorption of the ligature and subsequent separation of the severed tubal ends. (Reproduced with permission from Hoffman BL, Corton MM: Surgeries for benign gynecologic conditions. In Hoffman BL, Schorge JO, Bradshaw KD, et al: Williams Gynecology, 3rd ed. New York, McGraw-Hili Education, 201o6.)

Steps of salpingectomy are shown in Figure 39-3. he umbilical incision generally will need to be larger to allow an adequate view of the tube and mesosalpinx and to place clamps. With total salpingectomy, the entire mesosalpinx must be divided to free the fallopian tube.

In two small cohorts undergoing salpingectomy ater vaginal birth, surgical times were longer than for tubal occlusion, and in one report, blood loss was increased (Danis, 2016; Powell, 2017).

With salpingectomy and cesarean delivery, total blood loss rates were not statistically higher (Powell, 2017; Shinar, 2017).

After surgery, diet is given as tolerated. Ileus is infrequent and should prompt concern for bowel injury, albeit rare. Most women have an uncomplicated course and are discharged on the first postoperative day.

These techniques and other modiications basically consist of (1) ligation and resection at laparotomy as described earlier for puerperal sterilization; (2) application of permanent rings, clips, or inserts to the fallopian tubes by laparoscopy or hysteroscopy; or (3) electrocoagulation of a tubal segment, usually through a laparoscope. A detailed description and illustration of these can be found in Wiliams Gynecoloy, 3rd edition (hompson, 2016).

In the United States, a laparoscopic approach to interval tubal sterilization is the most common. The procedure is frequently performed in an ambulatory surgical setting under general anesthesia. In almost all cases, the woman can be discharged within several hours. Minilaparotomy using a 3-cm suprapubic incision is also popular, especially in resource-poor countries. Major morbidity is rare with either minilaparotomy or laparoscopy. lthough not often used, the peritoneal cavity can be entered through the posterior vaginal fornix via colpotomy to perform tubal interruption.

Pregnancy following sterilization is infrequent. The Collaborative Review of Sterilization (CREST) study followed 10,863 women who had undergone tubal sterilization from 1978 through 1986 (Peterson, 1996). he cumulative failure rate for the various tubal procedures was 18.5 per 1000 or approximately

FIGURE 39-3 A. With salpingectomy, the mesosalpinx is sequentially clamped, cut, and ligated. B. At the cornu, clamps are placed across the fallopian tube and its adjacent mesosalpinx prior to tubal transection. (Reproduced with permission from Stuart GS: Puerperal sterilization. In Yeomans ER, Hoffman BL, Gilstrap, III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili, 201o7.) 0.5 percent. The study found puerperal sterilization to be highly efective. The 5-year failure rate was 5 per 1000, and for 12 years, it was 7 per 1000.

Puerperal sterilization fails for two major reasons. First, sur gical errors occur and include transection of the round ligament or only partial transection of the tube. For this reason, both tubal segments are submitted for pathological confirmation.

Second, a fistulous tract or spontaneous reanastomosis may form between the severed tubal stumps.

Approximately 30 percent of pregnancies that follow a failed tubal sterilization procedure are ectopic. his rate is 20 percent for those following a postpartum procedure (Peterson, 1996, 1997). hus, any symptoms of pregnancy in a woman after tubal sterilization must be investigated, and an ectopic preg nancy excluded.

Overall, risks for ovarian cancer decline and for breast cancer are unafected following sterilization (Gaudet, 2013; Pearce, 2015). Women who have undergone tubal sterilization are highly unlikely to subsequently have salpingitis (Levgur, 2000). For menorrhagia and intermenstrual bleeding following tubal sterilization, most studies of the risk have found no association (DeStefano, 1985; Peterson, 2000; Shy, 1992).

Less objective but important psychological sequelae of sterilization have also been evaluated. In the CREST study, Costello (2002) found that tubal ligation did not change sexual interest or pleasure in 80 percent of women. In most of the 20 percent of women who did report a change, positive efects were 10 to 15 times more likely.

Invariably, a number of women express regrets regarding sterilization, and this is especially true if it is performed at a younger age (Curtis, 2006; Kelek:i, 2005). In the CREST study, Jamieson (2002) reported that 7 percent of women who had undergone tubal ligation had regrets by 5 years. his is not limited to their own sterilization, because 6.1 percent of women whose husbands had undergone vasectomy had similar regrets.

No woman should undergo tubal sterilization believing that subsequent fertility is guaranteed either by surgery or by assisted reproductive techniques. Both approaches are technically dificult, expensive, and not always successful. In general, pregnancy rates after tubal reversal favor women with age younger than 35 years, with 7 cm of remaining tube, with a short time from antecedent sterilization, and with isthmic-isthmic repairs. With reanastomosis via laparotomy, rates of live births range from 44 to 82 percent (Deieux, 2011; Malacova, 2015). The rate of ectopic pregnancy is 2 to 10 percent after reanastomosis (American Society for Reproductive Medicine, 2015). With reanastomosis to reverse Essure sterilization, only 27 percent of women had subsequent live births (Monteith, 2014).

Devices can be inserted via hysteroscopy to occlude the proximal fallopian tubes. he Essure micro insert has a ine stainless-steel inner coil enclosed in polyester fibers and an expandable outer coil of Nitinol-a nickel and titanium alloy (Fig. 39-4). he outer coil expands after placement, allowing the inner fibers to expand. These synthetic fibers incite a chronic inflammatory response to prompt local tissue ingrowth that leads to complete tubal lumen occlusion. For hysteroscopic placement, sedation, paracervical block, or both may be used, and in-oice insertion is often elected. Devices cannot be placed in all women, and some do not tolerate the procedure while awake (DuY, 2005). Bilateral placement is achieved in 81 to 98 percent of cases on a first attempt (la Chapelle, 2015).

FIGURE 39-4 Essure microinsert placement hysteroscopically and ingrowth of tissue. (Reproduced with permission from Thompson M, Kho K: Minimally invasive surgery. In Hoffman BL, Schorge JO, Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGraw-Hill,o201o6.)

Since the introduction of Essure, cited adverse events include abnormal bleeding, perforation of the uterus or fallopian tubes from device migration, and allergy or hypersensitivity reactions, especially to the nickel component (Al-Sai, 2013; IIao, 2015). Some events resulted in device removal that requires abdominal surgery (Casey, 2016; Lazorwitz, 2017). To provide more information of the risks and beneits, the Food and Drug Administration (2016) has drafted a black box warning and patient-decision checklist to aid counseling.

Because complete tubal blockage is not 100 percent, it must be conirmed by hysterosalpingography (HSG) 3 months following surgery (Bayer Healthcare, 2002). With such confirmation, eicacy rates for these devices reach 98 to 99 percent (Chudnof, 2015; Munro, 2014). In real-world settings, pregnancies following transcervical sterilization are most frequently attributed to conception before insertion or HSG and to noncompliance with HSG or its misinterpretation. Although data are limited to small case series, pregnancies conceived with Essure in place do not appear to be at increased risk from the device (Arora, 2014; Veersema, 2014).

Another insert, Adiana, also stimulates tissue ingrowth for tubal occlusion using a cylindrical, nonabsorbent silicone elastomer matrix. However, for inancial reasons, production of this device has now been discontinued by the manufacturer

Vasectomy is safer than tubal sterilization because it is less invasive and is performed with local analgesia (American College of Obstetricians and Gynecologists, 2017a). In a review to compare the two, Hendrix and associates (1999) found that, compared with vasectomy, female tubal sterilization rate, a 10-to 37 -fold failure rate, and costs three times as much.

Incision on left side of One disadvantage is that sterilizascrotum, and in tunica tion following vasectomy is not immediate. Complete release of sperm stored

V2" of duct removed

Incision on in the reproductive tract beyond the right side Ends are sealed interrupted vas deferens takes approximately 3 months or 20 ejaculations.Epididymis The American Urological Association recommends a postprocedural semen analysis at 8 to 16 weeks to document sterility (Sharlip, 2012). During the period before azoospermia is documented, another form of contraception should be used.

FIGURE 39-5 Anatomy of male reproductive system showing procedure for vasectomy.

The failure rate for vasectomy dur (Hologic, 2012). hat said, patients with these inserts may be encountered and can consider their device efective.

lthough not currently available in the United States, quinacrine pellets cause sclerosis at the tubal ostia. Placement at the uterine fundus with an IUD-type inserter method allows pellet migration into the tubal ostia. Of drawbacks, prior cancer associations have been disproved (Sokal, 201 Oa,b). Eicacy appears enhanced by technique modification. In one early cohort of 1335 treated women, pregnancy rates at 10 years were 12 percent (Sokal, 2008). Following insertion technique improvement, a 2-year failure rate of 1.2 percent was calculated by Lippes (2015).

Currently, up to a half million men in the United States undergo vasectomy each year (Barone, 2006; Eisenberg, 2010). And 5 percent of women rely on this method for contraception (Daniels, 2015). For sterilization, the vas deferens lumen is disrupted to block the passage of sperm from the testes. Most commonly, a no-scapel vasectomy (NS) accomplishes this with one specialized instrument that grasps the vas deferens and surrounding skin together. A second dissector tool punctures the skin and then isolates the vas (Rogers, 2013). As clariied by the American Urological Association, minimaly invasive vasectomy includes any vas isolation procedure, including the no-scalpel technique, which uses a skin incision measuringr:;1 cm and requires minimal vas dissection (Fig. 39-5) (Sharlip, 2012). Compared with conventional vasectomy that employs incisions > 1 cm and greater dissection, the no-scalpel technique is associated with fewer minor surgical complications, but each is equally efective (Cook, 2014).

ing the first year is 9.4 per 1000 procedures and 11.4 per 1000 at 2,r3, and 5 years Qamieson, 2004). Failures result from unprotected intercourse too soon after ligation, incomplete occlusion of the vas deferens, or recanalization (Awsare, 2005; Deneux-haraux, 2004).

Other than regrets, long-term consequences are rare. One is troublesome chronic scrotal pain, which develops in up to 15 percent of men (Leslie, 2007; vlanikandan, 2004). Previous concerns for atherogenesis, immune-complex mediated disease, testicular cancer, and prostate cancer have been allayed by a number of investigators (Bernal-Delgado, 1998; Giovannucci, 1992; Goldacre, 1983; M0ller, 1994).

Reanastomosis of the vas deferens can be completed most efectively using microsurgical techniques. In general, conception rates following reversal are adversely afected by longer duration from vasectomy, poor sperm quality found at reversal, and type of reversal procedure required (American Society for Reproductive Medicine, 2008).

Al-Safi ZA, Shavell VI, Hobson DT, et al: Analysis of adverse events with Essure hysteroscopic sterilization reported to the Manufacturer and User Facility Device Experience database. J Minim Invasive Gynecol 20(6):825, 2013

American College of Obstetricians and Gynecologists: Access to postpartum sterilization. Committee Opinion No. 530, July 2012, Reairmed 2016 American College of Obstetricians and Gynecologists: Benefits and risks of sterilization. Practice Bulletin No. 133, February 2013, Reairmed 2017a

American College of Obstetricians and Gynecologists: Salpingectomy for ovarian cancer prevention. Committee Opinion No. 620, January 2015b, Reairmed 2017b

American College of Obstetricians and Gynecologists: Sterilization of women: ethical issues and considerations. Committee Opinion No. 695, Apri 20l7c

American Society for Reproductive Medicine: Vasectomy reversal. Fertil Steril 90:S78, 2008

American Society for Reproductive Medicine: Role of tubal surgety in the era of assisted reproductive technology: a committee opinion. Fertil Steril 103(6):e37,n2015

Arora P, Arora RS, Cahill 0: Essure for management of hydrosalpinx prior to in vitro fertilisation-a systematic review and pooled analysis. B]OG 121(5):527,n2014

Awsare N, Krishnan ], Boustead GB, et al: Complications of vasectomy. Ann R Coli Surg Engl :406, 2005 Barone A, Hutchison PL, Johnson CH, et al: Vasectomy in the Unites States, 2002. ] U rol 176:232, 2006

Bayer Healthcare: Essure: instruction for use. 2002. Available at: http://www. hcp.essure-us.com/ assets/ pdf/Link%20 Essure%20 IFU. pdf. Accessed April 28, 2016

Benal-Delgado E, Latour-Perez ], Pradas-Arnal F, et al: The association between vasectomy and prostate cancer: a systematic review of the literature. Fertil Steril 0:201, 1998

Bucklin BA: Postpartum tubal ligation: timing and other anesthetic consideradons. Clin Obstet Gynecol 46(3):657, 2003

Casey], Aguirre F, Yunker A: Outcomes of laparoscopic removal of the Essure sterilization device for pelvic pain: a case series. Contraception 94(2): 190, 2016

Chudnof SG, Nichols JE ]r, Levie M: Hysteroscopic Essure inserts for permanent contraception: extended follow-up results of a phase III multicenter international study. J Minim Invasive Gynecol 22(6):95n1, 2015

Cook A, Pun A, Gallo MF, et al: Scalpel versus no-scalpel incision for vasectomy. Cochrane Database SYSt Rev 3:CD004112, 2014

Costello C, Hillis S, Marchbanks P, et al: he efect of interval tubal sterilizadon on sexual interest and pleasure. Obstet Gynecol 100:3, 2002

Curtis M, Mohllajee AP, Peterson HB: Regret following female sterilization at a young age: a systematic review. Contraception 3:205, 2006

Daniels K, Daugherty ], Jones ], et al: Current contraceptive use and variation by selected characteristics among women aged 15-44: United States, 2011-2013. Nat! Health Stat Report 86:1,n2015

Danis RB, Della Badia CR, Richard SD: Postpartum permanent sterilization: could bilateral salpingectomy replace bilateral tubal ligation? J Minim Invasive GynecoIn23(6):928, 2016

Deieux X, Morin Surroca M, Faivre E, et al: Tubal anastomosis after tubal sterilization: a review. Arch Gynecol Obstet 83(5):1n149,n201n1

Deneux-Tharaux C, Kahn E, Nazerali H, et al: Pregnancy rates after vasectomy: a survey of U.S. urologists. Contraception 69:401, 2004

DeStefano F, Perlman ]A, Peterson HB, et al: Long term risk of menstrual disturbances after tubal sterilization. Am J Obstet GynecoIn152:835, 1985

DuY S, Marsh F, Rogerson L, et al: Female sterilization: a cohort controlled comparative study of Essure versus laparoscopic sterilization. BJOG 112: 1522, 2005

Eisenberg ML, Lipshultz LI: Estimating the number of vasectomies performed annually in the United States: data from the National Survey of Family Growth. J Urol 184(5):2068,n2010

Food and Drug Administration: Labeling for permanent hysteroscopicallyplaced tubal implants itended for sterilization. 2016. Available at: http:// ww.fda.gov/downloads/MedicaIDevices/DeviceRegulationandGuidance/ GuidanceDocuments/UCM488020.pdf. Accessed April 28, 2016

Gaudet MM, Patel AV, Sun J, et al: Tubal sterilization and breast cancer incidence: results from the cancer prevention study II nuuition cohort and meta-analysis. Am J Epidemiol 7(6):492,n2013

Giovannucci E, Tosteson TD, Speizer FE, et al: A long-term study of mortality in men who have undergone vasectomy. N Engl ] Med 326: 1392, 1992 Goldacre ]M, Holford TR, Vessey MP: Cardiovascular disease and vasectomy.

N Engl ] Med 308:805, 1983

Hendrix NW, Chauhan SP, Morrison JC Sterilization and its consequences.

Obstet Gynecol Surv 66, 1999

Hofman BL, Corton MM: Surgeries for benign gynecologic conditions. In Hofman BL, Schorge JO, Bradshaw KD, et al: Williams Gynecology, 3rd ed. New York, McGraw-Hill Education, 2016

Hologic: Hologic announces second quarter iscal 2012 operating results. 2012.

Available online at: ile:/ / /C/Users/bhofm/Downloads/Hologic-AnnouncesSecond-Quarter-Fiscal-20 12-0perating-Results. pdf. Accessed May 19, 2016

Jamieson DJ, Costello C, Trussell ], et al: The risk of pregnancy after vasectomy. Obstet Gynecol 103:848, 2004

Jamieson DJ, Kaufman SC, Costello C, et al: A comparison of women's regret after vasectomy versus tubal sterilization. Obstet Gynecol 99: I073, 2002

Kelek:i S, Erdemoglu E, Kuduk S, et al: Risk factors for tubal ligation: regret and psychological efects. Impact of Beck Depression Inventoty. Contraception ,2005 la Chapel Ie CF, Veersema S, Brolmann HA, et al: Efectiveness and feasibility of hysteroscopic sterilization techniques: a systematic review and metaanalysis. Ferril Steriln103(6):1516, 2015

Lazorwitz A, Tocce K: A case series of removal of nickel-titanium sterilization microinserts from the uterine cornua using laparoscopic electrocautety for salpingectomy. Contraception 96(2):96, 2017

Leslie TA, Illing RO, Cranston DW, et al: he incidence of chronic scrotal pain after vasectomy: a prospective audit. BJU Int 100:n1330,n2007

Levgur M, Duvivier R: Pelvic inAammatory disease after tubal sterilization: a review. Obstet Gynecol Surv 55:41, 2000

Lippes J: Quinacrine sterilization (QS): time for reconsideration. Contraception 92(2):91, 2015

Madari S, Varma R, Gupta J: A comparison of the modified Pomeroy tubal ligation and Filshie clips for immediate postpartum sterilisation: a systematic review. Eur] Contracept Reprod Health Care 16(5):341,n2011

Malacova E, Kemp-Casey A, Bremner A, et al: Live delivety outcome after tubal sterilization reversal: a population-based study. Ferril Steril 104(4):92, 2015

Manikandan R, Srirangam SJ, Pearson E, et al: Early and late morbidity after vasectomy: a comparison of chronic scrotal pain at 1 and 10 years. BJU Int 93:571,n2004

Mao], pfeifer S, Schlegel P, et al: Safety and eicacy of hysteroscopic sterilization compared with laparoscopic sterilization: an observational cohort study. BM] 351:h5162, 2015

M01ler H, Knudsen LB, Lynge E: Risk of testicular cancer after vasectomy: cohort study of over 73,000 men. BM] 309:295, 1994

Moniz MH, Chang T, Heisler M, et al: Inpatient postpartum long-acting reversible conuaception and sterilization in the United States, 2008-2013. Obstet Gynecol 129(6): 1078,n20]

Monteith CW, Berger GS, Zerden ML: Pregnancy success after hysteroscopic sterilization reversal. Obstet Gynecol 124(6):1183,n2014

Munro MG, Nichols ]E, Levy B, et al: Hysteroscopic sterilization: lO-year retrospective analysis of worldwide pregnancy reportS. ] Minim Invasive Gynecol 21(2):245, 2014

Pearce CL, Stram DO, Ness RB, et al: Population distribution of lifetime risk of ovarian cancer in the United States. Cancer Epidemiol Biomarkers Prev 24(4):671,n2015

Peterson HB, ]eng G, Folger SG, et al: he risk of menstrual abnormalities after tubal sterilization. N Engl ] Med 343: 1681, 2000

Peterson HB, Xia Z, Hughes ]M, et al: The risk of ectopic pregnancy after tubal sterilization. U.S. Collaborative Review of Sterilization Working Group. N Engl J Med 336(11):762, 1997

Peterson HB, Xia Z, Hughes ]M, et al: The risk of pregnancy after tubal sterilization: findings from the U.S. Collaborative Review of Sterilization. m ] Obstet Gynecol 1 4: 1161, 1996

Potter JE, Stevenson A], White K, et al: Hospital variation in postpartum tubal sterilization rates in California and Texas. Obstet Gynecol 121 (1): 152,n2013

Powell CB, Alabaster A, Simmons S, et al: Salpingectomy for sterilization: change in practice in a large integrated health care system, 2011-2016. Obstet Gynecol 130(5):961,n2017

Rogers MD, Kolettis PN: Vasectomy. Urol Clin North Am 40(4):559, 2013

Sharlip 10, Belker AM, Honig S, et al: Vasectomy: AUA guideline. Outcomes of microsurgical vasovasostomy for vasectomy reversal: a meta-analysis and systematic review.n] Urol 188(6 Suppi):2482, 2012

Shinar S, Blecher Y, Alpern S, et al: Total bilateral salpingectomy versus partial bilateral salpingectomy for permanent sterilization during cesarean delivety. Arch Gynecol Obstet295(5):1185, 2017

Shy KK, Stergachis A, Grothaus LG, et al: Tubal sterilization and risk of subsequent hospital admission for menstrual disorders. Am ] Obstet Gynecol 166:n1698,n1992

Society of Gynecologic Oncologists: SGO Clinical Practice Statement: Salpingectomy for ovarian cancer prevention. Available at: https://www.sgo.org/ cl inical-practice/ gu idel i nes/ sgo-cl inical-p ractice-statemen t -sal pi ngecto m yfor-ovarian-cancer-prevention.l Accessed December 13,n2013

Sokal DC, Hieu do T, Loan NO, et al: Contraceptive efectiveness of two insertions of quinacrine: results from 10-year follow-up in Vietnam. Con 8:61, 2008

Sokal DC, Trujillo V, Guzman SC, et al: Cancer risk after sterilization with transcervical quinacrine: updated indings from a Chilean cohort. Contraception 81(1): 5,n2010a

Sokal DC, Vach TH, Nanda K, Quinacrine sterilization and gynecologic cancers: a case-control study in northen Vietnam. Epidemiology 21 (2): 164, 201 Ob

Stuart GS: Puerperal sterilization. In Yeomans ER, Hofman BL, Gilstrap, III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hill, 201

Thompson M, Kho K: Minimally invasive surgery. In Hofman BL, Schorge JO, Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGraw-Hill, 2016

Veersema S, Mijatovic V, Dreyer K, et al: Outcomes of pregnancies in women with hysteroscopically placed micro-inserts in situ. ] Minim Invasive Gynecol 21(3):492, 2014

TERMINOLOGY AND DIAGNOSIS .................. 710

INCIDENCE AND RISK FACTORS ................... 713

ETIOPATHOGENESIS ............................ 713

PATHOPHYSIOLOGY ............................ 717

PREDICTION.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 725

PREVENTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 726

PREECLAMPSIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 728

ECLAMPSIA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 734

MANAGEMENT CONSIDERATIONS ................. 738

LONG-TERM CONSEQUENCES .................... 744

An eclamptic convulsion sometimes occurs without warning, "like a bolt from a clear sky': in women who are apparenty in peect health. In the majoriy of cases, however, the outbreak is preceded or a longer or shorter period by premonitoy symptoms indicative of toxemia of pregnancy, among the more common being oedema, headache, epigastric pain, and possiby disturbances of vision.

-J. Whitridge Williams (1903)

At the time of this textbook's irst edition, it was accepted that "toxemia" preceded most cases of eclampsia. he central role of hypertension had not yet been discovered, and after many years, it became apparent that preeclampsia was a syndrome of which hypertension was only one important facet. Still, the mechanisms by which pregnancy incites or aggravates hypertension remain unsolved. Indeed, hypertensive disorders remain among the most signiicant and intriguing unsolved problems in obstetrics. hese disorders complicate 5 to 10 percent of all pregnancies, and together they are one of the deadly triad-along with hemorrhage and infection-that contributes greatly to maternal morbidity and mortality rates. Of hypertensive disorders, the preeclampsia syndrome, either alone or superimposed on chronic hypertension, is the most dangerous. As subsequently discussed, new-onset hypertension during pregnancy-termed gestational hypertension-is followed by signs and symptoms of preeclampsia almost half the time, and preeclampsia is identiied in 4 to 5 percent of all pregnancies (Martin, 2012).

he World Health Organization (WHO) systematically reviews maternal mortality worldwide, and in developed countries, 16 percent of maternal deaths were attributed to hypertensive disorders (han, 2006). In the United States from 201r1 to 2013, 7.4 percent of2009 pregnancy-related maternal deaths were caused by preeclampsia or eclampsia (Creanga, 2017). A similar rate was 10 percent in France from 2003 through 2007 (Saucedo, 2013). Importantly, more than half of these hypertension-related deaths were deemed preventable (Berg, 2005).

To update and codiy the terminology and classiication of hypertensive disorders of pregnancy, a Task Force of the American College of Obstetricians and Gynecologists (2013) has provided evidence-based recommendations for clinical practice. The previous basic classiication was retained and describes four types of hypertensive disease: 1.

2.

Chronic hypertension of any etiology 3.

4. Gestational hypertension-definitive evidence for the preeclampsia syndrome does not develop and hypertension resolves by 12 weeks postpartum.

Importantly, this classification diferentiates the preeclampsia syndrome from other hypertensive disorders because it is potentially more ominous.

• Diagnosis of Hypertensive Disorders

Hypertension is diagnosed empirically when appropriately taken blood pressure exceeds 140 mm Hg systolic or 90 mm Hg diastolic. Korotkofphase V is used to define diastolic pressure. Previously, incremental increases of 30 mm Hg systolic or 15 mm Hg diastolic above blood pressure values taken at midpregnancy had also been used as diagnostic criteria, even when absolute values were < 140/90 mm Hg. These incremental changes are no longer used to define hypertension, but it is recommended that such women be observed more closely because eclamptic seizures develop in some whose blood pressures have stayed below 140/90 mm Hg (Alexander, 2006). Also, a sudden rise in mean arterial pressure but still in a normal range-"delta hypertension"-may signiy preeclampsia (Macdonald-Wallis, 2012; Zeeman, 2007).

he systolic and diastolic blood pressure levels of 140/90 mm Hg have been arbitrarily used since the 1950s to define "hypertension" in nonpregnant individuals. However, these levels were selected by insurance companies to characterize a group of middle-aged men. It seems more realistic to deine normalrange blood pressures that fall between an upper and lower limit for a particular population-such as young, healthy, pregnant women. A schematic example using arbitrary mean arterial blood pressure readings is shown in Figure 40-1. Data curves for both women show blood pressure measurements near the ...Patient A ...Patient B )..:J,

C,

FIGURE 40-1 Schematic shows normal reference ranges for mean arterial blood pressure changes across pregnancy. Patient A (blue) has mean blood pressures near the 20th percentile throughout pregnancy. Patient B (red) has a similar pattern with mean pressures at the 25th percentile until approximately 36 weeks when her blood pressure begins to rise. By term, it is substantively higher and in the 75th percentile, but she is still considered "normotensive." 25th percentile until 32 weeks. These begin to rise in patient B, who by term has substantively higher blood pressures. However, her pressures are still < 140/90 mm Hg, and thus she is considered to be "normotensive." We use the term delta hypertension to describe this rather acute rise in blood pressure. Some of these women will go on to have obvious preeclampsia, and some even develop eclamptic seizures or HELLP (hemolysis, devatedliver enzyme levels, low 2latelet count) syndrome while still normotensive.

his diagnosis is made in women whose blood pressures reach 140/90 mm Hg or greater for the irst time after midpregnancy, but in whom proteinuria is not identiie. Almost half of these women subsequently develop preeclampsia syndrome. Even so, when blood pressure increases appreciably, it is dangerous to both mother and fetus to ignore this rise only because proteinuria has not yet developed. As Chesley (1985) emphasized, 10 percent of eclamptic seizures develop before overt proteinuria can be detected. Finally, gestational hypertension is reclassiied by some as transient hypertension if evidence for preeclampsia does not develop and the blood pressure returns to normal by 12 weeks postpartum.

Preeclampsia is best described as a pregnancy-speciic syndrome that can aect virtualy evey organ system. In addition, it heralds a higher incidence of cardiovascular disease later in life (p. 744). Although preeclampsia is much more than simply gestational hypertension with proteinuria, appearance ofproteinuria remains an important diagnostic criterion. Thus, proteinuria is an objective marker and relects the system-wide endothelial leak that characterizes the preeclampsia syndrome.

In some women with the preeclampsia syndrome, neither overt proteinuria nor fetal-growth restriction are features (Sibai, 2009). Because of this, the Task Force (2013) suggests other diagnostic criteria, which are shown in Table

Evidence of multiorgan involvement may include thrombocytopenia, renal dysfunction, hepatocellular necrosis, central nervous system perturbations, or pulmonary edema.

• Indicators of Preeclampsia Severity

The markers listed in Table 40-1 are also used to classiy preeclampsia syndrome severity. lthough many use a dichotomous "mild" and "severe" classiication, the Task Force (2013) discourages the use of "mild preeclampsia." It is problematic that there are criteria for the diagnosis of "severe" preeclampsia, but the default classiication is either implied or speciically termed as "mild," "less severe," or "nonsevere" (Alexander, 2003; Lindheimer, 2008b). here are no generally agreed-on criteria for "moderate" preeclampsia-an elusive third category. We use the criteria listed in Table 40-2, which are categorized as "severe" versus "nonsevere."

Some symptoms are considered ominous. Headaches or visual disturbances such as scotomata can precede eclampsia, which is a convulsion not attributable to another cause. The

TABLE 40-1. Classification and Diagnosis of Pregnancy-Associated Hypertension

Gestational hypertension Preeclampsia: Hypertension plus • 2300 mg/24 h, or

Urine protein: creatinine ratio 20.3, or

Platelet count < 1 OO,OOO/.LL 1.1 mg/dL or doubling of baselineb

Headache, visual disturbances, convulsions aRecommended only if sole available test. bNo prior renal disease.

CAST (aspartate transaminase) or ALT (alanine transaminase). BP = blood pressure.

Modified with permission from American College ofObstetricians and Gynecologists; Task Force on Hypertension in Pregnancy: Hypertension in pregnancy. Report ofthe American College ofObstetricians and Gynecologists'Task Force on

Hypertension in Pregnancy, Obstet Gynecol. 201n3 Nov;122(S):n seizures are generalized and may appear before, during, or after labor. The proportion that develops seizures later, after 48 hours postpartum, approximates 10 percent (Sibai, 2005; Zwart, 2008). Another symptom, epigastric or right upper quadrantpain, frequently accompanies hepatocellular necrosis, ischemia, and edema that ostensibly stretches Glisson capsule. This characteristic pain is frequently accompanied by elevated serum

TABLE40-2. Indicators of Severity of Gestational (< 1 OO,OOO/LL)

None to positive

None to positive aCompare with criteria in Table 40-1.

blncludes "mild" and "moderate" hypertension not specifically defined.

cMost disregard degrees of proteinuria to classify nonsevere or severe.

BP = blood pressure.

hepatic transaminase levels. Finally, thrombocytopenia also signifies worsening preeclampsia. It represents platelet activation and aggregation as well as microangiopathic hemolysis. Other factors indicative ofsevere preeclampsia include renal or cardiac involvement, obvious fetal-growth restriction, and early-onset disease.

he more profound these signs and symptoms, the less likely it is that they can be temporized, and the more likely that delivery will be required. A caveat is that dierentiation between nonsevere and severe gestational hypertension or preeclampsia can be misleading because what might be apparenty mild disease may progress rapidy to severe disease.

Regardless of its cause, any chronic hypertensive disorder predisposes a woman to develop superimposed preeclampsia syndrome. Chronic underlying hypertension is diagnosed in women with documented blood pressures > 140/90 mm Hg before pregnancy or before 20 weeks' gestation, or both. Hypertensive disorders can create diicult problems with diagnosis and management in women who are not irst seen until after midpregnancy. This is because blood pressure normally drops during the second and early third trimesters in both normotensive and chronically hypertensive women (see Fig. 40-1). Thus, a woman with previously undiagnosed chronic vascular disease who is seen before 20 weeks frequently has blood pressures within normal range. During the third trimester, however, as blood pressures return to their originally hypertensive levels, it may be diicult to determine whether hypertension is chronic or induced by pregnancy. Even a careful search for evidence of preexisting end-organ damage may be futile, as many ofthese women have mild disease and no evidence ofventricular hypertrophy, retinal vascular changes, or renal dysfunction.

In some with chronic hypertension, blood pressure rises to obviously abnormal levels, typically after 24 weeks' gestation. If new-onset or worsening baseline hypertension is accompanied by new-onset proteinuria or other indings listed in Table 40-1, then superimposed preeclampsia is diagnosed. Compared with "pure" preeclampsia, superimposed preeclampsia commonly develops earlier in pregnancy. It also tends to be more severe and more often is accompanied by fetal-growth restriction. he same criteria shown in Table 40-2 are also used to further characterize severity of superimposed preeclampsia.

Young and nulliparous women are particularly vulnerable to developing preeclampsia, whereas older women are at greater risk for chronic hypertension with superimposed preeclampsia. he incidence is markedly inluenced by race and ethnicity-and thus by genetic predisposition. In one study by the Maternal-Fetal Medicine Units (MFMU) Network, the incidence of preeclampsia was 5 percent in white, 9 percent in Hispanic, and 11 percent in African-American women (Myatt, 2012a,b). In addition, black women have greater morbidity (Shahul, 2015). In several worldwide studies reviewed by Staf and coworkers (2015), the incidence of preeclampsia in nulliparous populations ranged from 3 to 10 percent. he incidence of preeclampsia in multiparas also varies and ranges from 1.4 to 4 percent (Fisher, 2015).

Bartsch and associates (2016) extracted data from more than 25 million pregnancies and calculated relative risks for several clinical factors shown in Table 40-3. Others include the metabolic syndrome and hyperhomocysteinemia (Karumanchi, 2016a; Masoudian, 2016; Scholten, 2013). Pregnancies with a male fetus are also at slightly higher risk a askolka,

TABLE 40-3. Selected Clinical Risk Factors for Preeclampsia

APA = antiphospholipid antibody; ART = assisted reproductive technology; BMI = body mass index; CHTN = chronic hypertension; CKD = chronic kidney disease; SLE = systemic lupus erythematosus.

Data from Ba rtsch, 201 6.

2017). Although smoking during pregnancy causes various adverse pregnancy outcomes, ironically, it carries a reduced risk for hypertension during pregnancy (Bainbridge, 2005; Kraus, 2014). Other factors are human immunodeficiency virus (HIV) seropositivity and sleep-disordered breathing (Facco, 2017; Sansone, 2016).

For eclampsia, the incidence has declined in areas where health care is more readily available. In the United States in 1998, it afected 1 in 3250 births (Ventura, 2000). Except for

Iceland, which has an extremely low rate, in countries with adequate resources the incidence averages 1 in 2000 to 3000 deliveries (Andersgaard, 2006; Jaatinen, 2016; O'Connor, 2013; Royal College of Obstetricians and Gynaecologists, 2006; Zwart, 2008).

Any satisfactory theory concerning the origins of preeclampsia must account for the observation that gestational hypertensive disorders are more likely to develop in women with the following characteristics:

Are exposed to chorionic villi for the irst time

Are exposed to a superabundance of chorionic villi, as with twins or hydatidiform mole

Have preexisting conditions associated with endothelial cell activation or inflammation, such as diabetes, obesity, cardiovascular or renal disease, immunological disorders, or hereditary inluences

Are genetically predisposed to hypertension developing during pregnancy.

A fetus is not a requisite for preeclampsia to develop. And, although chorionic villi are essential, they need not be intrauterine. For example, preeclampsia can develop with an abdominal pregnancy (Worley, 2008). Regardless of precipitating etioloy, the cascade of events leading to the preeclampsia syndrome is characterized by abnormalities that result in systemic vascular endothelial damage with resultant vasospasm, transudation ofplasma, and ischemic and thrombotic sequelae.

• Phenotypic Expression of he preeclampsia syndrome varies widely in its clinical phenotypic expression. But, at least two major subtypes are diferentiated by whether or not remodeling of uterine spiral arterioles by endovascular trophoblasts is defective. his concept has given rise to the "two-stage disorder" theory of preeclampsia pathogenesis. According to Redman and coworkers (20 15a), stage 1 is caused by faulty endovascular trophoblastic remodeling that downstream causes the stage 2 clinical syndrome. Importantly, stage 2 can be modified by preexisting maternal conditions that are also manifest by endothelial cell activation or inlammation and are listed in the third prior bullet.

Such staging is artiicial, and it seems logical that preeclampsia syndrome presents clinically as a spectrum of worsening disease. Moreover, evidence is accruing that many "isoforms" exist as discussed subsequently. Examples include diferences in

FIGURE 40-2 Schematic representation of normal placental implantation shows proliferation of extravillous trophoblasts from an anchoring villus. These trophoblasts invade the decidua and extend into the walls of the spiral arteriole to replace the endothelium and muscular wall to create a dilated low-resistance vessel. With preeclampsia, defective implantation is characterized by incomplete invasion of the spiral arteriolar wall by extravillous trophoblasts. This results in a small-caliber vessel with high resistance to flow.

maternal and fetal characteristics, placental indings, and earlyversus late-onset disease (Phillips, 2010; Valensise, 2008; van der Merwe, 2010).

n imposing number of mechanisms have been proposed to explain the cause of preeclampsia. Those currently considered important include: 1.

Placental implantation with abnormal trophoblastic invasion of uterine vessels 2.

Immunological maladaptive tolerance between maternal, paternal (placental), and fetal tissues 3.

Maternal maladaptation to cardiovascular or inlammatory changes of normal pregnancy 4.

Genetic factors including inherited predisposing genes and epigenetic inluences.

Discussed in Chapter 5 (p. 88), normal implantation is characterized by extensive remodeling of the spiral arterioles within the decidua basalis (Fig. 40-2). Endovascular trophoblasts replace the vascular endothelial and muscular linings to enlarge the vessel diameter (Zhou, 1997). The veins are invaded only superficially.

In some cases of preeclampsia, however, trophoblastic invasion may be incomplete. With this, decidual vessels, but not myometrial vessels, become lined with endovascular trophoblasts. The deeper myometrial arterioles thus do not lose their endothelial lining and musculoelastic tissue, and their mean external diameter is only half that of corresponding vessels in normal placentas (Fisher, 2015). In general, the magnitude of defective trophoblastic invasion correlates with the severity of the hypertensive disorder (Madazli, 2000). And importantly, it is more prevalent in women with early-onset preeclampsia (Khodzhaeva, 2016). cMahon and associates (2014) found that lower levels of soluble antiangiogenic growth factors may be involved in this faulty endovascular remodeling.

From placental electron microscopy studies, early preeclamptic changes include endothelial damage, insudation of plasma constituents into vessel walls, proliferation of myointimal cells, and medial necrosis (De Wolf, 1980). Hertig (1945) referred to lipid accumulation in myointimal cells and macro phages as atherosis. These indings are more common in placentas from women diagnosed with preeclampsia before 34 weeks (Nelson, 2014b). Acute placental vascular atherosis may also identiy a group of women at greater risk for later atherosclerosis and cardiovascular disease (Staf, 2015). In pregnancy, the abnormally narrow lumen of spiral arterioles likely impairs placental blood flow. Diminished perfusion and a hypoxic environment eventually lead to release of placental debris or microparticles.

At this point, these changes incite a systemic inlammatory response, which is stage 2 of the preeclampsia syndrome (Lee, 2012; Redman, 2012). Defective placentation is posited to further cause the susceptible woman to develop gestational hypertension, the preeclampsia syndrome, preterm delivery, a growth-restricted fetus, and/or placental abruption (Brosens, 2011; Labarrere, 2017; Nelson, 2014b).

IVlaternal immune tolerance to paternally derived placental and fetal antigens is discussed in Chapter 5 (p. 95). Loss of this tolerance is another cited theory for preeclampsia (Erlebacher, 2013). Certainly, the histological changes at the maternalplacental interface are suggestive of acute graft rejection.

Inferential data also suggest that preeclampsia is an immunemediated disorder. For example, the risk of preeclampsia is appreciably enhanced in circumstances in which formation of blocking antibodies to placental antigenic sites might be impaired. In this scenario, the irst pregnancy would carry a higher risk. Tolerance dysregulation might also explain an ele vated risk when the paternal antigenic load is increased, that is, with two sets of paternal chromosomes-a "double dose."

Namely, women with molar pregnancies have a high incidence of early-onset preeclampsia. Women with a trisomy 13 fetus also have a 30-to 40-percent incidence of preeclampsia. hese women have elevated serum levels of antiangiogenic factors. he gene for one of these factors, soluble ins-like tyrosine kinase 1, is on chromosome 13 (Bdolah, 2006). Conversely, women previ ously exposed to paternal antigens, such as a prior pregnancy with the same partner, are "immunized" against preeclampsia.

his phenomenon is not as apparent in women with a prior abortion (Strickland, 1986). Multiparas impregnated by a new consort have a greater risk of preeclampsia (Mostello, 2002).

Redman and colleagues (2015a) reviewed the possible role of immune maladaptation in preeclampsia pathophysiology. In women destined to be preeclamptic, extravillous trophoblasts early in pregnancy express reduced amounts of immunosuppressive nonclassic human leukocyte antigen G (HLA G). Black women more commonly have the 1597 �C gene allele that further predisposes to preeclampsia (Loisel, 2013). hese changes may contribute to the defective placental vascularization in stage 1 of the preeclampsia syndrome. As discussed in Chapter 4 (p. 59), T-helper (h) lymphocytes during normal pregnancy are produced so that type 2 activity is increased in relation to type 1-so-called ype 2 bias (Redman, 2012, 2015a). h2 cells promote humoral immunity, whereas Th1 cells stimulate inlammatory cytoine secretion. Beginning in the early second trimester in women who develop preeclampsia, Th1 action is increased.

Inflammatory changes are believed to be a continuation of stage 1 alterations. In response to ischemia or other inciting causes, placental factors are released and begin a cascade of events (Davidge, 2015). Thus, antiangiogenic and metabolic factors and other inflammatory leukocyte mediators are thought to provoke systemic endothelial cell injury, which is used synonymously here with endothelial cel activation or dyfunction.

Endothelial cell dysfunction may result from an extreme activated state of leukocytes in the maternal circulation (Faas, 2000; Gervasi, 2001). Briefly, cytokines such as tumor necrosis factor-a (TNF-a) and the interleukins may contribute to the systemic oxidative stress associated with preeclampsia. This is characterized by reactive oxygen species and free radicals that lead to formation of self-propagating lipid peroxides (Manten, 2005). hese peroxides in turn generate highly toxic radicals that injure systemic vascular endothelial cells, modiy nitric oxide production by these cells, and interfere with prostaglandin balance. Other consequences of oxidative stress include production of the lipid-laden macrophage foam cells seen in placental atherosis, activation of systemic microvascular coagulation manifested by thrombocytopenia, and greater systemic capillary permeability relected by edema and proteinuria.

Preeclampsia appears to be a multifactorial, polygenic disorder. In one study of almost 1.2 million Swedish births, a genetic

Data from Buurma, 2013; Staines-Urias, 2012; Triche, 2014; Ward, 2014; Ye, 2016.

association for gestational hypertension and for preeclampsia was found (Nilsson, 2004). Ward and Taylor (2015) cite an incident risk for preeclampsia of 20 to 40 percent for daughters of preeclamptic mothers; 11 to 37 percent for sisters of preeclamptic women; and 22 to 47 percent for twins. Ethnoracial factors are important, as evidenced by the high incidence of preeclampsia in African-American women. It may be that Latina women have a lower incidence because of interactions of American Indian and white race genes (Shahabi, 2013).

he hereditary predisposition for preeclampsia likely stems from interactions of literally hundreds of inherited genesboth maternal and paternal-that control myriad enzymatic and metabolic functions throughout every organ system (Triche, 2014). Plasma-derived factors may induce some of these genes in preeclampsia (Mackenzie, 2012). Thus, the clinical manifestation in any given woman with the preeclampsia syndrome will occupy a spectrum. In this regard, phenotypic expression will difer among similar genotypes depending on interactions with environmental components (Yang, 2013).

Hundreds of genes have been studied for their possible association with preeclampsia (Buurma, 2013; Sakowicz, 2016; Ward, 2015). Several that may have a significant association with the syndrome are listed in Table 40-4. However, because of the complex phenotypic expression of preeclampsia, it is doubtful that anyrone candidate gene will be found responsible. Indeed, Majander and associates (2013) have linked preeclampsia predisposition to evenetal genes on chromosome 18.

The concept of vasospasm with preeclampsia has been advanced for a century (Volhard, 1918). Systemic endothelial activation causes vasospasm that elevates resistance to produce subsequent hypertension. Concurrently, systemic endothelial cell injury promotes interstitial leakage, and blood constituents, including platelets and ibrinogen, are deposited subendothelially. Endothelial junctional proteins are also disrupted, and the subendothelial region of resistance arteries undergoes ultrastructural change (Suzuki, 2003; Wang, 2002). The much larger venous circuit is similarly involved.

With diminished blood low because of maldistribution from vasospasm and interstitial leakage, ischemia of the surrounding tissues can lead to necrosis, hemorrhage, and other end-organ disturbances characteristic of the syndrome. One important clinical correlate to this is the markedly attenuated blood volume seen in women with severe preeclampsia (Zeeman, 2009).

Injury to systemic endothelial cells is now a centerpiece of preeclampsia pathogenesis (Davidge, 2015). In this scheme, protein factor(s)-likely placental-are secreted into the maternal circulation and provoke activation and dysfunction of the systemic vascular endothelium. Many facets of the clinical syndrome of preeclampsia are thought to result from these widespread endothelial cell changes.

Intact endothelium has anticoagulant properties. lso, systemic endothelial cells, by releasing nitric oxide, blunt the response of vascular smooth muscle to agonists. Injured or activated endothelial cells may produce less nitric oxide and may secrete substances that promote coagulation and greater sensitivity to vasopressors. Further evidence of endothelial activation includes the characteristic changes in glomerular capillary endothelial morphology, greater capillary permeability, and elevated blood concentrations of substances associated with endothelial activation. Likely, multiple factors in the plasma of preeclamptic women combine to exert these vasoactive efects (Myers, 2007; Walsh, 2009).

As discussed in Chapter 4 (p. 63), pregnant women normally develop refractoriness to infused vasopressors (AbdulKarim, 1961). Women with early preeclampsia, however, have enhanced vascular reactivity to infused norepinephrine and angiotensin II (Raab, 1956; Talledo, 1968). Moreover, increased sensitivity to angiotensin II clearly precedes the onset of gestational hypertension (Gant, 1974). Paradoxically, women who develop preterm preeclampsia have lower circulating levels of angiotensin II (Chase, 2017).

Several prostaglandins are thought to be central to preeclampsia syndrome pathophysiology. Specifically, the blunted pressor response seen in normal pregnancy is at least partially due to diminished vascular responsiveness mediated by endothelial prostaglandin synthesis. For example, compared with normal pregnancy, endothelial prostacyclin (PGI2) production is lower in preeclampsia. This action appears to be mediated by phospholipase A2 (Davidge, 2015). At the same time, thromboxane A2 secretion by platelets is increased, and the prostacyclin:thromboxane A2 ratio declines. The net result favors greater sensitivity to infused angiotensin II and, ultimately, vasoconstriction (Spitz, 1988). hese changes are apparent as early as 22 weeks' gestation in gravidas who later develop preeclampsia (Chavarria, 2003).

Nitric oxide is a potent vasodilator synthesized from I-arginine by endothelial cells. Inhibition of nitric oxide synthesis raises mean arterial pressure, lowers heart rate, and reverses the pregnancy-induced refractoriness to vasopressors. In humans, nitric oxide likely is the compound that maintains the normal low-pressure vasodilated state characteristic of fetoplacental perfusion (Myatt, 1992; Weiner, 1992). he efects of nitric oxide production in preeclampsia are unclear. It appears that the syndrome is associated with decreased endothelial nitric oxide synthase expression, thus resulting in lower nitric oxide activity (Davidge, 2015).

Endothelins are 21-amino-acid pep tides and potent vasoconstrictors. Endothelin-1 (ET -1) is the primary isoform produced by human endothelium (Karumanchi, 2016b). Plasma ET-1 levels are elevated in normotensive pregnant women, but women with preeclampsia have even higher levels (Ajne, 2003). According to Taylor and Roberts (1999), the placenta is not the source of increased ET -1 concentrations, and they likely arise from systemic endothelial activation. Interestingly, treatment of preeclamptic women with magnesium sulfate lowers ET -1 concentrations (Sagsoz, 2003). And, in animal studies, sildenafil reduces ET-1 concentrations (Gillis, 2016).

Placental vasculogenesis is evident by 21 days after conception. The list of pro-and antiangiogenic substances involved in placental vascular development is extensive, and the families of vascular endothelial growth factor (VEGF) and angiopoietin are the most studied. Angiogenic imbalance describes excessive amounts of antiangiogenic factors, which are thought to be stimulated by worsening hypoxia at the uteroplacental interface. Trophoblast of women destined to develop preeclampsia overproduces at least two antiangiogenic pep tides that enter the maternal circulation (Karumanchi, 20 16a).

First, soluble ins-like yrosine kinase i {sFlt-i} is a receptor for VEGF. As depicted in Figure 40-3, elevated maternal sFlt-1 levels inactivate and reduce circulating free placental growth factor (PIGF) and VEGF concentrations, leading to endothelial dysfunction (Maynard, 2003). Importantly, sFlt-1 levels begin to rise in maternal serum months before preeclampsia is evident (Fig. 40-4). These high levels in the second trimester are associated with a doubling of the risk for preeclampsia (Haggerty, 2012). This divergence from normal levels appears to develop even sooner with early-onset preeclampsia (Vatten, 2012). These factors are also operative in pregnancies complicated by fetal-growth restriction (Herraiz, 2012).

A second antiangiogenic peptide, soluble endoglin (sEng), inhibits various transforming growth factor beta (TGF-3) isoforms from binding to endothelial receptors (see Fig. 40-3). Endoglin is one of these receptors. Decreased binding to endoglin diminishes endothelial nitric oxide-dependent vasodilatation. Serum levels of sEng also begin to rise months before clinical preeclampsia develops (Haggerty, 2012). Interestingly, metformin reduces antiangiogenic secretion from human tissues (Brownfoot, 2016).

In one systematic review, third-trimester elevation of sFlt-1 levels and lower PIGF concentrations correlate with and soluble endoglin (sEng).

preeclampsia development after 25 weeks' gestation (Widmer, 2007). Subsequently, Haggerty and coworkers (2012) reported that doubling of expressions of sFlt-1 and sEng increased the preeclampsia risk by 39 and 74 percent, respectively. The cause :J• :JE

FIGURE 40-4 Angiogenic and antiangiogenic factors in normotensive (N) and preeclamptic (PE) women across pregnancy. Both pairs of factors are significantly divergent by 23 to 26 weeks' gestation. sFlt = soluble fms-like tyrosine kinase 1; PIGF = placental growth factor. (Data from Myatt, 201o3.) of placental overproduction of anti angiogenic proteins remains an enigma. here is a racial-ethnic diference in their secretion (Yang, 2016). Concentrations of the soluble forms are not higher in fetal circulation or amnionic fluid of preeclamptic women, and their levels in maternal blood dissipate after delivery (Staf, 2007).

Clinical research aims to employ antiangiogenic proteins in the prediction and diagnosis of preeclampsia. One preliminary report described therapeutic apheresis to reduce sFlt-1 levels (Thadhani, 2016).

Evidence for preeclampsia manifestation begins early in pregnancy with covert pathophysiological changes that gain momentum across gestation and eventually become clinically apparent. Unless delivery supervenes, these changes ultimately lead to multiorgan involvement with a clinicl spectrum ranging from meager findings to one of cataclysmic deterioration. As discussed, these are thought to be a consequence of endothelial dysfunction, vasospasm, and ischemia. Although the many maternal consequences of the preeclampsia syndrome are usually described in terms of individual organ systems, they frequently are multiple and overlap .

Cardiovascular disturbances are common with preeclampsia syndrome. hese are related to: (1) greater cardiac afterload caused by hypertension; (2) cardiac preload, which is reduced by a pathologically diminished volume expansion during pregnancy and which is increased by intravenous crystalloid or oncotic solutions; and (3) endothelial activation leading to interendothelial extravasation of intravascular fluid into the extracellular space and, importantly, into the lungs.

The cardiovascular aberrations of pregnancy-related hypertensive disorders vary depending on several modifiers. These factors include preeclampsia severity, hypertension severity, presence of underlying chronic disease, and the part of the clinical spectrum in which these are studied. In some women, these cardiovascular changes may precede hypertension (De Paco, 2008; Easterling, 1990; Khalil, 2012; Melchiorre, 2013). Nevertheless, with the clinical onset of preeclampsia, cardiac outpur declines, due at least in part to greater peripheral resistance. When assessing cardiac function in preeclampsia, consideration is given to echo cardiographic measures ofmyocardial function and to clinically relevant ventricular function.

blood loss incurred at delivery. Anemia may also partially result from greater erythrocyte destruction as subsequently described.

The platelet count is routinely measured in women with any form of gestational hypertension. Decreased platelet concentra tions with eclampsia were described more than 100 years ago.

The frequency and intensity of thrombocytopenia vary and are dependent on the severity and duration of the preeclampsia syn drome (Heilmann, 2007; Hupuczi, 2007). Overt thrombocy topenia-deined by a platelet count < 100,000/�L-indicates severe disease (see Table 40-2). In general, the lower the platelet count, the higher the rates of maternal and fetal morbidity and mortality (Leduc, 1992). In most cases, delivery is advisable because worsening thrombocytopenia usually ensues. Mter delivery, the platelet count may continue to decline for the irst day or so. It then usually rises progressively to reach a normal level within 3 to 5 days. As discussed later (p. 722), in some instances with HELLP syndrome, the platelet count continues to fall after delivery. If these do not reach a nadir until 48 to 72 hours, then preeclampsia syndrome may be incorrectly attrib uted to one of the thrombotic microangiopathies discussed in

Chapter 56 (p. 1088).

Myriad other platelet alterations are attributed to the preeclampsia syndrome. hese were reviewed by Kenny and coworkers (2015) and include platelet activation with increased .-degranulation producing �-thromboglobulin, factor 4, and enhanced clearance. Paradoxically, in most studies, in vitro platelet aggregation is reduced compared with the normal increase that is characteristic of pregnancy. This likely is due to platelet "exhaustion" following in vivo activation. Although the cause is unknown, immunological processes or simply platelet deposition at sites of endothelial damage may be implicated. Levels of platelet-bound and circulating platelet-bindable immunoglobulins are elevated, which suggests platelet surface alterations.

Abnormally low platelets do not develop in the fetuses or neonates born to preeclamptic women despite severe maternal thrombocytopenia (Kenny, 2015; Pritchard, 1987). Thus, maternal thrombocytopenia in a hypertensive woman is not a etal indication or cesarean delivery.

Severe preeclampsia is frequently accompanied by hemolysis, which manifests as elevated serum lactate dehydrogenase levels and reduced haptoglobin levels. Other evidence comes from schizocytosis, spherocytosis, and reticulocytosis in peripheral blood (Cunningham, 1985; Pritchard, 1954, 1976). hese derangements result in part from microangiopathic hemoysis caused by endothelial disruption with platelet adherence and ibrin deposition. Cunningham and coworkers (1995) postulated that erythrocyte morphology was partially caused by serum lipid alterations. Related, substantively decreased longchain fatty acid content is found in erythrocytes of preeclamptic women (Mackay, 2012).

Mter early reports of hemolysis and thrombocytopenia with severe preeclampsia, descriptions were added of abnormally elevated serum liver transaminase levels that indicated hepatocellular necrosis (Chesley, 1978). Weinstein (1982) referred to this combination of events as the HELLP syndrome-and this term now is used worldwide. Also, facets of the HELLP syndrome are included in criteria that diferentiate severe from nonsevere preeclampsia (see Table 40-2). he HELLP syndrome is discussed further in that section (p. 722).

Subtle changes consistent with intravascular coagulation, and less often erythrocyte destruction, commonly are found with preeclampsia and especially eclampsia (Cunningham, 2015; Kenny, 2015). Some of these changes include elevated factor VIII consumption, increased levels of ibrinopeptides A and B and of D-dimers, and reduced levels of regulatory proteinsantithrombin III and proteins C and S. Coagulation aberrations generally are mild and are seldom clinically signiicant (Kenny, 2015; Pritchard, 1984). Unless placental abruption is comorbid, plasma ibrinogen levels do not difer remarkably from levels found in normal pregnancy. Fibrin degradation products such as D-dimers are minimally elevated. As preeclampsia worsens, so do abnormal indings with thromboelastography (Pisani-Conway, 2013). Despite these changes, routine laboratory assessments of coagulation, such as prothrombin time (PT), activated partial thromboplastin time (aPTT), and plasma ibrinogen level, are not required in the management of pregnancy-associated hypertensive disorders.

Plasma levels of renin, angiotensin II, angiotensin 1-, aldosterone, deoxycorticosterone, and atrial natriuretic peptide (ANP) are substantively augmented during normal pregnancy. ANP is released during atrial wall stretching from blood volume expansion, and it responds to cardiac contractility (Chap. 4, p. 63). Levels of serum ANP rise in pregnancy, and its secretion is further enhanced in women with preeclampsia (Luft, 2009). Levels of its precursor-proatrial natriuretic peptide-are also increased in preeclampsia (Sugulle, 2012). Vasopressin levels are similar in nonpregnant, normally pregnant, and preeclamptic women even though the metabolic clearance is elevated in the latter two (Durr, 1999) .

In women with severe preeclampsia, the volume of extracellular luid, manifest as edema, is usually much greater than that in normal pregnant women. As discussed, the mechanism responsible for pathological luid retention is endothelial injury (Davidge, 2015). In addition to generalized edema and proteinuria, these women have reduced plasma oncotic pressure. his reduction creates a iltration imbalance and further displaces intravascular luid into the surrounding interstitium. Electrolyte concentrations do not difer appreciably in women with preeclampsia compared with those of normal pregnant women.

Following an eclamptic convulsion, the serum pH and bicarbonate concentration are lowered due to lactic acidosis and compensatory respiratory loss of carbon dioxide. he intensity of acidosis relates to the amount of lactic acid producedmetabolic acidosis-and the rate at which carbon dioxide is exhaled-respiratory acidosis.

During normal pregnancy, renal blood flow and glomerular filtration rate rise appreciably (Chap. 4, p. 65). With preeclampsia, several reversible anatomical and pathophysiological changes ensue. Of clinical importance, renal perfusion and glomerular iltration are reduced. Levels that are much less than normal nonpregnant values are infrequent and are the consequence of severe disease. Most of the decrement in glomerular filtration is from higher renal aferent arteriolar resistance that may be elevated up to fivefold (Conrad, 2015; Comelis, 201r1). Morphological changes are characterized by glomerular endotheliosis, which blocks the barrier that allows filtration. Diminished iltration causes serum creatinine levels to rise to values seen in nonpregnant individuals, that is, 1 mg/ mL, and sometimes higher (Lindheimer, 2008a). Abnormal values usually begin to normalize 10 days or later after delivery (Comelis, 2011; Spaan, 2012a).

In most preeclamptic women, the urine sodium concentration is elevated. Urine osmolality rises, urine:plasma creatinine ratio is elevated, and fractional excretion of sodium is low, which all indicated that a prerenal mechanism is involved. Sodium-containing crystalloid infusion raises left ventricular illing pressure, and although oliguria temporarily improves, rapid infusions may cause clinically apparent pulmonary edema. Intensive intravenous fluid therapy is not indicated as "treatment" for preeclamptic women with oliguria unless urine output is diminished from hemorrhage or luid loss from vomiting or fever.

Plasma uric acid concentration is typically elevated in preeclampsia. The elevation exceeds that attributable to the reduction in glomerular filtration rate and likely is also due to enhanced tubular reabsorption (Chesley, 1945). At the same time, preeclampsia is associated with diminished urinary excretion of calcium, perhaps because of greater tubular reabsorption (Taufield, 1987).

As shown in Table 40-1, detection of proteinuria helps to establish the diagnosis of preeclampsia. Abnormal protein excretion is empirically deined by 24-hour urinary excretion exceeding 300 mg; a urine protein:creatinine ratio �0.3; or persistent protein values of 30 mg/ dL (1 + dipstick) in random urine samples. Although worsening or nephrotic-range proteinuria has been considered by most to be a sign of severe disease, this does not appear to be the case (Airoldi, 2007). Certainly, this concept was not accepted by the 20r13 Task Force.

Problematically, the optimal method of establishing abnormal levels of either urine protein or albumin remains to be defined. For a 24-hour quantitative specimen, the "consensus" threshold value used is �300 mg/24 h (American College of Obstetricians and Gynecologists, 2013). Using a urinary protein excretion threshold of 165 mg in a 12-hour sample shows equivalent eicacy (Stout, 2015; Tun, 2012).

Determination of urinary protein:creatmme ratio may supplant the cumbersome 24-hour quantiication (Kyle, 2008; Morris, 2012). Chen and associates (2008) found that clean-catch and catheterized urine specimens correlate well. In one systematic review, random urine protein:creatinine ratios below 130 to 150 mg/ g, that is, 0.13 to 0.15, indicate a low likelihood of proteinuria exceeding 300 mg/ d (Papanna, 2008). Ratios <0.08 or > 1.19 have negative-or positive-predictive values of86 and 96 percent, respectively (Stout, 2013). However, midrange ratios, that is, 300 mg/g or 0.3, have poor sensitivity and specificity. Thus, many recommend that with midrange ratio values, 24-hour protein excretion should be quantified.

With urine dipstick assessment, determinations depend on urine concentration and are notorious for false-positive and -negative results. hus, assessment may show a dipstick value of 1 + to 2+ from concentrated urine specimens from women who excrete < 300 mg/ d.

Importantly, proteinuria may develop late, and some women may already be delivered or have had an eclamptic convulsion before it appears. For example, 10 to 15 percent of women with HELLP syndrome do not have proteinuria at presentation (Sibai, 2004). In one report, 17 percent of eclamptic women did not have proteinuria by the time of seizures (Zwart, 2008).

Sheehan and Lynch (1973) frequently found changes identifiable at autopsy by light and electron microscopy in the kidneys of eclamptic women. Glomeruli are enlarged by approximately 20 percent, they are "bloodless," and capillary loops variably are dilated and contracted. Endothelial cells are swollen-termed glomerular capillay endotheliosis (Spargo, 1959). Endothelial cells are often so swollen that they block or partially block the capillary lumens (Fig. 40-7) (Hecht, 2017). Homogeneous subendothelial deposits of proteins and fibrin-like material are seen.

Endothelial swelling may result from angiogenic protein "withdrawal" caused by the complexing of free angiogenic proteins with a compatible circulating antiangiogenic protein receptor (see Fig. 40-3). The angiogenic proteins are crucial for podocyte health, and their inactivation leads to podocyte dysfunction and endothelial swelling (Conrad, 2015; Karumanchi, 2009). Also, eclampsia is characterized by greater excretion of these epithelial podocytes (Wagner, 2012; White, 2014).

Although mild degrees of acute kidney injury are encountered, clinically apparent acute tubular necrosis is almost invariably induced by comorbid hemorrhage with hypovolemia and hypotension (Chap. 41, p. 755). his is usually caused by severe obstetrical bleeding-especially placental abruption-coupled with inadequate blood replacement. Drakeley and coworkers (2002) described 72 women with preeclampsia and renal failure. Half had HELLP syndrome, and a third had placental abruption. In one review of 183 women with HELLP syndrome, 5 percent had kidney injury (Haddad, 2000). Of those with renal injury, half had placental abruption, and most had postpartum hemorrhage. Last, irreversible renal cortical necrosis develops rarely (Chap. 53, p. 1037).

Ofwomen with preeclampsia, serial echocardiographic studies document diastolic dysfunction in 40 to 45 percent (Guirguis, 2015; Melchiorre, 2012). With this dysfunction, ventricles do not properly relax and cannot ill properly. In some of these women, functional diferences persist up to 4 years after delivery (Evans, 2011; Orabona, 2017). Diastolic dysfunction stens from ventricular remodeling, which is judged to be an adaptive response to maintain normal contractility despite the increased afterload ofpreeclampsia. High levels ofantiangiogenic proteins may be contributory (Shahul, 2016). In the otherwise healthy pregnant woman, these changes are usually clinically inconsequential. But when combined with underlying ventricular dysfunction-for example, concentric ventricular hypertrophy from chronic hypertension-further diastolic dysfunction may cause cardiogenic pulmonary edema (Wardhana, 2017). his is discussed further in Chapters 47 (p. 918) and 49 (p. 964).

Despite the relatively high frequency of diastolic dysfunction with preeclampsia, clinical cardiac function in most afected women is appropriate (Hibbard, 2015). In some preeclamptic women, cardiac troponin levels are slightly elevated, and amino-terminal pro-brain natriuretic peptide (Nt pro-BNP) levels are elevated with severe preeclampsia (Pergialiotis, 2016; Zachary, 2017). Importantly, both normally pregnant women and those with preeclampsia syndrome can have normal or slightly hyperdynamic ventricular function (Fig. 40-5). hus, both have a cardiac output that is appropriate for leftsided illing pressures. Filling pressures are dependent on the volume of intravenous fluids. Thus, aggressive hydration results in overtly hyperdynamic ventricular function. his is .J,

FIGURE 40-5 Ventricular function in normally pregnant women (striped area) and in women with eclampsia (boxed area) is plotted on a Braunwald ventricular function cur e. Normal values are from Clark (1989), and those for eclampsia are from Hankins (1984). PCWP = pulmonary capillary wedge pressure; LVSWI = left ventricular stroke work index.

accompanied by elevated pulmonary capillary wedge pressures, and pulmonary edema may develop despite normal ventricular function. This is because of an alveolar endothelial-epithelialrleak, and it is compounded by decreased oncotic pressure from a low serum albumin concentration. In sum, aggressive fluid administration to otherwise normal women with severe preeclampsia substantially elevates normal leftsided filling pressures and raises a physiologically normal cardiac output to hyperdynamic levels.

Hemoconcentration is a hallmark ofeclampsia. This concept was precisely quantiied by Zeeman and colleagues (2009), who expanded the prior observations of Pritchard and associates (1984). hey showed in eclamptic women that the normally expected pregnancy blood volume expansion is severely curtailed (Fig. 40-6). Women ofaverage size have a blood volume of 3000 mL, and during the last several weeks of a normal pregnancy, this averages 4500 mL. With eclampsia, however, much or all of the anticipated 1500 mL excess is lost. Such hemoconcentration results from generalized vasospasm that follows endothelial activation and leakage of plasma into the interstitial space. In women with preeclampsia, and depending on its severity, hemoconcentration is usually not as marked.

hese changes have substantial clinical consequences. Importantly, women with severe hemoconcentration are unduly sensitive to blood loss at delivery that otherwise may be considered normal. Vasospasm and endothelial leakage of plasma persist for a variable time ater delivery as the endothelium is restored to normalcy. u this takes place, vasoconstriction reverses, and s the blood volume reexpands, the hematocrit usully falls. Importanty} a substantive cause ofthisall in hematocrit} however} is usualy the :J0

FIGURE 40-6 Total blood volumes in normotensive women compared with those with eclampsia. The vertical extensions are one standard deviation from the mean. In eclamptic women, blood volume is minimally increased compared with a subsequent normotensive pregnancy. (Data from Zeeman, 2009.)

Liver involvement with preeclampsia may clinically display at least three manifestations. Narrow First, pain is considered a sign of interspace severe disease. It typically manifests by moderate-to-severe right upper quadrant or midepigasEndothelial tric pain and tenderness. Such swelling women usually have elevated serum aspartate transaminase (AST) or alanine transaminase (AL T) levels. In some cases, however, the amount of hepatic tissue involved with infarction may be surprisingly extensive yet still clinically insignificant (N elson, 2017). In our experiences, infarction may be worsened by FIGURE 40-7 Schematic showing glomerular capillary endotheliosis. The capillary of the normal hypotension from obstetrical glomerulus shown on the left has wide endothelial fenestrations, and the pedicels emanating hemorrhage, and it occasion from the podocytes are widely spaced (arrow). The illustration on the right is of a glomerulus with changes induced by the preeclampsia syndrome. The endothelial cells are swollen and their fenes called shock liver (Alexander, trae narrowed, as are the pedicels that now abut each other.

2009; Yoshihara, 2016).

Second, elevations of serum • Liver AST and ALT levels are markers for severe preeclampsia. Values seldom exceed 500 U/L, but levels reaching more than 2000

The characteristic hepatic lesions with eclampsia are regions of U/L have been reported (Chap. 55, p. 1058). In general, serumperiportal hemorrhage in the liver periphery (Hecht, 2017).

concentrations inversely follow platelet levels, and they bothHowever, lesions as extensive as those shown in Figure 40-8 are usually normalize within 3 days following delivery.

unusual. Sheehan and Lynch (1973) described that some degree As a third presentation, hemorrhagic infarction may extend of hepatic infarction accompanied hemorrhage in almost half of to form a hepatic hematoma. This in turn can extend to form women who died with eclampsia. hese findings corresponded a subcapsular hematoma that may rupture. Computed tomogwith reports during the 1960s that described elevated serum raphy (CT) scanning or magnetic resonance (MR) imaginghepatic transaminase levels. Along with the earlier observations greatly aids diagnosis (Fig. 40-9). Unruptured hematomasby Pritchard and associates (1954), who described hemolysis are probably more common than clinically suspected and areand thrombocytopenia with eclampsia, this constellation of more likely to be found with HELLP syndrome. Althoughhemolysis, hepatocellular necrosis, and thrombocytopenia was later termed HELLP syndrome.

FIGURE 40-8 Gross liver specimen from a woman with preeclampsia who died from aspiration Periportal hemorrhagic necrosis was seen microscopically. (Reproduced with permission from Cunningham FG: Liver disease complicating pregnancy. Williams Obstetrics, 19th ed. (Suppl 1), Norwalk, Appleton & Lange, 1993.) a woman with severe HELLP syndrome and right-upper quadrant pain. A large subcapsular hematoma (asterisk) is seen confluent with intrahepatic infarction and hematoma (arrowhead). Numerous flameshaped hemorrhages are seen at the hematoma interface (arrows).

FIGURE 40-11 Composite illustration showing location of cerebral hemorrhages and petechiae in women with eclampsia. Insert shows the level of the brain from which the main image was constructed. (Data from Sheehan, 1973.) once considered a surgical condition, current management of a hepatic hematoma usually consists of observation unless bleeding is ongoing. In some cases, however, prompt surgical intervention or angiographic embolization may be lifesaving. In one review of 180 cases of hepatic hematoma or rupture, 94 percent of afected gravidas had HELLP syndrome, and in 90 percent of the total, the capsule had ruptured (Vigil-De Gracia, 2012). The maternal mortality rate was 22 percent, and the perinatal mortality rate was 31 percent. In rare cases, liver transplantation is necessary (Hunter, 1995; Wicke, 2004).

Acute fatty liver of pregnancy is sometimes confused with preeclampsia (Nelson, 2013; Sibai, 2007a). It too has an onset in late pregnancy, and often there is accompanying hypertension, elevated serum transaminase and creatinine levels, and thrombocytopenia. However, the hallmark of acute fatty liver is significant liver dysfunction, and Table 55-1 (p. 1059) highlights these clinical diferences.

Last, no convincing data link pancreatic involvement with preeclampsia syndrome (Sheehan, 1973). Thus, the occasional case of concurrent hemorrhagic pancreatitis is likely unrelated (Lynch, 2015; Swank, 2012). In our experiences from Parkland Hospital, amylase levels were seldom elevated in preeclamptic women (Nelson, 2014a).

There is no universally accepted strict deinition of HELLP syndrome, and thus its incidence varies by investigator. In the previously noted study of 183 women with HELLP syndrome, 40 percent had adverse outcomes, and two mothers died (Haddad, 2000). Complications included eclampsia in 6 percent, placental abruption-10 percent, acute kidney injury-5 percent, and pulmonary edema-10 percent. Stroke, hepatic hematoma, coagulopathy, acute respiratory distress syndrome, and sepsis were other serious complications.

Women with preeclampsia and HELLP syndrome typically have worse outcomes than preeclamptic women without the HELLP constellation (Kozic, 2011; Martin, 2012, 2013). In one review of693 women with HELLP syndrome, 10 percent had concurrent eclampsia (Keiser, 2011). Sep and associates (2009) described a significantly higher risk for complications in women with HELLP syndrome compared with those with "isolated preeclampsia." These included eclampsia-15 versus 4 percent; preterm birth-93 versus 78 percent; and perinatal mortality rate-9 versus 4 percent, respectively. Because of these marked clinical diferences, it has been postulated that HELLP syndrome has a distinct pathogenesis (Reimer, 2013; Vaught, 2016).

Headaches and visual symptoms are common with severe preeclampsia, and associated convulsions deine eclampsia. The earliest anatomical descriptions of brain involvement came from autopsy specimens, but CT and MR imaging and Doppler studies have added many important insights.

FIGURE 40-10 This autopsy brain slice shows a fatal hypertensive hemorrhage in a primigravida with eclampsia.

From early anatomical descriptions, brain pathology accounted for only about a third of fatal cases such as the one shown in Figure 40-10. In fact, most deaths were from pulmonary edema, nd brain lesions were coincidental. Thus, lthough gross intracerebral hemorrhage was seen in up to 60 percent of eclamptic women, it was fatal in only half of these (Melrose, 1984; Richards, 1988; Sheehan, 1973). s shown in Figure 40-11, other principal lesions found at autopsy of eclamptic women were cortical and subcortical petechial hemorrhages. The classic microscopic vascular lesions consist of fibrinoid necrosis of the arterial wall and perivascular micro infarcts and hemorrhages. Other frequently described major lesions include subcortical edema, multiple nonhemorrhagic areas of "sotening" throughout the brain, and hemorrhagic areas in the white matter (Hecht, 2017). here also may be hemorrhage in the basal ganglia or pons, sometimes with rupture into the ventricles.

Clinical, pathological, and neuroimaging findings have led to two general theories to explain cerebral abnormalities with eclampsia. Importantly, endothelial cell dysfunction that characterizes the preeclampsia syndrome likely is a key in both. The first theory suggests that in response to acute and severe hypertension, cerebrovascular overregulation leads to vasospasm (Trommer, 1988). In this scheme, diminished cerebral blood low is hypothesized to result in ischemia, cytotoxic edema, and eventually tissue infarction. Little objective evidence supports this mechanism.

he second theory is that sudden elevations in systemic blood pressure exceed the normal cerebrovascular autoregulatory capacity (Hauser, 1988; Schwartz, 2000). Regions of forced vasodilation and vasoconstriction develop, especially in arterial boundary zones. At the capillary level, disruption of end-capillary pressure causes increased hydrostatic pressure, hyperperfusion, and extravasation of plasma and red cells through endothelial tight-junction openings. his leads to vasogenic edema. he recent description of a central nervous system lymphatic vasculature lends credibility to this theory (Louveau, 2015).

he most likely mechanism is a combination of the two.

hus, a preeclampsia-associated interendothelial cell leak develops at blood pressure (hydraulic) levels much lower than those that usually cause vasogenic edema and is coupled with a loss of upper-limit autoregulation (Fugate, 2015; Zeeman, 2009). With imaging studies, these manifest as theposterior reversible encephalopathy syndrome (Fig. 40-12) (Fugate, 2015; Hinchey, 1996). he lesions of this syndrome principally involve the posterior brain-the occipital and parietal cortices. But, in at least a third of cases, other areas are involved (Edlow, 2013; Zeeman, 2004a).

FIGURE 40-12 Cranial magnetic-resonance imaging in a nullipara with eclampsia. Multilobe T2-FLAIR high-signal lesions are apparent. FLAIR = fluid-attenuated inversion recovery. (Used with permission from Dr. Gerda Zeeman.)

Autoregulation is the mechanism by which cerebral blood flow sion pressure. Remember that cerebral perfusion pressure is the sure. In nonpregnant individuals, this autoregulation protects the brain from hyperperfusion when mean arterial pressures rise to as high as 160 mm Hg. hese are pressures far greater than those seen in all but a very few women with eclampsia. Thus, to explain eclamptic seizures, it was theorized that autoregu lation must be altered by pregnancy. Studies by Cipolla and colleagues (2007, 2009, 2015) have convincingly shown that autoregulation is unchanged across pregnancy in rodents. But, some investigators have provided evidence of impaired auto regulation in women with preeclampsia a anzarik, 2014; van

Veen, 2013).

Zeeman and associates (2003) showed that cerebral blood flow during the irst two trimesters of normal pregnancy is similar to nonpregnant values. But during the last trimester, low significantly drops by 20 percent. his group also found greater cerebral blood low in this trimester in women with severe preeclampsia compared with that in normotensive pregnant women (Zeeman, 2004b). Taken together, these findings suggest that eclampsia occurs when cerebral hyperperfusion forces capillary luid interstitially because of endothelial damage. This leak leads to perivascular edema characteristic of the preeclampsia syndrome.

Several neurological manifestations typiy the preeclampsia syndrome. Each signiies severe involvement and requires immediate attention.

First, headache and scotomata are thought to arise from cerebrovascular hyperperusion that has a predilection for the occipital lobes. Up to 75 percent of women have headaches, and 20 to 30 percent have visual changes preceding eclamptic convulsions (Sibai, 2005; Zwart, 2008). The headaches may be mild to severe and intermittent to constant. In our experiences, they are unique in that they do not usually respond to traditional analgesia, but they frequently improve ater magnesium sulfate infusion.

Convulsions are diagnostic for eclampsia. These are caused by excessive release of excitatory neurotransmitters-especially glutamate; massive depolarization of network neurons; and bursts of action potentials (Meldrum, 2002). Clinical and experimental evidence suggests that extended seizures can cause signiicant brain injury and later brain dysfunction.

Blindness is rare with preeclampsia alone, but it complicates eclamptic convulsions in up to 15 percent of women (Cunningham, 1995). Blindness may develop up to a week or more following delivery (Chambers, 2004). There are at least two ypes of blindness, as discussed subsequently.

Generalized cerebral edema may develop and is usually manifest by mental status changes that vary from confusion to coma. This situation is particularly dangerous because fatal transtentorial herniation can result.

Last, women with eclampsia have been shown to have some cognitive decline when studied 5 to 10 years following an eclamptic pregnancy. This is discussed further in the inal section (p. 745).

With CT imaging, localized hypodense lesions at the gray-and white-matter junction, primarily in the parietooccipital lobes, are typically found in eclampsia. Such lesions may also be seen in the frontal and inferior temporal lobes, the basal ganglia, and thalamus (Brown, 1988). These hypodense areas correspond to petechial hemorrhages and local edema. Edema of the occipital lobes or difuse cerebral edema may cause symptoms such as blindness, lethargy, and confusion (Cunningham, 2000). Widespread edema can appear as marked compression or even obliteration of the cerebral ventricles. Such women may develop signs of impending life-threatening trans tentorial herniation.

Several MR imaging acquisitions are used to study eclamptic women. Common findings are hyperintense T2lesions-namely, posterior reversible encephalopathy syndrome (PRES)-in the subcortical and cortical regions of the parietal and occipital lobes (see Fig. 40-12). Also, the basal ganglia, brainstem, and cerebellum are relatively commonly involved (Brewer, 2013; Zeeman, 2004a). Again, these lesions represent focal cerebral edema. Although these PRES lesions are almost universal in women with eclampsia, their incidence in women with preeclampsia approximates 20 percent (Mayama, 2016). Lesions are more likely in women who have severe disease and who have neurological symptoms. And although usully reversible, a fourth of these hyperintense lesions represent cerebral infarctions that have persistent indings (Loureiro, 2003; Zeeman, 2004a).

Scotomata, blurred vision, or diplopia are common with severe preeclampsia and eclampsia. hese usually improve with magnesium sulfate therapy and/or lowered blood pressure. Blindness is less common, is usually reversible, and may arise from three potential areas. These are the visual cortex of the occipital lobe, the lateral geniculate nuclei, and the retina. In the retina, pathological lesions may be ischemia, infarction, or detachment (Handor, 2014; Roos, 2012).

Occipital blindness is also called amaurosis-from the Greek dimming. With imaging, afected women usually have evidence of extensive occipital lobe vasogenic edema. Of 15 women cared for at Parkland Hospital, occipital blindness lasted from 4 hours to 8 days, but it resolved completely in all cases (Cunningham, 1995). Rarely, extensive cerebral infarctions may result in total or partial visual defects.

Blindness from retinal lesions is caused either by serous retinal detachment or rarely by retinal infarction, which is termed Purtscher retinopathy 40-13). Serous retinal detachment is usually unilateral and seldom causes total visual loss. In fact, asymptomatic serous retinal detachment is relatively common with preeclampsia (Saito, 1998). In most cases of eclampsiaassociated blindness, visual acuity subsequently improves. However, if blindness is caused by retinal artery occlusion, vision may be permanently impaired (Lara-Torre, 2002; Moseman, 2002; Roos, 2012).

Clinical manifestations suggesting widespread cerebral edema are worrisome. During 13 years at Parkland Hospital, 10 of 175 women (6 percent) with eclampsia were diagnosed with

FIGURE 40-1 3 Purtscher retinopathy caused by choroidal ischemia and infarction in preeclampsia syndrome. Ophthalmoscopy shows scattered yellowish, opaque lesions of the retina (arrows). (Reproduced with permission from Lam OS, Chan W: Images in clinical medicine. Choroidal ischemia in preeclampsia. N Engl J Med 344(1o0):739,o2001o.) symptomatic cerebral edema (Cunningham, 2000). Symptoms ranged from lethargy, confusion, and blurred vision to obtundation and coma. In most cases, symptoms waxed and waned. Mental status changes generally correlated with the degree of involvement seen with CT and MR imaging studies. These women are very susceptible to sudden and severe blood pressure elevations, which can acutey worsen the already widespread vasogenic edema. Thus, careful blood pressure control is essential. In the 10 women with generalized edema, three became comatose and had imaging indings of trans tentorial herniation, from which one died. Consideration is given for treatment with mannitol or dexamethasone.

Compromised utero placental perfusion is almost certainly a major culprit in the greater perinatal morbidity and mortality rates seen with preeclampsia (Harmon, 2015). Defects in endovascular trophoblastic invasion with the preeclampsia syndrome were discussed earlier (p. 714). hus, measurement of uterine, intervillous, and placental blood low would likely be informative. Attempts to assess these in humans have been hampered by several obstacles that include inaccessibility of the placenta, the complexity of its venous eiuent, and the need for radioisotopes or invasive techniques.

Measurement of uterine artery blood low velocity has been used to estimate resistance to uteroplacental blood low (Chap. 17, p. 339). Vascular resistance is estimated by comparing arterial systolic and diastolic velocity waveforms. By the completion of placentation, impedance of uterine artery blood low is markedly decreased, but with abnormal placentation, abnormally high resistance persists (Everett, 2012; Ghidini, 2008; Napolitano, 2012). Earlier studies were done to assess this by measuring peak systolic:diastolic velocity ratios from uterine and umbilical arteries in preeclamptic pregnancies. In some cases, but certainly not all, there was higher resistance (Fleischer, 1986; Trudinger, 1990).

Another Doppler waveform-uterine artery "notching"has been associated with elevated risks for preeclampsia or fetal-growth restriction (Groom, 2009). In the MFMU Network study reported by Myatt and colleagues (2012a), however, notching had a low predictive value except for early-onset severe disease.

Resistance in uterine spiral arteries has also been measured. Impedance was higher in peripheral than in central vessels-a "ring-like" distribution (Matijevic, 1999). Mean resistance values were greater in all women with preeclampsia compared with those in normotensive controls. One study used MR imaging and other techniques to assess placental perfusion ex vivo in myometrial arteries removed from women with preeclampsia or fetal-growth restriction (Ong, 2003). In both conditions, myometrial arteries exhibited endothelium-dependent vasodilatory response. Moreover, other pregnancy conditions are also associated with increased resistance (Urban, 2007). One major adverse efect, fetal-growth restriction, is discussed in Chapter 44 (p. 847).

de Almeida Pimenta and colleagues (2014) assessed placental vascularity using a three-dimensional power Doppler histogram and described a placental vasculariy index. This index value was reduced in women with any pregnancy-associated hypertensive disorders-1l.1 percent compared with 15.2 percent in normal controls.

Despite these indings, evidence for compromised uteroplacental circulation is found in only a few women who go on to develop preeclampsia. Indeed, when preeclampsia develops during the third trimester, only a third of women with severe disease have abnormal uterine artery velocimetry (Li, 2005). In a study of 50 women with HELLP syndrome, only a third had abnormal uterine artery waveforms (Bush, 2001). In general, the extent of abnormal waveforms correlates with severity of fetal involvement (Ghidini, 2008; Groom, 2009).

Various biological markers implicated in the preeclampsia syndrome have been measured to help predict its development. Although most have been evaluated in the irst half of pregnancy, some have been tested as predictors of severity in the third trimester (Chaiworapongsa, 2013; Lai, 2013; Mosimann, 2013). Others have been used to forecast recurrent preeclampsia (Demers, 2014; Eichelberger, 2015). Some of these tests are listed in Table 40-5, which is by no means all inclusive.

Overall, these eforts have resulted in testing strategies with poor sensitivity and with poor positive-predictive values for preeclampsia (Conde-Agudelo, 2015; Odibo, 2013). Currenty, no screening tests or preecampsia are predictaby reliable, vali, and economical However, combinations of tests, some yet to be adequatelyevaluated, may be promising (Gallo, 2016; Olsen, 2012).

Most tests in this category are cumbersome, time consuming, and overall inaccurate. To evaluate blood pressure changes, three tests assess the blood pressure rise in response to a stimulus. In one, women at 28 to 32 weeks' gestation rest in the left lateral decubitus position and then roll to the supine position. With this rol-over test, increased blood pressure with this maneuver signifies a positive test. he isometric exercise

TABLE 40-5. Predictive Tests for Development of the Preeclampsia Syndrome

Roll-over test, isometric handgrip or cold pressor test, pressor response to aerobic exercise, angiotensin-II infusion, midtrimester mean arterial pressure, platelet angiotensin-II binding, renin, 24-hour ambulatory blood pressure monitoring, uterine artery r fetal transcranial Doppler velocimetry

Human chorionic gonadotropin (hCG), alpha-fetoprotein (AFP), estriol, pregnancy-associated protein A (PAPP A), inhibin A, activin A, placental protein 13, procalcitonin, corticotropinreleasing hormone, A disintegrin, ADAM-12, kisspeptin

Serum uric acid, microalbuminuria, urinary calcium or kallikrein, microtransferrinuria, N-acetyl-3-glucosaminidase, cystatin C, podocyturia, podocalyxin

Platelet count and activation, fibronectin, endothelial adhesion molecules, prostaglandins, prostacyclin, MMP-9, thromboxane, C-reactive protein, cytokines, endothelin, neurokinin B, homocysteine, lipids, insulin resistance, resistin, antiphospholipid antibodies, plasminogen activator-inhibitor (PAl), leptin, p-selectin, angiogenic and antiangiogenic factors such as placental growth factor (PIGF), vascular endothelial growth factor (VEGF), fms-like tyrosine kinase receptor-1 (sFlt-1), endoglin

Antithrombin-III(AT-3), atrial natriuretic peptide (ANP), 32-microglobulin, haptoglobin, transferrin, ferritin, 25-hydroxyvitamin 0, genetic markers, cell-free fetal DNA, serum and urine proteomics and metabolomic markers, hepatic aminotransferases

ADAM 12 = ADAM metallopeptidase domain 12; MMP = matrix metalloproteinase. Adapted from Conde-Agudelo, 2015, Duckworth, 2016.

test employs the same principle by squeezing a handball. The angiotensin 11 infusion test is performed by giving incrementally increasing doses intravenously, and the hypertensive response is quantiied. In an updated metaanalysis, sensitivities of all three tests were reported to range from 55 to 70 percent, and specificities approximated 85 percent (CondeAgudelo, 2015).

Uterine artey Doppler velocimety is posited to relect faulty trophoblastic invasion of the spiral arteries. his failure results in diminished placental perfusion and upstream greater uterine artery resistance. Increased uterine artery velocimetry determined by Doppler ultrasound in the first two trimesters might provide indirect evidence of this process and thus serve as a predictive test for preeclampsia (Dar, 2010; Groom, 2009). Elevated low resistance results in an abnormal vessel waveform represented by an exaggerated diastolic notch. hese indings have value for prediction of fetal-growth restriction but not preeclampsia (American College of Obstetricians and Gynecologists, 2015). Several low velocity waveforms have been investigated for preeclampsia prediction, however, none is suitable for clinical use (CondeAgudelo, 2015; Kleinrouweler, 2012; Myatt, 2012a).

Several serum analytes have been proposed to help predict preeclampsia (see Table 40-5). Newer ones are continually added. In general, none of these tests are clinically beneicial for hypertension prediction.

Hyperuricemia likely results from reduced uric acid clearance from diminished glomerular filtration, increased tubular reabsorption, and decreased secretion. Cnossen and coworkers (2006) reported that its sensitivity to detect preeclampsia ranged from 0 to 55 percent, and speciicity was 77 to 95 percent.

Isolated gestational proteinuria is a risk factor for preeclampsia Qayaballa, 2015; Morgan, 2016; Yamada, 2016). As a predictive test for preeclampsia, microalbuminuria has sensitivities that range from 7 to 90 percent and specificities that span 29 to 97 percent (Conde-Agudelo, 2015).

Endothelial activation and inflammation are major participants in the pathophysiology of the preeclampsia syndrome. As a result, compounds such as those listed in Table 40-5 are found to be elevated in circulating blood of afected women, and some have been assessed for their predictive value.

First, ibronectins are high-molecular-weight glycoproteins released from endothelial cells and extracellular matrix following endothelial injury. However, in one systematic review, neither cellular nor total ibronectin levels were clinically useful to predict preeclampsia (Leeflang, 2007).

Thrombocytopenia and platelet dysfunction are integral features of preeclampsia. Platelet activation causes augmented destruction and lower concentrations. Mean platelet volume rises because of platelet immaturity (Kenny, 2015). Although markers of coagulation activation, described earlier (p. 719), are elevated, the substantive overlap with levels in normotensive pregnant women stultiies their predictive value.

Markers of oxidative stress were also hoped to predict preeclampsia. Namely, associated higher levels of lipid peroxides coupled with decreased antioxidant activity raised this possibility. Other markers include iron, transferrin, and ferritin; resistin; hyperhomocysteinemia; blood lipids, including triglycerides, free fatty acids, and lipoproteins; and antioxidants such as ascorbic acid and vitamin E (Christiansen, 2015; CondeAgudelo, 2015; D'Anna, 2004; Mackay, 2012; Mignini, 2005). However, these have not been found to be predictive.

Last, an imbalance in antiangiogenic factors is linked to preeclampsia etiopathogenesis. For example, serum levels ofVEGF and PIGF begin to drop before clinical preeclampsia develops. And, recall from Figure 40-4 that at the same time, levels of some antiangiogenic factors, such as sFlt-1 and sEng, begin to rise (Karumanchi, 2016a; Maynard, 2008). With some of these factors, sensitivities for all cases of preeclampsia ranged from 30 to 50 percent, and specificity approximated 90 percent (Conde-Agudelo, 2015). heir predictive accuracy is higher for early-onset preeclampsia (Redman, 2015b; Tsiakkas, 2016). Determination of the sFlt-lIPIGF ratio in women admitted near 37 weeks' gestation to exclude preeclampsia was useful as a predictive factor (Baltajian, 2016; Zeisler, 2016a,b). These results suggest a clinical role for preeclampsia prediction, especially later in pregnancy (Ducworth, 2016; Gallo, 2016). They may also predict adverse pregnancy outcomes in women with lupus and comorbid anti phospholipid antibodies (Kim, 2016).

As discussed in Chapter 13 (p. 273), cell-free DNA (cfDNA) can be detected in maternal plasma. It is hypothesized that cDNA is released in preeclampsia by accelerated apoptosis of cytotrophoblasts (DiFederico, 1999). One MFMU Network study found no correlation between total cfDNA levels and preeclampsia (Silver, 2017).

Proteomic, metabolomic, and transcriptomic technologies can be employed to study serum and urinary proteins and cellular metabolites. These have opened new vistas for preeclampsia prediction, and preliminary studies indicate that these may become useful (Bahado-Singh, 2013; Carty, 2011; Ma, 2014; Myers, 2013).

Various strategies used to prevent or modiy preeclampsia severity have been evaluated. Some are listed in Table 40-6. In general, none of these has been found to be convincingly and reproducibly efective.

Dietary "treatment" for preeclampsia has produced some interesting abuses (Chesley, 1978). A low-salt diet was one of the earliest research eforts to prevent preeclampsia (De Snoo, 1937). This was followed by years of inappropriate diuretic therapy. Although these practices were discarded, it ironically

TABLE 40-6. Some Methods to Prevent Preeclampsia That Have Been Evaluated in Randomized Trials

Dietary manipulation-low-salt diet, calcium or fish oil

Exercise-physical activity, stretching

Cardiovascular drugs-diuretics, antihypertensive drugs

Antioxidants-ascorbic acid (vitamin C), a-tocopherol (vitamin E), vitamin D

Antithrombotic drugs-low-dose aspirin, aspirin/ dipyridamole, aspirin + heparin, aspirin + ketanserin

Modified from Staff, 2015.

was not until relatively recently that the irst randomized trial was done and showed that a sodium-restricted diet was inefective in preventing preeclampsia (Knuist, 1998).

Regular exercise during pregnancy is linked to a lower risk of developing preeclampsia (Barakat, 2016; Morris, 2017). Also, in one systematic review, a trend toward risk reduction with exercise was noted (Kasawara, 2012). Only a few studies have been randomized, and thus, more research is needed (Staf, 2015).

Somewhat related, Abenhaim and coworkers (2008) reported a retrospective cohort study of 677 nonhypertensive women hospitalized for bed rest because of threatened preterm delivery. When outcomes of these women were compared with those of the general obstetrical population, bed rest was associated with a signiicantly reduced relative risk-0.27-of developing preeclampsia. From two small randomized trials, prophylactic bed rest for 4 to 6 hours daily at home was successful in signiicantly lowering the incidence of preeclampsia in women with normal blood pressures (\1eher, 2006).

Calcium supplementation has been studied in several trials, including one by the National Institute of Child Health and Human Development (NICHD) that included more than 4500 low-risk nulliparas (Levine, 1997). Calcium supplementation did not prevent preeclampsia or pregnancy-associated hypertension. In one metaanalysis, increased calcium intake in high-risk women lowered the risk for preeclampsia (Patrelli, 2012). However, in aggregate, most of these trials have shown that unless women are calcium deficient, supplementation has no salutary efects (Sanchez-Ramos, 2017; Staf, 2015).

Cardioprotective aty acids found in some fatty fishes are plentiful in diets of Scandinavians and American Eskimos. Because supplementation with these fatty acids likely prevents inflammatory-mediated atherogenesis, it was posited that they might also prevent preeclampsia. Unfortunately, randomized trials conducted thus far have shown no such beneits from ish oil supplementation (Makrides, 2006; Olafsdottir, 2006; Zhou, 2012).

Because of the putative efects of sodium restriction for preeclampsia prevention, diuretic therapy became popular with the introduction of chlorothiazide in 1957 (Finnerty, 1958; Flowers, 1962). In one metaanalysis of nine randomized trials with more than 7000 pregnancies, women given diuretics had a lower incidence of edema and hypertension but not of preeclampsia (Churchill, 2007). Because women with chronic hypertension are at high risk for preeclampsia, several randomized trials have evaluated various antihypertensive drugs to reduce the incidence of superimposed preeclampsia (Chap. 50, p. 980). A critical analysis of these trials by Staf and coworkers (2015) failed to demonstrate benefits for this goal.

Data imply that an imbalance between oxidant and antioxidant activity plays a role in preeclampsia pathogenesis. Thus, naturally occurring antioxidants-vitamins C, D, and Emight reduce such oxidation. Several randomized studies have assessed antioxidant vitamin supplementation for women at high risk for preeclampsia (Poston, 2006; Rumbold, 2006; Villar, 2009). he Combined Antioxidant and Preeclampsia Prediction Studies (CAPPS) by the MFMU Network included almost 10,000 low-risk nulliparas (Roberts, 2010). None of these studies showed reduced preeclampsia rates in women provided vitamins C and E compared with those given placebo.

Statins were proposed to prevent preeclampsia because they stimulate hemoxygenase-1 expression, which inhibits sFlt-1 release. Preliminary animal data suggest that statins may prevent hypertensive disorders of pregnancy (Lewis, 2017). The MFMU Network plans a randomized trial to test pravastatin for this purpose (Costantine, 2013, 2016).

Meormin inhibits hypoxic inducible actor 1. by lowering mitochondrial electron transport chain activity. It reduces sFlt-1 and sEng activity and thus has potential to prevent preeclampsia (Brownfoot, 2016). However, clinical studies are lacking.

As noted earlier (p. 715), preeclampsia is characterized by vasospasm, endothelial cell dysfunction, and inlammation, as well as activation of platelets and the coagulation-hemostasis system. Other sequelae include placental infarction and spiral artery thrombosis (Nelson, 2014b). Thus, antithrombotic agents have been evaluated to reduce the incidence of preeclampsia.

Low-molecular-weight heparin for prophylaxis has been studied in several randomized trials. Rodger and colleagues (2016) performed a metaanalysis using individual patient data from 963 women. The risk for recurrent preeclampsia, abruption, or fetal-growth restriction was similar in women receiving heparin or placebo.

Aspirin, in low oral doses of 50 to 150 mg daily, efectively inhibits platelet thromboxane A2 biosynthesis but has minimal efects on vascular prostacyclin production (Wallenburg, 1986). Still, several clinical trials have shown limited benefits in preeclampsia prevention. For example, a randomized trial from the MFMU Network found that risks for adverse outcomes were not significantly reduced with aspirin therapy (Caritis, 1998). Some combined reports, however, are more favorable. The Paris Collaborative Group performed a metaanalysis that included 31 randomized trials involving 32,217 women (Askie, 2007). For women assigned to receive antiplatelet agents, the relative risk for preeclampsia, superimposed preeclampsia, preterm delivery, or any adverse pregnancy outcome was significantly decreased by 10 percent. Other metaanalyses report marginal benefits of low-dose aspirin for prevention of severe preeclampsia (Roberge, 2012; Villa, 2013). Recently, one randomized trial of more than 1600 women at high risk for preterm preeclampsia provided low-dose aspirin from 11 to 14 weeks' gestation until 36 weeks to prevent recurrence. The rate of preterm recurrence was 1.6 percent in the aspirin group compared with 4.3 percent in the placebo arm (Rolnik, 2017).

In recent dueling metaanalyses, Roberge and colleagues (2017) found that aspirin prophylaxis initiated before 16 weeks' gestation was associated with a signiicant risk reductionabout 60 percent-for preeclampsia and fetal-growth restriction. Moreover, they found a dose-response efect. At the same time, Meher and associates (2017) performed an individual participant data metaanalysis and reported a much lower-about 10 percent-risk reduction that was significant whether therapy was initiated before or after 16 weeks.

Meanwhile, the U.S. Preventive Services Task Force recommends low-dose aspirin prophylaxis for women at high risk for preeclampsia (Henderson, 2014). Because of this, the American College of Obstetricians and Gynecologists (2016b) issued a Practice Advisory that recommends low-dose aspirin be given between 12 and 28 weeks' gestation to help prevent preeclampsia in high-risk women. This includes those with a history of preeclampsia and those with twins, chronic hypertension, overt diabetes, renal disease, and autoimmune disorders. These results have also raised the question as to whether al pregnant women should be given aspirin (Mone, 2017). At this time, our answer is "no."

Low-dose aspirin coupled with heparin mmgates thrombotic sequelae in women with lupus anticoagulant (Chap. 59, p. 1145). Because of a similarly high prevalence of placental thrombotic lesions found with severe preeclampsia, trials have assessed the possible merits of such treatments for women with prior preeclampsia. In two randomized trials, women with a history of early-onset preeclampsia were given an aspirin therapy or an enoxaparin plus aspirin regimen (Groom, 2017; Haddad, 2016). Outcomes were similar. From their reviews, Sergis and associates (2006) reported better pregnancy outcomes in women with prior severe preeclampsia given low-molecularweight heparin plus low-dose aspirin compared with those given low-dose aspirin alone. Similar indings were reported by de Vries and coworkers (2012).

Pregnancy complicated by gestational hypertension is managed based on its severity, presence of preeclampsia, and gestational age. Preeclampsia cannot always be diagnosed definitively. hus, the Task Force (2013) recommends more frequent prenatal visits if preeclampsia is "suspected." Increases in systolic and diastolic blood pressure can be either normal physiological changes or signs of developing patholoy. Heightened surveillance permits more prompt recognition of ominous changes in blood pressure, critical laboratory findings, and clinical signs and symptoms (Macdonald-Wallis, 2015).

The basic management objectives for any pregnancy complicated by preeclampsia are: (1) termination of pregnancy with the least possible trauma to mother and fetus, (2) birth of a healthy newborn that subsequently thrives, and (3) complete restoration of health to the mother. In many women with preeclampsia, especially those at or near term, all three objectives are served equally well by induction of labor. One of the most important clinical questions or succesul management is precise knowledge of etal age.

• Early Diagnosis of Preeclampsia

Traditionally, the frequency of prenatal visits is increased during the third trimester, and this aids early detection of preeclampsia. Women without overt hypertension, but in whom eary developing preeclampsia is suspected during routine prenatal visits, are seen more frequenty. For many years at Parkland Hospital, women with new-onset diastolic blood pressures >80 mm Hg but <90 mm Hg or with sudden abnormal weight gain of more than 2 pounds per week have, at minimum, returned for visits at 7 -day intervals. Outpatient surveillance is continued unless overt hypertension, proteinuria, headache, visual disturbances, or epigastric pain supervenes.

Women with overt new-onset hypertension-either diastolic pressures �90 mm Hg or systolic pressures � 140 mm Hg-are admitted to determine if the increase is due to preeclampsia, and if so, to evaluate its severity.

With hospitalization, a systematic evaluation is instituted to include:

Detailed examination, which is coupled with daily scrutiny for clinical indings such as headache, visual disturbances, epigastric pain, and rapid weight gain

Quantification of proteinuria or urine protein:creatmme

Blood pressure readings with an appropriate-size cuf every 4 hours, except between 2400 and 0600 unless previous readings are elevated

Measurements of plasma or serum creatinine and hepatic transaminase levels and a hemogram that includes a platelet count. The frequency of testing is determined by hypertension severity. Although some recommend measurement of serum uric acid and lactate dehydrogenase levels and coagulation studies, their value has been questioned (CondeAgudelo, 2015; Thangaratinam, 2006).

Evaluation of fetal size and well-being and amnionic luid volume, by either physical examination or sonography.

Reduced physical activity throughout much of the day is likely beneficial, but as the 2013 Task Force concluded, absolute bed rest is not desirable. Ample protein and calories are included in the diet, and sodium and fluid intake are not limited or forced.

In sum, goals of evaluation include early identification of preeclampsia or worsening of the syndrome and development of a management plan for timely delivery. Fortunately, many cases are suiciently mild and near enough to term that they can be managed conservatively until labor commences spontaneously or until the cervix becomes favorable for labor induction. Complete abatement 0/ al signs and symptoms, however, is uncommon until ater delivery. If severe preeclampsia is diagnosed using the criteria in Table 40-2, further management is subsequently described.

Termination o/pregnancy is the ony cure or preeclampsia. Head ache, visual disturbances, or epigastric pain are indicative that convulsions may be imminent, and oliguria is another ominous sign. Severe preeclampsia demands anticonvulsant and often antihypertensive therapy, followed by delivery. Treatment for eclampsia is identical. The prime objectives are to forestall con vulsions, to prevent intracranial hemorrhage and serious dam age to other vital organs, and to deliver a healthy newborn.

his is true even when the cervix is unfavorable (T ajik, 2012). Labor induction is carried out, usually with preinduc tion cervical ripening with a prostaglandin or osmotic dilator (Chap. 26, p. 505).

Concerns stemming from an unfavorable cervix, a perceived sense of urgency because of preeclampsia severity, and a need to coordinate neonatal intensive care have led some to advocate cesarean delivery. Alexander and colleagues (1999) reviewed 278 singleton liveborn neonates weighing 750 to 1500 g delivered of women with severe preeclampsia at Parkland Hospital. In half of the women, labor was induced, and the remainder underwent cesarean delivery without labor. Induction was successful in accomplishing vaginal delivery in a third, and it was not harmful to very-low-birthweight neonates. Others have reported similar observations (Alanis, 2008; Roland, 2017). However, whenever it appears that induction almost certainly will not succeed or attempts have failed, then cesarean delivery is indicated.

For a woman near term, with a soft, partially efaced cervix, even a milder degree of preeclampsia probably carries more risk to the mother and her fetus-newborn than does induction of labor (Tajik, 2012). A randomized trial of 756 women with mild preeclampsia supported delivery after 37 weeks' gestation (Koopmans, 2009).

When the fetus is preterm, the tendency is to temporize in the hope that additional weeks in utero will reduce the risk of neonatal death or serious morbidity from prematurity. Such a policy certainly is justified in milder cases. Assessments of fetal well-being and placental function are performed, especially when the fetus is immature. Most recommend frequent performance of nonstress testing or biophysical proiles to assess fetal well-being (American College of Obstetricians and Gynecologists, 20 16a). Several tests can be used to provide evidence of lung maturity (Chap. 34, p. 638). An sFlt-lIPlGF ratio <38 is predictive of the short-term absence of preeclampsia, but this ratio testing is still investigational (Zeisler, 2016a,b). Also, women with higher ratios tend to have more adverse outcomes (Baltajian, 2016).

The decision to deliver late-preterm fetuses is less clear. Barton and coworkers (2011) reported excessive neonatal morbidity in women delivered before 38 weeks despite having stable, mild, nonprotein uric hypertension. The Netherlands study of 4316 newborns delivered, between 34°/7 and 36617 weeks also described substantive neonatal morbidity in these cases (Langenveld, 201l). Another Dutch study-HYPITAT-II-randomly assigned women with nonsevere hypertension between 34 and 37 weeks to immediate delivery or to expectant management (Broekhuijsen, 2015). Immediate delivery reduced the risks for adverse maternal outcomes-I. 1 versus 3.1 percent. However, it increased the risk for neonatal respiratory distress syndrome-5.7 versus 1. 7 percent.

For women with mild-to-moderate stable hypertension is continued. During surveillance, reduced physical activity throughout much of the day, at least intuitively, seems beneicial.

That said, complete bed rest is not recommended by the 2013

Task Force. First, this is pragmatically unachievable because of the severe restrictions it places on otherwise well women.

Also, it likely predisposes to thromboembolism (Knight, 2007).

To reduce activity, several studies have addressed the beneits of inpatient care and outpatient management.

he concept of prolonged hospitalization for women with hypertension arose during the 1970s. At Parkland Hospital, an inpatient antepartum unit was established in 1973 by Dr. Peggy Whalley in large part to provide care for such women. Initial results from this unit were reported by Hauth (1976) and Gilstrap (1978) and their coworkers. Most hospitalized womenJJ have a beneficial response characterized by amelioration or improvement of hypertension. These women are not "cure, and neary 90 percent have recurrent hypertension bore or during labor. By 2016, more than 10,000 nulliparas with mild-to-moderate, early-onset hypertension during pregnancy had been managed successfully in this unit. Provider costsnot charges-for this relatively simple physical facility, modest nursing care, no drugs other than iron and folate supplements, and few essential laboratory tests are minimal compared with the cost of neonatal intensive care for a preterm neonate. Importantly, none of these women have sufered thromboembolic disease.

Many clinicians believe that further hospitalization is not warranted if hypertension abates within a few days, and this has legitimized third-party payers to deny hospitalization reimbursement. Consequently, many women with mild-tomoderate hypertension are managed at home. Outpatient management may continue as long as preeclampsia syndrome does not worsen and fetal jeopardy is not suspected. Sedentary activity throughout the greater part of the day is recommended. These women are instructed in detail to report symptoms. Home blood pressure and urine protein monitoring or frequent evaluations by a visiting nurse may prove beneficial.

To assess this approach, 11r82 nulliparas with mild gestational hypertension-20 percent had proteinuria-were managed with home health care (Barton, 2002). Their mean gestational ages were 32 to 33 weeks at enrollment and 36 to 37 weeks at delivery. Severe preeclampsia developed in approximately 20 percent, about 3 percent developed HELLP syndrome, and two

Day Unit 24 57 23 36 0 39.8 1n.1 3320 0 Usual Care 30 54 21 36.5 21 39 5.1 3340 0 Turnbull (2004) 374b Hospitalization 125 63 0 35.9 22 39 S.5 3330 3.S 0 Day Unit 249 62 0 36.2 22 39.7 7.2 3300 2.3 0 aExciuded women with proteinuria at study entry.

blncluded women with sl+ proteinuria.

BW = birthweight; EGA = estimated gestational age; HTN = hypertension; Parao= nulliparas; PMR = perinatal mortality rate; Prot = proteinuria; SGA = small for gestational age.

women had eclampsia. Perinatal outcomes were generally good. In approximately 20 percent, there was fetal-growth restriction, and the perinatal mortality rate was 4.2 per 1000 births.

Several studies have compared continued hospitalization and outpatient care. In a pilot study from Parkland Hospital, 72 nulliparas with new-onset hypertension from 27 to 37 weeks were assigned either to continued hospitalization or to outpatient care (Horsager, 1995). he only significant diference was that women in the home care group developed severe preeclampsia significantly more frequently than hospitalized women42 versus 25 percent. In another trial, ater hospital evaluation, 218 women with mild gestational nonprotein uric hypertension were similarly divided (Crowther, 1992). As shown in Table 40-7, the mean hospital duration was 22.2 days for women with inpatient management compared with only 6.5 days in the home care group. Preterm delivery before 34 and before 37 weeks' gestation was increased twofold in the outpatient group. However, maternal and newborn outcomes were otherwise similar.

Another approach, popular in Europe, is day care (Milne, 2009). In one study, 54 women with hypertension after 26 weeks' gestation were assigned to either day care or routine outpatient management (see Table 40-7) (Tufnell, 1992). Progression to overt preeclampsia and labor inductions were signiicantly greater in the routine outpatient management group. In another, 395 women participated in either day care or inpatient management (Turnbull, 2004). Almost 95 percent had mild-to-moderate hypertension. Of enrolled women, 288 lacked proteinuria, and 86 had � 1 + proteinuria. There were no perinatal deaths, and none of the women developed eclampsia or HELLP syndrome. Costs for either scheme were not signiicantly diferent, and general satisfaction favored day care.

In sum, either inpatient or close outpatient management is appropriate for a woman with mild de novo hypertension, including those with nonsevere preeclampsia. Most of these studies were carried out in academic centers with dedicated management teams. hat said, the key to success is close surveillance and a conscientious patient with good home support.

he use of antihypertensive drugs to prolong pregnancy or modiY perinatal outcomes in pregnancies complicated by various hypertensive disorders has been of considerable interest. Treatment for women with chronic hypertension complicating pregnancy is discussed in detail in Chapter 50 (p. 980).

Drug treatment for early mild preeclampsia has been disappointing (Table 40-8). Sibai and colleagues (1987a) reported that women given labetalol had significantly lower mean blood pressures. However, mean pregnancy prolongation, gestational age at delivery, and birthweight did not difer between groups. he cesarean delivery rate and the number of newborns admitted to special-care nurseries were also similar. The requency of growth-restricted neonates was doubled in women given labetalol-19 versus 9 percent. The three other studies listed in Table 40-8 compared labetalol or the calcium-channel blockers nifedipine and isradipine against placebo. Except for fewer episodes of severe hypertension, none of these studies showed any benefits from antihypertensive treatment (Magee, 2015). Similar conclusions were reached by Abalos and associates (2014), who reviewed 49 randomized trials of active antihypertensive therapy compared with either no treatment or placebo given to women with mild-to-moderate gestational hypertension.

Up through the early 1990s, the prevailing\practice was that women with severe preeclampsia were usually delivered without delay. However, another approach for women with preterm severe preeclampsia has also been advocated. This approach calls for "conservative" or "expectant" management with the aA11 women had preeclampsia.

blncludes postpartum hypertension.

cp < .05 when study drug compared with placebo.

HTN = hypertension; NS = not stated.

aim of improving neonatal outcome without compromising maternal safety. Aspects of such management always include careful daily-and usually more frequent-inpatient monitoring of the mother and her fetus.

Expectant Management of Preterm Severe Preeclampsia

Theoretically, antihypertensive therapy has potential application when severe preeclampsia develops before intact neonatal survival is likely. Such management is controversial, and it may be dangerous. In one of the irst studies, Sibai and the Memphis group (1985) attempted to prolong pregnancy because of fetal immaturity in 60 women with severe preeclampsia between 18 and 27 weeks. The results were disastrous. The perinatal mortaliy rate was 87 percent. Although no mothers die, 13 su.ired placental abruption, 10 had eclampsia, three developed renal ailure, two had hypertensive encephalopathy, one had an intracerebral hemorrhage, and another had a ruptured hepatic hematoma.

Because of their early study, the Memphis group redeined criteria and performed a randomized trial of aggressive versus expectant management for 95 women who had severe preeclampsia but with more advanced gestations of 28 to 32 weeks (Sibai, 1994). Women with HELLP syndrome were excluded rom this tria. Aggressive management included glucocorticoid administration for fetal lung maturation followed by delivery in 48 hours. Expectantly managed women were observed at bed rest and given either labetalol or nifedipine orally for severe hypertension. In this study, pregnancy was prolonged for a mean of 15.4 days in the expectant management group. An overall improvement in neonatal outcomes was also reported.

Following these experiences, expectant management became more commonly practiced, but with the caveat that women with HELLP syndrome or growth-restricted fetuses were usually excluded. But in a subsequent follow-up observational study, the Memphis group compared outcomes in 133 preeclamptic women with and 136 without HELLP syndrome who presented between 24 and 36 weeks (Abramovici, 1999). Women were subdivided into three study groups. The first group included those with complete HELLP syndrome. The second group included women with partial HELLP syndromedeined as either one or two but not all three of the deining laboratory values. The third group included women who had severe preeclampsia without HELLP syndrome. Perinatal outyrcomes were similar in each group, and importantly, outcomes were not improved with procrastination. Despite this, the investigators concluded that women with partial HELLP syndrome and those with severe preeclampsia alone could be managed expectantly. Those with fetal-growth restriction generally have shorter interval-to-delivery durations (McKinney, 2016).

Sibai and Barton (2007b) reviewed expectant management of severe preeclampsia from 24 to 34 weeks. More than 1200 women were included, and although the average time gained ranged from 5 to 10 days, the maternal morbidity rates were formidable. Serious complications in some of these and in later studies included placental abruption, HELLP syndrome, pulmonary edema, renal failure, and eclampsia (Table 40-9). Moreover, perinatal mortality rates averaged 90 per 1000 births. Fetal-growth restriction was common, and in the studies from The Netherlands, it was an astounding 94 percent (Ganzevoort, 2005a,b). Perinatal mortality rates are disproportionately high in these growth-restricted neonates, but maternal outcomes are not appreciably diferent (Haddad, 2007; Shear, 2005). The MEXPRE Latin Study was a multicenter trial that randomly assigned 267 women with severe preeclampsia at 28 to 32 weeks to prompt delivery or to expectant management (VigilDe Gracia, 2013). The perinatal mortality rate approximated

Ganzevoort (2005a, b) 216 11 1.8 18 3.6 NS 1.8

Bombrys (2009) 66 5 11 8 9 3 0 27 1.5

Abdel-Hady (2010) 211 12 3.3 7.6 0.9 6.6 0.9 NS 48 Vigil-De Gracia (2013) 131 10.3 7.6 14 1.5 4.5 0.8 22 8.7

Range 91n0 5-1n2 1.8-23 4.6-27 0.9-3.9 2.3-6.6 0.9-1n8 27-94 1.5-48 alncludes one maternal death.

AKI = acute kidney injury; EGA = estimated gestational age; FGR = fetal-growth restriction; HELLP = hemolysis, elevated liver enzyme levels, low platelet count syndrome; NS = not stated; PMR = perinatal mortality rate; Pulm. = pulmonary.

9 percent in each group, the composite neonatal morbidity outcome was not improved with expectant management. On the other hand, fetal-growth restriction-22 versus 9 percent-and placental abruption-7.6 versus 1.5 percent-were significantly higher in the group managed expectantly.

Expectant Management of Midtrimester Severe Preeclampsia

Several small studies have focused on expectant management of severe preeclampsia syndrome bore 28 weeks. In their review, Bombrys and coworkers (2008) found eight such studies that included nearly 200 women with severe preeclampsia with an onset <26 completed weeks. Maternal complications were common. Because no neonates survived when delivered before 23 weeks, the Task Force (2013) recommends pregnancy termination in these cases. For women with slightly more advanced pregnancies, however, the decision is less clear. For example, at 23 weeks' gestation, the perinatal survival rate was 18 percent, but long-term perinatal morbidity is yet unknown. For women with pregnancies at 24 to 26 weeks, perinatal survival approached 60 percent, and it averaged almost 90 percent for those at 26 weeks.

At least five observational studies of women with severe midtrimester preeclampsia who were managed expectantly have been published since 2005 (AbdelHady, 2010; Belghiti, 2011; Bombrys,

Admit to L&D

Contraindications to conservative management

Eclampsia, pulmonary edema, HELLP syndrome

Significant renal dysfunction, coagulopathy

Frequent evaluation: vital signs, UOP

Serial lab evaluation of re n.aI function and for HELLP syndrome

Daily fetal assessment and evaluation of serial growth and amnionic fluid

FIGURE 40-14 Clinical management algorithm for severe preeclampsia at <34 weeks. HELLP = hemolysis, elevated liver enzyme levels, low platelet count; L&D = labor and delivery; MgS04= magnesium sulfate; UOP = urine output. (Adapted from the Society for 2008; Budden, 2006; Gaugler-Senden, Maternal-Fetal Medicine, 2011.) 2006). Maternal complications developed in 60 percent, and there was one maternal death. he perinatal mortality rate was 650 per 1000 births. At this time, no comparative studies attest to perinatal benefits of such expectant treatment versus early delivery in the face of serious maternal complications, which approach rates of 50 percent. We do not recommend such management.

To enhance fetal lung maturation, glucocorticoids have been administered to women with severe hypertension who are remote from term. Treatment does not seem to worsen maternal hypertension, and a lower incidence of respiratory distress and improved fetal survival rates have been cited. hat said, only one randomized trial has evaluated corticosteroids given to hypertensive women for fetal lung maturation. his trial included 218 women with severe preeclampsia between 26 and 34 weeks' gestation who were randomly assigned to betamethasone or placebo administration (Amorim, 1999). Rates of neonatal complications that included respiratory distress, intraventricular hemorrhage, and death were reduced significantly when betamethasone was given compared with placebo. On the heaviy weighted negative side, there were two maternal deaths and 18 stillbirths. We add these indings to buttress our unenthusiastic acceptance of attempts to prolong gestation in many of these women (Alexander, 2015; Bloom, 2003).

Taken in toto, these studies do not show overwhelming beneits compared with maternal risks for expectant management of severe preeclampsia in women with gestations from 24 to 32 weeks. Despite these caveats, the Society for MaternalFetal Medicine (201r1) has determined that such m�nagement is a reasonable alternative in selected women with severe preeclampsia before 34 weeks (Fig. 40-14). The Task Force (2013) supports this recommendation. As shown in Table 40-10, such management calls for in-hospital maternal and fetal surveillance with delivery prompted by evidence for worsening severe preeclampsia or maternal or fetal compromise. Although attempts are made for vaginal delivery in most cases, the likelihood of cesarean delivery rises with decreasing gestational age.

Our view is more conservative. Undoubtedly, the overriding reason to terminate pregnancies with severe preeclampsia is maternal safety. Indeed, it seems obvious that a delay to prolong gestation in women with severe preeclampsia may have serious maternal consequences (see Table 40-9). These observations are even more pertinent when considered with the absence of convincing evidence that perinatal outcomes are markedly improved by the average prolongation of pregnancy by approximately 1 week. If undertaken, the caveats that mandate delivery shown in Table 40-10 should be strictly heeded.

• Corticosteroids to Ameliorate HELLP Syndrome

At least three randomized trials have evaluated the beneits of glucocorticoids given to improve the laboratory abnormalities

TABLE 40-1 0. Indications for Delivery in Women

Delivery ater Maternal Stabilization:

Delay Delivery 48 hr If Possible:

Thrombocytopenia < 1 OO,OOO/�L

Hepatic transaminase levels twice upper limit of normal alnitial dose only, do not delay delivery.

From the Society for Maternal-Fetal Medicine, 2011, and the Task Force of the American College of Obstetricians and Gynecologists, 201n3.

associated with HELLP syndrome. First, Fonseca and associates (2005) randomly assigned 132 women with HELLP syndrome to either dexamethasone or placebo administration. Outcomes assessed included hospitalization length, recovery time of abnormal laboratory test results, resolution of clinical parameters, and complications that included acute renal fail ute, pulmonary edema, eclampsia, and death. None of these was signiicantly diferent between the two groups. In another study, 105 postpartum women with HELLP syndrome were assigned to dexamethasone or placebo treatment (Katz, 2008). Outcomes were analyzed similarly to the Fonseca study, and no advantage to dexamethasone was found (Fig. 40-15). In the third study, preeclamptic women were given either placebo or methylprednisolone if their platelet count was between 50,000 and 150,000/�L (Pourrat, 2016). No benefits were gained from corticosteroid therapy. Because of these indings, the 2013 Task Force does not recommend corticosteroid treatment for thrombocytopenia with HELLP syndrome.

In several preliminary studies, therapies have attempted to lower serum levels or mitigate the action of antiangiogenic factors. Some of these include therapeutic apheresis, done to lower sFlt-1 levels (Thadhani, 2016). Pravastatin has been given for preeclampsia prevention (Cleary, 2014). Sildenail citrate, a phosphodiesterase inhibitor, has been provided to promote vasodilation (Trapani, 2016; Vigil-De Gracia, 2016). In a recent randomized trial of 120 women with early-onset preeclampsia, an recombinant antithrombin infusion compared and occasionally anuria develops. There may be hemoglobinuria, but hemoglobinemia is rare. Often, facial and peripheral edema is pronounced, but it may be absent (Fig. 40-17).

FIGURE 40-1 7 Severe edema in a young nullipara with antepartum preeclampsia. (Used with permission from Dr. Nidhi Shah.)

As with severe preeclampsia, urinary output rises after delivery and is usually an early sign of improvement. With renal dysfunction, serum creatinine levels are serially monitored. Proteinuria and edema ordinarily disappear within a week postpartum. In most cases, blood pressure returns to normal within a few days to 2 weeks after delivery (Berks, 2009). As subsequently discussed, persisting and severe hypertension likely predicts underlying chronic vascular disease (Podymow, 2010).

In antepartum eclmpsia, labor may begin spontaneously shortly ater convulsions ensue and may progress rapidly. If the convulsions occur during labor, contractions may increase in frequency and intensity, and the duration oflabor may be shortened. Because of maternal hypoxemia and lactic acidemia caused by convulsions, fetal bradycardia oten follows a seixure (Fig. 40-18). he fetal heart rate usually recovers within 2 to 10 minutes (Ambia, 2018). If it persists more than about 10 minutes, another cause of bradycardia, such as placental abruption or imminent delivery, should be considered.

Pulmonary edema may follow shortly after eclamptic convulsions or to several hours later. This up usually is caused by aspiration pneumonitis from gastric-content inhalation during vomiting that frequently accompanies convulsions. In some women, pulmonary edema may be caused by ventricular failure from increased aterload that results from severe hypertension. Both pulmonary edema and hypertension can be further aggravated by vigorous intravenous fluid administration (Dennis, 2012b). Such pulmonary edema from ventricular failure is more common in morbidly obese women and in those with previously unappreciated chronic hypertension.

Occasionally, sudden death occurs synchronously with an eclamptic convulsion, or it follows shortly thereafter. Most often in these cases, a massive cerebral hemorrhage is the cause (see Fig. 40-10). Hemiplegia may result from sublethal hemorrhage. Cerebral hemorrhages are more likely in older women with underlying chronic hypertension.

In approximately 10 percent of eclamptic women, some degree of blindness follows a seizure. The causes of blindness or impaired vision were discussed earlier (p. 724). Blindness with severe preeclampsia without convulsions usually stems from retinal detachment (Vigil-De Gracia, 2011). Conversely, blindness with eclampsia is typically due to occipital lobe edema (Cunningham, 1995). In both instances, however, the prognosis for return to normal function is good and is usually complete within 1 to 2 weeks postpartum.

Up to 5 percent of women with eclampsia have substantively altered consciousness, including persistent coma, following a seizure. This is due to extensive cerebral edema, and associated trans tentorial herniation may cause death (p. 723).

Rarely, eclampsia is followed by psychosis, and the woman becomes violent. This may last for several days to 2 weeks. The prognosis for return to normal function is good, provided there was no preexisting mental illness. It is presumed to be similar to postpartum psychosis discussed in Chapter 61 (p. 1179). Antipsychotic medications have proven efective in the few cases of posteclampsia psychosis treated at Parkland Hospital.

Generally, eclampsia is more likely to be diagnosed too frequently rather than overlooked. Epilepsy, encephalitis, meningitis, brain rumor, neurocysticercosis, amnionic fluid embolism, postdural puncture cephalalgia, and ruptured cerebral aneurysm during late pregnancy or in the puerperium may simulate eclampsia. Until other such causes are excluded, however, all pregnant women with convulsions should be considered to have eclampsia.

FIGURE 40-18 Fetal heart rate tracing shows fetal bradycardia following an intrapartum eclamptic convulsion. Bradycardia resolved and beat-to-beat variability returned approximately 5 minutes following the seizure.

• Management of Eclampsia

Magnesium sulfate is highly efective to prevent convulsions in women with preeclampsia and to stop them in those with eclampsia. In his review, Chesley (1978) cited observational data by Pritchard and colleagues (1955, 1975) from Parkland Hospital and from his own institution. At that time, most eclampsia regimens in the United States adhered to a similar philosophy, and it is still in use today: 1.

Control of convulsions using an intravenously administered loading dose of magnesium sulfate that is followed by a maintenance dose, usually intravenous, of magnesium sulfate 2.

Intermittent administration of an antihypertensive medication to lower blood pressure whenever it is considered dangerously high 3.

Avoidance of diuretics unless pulmonary edema is obvious, limitation of intravenous luid administration unless fluid loss is excessive, and avoidance of hyperosmotic agents 4.

Delivery of the fetus to resolve preeclampsia.

• Magnesium Sulfate to Control Convulsions

Magnesium sulfate administered parenterally is an efective anticonvulsant that avoids producing central nervous system depression. It may be given intravenously by continuous inusion or intramuscularly by intermittent injection (Table 40-11). The dosages for severe preeclampsia are the same as for eclampsia. Because labor and delivery is a more likely time for convulsions to develop, women with preeclampsia-eclampsia usually are given magnesium sulfate during labor and for 24 hours postpartum.

In the United States, magnesium sulfate is almost universally administered intravenously. Of concern, magnesium sulfate solutions, although inexpensive to prepare, are not readily available in all parts of the developing world. And even when the solutions are available, the technology to infuse them may not be. herefore, it should not be overlooked that the drug can be administered intramuscularly and that this route is as efective as intravenous administration (Salinger, 20l3). In two reports from India, intramuscular regimens were nearly equivalent in preventing recurrent convulsions and maternal deaths in women with eclampsia (Chowdhury, 2009; lana, 20l3). hese observations comport with earlier ones from Parkland Hospital (Pritchard, 1975, 1984).

Magnesium suate is not given to treat hypertension. Magnesium most likely exerts a specific anticonvulsant action on the cerebral cortex. Typically, the mother stops convulsing after the initial 4-g loading dose. By an hour or two, she regains consciousness suiciently to be oriented to place and time.

he magnesium sulfate dosage regimens presented in Table 40-11 usually result in plasma magnesium levels illustrated in Figure 40-19. When magnesium sulfate is given to arrest eclamptic seizures, 10 to 15 percent of women will have a subsequent convulsion. If so, an additional 2-g dose of magnesium sulfate in a 20-percent solution is slowly administered intravenously. In a small woman, this additional 2-g dose may be used once, but it can be given twice if needed in a larger woman. In only 5 of 245 women with eclampsia at Parkland Hospital was it necessary to use alternative supplementary anticonvulsant medication to control convulsions (Pritchard, 1984). For these, an intravenous barbiturate is given slowly. Midazolam or lorazepam may also be given in a small single dose, but prolonged use is avoided because it is associated with a higher mortality rate from aspiration pneumonia (Royal College of Obstetricians and Gynaecologists, 2006).

TABLE 40-1 1. Magnesium Sulfate Dosage Schedule for Severe Preeclampsia and EclampSia

Give 4-to 6-g loading dose of magnesium sulfate diluted in 100 mL of IV fluid administered over 15-20 min Begin 2 g/hr in 100 mL of IV maintenance infusion. Some recommend 1 g/hr

Monitor for magnesium toxicity:

Assess deep tendon reflexes periodically Some measure serum magnesium level at 4-6 hr and adjust infusion to maintain levels between 4 and 7 mEq/L (4.8 to 8.4 mg/dL)

Measure serum magnesium levels if serum creatininen::1.0 mg/dL Magnesium sulfate is discontinued 24 hr ater delivery

Give 4 g of magnesium sulfate (MgS04·7H20 USP) as a 20% solution intravenously at a rate not to exceed 1 g/min

Follow promptly with 109 of 50% magnesium sulfate solution, one half (5 g) injected deeply in the upper outer quadrant of each buttock through a 3-inch-long 20-gauge needle. (Addition of 1.0 mL of 2% lidocaine minimizes discomfort.) If convulsions persist ater 15 min, give up to 2 g more intravenously as a 20% solution at a rate not to exceed 1 g/min. If the woman is large, up to 4 g may be given slowly.

Every 4 hr thereater, give 5 g of a 50% solution of magnesium sulfate injected deeply in the upper outer quadrant of alternate buttocks, but only after ensuring that:

The patellar reflex is present, Respirations are not depressed, and

Urine output the previous 4 hr exceeded 100 mL Magnesium sulfate is discontinued 24 hr after delivery :J01500 250 deficits, prolonged coma, or atypical eclampsia (Sibai,r2012) .

200 • Clinical Findings with Eclampsia

Eclamptic seizures may be violent, and the woman must be protected, especially her air150 C way. So forceful are the muscular movements

J,..

U :L,that the woman may throw herself out of her -0 bed, and if not protected, her tongue is bitten aby the violent action of the jaws (Fig. 40-16).

his phase, in which the muscles alternately contract and relax, may last approximately a minute. Gradually, the muscular movements become smaller and less frequent, and finally the woman lies motionless.

After a seizure, the woman is postictal, but in some, a coma of variable duration ensues. When the convulsions are infrequent, the

Days after treatment woman usually recovers some degree of con sciousness ater each attack. As the woman arouses, a semiconscious combative state may nase (ASn levels in women with HELLP syndrome assigned to receive treatment with dexamethasone or placebo. (Data from Katz, 2008.) with saline aforded the same interval-to-delivery timing (Sibai,r2017).

Preeclampsia complicated by generalized tonic-clonic convulsions appreciably raises the risk to both mother and fetus. In an earlier report, Mattar and Sibai (2000) described outcomes in 399 consecutive women with eclampsia from 1977 through 1998. Major maternal complications included placental abruption-10 percent, neurological deicits-7 percent, aspiration pneumonia-7 percent, pulmonary edema-5 percent, cardiopulmonary arrest-4 percent, and acute renal failure4 percent. Moreover, 1 percent of these women died. Several subsequent reports similarly described excessive maternal morbidity and mortality rates with eclampsia that also included HELLP syndrome, pulmonary embolism, and stroke (Andersgaard, 2006; Knight, 2007). In he Netherlands, there were three maternal deaths among 222 eclamptic women (Zwart, 2008). Data from Ireland and Australia are similar (O'Connor, 2013; Thornton, 2013). In perspective, this is a thousandfold increase above the overall maternal death rates for these countries.

Almost without exception-but at times unnoticed-preeclampsia precedes the convulsion onset. Eclampsia is most common in the last trimester and becomes increasingly frequent as term approaches. In more recent years, the incidence of postpartum eclampsia has declined. his is presumably related to improved access to prenatal care, earlier detection of antepartum preeclampsia, and prophylactic use of magnesium sulfate (Chames, 2002). Importantly, other diagnoses should be considered in women with convulsions more than 48 hours postpartum or in women with focal neurological ensue. In severe cases, coma persists from one convulsion to another, and death may result. In rare instances, a single convulsion may be followed by coma from which the woman may never emerge. As a rule, however, death does not occur until after frequent convulsions. Finally and also rarely, convulsions continue unabatedstatus epilepticus-and require deep sedation and even general anesthesia to obviate anoxic encephalopathy.

he respiratory rate ater an eclamptic convulsion is usually increased and may reach 50 or more per minute in response to hypercarbia, lactic acidemia, and transient hypoxia. Cyanosis may be observed in severe cases. High fever is a grave sign as it likely emanates from cerebrovascular hemorrhage.

Proteinuria is usually, but not always, present as discussed earlier (p. 720). Urine output may be diminished appreciably,

FIGURE 40-16 Hematoma of tongue from laceration during an eclamptic convulsion. Thrombocytopenia may have contributed to the bleeding.

:s,

FIGURE 40-19 Serum magnesium concentration in normotensive and preeclamptic women following a 4-g loading dose of magnesium sulfate and 2 g/h infusion. (Data from Brookfield, 2016.)

Maintenance magnesium sulfate therapy has traditionally been continued for 24 hours after delivery. For eclampsia that develops postpartum, magnesium sulfate is administered for 24 hours after the onset of convulsions. A few investigators have truncated this therapy duration to 12 hours and found no seizures (Anjum, 2016; Ehrenberg, 2006; Kashanian, 2016). And more recently, Ludmir and colleagues (2017) described salutary outcomes when magnesium sulfate therapy was stopped after delivery. That said, these studies are small, and the abbreviated magnesium regimen needs further study before being routinely implemented.

Using United States Pharmacopeia (USP) standards, magnesium sulfate USP is MgS04·7H20, and it contains 8.12 mEq magnesium per 1 g. Parenterally administered magnesium is cleared almost totally by renal excretion, and magnesium intoxication is unusual when the glomerular iltration rate is normal or only slightly reduced. Adequate urine output usualy correlates with preserved glomerular iltration rates. That said, magnesium excretion is not urine Row dependent, and urinary volume per unit time does not, per se, predict renal unction. Thus, serum creatinine leves must be mesured to etect a decreased glomeruar iltration rate.

Eclamptic convulsions are almost always prevented or arrested by plasma magnesium levels maintained at 4 to 7 mEq/L, 4.8 to 8.4 mg/dL, or 2.0 to 3.5 mmollL. But, one review of magnesium pharmacokinetics showed that most regimens result in much lower serum magnesium levels (Okusanya, 2016). This was especially true if only 1 g/hr was infused (Yefet, 2017). Importantly, the obesity epidemic has afected these observations (Cunningham, 2016). Tudela and colleagues (2013) described our observations from Parkland Hospital with magnesium administration to obese women. More than 60 percent of women whose body mass index (BMI) exceeded 30 kg/mrand who were receiving the 2 g/hr dose had sub therapeutic levels at 4 hours. hus, obese women would require 3 gl hr to maintain efective plasma levels. That said, most currently do not recommend routine magnesium level measurements (American College of Obstetricians and Gynecologists, 2013; Royal College of Obstetricians and Gynaecologists, 2006).

Patellar reRexes disappear when the plasma magnesium level reaches 10 mEq/L-about 12 mgl dL-presumably because of a curariform action. This sign serves to warn of impending magnesium toxicity. When plasma levels rise above 10 mEq/L, breathing becomes weakened. At 12 mEq/L or higher levels, respiratory paralysis and respiratory arrest follow (Somjen, 1966). Treatment with cacium gluconate or cacium chloride, 1 g intravenousy, along with discontinuation of forther manesium suate, usualy reverses mid-to-moderate respiratory depression. One of these agents should be readily available whenever magnesium is being infused. Unfortunately, the efects of intravenously administered calcium may be short-lived if there is a steady-state toxic level. For severe respiratory depression and arrest, prompt tracheal intubation and mechanical ventilation are lifesaving. Direct toxic efects on the myocardium from high levels of magnesium are uncommon (McCubbin, 1981; Morisaki, 2000).

Because magnesium is cleared almost exclusivey by renal excre . tion, the dosages described wil become excessive if glomerular il tration is substantialy decreased. The initial 4-g loading dose of magnesium sulfate can be safely administered regardless of renal function. It is important to administer the standard load ing dose and not to reduce it under the mistaken conception that diminished renal function requires it. This is because after distribution, a loading dose achieves the desired therapeutic level, and the infusion maintains the steady-state level. Thus, ony the maintenance infusion rate should be altered with dimin ished glomerular iltration rate. Renal function is estimated by measuring plasma creatinine. Whenever plasma creatinine lev els arer> 1.0 mg/mL, serum magnesium levels are determined to guide the infusion rate.

After a 4-g intravenous dose administered over 15 minutes, mean arterial pressure falls slightly, accompanied by a 13-percent rise in cardiac index (Cotton, 1986b). Thus, magnesium lowers systemic vascular resistance and mean arterial pressure. At the same time, cardiac output is increased. These indings are coincidental with transient nausea and Rushing, and the cardiovascular efects persist for only 15 minutes despite continued magnesium infusion.

Thurnau and associates (1987) showed that magnesium therapy led to a small but signiicant rise in the total magnesium concentration in the cerebrospinal Ruid. The magnitude of the elevation was directly proportional to the corresponding serum concentration.

Magnesium has anticonvulsant and neuroprotective efects in several animal models. Some proposed mechanisms of action include: (1) reduced presynaptic release of the neurotransmitter glutamate, (2) blockade of glutamatergic N-methyl-D-aspartate (NMDA) receptors, (3) potentiation of adenosine action, (4) improved calcium bufering by mitochondria, and (5) blockage of calcium entry via voltage-gated channels (Arango, 2008; Wang, 2012).

In the uterus, relatively high serum magnesium concentrations depress myometrial contractility both in vivo and in vitro. With the suggested regimen, myometrial depression has not been observed, except for a transient decline in activity during and immediately ater the initial intravenous loading dose (Leveno,

TABLE 40-12. Randomized Comparative Trials of Magnesium Sulfate Versus Phenytoin and Diazepam to Prevent Recurrent Eclamptic Convulsions

Recurrent seizuresa 60/453 (1n3%) 126/452 (28%) 22/388 (5.6%) 66/389 (1n7%) Matenal deathsb 10/388 (2.6%) 20/387 (5.2%) 17/453 (3.8%) 24/452 (5.3%) aA11 comparisons p < 0.01n.

blndividual comparisons nonsignificant, combined comparison p < .05. Data from Eclampsia Trial Collaborative Group, 1995.

1998; Szal, 1999; Witlin, 1997). Blood loss at delivery is not increased by standard magnesium treatment (Graham, 2016). However, inhibition of uterine contractility is magnesium dose dependent, and serum levels of at least 8 to 10 mEq/L are necessary to inhibit uterine contractions (Watt-Morse, 1995).

Magnesium administered parenterally promptly crosses the placenta to achieve equilibrium in fetal serum and less so in amnionic fluid (Hallak, 1993). Levels in amnionic luid rise with the duration of maternal infusion (Gortzak-Uzan, 2005). Magnesium sulfate has small but signiicant efects on the fetal heart rate pattern-specifically beat-to-beat variability (Hallak, 1999). Duy and associates (2012) reported a lower heart rate baseline that was within the normal range; decreased variability; and fewer prolonged decelerations. They noted no adverse outcomes.

Overall, maternal magnesium therapy appears safe for perinates (Drassinower, 2015). One MFMU Network study of more than 1500 exposed preterm neonates found no association between the need for neonatal resuscitation and cord blood magnesium levels Qohnson, 2012). Still, a few neonatal adverse events are associated with its use. In a Parkland Hospital study of 6654 mostly term, exposed newborns, 6 percent had hypotonia (Abbassi-Ghanavati, 2012). In addition, exposed neonates had lower 1-and 5-minute Apgar scores, a higher intubation rate, and more admissions to the special care nursery. The study showed that neonatal depression occurs only if hypermagnesemia at delivery is severe.

Observational studies suggest a protective efect of magnesium against the development of cerebral palsy in very-Iowbirthweight newborns (Nelson, 1995; Schendel, 1996). At least ive randomized trials have also assessed neuroprotective efects in preterm neonates. These findings are discussed in detail in Chapter 42 (p. 824). Nguyen and colleagues (2013) expanded this possibility to include term newborn neuroprotection, but data were insuicient to draw conclusions.

Last, in cases of preterm labor, magnesium has been given for several days for tocolysis (Chap. 42, p. 826). Administration in these instances has been associated with neonatal osteopenia (American College of Obstetricians and Gynecologists, 20 16c).

The multinational Eclampsia Trial Collaborative Group study (1995) involved 1687 women with eclampsia randomly allocated to one of three diferent anticonvulsant regimens: magnesium sulfate, diazepam, or phenytoin (Table 40-12). In aggregate, magnesium sulfate therapy was associated with a significantly lower incidence of recurrent seizures (9.7 percent) compared with women given phenytoin (28 percent) or diazepam (17 percent). Importantly, the aggregate maternal death rate of 3.2 percent with magnesium sulfate was signiicantly lower than that of 5.2 percent for the other two regimens.

In their review of more than 9500 treated women, Smith and coworkers (2013) reported the overall rate of absent patellar tendon reflexes to be 1.6 percent; respiratory depression, 1.3 percent; and calcium gluconate administration, 0.2 percent. Only one mother died due to magnesium toxicity. Our experiences are similar. In the more than 60 years of magnesium use at Parkland Hospital, only one woman has died from an overdose (P ri tchard, 1984).

Dangerous hypertension can cause cerebrovascular hemorrhage and hypertensive encephalopathy, and it can trigger eclamptic convulsions in women with preeclampsia. Other complications include placental abruption and congestive heart failure induced by elevated hypertensive afterload.

Because of these serious sequelae, the working group for the National High Blood Pressure Education Program (NHBPEP) (2000) and the 2013 Task Force recommend treatment to lower systolic pressures to or below 160 mm Hg and diastolic pressures to or below llO mm Hg. Martin and associates (2005, 2016) reported provocative observations that highlight the importance of treating systolic hypertension. They described 28 selected women with severe preeclampsia who sufered an associated stroke. Most (93 percent) were hemorrhagic strokes, and all women had systolic pressures > 160 mm Hg before sufering their stroke. By contrast, only 20 percent of these same women had diastolic pressures > 110 mm Hg.

From other observations, it seems likely that at least half of serious hemorrhagic strokes associated with preeclampsia are in women with chronic hypertension (Cunningham, 2005). Long-standing hypertension results in development of CharcotBouchard aneuysms in the deep penetrating arteries of the lenticulostriate branch of the middle cerebral arteries. hese vessels supply the basal ganglia, putamen, thalamus, and adjacent deep white matter, as well as the pons and deep cerebellum. These unique aneurysmal weakenings predispose these small arteries to rupture during sudden hypertensive episodes.

Several drugs are available to rapidly lower dangerously elevated blood pressure in women with pregnancy-associated hypertension. he three most commonly employed are hydralazine, labetalol, and nifedipine. For years, parenteral hydralazine was the only one of these three available. But when parenteral labetalol was later introduced, it was proven to be equally efective for obstetrical use. Orally administered nifedipine has since also gained popularity. ll three of these are recommended as first-line agents by the American College of Obstetricians and Gynecologists (2017 a).

This is probably still the most commonly used antihypertensive agent in the United States for treatment of women with severe gestational hypertension. Hydralazine is administered intravenously with a 5-to 10-mg initial dose, and this is followed by 10-mg doses at 15-to 20-minute intervals until a satisfactory response is achieved. Although we will administer a third dose, the American College of Obstetricians and Gynecologists (2017 a) recommends labetalol therapy if severe hypertension persists after the second dose. Antepartum or intrapartum, the target response is a decline in systolic pressure to < 160 mm Hg and diastolic blood pressure to 90 to 110 mm Hg. Lower diastolic pressures risk compromised placental perfusion. Hydralazine has proven remarkably efective to prevent cerebral hemorrhage. Its onset of action can be as rapid as 10 minutes. Although repeated administration every 15 to 20 minutes may theoretically lead to undesirable hypotension, this has not been our experience when given in these 5-to 10-mg increments.

At Parkland Hospital, between 5 and 10 percent of all women with intrapartum hypertensive disorders are given a parenteral antihypertensive agent. Antepartum, we usually give hydralaxine as described. We do not limit the total dose, and seldom is a second antihypertensive agent needed. We estimate that by severe superimposed preeclampsia, and hydralazine was injected more frequently than recommended. Her blood pressure in less than 1 hour dropped from 240-270/130-150 mm Hg to 1r10/80 mm Hg. Fetal heart rate decelerations characteristic of utero placental insuiciency became evident. Decelerations persisted until her blood pressure was increased with rapid crystalloid infusion. In some cases, this fetal response to diminished uterine perfusion may be confused with placental abruption and may result in unnecessary and potentially dangerous emergency cesarean delivery.

This efective intravenous antihypertensive agent is an Q-and nonselective 3-blocker. Some prefer its use over hydralazine because of fewer side efects. At Parkland Hospital, we give 10 mg intravenously initially. If the blood pressure has not decreased to the desirable level in 10 minutes, then 20 mg is given. The next 10-minute incremental dose is 40 mg and is followed by another 40 mg if needed. If a salutary response is not achieved, then an 80-mg dose is given. Sibai (2003) recommends 20 to 40 mg every 10 to 15 minutes as needed and a maximum dose of 220 mg per treatment cycle. The American College of Obstetricians and Gynecologists (2017a) recommends starting with a 20-mg intravenous bolus. If not efective within 10 minutes, this is followed by 40 mg, then 80 mg every 10 minutes. If hypertension persists, hydralazine is then given.

Comparative studies of hydralazine versus labetalol show equivalent results (Umans, 2015). In one trial, labetalol lowered blood pressure more rapidly, and associated tachycardia was minimal. But, hydralazine lowered mean arterial pressures to safe levels more efectively (Mabie, 1987). In another trial, maternal and neonatal outcomes were similar (Vigil-De Gracia, 2007). Hydralazine causes significantly more maternal tachycardia and palpitations, whereas labetalol more frequently leads to maternal hypotension and bradycardia. Both drugs have been associated with a reduced frequency of fetal heart rate accelerations (Cahill, 2013). Labetalol is not given to asthmatic women.

FIGURE 40-20 Hydralazine was given at 5-minute intervals instead of 15-minute intervals. The there is a tendency to give a larger initial dose of hydralazine. But, this must be avoided. The response 100 not be predicted by hypertension severity. Thus, our protocol is to o 15 30 45 15 always administer 5 mg as the ini-Time (hours) tial dose. n adverse response to exceeding this initial dose is shown mean arterial pressure dropped from 180 to 90 mm Hg within 1 hour and was associated with in Figure 40-20. This woman had fetal bradycardia. Rapid crystalloid infusion raised the mean pressure to 115 mm Hg, and the fetus chronic hypertension complicated recovered.

his orally administered calcium-channel blocking agent has become popular because of its eicacy to control acute pregnancy-related hypertension. he American College of Obstetricians and Gynecologists (2017a), the NHBPEP Working Group (2000), and the Royal College of Obstetricians and Gynaecologists (2006) recommend a 10-mg initial immediate-release oral dose to be followed in 20 to 30 minutes with 10 to 20 mg if necessary. If not satisfactory, this is followed by labetalol. Nedipine given sublingualy is no longer recommended. his route is associated with dangerously rapid and extensive efects. Randomized trials that compared nifedipine with labetalol found neither drug definitively superior, but nifedipine lowered blood pressure more quickly (Scardo, 1999; Shekhar, 2016; Vermillion, 1999). Finally, nifedipine does not potentiate magnesium-related efects (Magee, 2015).

A few other generally available antihypertensive agents have been tested in clinical trials but are not widely used (Umans, 2015). These include verapamil, nitroglycerin, nitroprusside, ketanserin, nicardipine, and nimodipine (Belfort, 1990, 2003; Bolte, 2001; Cornette, 2016). There are also experimental antihypertensive drugs that may become useful for preeclampsia treatment (Lam, 2013).

Potent loop diuretics can further compromise placental perfusion. Immediate efects include redistribution of the intravascular volume, which most oten is already reduced in severe preeclampsia (p. 718). herefore, before delivery, diuretics are not used to lower blood pressure (Zeeman, 2009; Zondervan, 1988). We use antepartum furosemide or similar drugs solely to treat pulmonary edema.

Lactated Ringer solution is administered routinely at a rate between 60 and 125 mL per hour, unless luid loss is unusual from vomiting, diarrhea, or diaphoresis, or, more likely, excessive blood loss with delivery. Oliguria is common with severe preeclampsia. hus, coupled with the knowledge that maternal blood volume is likely constricted compared with that of normal pregnancy, it is tempting to administer intravenous fluids more vigorously. But controlled, conservative luid administration is preferred for the typical woman with severe preeclampsia who already has excessive extracellular luid that is inappropriately distributed between intravascular and extravascular spaces. Infusion of large luid volumes enhances the maldistribution and thereby appreciably elevates the risk of pulmonary and cerebral edema (Dennis, 2012a; Sciscione, 2003; Zinaman, 1985). hus, for preeclamptic women with anuria, small incremental boluses can be given to maintain urine output above 30 mL per hour. Diminished intravascular volume from hemorrhage or luid loss from vomiting or fever can similarly be replaced by gradual incremental boluses. For labor analgesia with neuraxial analgesia, crystalloid solutions are infused slowly in graded amounts (Chap. 25, p. 496).

Women with severe preeclampsia who develop pulmonary edema most often do so postpartum (Cunningham, 1986, 2012; Zinaman, 1985). With suspected pulmonary edema in the eclamptic woman, aspiration of gastric contents, which may be the result of convulsions, anesthesia, or oversedation, should be excluded. here are three common causes of pulmonary edema in women with severe preeclampsia syndromepulmonary capillary permeability edema, cardiogenic edema, or a combination of the two.

Some women with severe preeclampsia-especially if given vigorous fluid replacement-will have mild pulmonary congestion secondary to permeability edema. his is caused by normal pregnancy changes magnified by the preeclamp�ia syndrome. Importantly, plasma oncotic pressure drops appreciably in normal term pregnancy because of decreased serum albumin concentration, and oncotic pressure falls even more with preeclampsia (Zinaman, 1985). Moreover, both increased extravascular luid oncotic pressure and increased capillary permeability are found in women with preeclampsia (Brown, 1989; 0ian, 1986).

Knowledge concerning cardiovascular and hemodynamic pathophysiological alterations associated with severe preeclampsia-eclampsia has accrued from studies done using invasive monitoring and a low-directed pulmonary artery catheter (see Fig. 40-5). Two conditions frequently cited as indications are preeclampsia associated with oliguria and that associated with pulmonary edema (Clark, 2010). Somewhat ironically, it is usually vigorous treatment of the former that results in most cases of the latter. The Task Force (2013) recommends against routine invasive monitoring. Such monitoring is best reserved for severely preeclamptic women with accompanying cardiac disease, renal disease, or both or with refractory hypertension, oliguria, and pulmonary edema.

Because the preeclampsia syndrome is associated with hemoconcentration, some have inused various fluids, starch polymers, albumin concentrates, or combinations thereof to expand blood volume (Ganzevoort, 2004). Older observational studies describe serious complications-especially pulmonary edema-with volume expansion (Benedetti, 1985; LOpez-Llera, 1982; Sibai, 1987b).

he Amsterdam randomized study reported by Ganzevoort and coworkers (2005a,b) was a well-designed investigation done to evaluate volume expansion. A total of216 women with severe preeclampsia were enrolled between 24 and 34 weeks' gestation. he study included women whose preeclampsia was complicated by HELLP syndrome, eclampsia, or fetal-growth restriction. In the group randomly assigned to volume expansion, each woman was given 250 mL of 6-percent hydroxyethyl starch infused over 4 hours twice daily. heir outcomes were compared with a control group, and none of these outcomes were significantly diferent (Table 40-13). Importantly, serious maternal morbidity and a substantive perinatal mortality rate accompanied their "expectant" management (see Table 40-9).

Pulmonary edema 2.9

Placental abruption 3.8 l.0

Prolongation of pregnancy (mean) 11n.6 d 6.7 d

EGA at death (mean) 26.7 wk 26.3 wk

Prolongation of pregnancy (mean) 10.5 d 7.4 d

EGA at delivery (mean) 31.6 wk 31.4 wk

Neonatal death (%) 7.6 8.1 0.05.

EGA = estimated gestational age; HELLP = hemolysis, elevated liver enzyme levels, low platelet count; RDS = respiratory distress syndrome.

Data from Ganzevoort, 2005a, b.

• Neuroprophylaxis-Prevention of Seizures aL studies, magnesium suate was reported to be superior to the Several randomized trials have tested the eicacy of seizure comparator agent to prevent eclampsia. Four of the larger studies prophylxis for women with gestational hypertension, with or are summarized in Table 40-14. In the study from Parland without proteinuria. In most of these, magnesium sulfate was Hospital, magnesium sulfate therapy was superior to phenycompared with another anticonvulsant or with a placebo. In toin to prevent eclamptic seizures in women with gestational

TABLE 40-14. Randomized Comparative Trials of Prophylaxis with Magnesium Sulfate and Placebo or Another Anticonvulsant in Women with Gestational Hypertension

No. with Seizures/Total No. Treated (%)

Gestational hypertensionb 0/1n049 (0) 10/1n089 (0.9) P < 0.001

Severe preeclampsia 1/345 (0.3) 1n1/340 (3.2) RR = 0.09 (0.1-0.69)

Severe preeclampsia 40/5055 (0.8) 96/5055 (1n.9) RR = 0.42 (0.26-0.60)

Severe preeclampsia 7/831 (0.8) 21/819 (2.6) RR = 0.33 (0.14-0.77) aAIl comparisons significant p < 0.05.

blncluded women with and without proteinuria and those with all severities of preeclampsia. (Magpie Trial Collaboration Group, 2002.

RR = relative risk.

hypertension or preeclampsia (Lucas, 1995). In another, magnesium sulfate and nimodipine-a calcium-channel blocker with specific cerebral vasodilator activity-were compared in 1650 women with severe preeclampsia (Belfort, 2003). The rate of eclampsia was more than threefold higher for women allocated to the nimodipine group-2.6 versus 0.8 percent.

he largest comparative study was Manesium Suate or Prevention of Eclampsia reported by the Magpie Trial Collaboration Group (2002). More than 10,000 women with severe preeclampsia from 33 countries were randomly allocated to treatment with magnesium sulfate or placebo. Women given magnesium had a 58-percent significantly lower risk of eclampsia than those given placebo. In follow-up data of infants born to these mothers given magnesium sulfate, child behavior at approximately 18 months did not difer in those exposed compared with those not exposed to magnesium sulfate (Smyth, 2009).

Who Should Be Given Magnesium Sulfate?

Magnesium will prevent proportionately more seizures in women with correspondingly worse disease. However, severity is diicult to quantiy, and thus deciding which individual woman might benefit most from neuroprophylaxis is diicult. The 2013 Task Force recommends that women with either eclampsia or severe preeclampsia should be given magnesium sul ate prophylaxis. Again, criteria that establish "severity" are not totally uniform (see Table 40-2). At the same time, however, the 2013 Task Force suggests that women with "mild" preeclampsia do not need magnesium sulfate neuroprophylaxis. The conundrum is whether or not to give neuroprophylaxis to any of these women with "nonsevere" gestational hypertension or preeclampsia (Alexander, 2006).

In most other countries, and principally following dissemination of the Magpie Trial Collaboration Group (2002) study results, magnesium sulfate is now recommended for women with severe preeclampsia. In some, however, debate continues concerning whether therapy should be reserved for women who have an eclamptic seizure. We believe that eclamptic seizures are dangerous (pp. 722 and 745). Maternal mortality rates of up to 5 percent have been reported even in recent studies. Moreover, perinatal mortality rates are substantially increased (Abd EI Aal, 2012; Knight, 2007; Ndaboine, 2012; Schutte, 2008; von Dadelszen, 2012). Finally, the possibility of adverse longterm neuropsychological and vision-related sequelae of eclampsia have raised additional concerns that eclamptic seizures are not "benign."

Because of the foregoing, there is uncertainty about which women with nonsevere gestational hypertension should be given magnesium sulfate neuroprophylaxis. An opportunity to address these questions was aforded by a change in our prophylaxis protocol at Parkland Hospital. Before this time, the risk of eclampsia without magnesium prophylaxis was approximately 1 in 100 for women with mild preeclampsia (Lucas, 1995). Up until 2000, all women with gestational hypertension were given magnesium prophylaxis intramuscularly. Mter 2000, we instituted a standardized protocol for intravenously administered magnesium sulfate (Alexander, 2006). At the same time, we

TABLE 40-15. Selective versus Universal Magnesium

Sulfate Prophylaxis: Parkland Hospital

Criteria to Define Severe Gestational

In a woman with new-onset proteinuric hypertension, at least one of the following criteria is required:

Systolic BP : 160 r diastolic BP : 110 mm Hg

Proteinuria :2+ by dipstick in a catheterized urine

Serum creatininen> 1n.1 mg/dL

Platelet count < 1OO,OOO/1L above upper limit of normal range

BP = blood pressure. Criteria based on those from [Jational High Blood Pressure Education Program Working Group, 2000; American (ollege of Obstetricians and Gynecologists, 2012; cited by Alexander, 2006.

also changed our practice of universal seizure prophylaxis for all women with gestational hypertension to one of selective prophylaxis given only to women who met our criteria for severe gestational hypertension. These criteria, shown in Table 40-15, included women with :2+ proteinuria measured by dipstick in a catheterized urine specimen.

Following this protocol change, 60 percent of 6518 women with gestational hypertension during a 4Y2-year period were given magnesium sulfate neuroprophylaxis. The remaining 40 percent with nonsevere hypertension were not treated, and of these, 27 women developed eclamptic seizures-1 in 92. The seizure rate was only 1 in 358 for 3935 women with criteria for severe disease who were given magnesium sulfate, and thus these cases were treatment failures.

To assess morbidity, outcomes in 87 eclamptic women were compared with outcomes in all 6431 noneclamptic severely hypertensive women (Alexander, 2006). lthough most maternal outcomes were similar, almost a fourth of women with eclampsia who underwent emergent cesarean delivery required general anesthesia. his is a great concern because eclamptic women have laryngotracheal edema and are at a higher risk for failed intubation, gastric acid aspiration, and death. Neonatal outcomes were also a concern because the composite morbidity was increased tenfold in eclamptic compared with noneclamptic women-12 versus 1 percent, respectively. These outcomes included cord artery pH <7.0; 5-minute Apgar score <4; or unanticipated admission of a term newborn to an intensive care nursery.

Thus, if one uses the Parkland criteria for nonsevere gestational hypertension, approximately 1 of 100 such women who are not given magnesium sulfate prophylaxis can be expected to have an eclamptic seizure. A fourth of these women likely will require emergent cesarean delivery with attendant maternal and perinatal morbidity and mortality from general anesthesia. From this, the major question regarding management of nonsevere gestational hypertension remains whether it is acceptable to avoid unnecessary treatment of 99 women to risk eclampsia in one? he answer appears to be yes as suggested by the 20 13 Task Force. At Parkland Hospital, we only give magnesium neuroprophylxis to women with severe criteria.

During the past 20 years, the use of conduction analgesia for women with preeclampsia syndrome has proven ideal. Initial problems with this method included hypotension and diminished uterine perfusion caused by sympathetic blockade in preeclamptic women, with already attenuated hypervolemia. But pulmonary edema was mitigated by techniques that used slow induction of epidural analgesia with dilute solutions of anesthetic agents. his countered the need for rapid infusion of large volumes of crystalloid or colloid to correct maternal hypotension from neural blockade (Hogg, 1999; Wallace, 1995). These techniques are described in detail in Chapter 25 (p. 496). Importantly, epidural blockade avoids general anesthesia, in which the stimulation of tracheal intubation may cause sudden severe hypertension. Such blood pressure spikes, in turn, can cause pulmonary edema, cerebral edema, or intracranial hemorrhage. Finally, tracheal intubation may be particularly diicult and thus hazardous in women with airway edema due to preeclampsia (American College of Obstetricians and Gynecologists, 20 17b).

At least three randomized studies have been performed to compare these methods of analgesia and anesthesia. Wallace and colleagues (1995) studied 80 women at Parkland Hospital with severe preeclampsia who were to undergo cesarean delivery. They had not been given labor epidural analgesia and were randomly assigned to receive general anesthesia, epidural analgesia, or combined spinal-epidural analgesia. heir average preoperative blood pressures approximated 170/110 mm Hg, and all had proteinuria. Maternal and perinatal outcomes in each group were similar. Maternal hypotension resulting from regional analgesia was managed with judicious intravenous fluid administration. In women undergoing general anesthesia, maternal blood pressure was managed to avoid severe hypertension. here were no serious maternal or fetal complications attributable to any of the three anesthetic methods. It was concluded that all three are acceptable for use in women with pregnancies complicated by severe preeclampsia if steps are taken to ensure a careful approach to the selected method.

Another randomized study included 70 women with severe preeclampsia receiving spinal analgesia versus general anesthesia for cesarean delivery (Dyer, 2003). Their maternal and fetal outcomes were equivalent. In a third study, 116 women with severe preeclampsia received either epidural or patient-controlled intravenous meperidine analgesia during labor (Head, 2002). More women-9 percent-from the group assigned to epidural analgesia required ephedrine for hypotension. As expected, pain relief was superior in the epidural group. Maternal and neonatal complications were similar between groups, and one woman in each group developed pulmonary edema. Importantly, epidural analgesia is not considered treatment of preeclampsia (Lucas, 2001; Ray, 2017).

Judicious fluid administration is essential in severely preeclamptic women who receive regional analgesia. Vigorous crystalloid infusion with epidural blockade in women with severe preeclampsia elevates pulmonary capillary wedge pressures (Newsome, 1986). Aggressive volume replacement in preeclamptic women raises their risk for pulmonary edema, especially in the first 72 hours postpartum (Clark, 1985; Cotton, 1986a). Finally, most cases of pharyngolaryngeal edema are related to aggressive volume therapy (Heller, 1983).

Hemoconcentration or lack of norml pregnancy-induced hyper volemia is an almost predictable feature of severe preeclampsia eclampsia (see Fig. 40-7) (Zeeman, 2009). These women, who consequenty ack nomal pregnany hypervoemia, are much less toer ant of even normal blood oss than are nomotensive pregnant women.

Importantly, an appreciable fall in blood pressure soon ater delivery most oten means excessive blood loss and not sudden resolution of vasospasm and endothelial damage. When oliguria follows delivery, the hematocrit should be evaluated frequently to help detect excessive blood loss. If identiied, hemorrhage should be treated appropriately by crystalloid and blood transusion.

Although severe postpartum hypertension usually follows labor and delivery complicated by hypertension, 8 percent of women develop de novo hypertension postpartum (Goel, 2015). In either case, if diiculty arises in controlling severe hypertension or if intravenous hydralazine or labetalol are being used repeatedly, then oral regimens can be given. Examples include labetalol or another 3-blocker, or nifedipine or another calcium-channel blocker (Sharma, 2017). Women so treated are less likely to require readmission (Hirshberg, 2016). Persistent or refractory hypertension is likely aggravated by mobilization of pathological interstitial fluid and redistribution into the intravenous compartment, underlying chronic hypertension, or usually both (Sibai, 2012; Tan, 2002). Chronic, but not sporadic, administration of some nonsteroidal antiinflammatory drugs, namely ibuprofen, may aggravate postpartum hypertension in those with preeclampsia (Vigil-De Gracia, 2017; Viteri, 2017). In women with chronic hypertension and let-ventricular hypertrophy, severe postpartum hypertension can cause pulmonary edema from cardiac failure (Cunningham, 1986,2012; Sibai, 1987a).

Because persistence of severe hypertension corresponds to the onset and length of diuresis and extracellular fluid mobilization, it seems logical that furosemide-augmented diuresis might serve to hasten blood pressure control. One randomized trial included 264 postpartum preeclamptic women who, ater onset of spontaneous diuresis, were assigned to 20-mg oral furosemide given daily or to no therapy (Ascarelli, 2005). Women with mild disease had similar blood pressure control regardless of whether they received treatment or placebo. However, ater 2 days, women with severe preeclampsia who were treated, compared with those receiving placebo, had a lower mean systolic blood pressure-142 versus 153 mm Hg. They also less frequently required supplemental antihypertensive therapy during the remainder of hospitalization-14 versus 26 percent, respectively. In a recent randomized study, Veena and colleagues (2017) treated severe postpartum eclampsia with nifedipine plus furosemide or nifedipine alone. They reported that this prophylactic therapy signiicantly lowered the need for an additional antihypertensive-26 versus 8 percent, respectively.

We use a simple method to estimate excessive extracellular! interstitial luid. he posparum weight is compared with the most recentprenatal weight, either from the last clinic visit or on admission for delivery. Typically, soon ater delivery, maternal weight should be reduced by at least 10 to 15 pounds depending on newborn and placental weight, amnionic luid volume, and blood loss. Because of various interventions, especially intravenous crystalloid inusions given with labor epidural analgesia or during operative vaginal or cesarean delivery, women with severe preeclampsia oten have an immediate postpartum weight in excess of their st prenatal weight. If this weight increase is associated with severe persistent postpartum hypertension, then diuresis with intravenous urosemide is usually helpul in controlling blood pressure.

Occasionally, women have an atypical syndrome in which severe preeclampsia-eclampsia persists despite delivery. Martin and colleagues (1995) described 18 such women whom they encountered during a 10-year period. hey advocate single or multiple plasma exchange for these women. In some cases, 3 L of plasma was exchanged three times-a 36-to 45-donor unit exposure for each patient-before a response was forthcoming. Others have described plasma exchange performed in postpartum women with HELLP syndrome (Forster, 2002; Obeidat, 2002). In all of these cases, however, the distinction between HELLP syndrome and thrombotic thrombocytopenic purpura or hemolytic uremic syndrome was not clear (Tsai, 2016).

In our experiences with more than 50,000 women with gestational hypertension among nearly 450,000 pregnancies cared for at Parkland Hospital through 2017, we have encountered very few women with persistent postpartum hypertension, thrombocytopenia, and renal dysfunction who were diagnosed as having a thrombotic micro angiopathy (Dashe, 1998). hese latter syndromes complicating pregnancy were reviewed by Martin (2008) and George (2013) and their colleagues, who conclude that a rapid diagnostic test for ADAMTS-13 enzyme activity might be helpful to diferentiate most of these syndromes.

his is another cause of persistent hypertension, "thunderclap" headaches, seizures, and central nervous system indings. It is a form of postpartum angiopathy. Reversible cerebral vasoconstriction syndrome is characterized by difuse segmental constriction of cerebral arteries and may be associated with ischemic and hemorrhagic strokes. his syndrome has several inciting causes that include pregnancy, and particularly preeclampsia (Ducros, 2012). It is more common in women, and in some cases, vasoconstriction may be so severe as to cause cerebral ischemia and infarction. he appropriate management is not known at this time (Edlow, 2013).

Defective remodeling of the spiral arteries in some placentas is posited as a cause of at least one preeclampsia phenotype. Specifically, lack of deep placentation is linked with preeclampsia, placental abruption, fetal-growth restriction, and preterm birth (Wikstrom, 2011). With this type of "overlap syndrome," hypertensive disorders may serve as markers for subsequent preterm labor and fetal-growth restriction. For example, even in subsequent nonhypertensive pregnancies, women who had preterm preeclampsia are at higher risk for preterm birth and growth-restricted neonates (Bramham, 2011; Connealy, 2014; Palatnik, 2016).

In addition, women who have had either gestational hypertension or preeclampsia risk developing hypertension in future pregnancies (Lykke, 2009b). Generally, the earlier preeclampsia is diagnosed during the index pregnancy, the greater the likelihood of recurrence. And, the recurrence risk for preeclampsia is elevated further in women with the metabolic syndrome (Stekkinger, 2015). Sibai and colleagues (1986, 1991) found that nulliparas diagnosed with preeclampsia before 30 weeks had a recurrence risk as high as 40 percent during a subsequent pregnancy. In a prospective study of 500 women previously delivered for preeclampsia at 37 weeks, the recurrence rate in a subsequent gestation was 23 percent (Bramham, 2011).

As perhaps expected, women with HELLP syndrome have a substantive risk for recurrence in subsequent pregnancies. In two studies, the risk ranged from 5 to 26 percent, but the true recurrence risk likely lies beween these two extremes (Habli, 2009; Sibai, 1995). Even if HELLP syndrome does not recur with subsequent pregnancies, again incidences of preterm delivery, fetal-growth restriction, placental abruption, and cesarean delivery are increased (Habli, 2009; Hnat, 2002).

Evidence has accrued that the preeclampsia syndrome is a marker for subsequent long-term cardiovascular and related morbidity and mortality (Table 40-16). hus, women with hypertension identified during pregnancy should be evaluated during the first several months postpartum. he working group of the NHBPEP (2000) concluded that hypertension attributable to pregnancy should resolve within 12 weeks of delivery. Hypertension persisting beyond this time is considered chronic (Chap. 50, p. 976). he Magpie Trial Follow-Up Collaborative Group (2007) reported that 20 percent of 3375 preeclamptic women seen at a median of 26 months postpartum had hypertension. Importantly, even if hypertension does not persist in the short term, convincing evidence suggests a higher risk for long-term cardiovascular morbidity.

Any hypertension during pregnancy is a risk marker for morbidity and mortality in later life (American College of Obstetricians and Gynecologists, 2013; Bellamy, 2007). In a case-control study from Iceland, Arnadottir and associates (2005) reported

TABLE 40-16. Some Long-Term Consequences in Women with Preeclampsia Syndrome the prevalences of ischemic heart disease-24 versus 15 percent, and stroke-9.5 versus 6.5 percent, were significantly increased in women who had gestational hypertension compared with normotensive controls. In a Swedish population study of more than 400,000 women, those with recurrent preeclampsia have systolic dysfunction and a greater incidence of ischemic heart disease (Valensise, 2016). Diastolic dysfunction is also more common (Bokslag, 2017). Preeclampsia is also a risk for coronary artery calciication and idiopathic cardiomyopathy (Behrens, 2016; White, 2016).

Lyke and associates (2009a) cited indings from a Danish registry of more than 780,000 nulliparas. After a mean followup of almost 15 years, the incidence of chronic hypertension was fivefold higher in those who had gestational hypertension, 3.5-fold greater after mild preeclampsia, and sixfold higher after severe preeclampsia. After two hypertensive pregnancies, this incidence rose sixfold. Moreover, these women with pregnancy-associated hypertension are at increased risk for ype 2 diabetes (Rice, 2016). And, preeclampsia is a risk factor for later diabetic retinopathy and retinal detachment (Auger, 2017; Beharier,r2016).

As emphasized by several investigators, other cofactors or comorbidities are related to acquisition of these long-term adverse outcomes (Gastrich, 2012; Harskamp, 2007; Hermes, 2012; Spaan, 2012b). These include the metabolic syndrome, diabetes, obesity, dyslipidemia, and atherosclerosis (Kajantie, 2017; Orabona, 2016; Stekkinger, 2015).

Individuals who are born pre term have greater ventricular mass later in life (Lewandowski, 20l3). And, women who have preeclampsia and who develop chronic hypertension later in life have an increased ventricular mass index before they become hypertensive (Ghossein-Doha, 2013). Finally, in at least some of these women, hypertensive cardiovascular pathologies appear to have begun near the time of their own births. A similar phenomenon is associated with preterm birth and with fetal-growth disorders.

Preeclampsia is also a marker for subsequent renal disease. lmost 15 percent of previously preeclamptic women have renal dysfunction (Lopes van Balen, 2017). In a 40-year study of Norwegian birth and end-stage renal disease linked registries, although the absolute risk of renal failure was small, preeclampsia was associated with a fourfold greater risk (Vikse, 2008). Women with recurrent preeclampsia had an even higher risk. These data need to be considered in light of the indings that 15 to 20 percent of women with preeclampsia who undergo renal biopsy have evidence of chronic renal disease (Chesley, 1978). In another long-term study, Spaan and coworkers (2009) compared formerly preeclamptic women with a cohort of women who were normotensive at delivery. At 20 years following delivery, preeclamptic women were signiicantly more likely to be chronically hypertensive-55 versus 7 percent-compared with control women. They also had higher peripheral vascular and renovascular resistance and decreased renal blood low. These data do not permit conclusions as to cause versus efect.

Until recently, eclamptic seizures were believed to have no signiicant long-term sequelae. However, this may not be the case (heilen, 2016). Recall that almost all eclamptic women have multifocal areas of perivascular edema, and approximately a fourth also have areas of cerebral infarction (Zeeman, 2004a).

In several long-term follow-up studies in women with severe preeclampsia and eclampsia, brain white-matter lesions that followed eclamptic convulsions persist (Aukes, 2007, 2009, 2012). Speciically, when studied with MR imaging at a mean of 7 years, 40 percent of formerly eclamptic women had more numerous and larger aggregate white matter lesions compared with 17 percent of normotensive control women. These investigators later also observed these white-matter lesions in preeclamptic women without convulsions (Aukes, 2012). And, Siepmann and associates (2017) documented temporal lobe white matter changes and reduced cortical volume in previously preeclamptic women. In studies designed to assess clinical relevance, formerly eclamptic women had subjectively impaired cognitive functioning (Postma, 2014). Wiegman and associates (2012) reported that formerly eclamptic women at approximately 10 years had lower vision-related quality of life compared with control subjects. This likely coincides with an elevated risk for retinopathy described by Auger and colleagues (2017). Because no baseline studies were done before these women sufered from preeclampsia or eclampsia, the investigators appropriately concluded that a cause versus an efect of these white-matter lesions remains unknown.

Abalos E, Duley L, Steyn DW, et al: Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev 2:CD002252, 2014

Abbassi-Ghanavati M, Alexander ]M, McIntire DD: Neonatal efects of magnesium sulfate given to the mother. Am] Perinatol 29(10):795, 2012

Abd EI Aal DE, Shahin AY: Management of eclampsia at Assiut University Hospital, Egypt. Int] Gynaecol Obstet 116(3):232, 2012

Abdel-Hady ES, Fawzy M, EI-Negri M, et al: Is expectant management of early-onset severe preeclampsia worthwhile in low-resource settings? Arch Gynecol Obstet 282(1):23, 2010

Abdul-Karim R, Assali NS: Pressor response to angiotonin in pregnant and nonpregnant women. Am] Obstet Gynecol 82:246, 1961

Abenhaim HA, Bujold E, Benjamin A, et al: Evaluating the role of bedrest on the prevention of hypertensive disease of pregnancy and growth restriction.

Hypertens Pregnancy 27(2):197,s2008 .

Abramovici D, Friedman SA, Mercer BM, et al: Neonatal outcome m severe preeclampsia at 24 to 36 weeks' gestation: does the HELLP (hemolysis, elevated liver enzyme, and low platelet count) syndrome matter? Am ] Obstet Gynecol 180:221, 1999

Airoldi ], Weinstein L: Clinical significance of proteinuria in pregnancy.

Obstet Gynecol Surv 62: 11 ,2007

Ajne G, WolfK, Fyhrquist F, et al: Endothelin converting enzyme (ECE) aCtIvity in normal pregnancy and preeclampsia. Hypertens Pregnancy 22:215, 2003s

Alanis MC, Robinson C], Hulsey TC, et al: Early-onset severe preeclampSia: induction of labor vs elective cesarean delivery and neonatal outcomes. Am ] Obstet Gynecol 199:262.e1, 2008

Alexander ]M, Bloom SL, McIntire DD, et al: Severe preeclampsia and the very low-birthweight infant: is induction of labor harmful? Obstet Gynecol 93:485, 1999

Alexander ]M, Cunningham FG: Management. In Taylor RN, Roberts ]M, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsrerdam, Academic Press, 2015

Alexander ]M, McIntire DD, Leveno K], et al: Magnesium sulfate for the prevention of eclampsia in women with mild hypertension. Am ] Obstet Gynecol 189:S89, 2003

Alexander ]M, McIntire DD, Leveno K], et al: Selective magnesium sulfate prophylaxis for the prevention of eclampsia in women with gestational hypertension. Obstet Gynecol 108:826,2006

Alexander ]M, Sarode R, McIntire DD, et al: Use of whole blood in the management of hypovolemia due to obstetric hemorrhage. Obstet Gynecol 113(6): 1320,s2009

AmbiaM, Yule CS, Wells E: Does fetal bradycardia during eclamptic seizure necessitate emergent cesarean delivety? Unpublished data, 2018

American College of Obstetricians and Gynecologists: Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstet Gynecol 122: 1122, 2013

American College of Obstetricians and Gynecologists: Fetal growth restriction.

Practice Bulletin No. 134, May 2013, Reairmed 2015

American College of Obstetricians and Gynecologists: Antepartum fetal surveillance. Practice Bulletin No. 145, ]uly 2014, Reairmed 2016a

American College of Obstetricians and Gynecologists: Low-dose aspirin and prevention of preeclampsia: updated recommendations. Practice Advisory July 11, 2016b

American College of Obstetricians and Gynecologists, Society �or Mat�r�alFetal Medicine: Magnesium sulfate use in obstetrics. Committee OpmlOn No. 652, January 2016c

American College of Obstetricians and Gynecologists: Emergent therapy for acute onset, severe hypertension during pregnancy and the postpartum period. Committee Opinion No. 692, April 2017 a . .

American College of Obstetricians and Gynecologists: Obstetric analgesia and anesthesia. Practice Bulletin No. 177, April 2017b

Amorim MM, Santos LC, Faundes A: Corticosteroid therapy for prevention of respiratory distress syndrome in severe preeclampsia. Am ] Obstet Gynecol 180:1283,s1999

Andersgaard AB, Herbst A, Johansen M, et al: Eclampsia in Scandinavia: incidence, substandard care, and potentially preventable cases. Acta Obstet Gynecol 85:929, 2006

Anjum S, Goel N, Shrama R, et al: Maternal outcomes after 12 hours and 24 hours of magnesium sulfate therapy for eclampsia. Int ] Gynaecol Obstet 132(1):68,s2016

Arango MF, Mejia-Mantilla ]H: Magnesium for acute traumatic brain injury.

Cochrane Database Syst Rev 4:CD005400, 2008 rnadottir GA, Geirsson RT, Arngrimsson R, et al: Cardiovascular death in women who had hypertension in pregnancy: a case-control study. B]OG 112:286,2005 Ascarelli MH, Johnson V, McCreary H, et al: Postpartum preeclampsia management with furosemide: a randomized clinical trial. Obstet Gynecol 105:29,s2005

Askie LM, Henderson-Smart D], Stewart A: Antiplatelet agents for the prevention of preeclampsia: a meta-analysis of individual data. Lancet 369: 179, 2007

Auger N, Fraser WD, Paradis G, et al: Preeclampsia and long-term risk of maternal retinal disorders. Obstet Gynecol 129(1):42, 2017

Aukes AM, de Groot]c, Aarnoudse ]G, et al: Brain lesions several years after eclampsia. Am] Obstet Gynecol 200(5):504.el, 2009 AukesM, de Groot]C, Wiegman M], et al: Long-term cerebral imaging after pre-eclampsia. B]OG 119(9):1117,2012

Aukes AM,sWessei I, Dubois M, et al: Self-reported cogllltive functlonmg in formerly eclamptic women. Am] Obstet Gynecol 197(4):365.el, 2007 Bahado-Singh RO, Akolekar R, Mandai R, et al: First-trimester metabolomic detection of late-onset preeclampsia. Am ] Obstet Gynecol 208(1):58.e1, 2013 Bainbridge SA, Sidle EH, Smith GN: Direct placental efects of cigarette smoke protect women from pre-eclampsia: the specific roles of carbon monoxide and antioxidant systems in the placenta. Med Hypotheses 64: 17,s2005 Baltajian K, Bajracharya S, Salahuddin S, et al: Sequential plasma angiogenic factors levels in women with suspected preeclampsia. Am] Obstet Gynecol 215(I):89.e1,2016 Barakat R, Pelaez M, Cordero Y, et al: Exercise during pregnancy protects against hypertension and macrosomia: randomized clinical trial. Am ] Obstet GynecoIs214:649.e1, 2016 Barton CR, Barton ]R, O'Brien ]M, et al: Mild gestational hypertension: differences in ethnicity are associated with altered outcomes in women who undergo outpatient treatment. Am] Obstet Gynecol 186:896,2002

Barton ], Barton L, Istwan N, et al: Elective delivery at 34°17 to 366r weeks' gestation and its impact on neonatal outcomes in women with stable mild gestational hypertension. Am] Obstet Gynecol 204(1):44.e1, 2011

Bartsch E, Medcalf E, Park AL, et al: Clinical risk factors for preeclampSia determined in early pregnancy: systematic review and meta-analysis of large cohort studies. BM] 353:i 1753, 2016

Bdolah Y, Palomaki GE, Yaron Y, et al: Circulating angiogenic proteins in trisomy 13. Am] Obstet Gynecol 194(1):239,2006

Beharier 0, Davidson E, Sergienko R, et al: Preeclampsia and future risk for matenal ophthalmic complications. Am] Perinatol 33(7):703, 2016 Behrens I, Basit S, Lykke ]A, et al: Association between hypertensive disorders of pregnancy and later risk of cardiomyopathy.s]AMA 315(10)1026,s2016 Belfort M, Anthony], Saade G, et al: A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia. N Engl] Med 348:304, 200�

Belfort MA, Anthonys], Buccimazza A, et al: HemodynamiC changes assocIated with intravenous infusion of the calcium antagonist verapamil in the treatment of severe gestational proteinuric hypertension. Obstet Gynecol 75:970, 1990

Belghiti], Kayem G, Tsatsaris V, et al: Benefits and risks of �xpectan� management of severe preeclampsia at less than 26 weeks gestation: the Impact of gestational age and severe fetal growth restriction. Am ] Obstet Gynecol 205(5):465.e1,s2011

Bellamy L, Casas ]P, Hingorani AD, et al: Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BM] 335:974, 2007

Benedetti T], Kates R, Williams V: Hemodynamic observations in severe preeclampsia complicated by pulmonary edema. Am ] Obstet Gynecol 152:330, 1985

Berg C], Harper MA, Atkinson SM, et al: Preventability of pregnancy-related deaths. Obstet Gynecol 106: 1228, 2005

Berks D, Steegers A, Molas M, et al: Resolution of hypertension and proteinuria after preeclampsia. Obstet Gynecol 114(6):1307,2009

Bloom SL, Leveno K]: Corticosteroid use in special circumstances: preterm ruptured membranes, hypertension, fetal growth restriction, multiple fetuses. Clin Obstet Gynecol 46: 150, 2003

Bokslag A, Franssen C, Teunissen PW, et al: Higher prevalence of diasto�ic dysfunction in women who have had a decade ago early onset preeclampSia. Abstract No. 66, Am] Obstet Gynecol 216:S47, 2017

Bolte AC, van Eyck], Gafar SF, et al: Ketanserin for the treatment of preeclampsia. ] Perinat Med 29: 14, 2001

Bombrys AE, Barton ]R, Habli M, Sibai BM: Expectant management of severe preeclampsia at 27(0/7) to 33(6/7) weeks' gestation: maternal and perinatal outcomes according to gestational age by weeks at onset of expectant management. Am] Perinatol 26:441, 2009

Bombtys E, Barton ]R, Nowacki EA, et al: Expectant management of severe preeclampsia at less than 27 weeks' gestation: maternal and perinatal outcomes according to gestational age by weeks at onset of expectant management. Am] Obstet Gynecol 199:247.e1, 2008

Bramham K, Briley AL, Seed P, et al: Adverse maternal and perinatal outcomes in women with previous preeclampsia: a prospective study. Am ] Obstet GynecoIn204(6):512.e1,n2011

Brewer ], Owens MY, Wallace K, et al: Posterior reversible encephalopathy syndrome in 46 of 47 patients with eclampsia. Amn] Obstet Gynecol 208(6):468.e1,n2013

Broekhuijsen K, van Baaren G], van Pampus MG, et al: Immediate delivery versus expectant monitoring for hypertensive disorders of pregnancy between 34 and 37 weeks of gestation (HYPITAT-II): an open-label, randomised controlled trial. Lancet 385(9986):2492, 2015

Brookield F, Su F, Elkomy MH, et al: Pharmacokinetics and placental transfer of magnesium sulfate in pregnant women. Am J Obstet Gynecol 214:737.e1,n2016

Brosens I, Pijnenborg R, Vercruysse L, et al: The "Great Obstetrical Syndromes" are associated with disorders of deep placentation. Am ] Obstet GynecoI204(3):193,n2011

Brown CE, Purdy P, Cunningham FG: Head computed tomographic scans in women with eclampsia. Am] Obstet Gynecol 159(4):915, 1988

Brown A, Zammit VC, Lowe SA: Capillary permeabiliry and extracellular Auid volumes in pregnancy-induced hypertension. Clin Sci 77:599, 1989

Brownfoot Fe, Hastie R, Hannan N], et al: Metformin as a prevention and treatment for preeclampsia: efects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction. Am J Obstet Gynecol 214(3):356.e1, 2016

Budden A, Wilkinson L, Buksh M], et al: Pregnancy outcomes in women presenting with pre-eclampsia at less than 25 weeks gestation. Aust N Z ] Obstet GynaecoIn46(5):407, 2006

Bush KD, O'Brien JM, Barton JR: The utility of umbilical artery Doppler investigation in women with HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome. Am J Obstet Gynecol 184: 1087, 200n1

Buurma A], Turner R], Driessen ]H, et al: Genetic variants in pre-eclampsia: a meta-analysis. Hum Reprod Update 19(3):289,n2013

Cahill A, Odibo A, Roehl K, et al: Impact of intrapartum antihypertensives on electronic fetal heart rate (EFM) patterns in labor. Abstract No. 615, Am J Obstet Gynecoln208(1 Suppi):S262, 2013

Caritis 5, Sibai B, Hauth J, et al: Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl ] Med 338(1n1):70, 1998

Carty OM, Siwy J, Brennand JE, et al: Urinary proteomics for prediction of preeclampsia. Hypertension 57(3):561, 2011

Chaiworapongsa T, Robero R, Korzeniewski SJ, et al: Maternal plasma concentrations of angiogeniclantiangiogenic factors in the third trimester of pregnancy to identiy the patient at risk for stillbirth at or near term and severe late preeclampsia. Am J Obstet GynecoI208(4):287.e1, 2013

Chambers A, Cain W: Postpartum blindness: two cases. Ann Emerg Med 43:243, 2004

Chames MC, Livingston ]C, Ivester TS, et al: Late postpartum eclampsia: a preventable disease? Am] Obstet Gynecol 186: 1174, 2002

Chase L, McBride CA, Badger, et al: Association of pre-pregnancy and longitudinal change in angiotensin-II with preterm preeclampsia. Abstract No. 934, Am] Obstet Gynecol 216:5530, 2017

Chavarria ME, Lara-Gonzalez L, Gonzalez-Gleason A, et al: Prostacyclin/ thromboxane early changes in pregnancies that are complicated by preeclampsia. Am ] Obstet Gynecol 188:986, 2003

Chen BA, Parviainen K, Jeyabalan A: Correlation of catheterized and clean catch urine protein/creatinine ratios in preeclampsia evaluation. Obstet Gynecol 11n2:606,n2008

Chesley LC: Diagnosis of preeclampsia. Obstet Gynecol 65:423, 1985 Chesley LC (ed): Hypertensive Disorders in Pregnancy. Appleton-CenturyCrofts, New York, 1978

Chesley Le, Williams LO: Renal glomerular and tubular function in relation to the hyperuricemia of preeclampsia and eclampsia. Amn] Obstet Gynecol 50:367, 1945

Chowdhury ]R, Chaudhuri 5, Bhattacharyya N, et al: Comparison of intramuscular magnesium sulfate with low dose intravenous magnesium sulfate regimen for treatment of eclampsia.] Obstet Gynaecol Res 35:119,n2009

Christiansen M, Hedley PL, Placing 5, et al: Maternal serum resistin is reduced in irst trimester preeclampsia pregnancies and is a marker of clinical severity. Hypertens Pregnancy 34(4):422,n2015

Churchill 0, Beever GO, Meher S, et al: Diuretics for preventing preeclampsia.

Cochrane Database Syst Rev 1 :CD004451, 2007

Cipolla MJ: Brief review: cerebrovascular function during pregnancy and eclampsia. Hypertension 50: 14, 2007

Cipolla MJ, Smith J, Kohlmeyer MM, et al:· SKCa and IKCa channels, myogenic tone, and vasodilator responses in middle cerebral arteries and parenchymal arterioles: efect of ischemia and reperfusion. Stroke 40(4): 1451,n2009

Cipolla M], Zeeman GG, Cunningham FG: Cerebrovascular (patho)physiology in preeclampsia/eclampsia. In Taylor RN, Roberts ]M, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 2015

Clark SL, Dildy GA III: Pulmonary artery catheterization. In Belfort M, Saade GR, Foley MR, et al (eds): Critical Care Obstetrics, 5th ed. West Sussex, Wiley-Blackwell, 2010

Clark SL, Cotton DB, Wesley L, et al: Central hemodynamic assessment of normal term pregnancy. m] Obstet Gynecol 161:1439, 1989

Clark SL, Divon MY, Phelan ]P: Preeclampsia/eclampsia: hemodynamic and neurologic correlations. Obstet Gynecol 66:337, 1985

Cleary KL, Roney K, Costantine M: Challenges of studying drugs in pregnancy for of-label indications: pravastatin for preeclampsia prevention. Semin PerinaroIn38:523,n2014

Cnossen ]5, de Ruyter-Hanhijavi H, van der Post JA, et al: Accuracy of serum uric acid determination in predicting pre-eclampsia: a systematic review. Acta Obstet Gynecol Scand 85(5):519, 2006

Coetzee EJ, Dommisse J, Anthony]: A randomised controlled trial of intravenous magnesium sulphate versus placebo in the management of women with severe pre-eclampsia. B]OG 105(3):300, 1998

Conde-Agudelo A, Romero R, RobertS JM: Tests to predict preeclampsia. In Taylor RN, Roberts ]M, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 2015

Connealy B, Carreno e, Kase B, et al: A history of prior preeclampsia as a risk factor for preterm birth. Am J Perinatol 31(6):483, 2014

Conrad P, Stillman I, Lindheimer MD: he kidney in normal pregnancy and preeclampsia. In Taylor N, Roberts ]M, Cunningham FG (eds): Chesley's Hypenensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 2015

Conelis T, Odutayo A, Keunenn], et al: he kidney in normal pregnancy and preeclampsia. Semin Nephrol 31(1):4, 2011

Cornetten], Buijs EA, Duvekot J], et al: Hemodynamic efects of intravenous nicardipine in severely preeclamptic women with a hypertensive crisis. Ultrasound Obstet GynecoIn47(1):89, 2016

Costantine MM, Cleary K, Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric-Fetal Pharmacology Research Units Network: Pravastatin for the prevention of preeclampsia in high-risk pregnant women. Obstet Gynecol 121(2 Pt 1):349,n2013

Costantine MM, Cleary K, Hebert MF, et al: Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial. Am] Obstet Gynecol 214:720. e1,n2016

Cotton DB, Jones MM, Longmire 5, et al: Role of intravenous nitroglycerine in the treatment of severe pregnancy-induced hypertension complicated by pulmonary edema. Am J Obstet Gynecol 154:91, 1986a

Cotton DB, Longmire 5, Jones MM, et al: Cardiovascular alterations in severe pregnancy-induced hypertension: efects of intravenous nitroglycerin coupled with blood volume expansion. Am J Obstet Gynecol 154: 1053, 1986b

Creanga AA, Syverson C, Seed K, et al: Pregnancy-related mortaliry in the United States, 2006-2010. Obstet Gynecol 130(2):366,n2017

Crowther CA, Bouwmeester AM, Ashurst HM: Does admission to hospital for bed rest prevent disease progression or improve fetal outcome in pregnancy complicated by non-proteinuric hypertension? B]OG 99:13, 1992

Cunningham FG: Liver disease complicating pregnancy. Williams Obstetrics, 19th ed. (Suppl 1). Norwalk, Appleton & Lange, 1993

Cunningham FG: Peripartum cardiomyopathy: we've come a long way, but ...n. Obstet Gynecol 120(5):992, 2012

Cunningham FG: Severe preeclampsia and eclampsia: systolic hypertension is also important. Obstet Gynecol 105(2):237,n2005

Cunningham FG, Fenandez CO, Henandez C: Blindness associated with preeclampsia and eclampsia. Am] Obstet Gynecol 172: 1291, 1995

Cunningham FG, Lowe T, Guss 5, et al: Erythrocyte morphology in women with severe preeclampsia and eclampsia. Am ] Obstet Gynecol 153:358, 1985

Cunningham FG, Nelson DB: Disseminated intravascular coagulation syndromes in obstetrics. Obstet Gynecol 126(5):999,n2015

Cunningham FG, Nelson DB: Magnesium sulphate: too much of a good thing? B]OG 123:356,n2016

Cunningham FG, Pritchard JA, Hankins GO, et al: Peripartum heart failure: idiopathic cardiomyopathy or compounding cardiovascular events? Obstet :157, 1986

Cunningham FG,

T wiclder 0: Cerebral edema complicating eclampsia. Am J Obstet Gynecol 182:94, 2000

D'Anna R, Baviera G, Corrado F, et al: Plasma homocysteine in early and late pregnancy complicated with preeclampsia and isolated intrauterine growth restriction. Acta Obstet Gynecol Scand 83: 155, 2004

Dar P, Gebb J, Reimers L, et al: First-trimester 3-dimensional power Doppler of the uteroplacental circulation space: a potential screening method for preeclampsia. Am J Obstet Gynecol 203(3):238.e1, 2010

Dashe JS, Ramin SM, Cunningham FG: The long-term consequences of thrombotic microangiopathy (thrombotic thrombocytopenic purpura and hemolytic uremic syndrome) in pregnancy. Obstet GynecoIn91:662, 1998

Davidge S, de Groot C, Taylor N: Endothelial cell dysfunction and oxidative stress. In Taylor N, Roberts JM, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 2015 de Almeida Pimenta EJ, Silva de Paula CF, Duarte Bonini Campos JA, et al: hree-dimensional sonographic assessment of placental volume and vascularization in pregnancies complicated by hypertensive disorders. J Ultrasound Med 33(3):483, 2014

Demers S, Bujold E, Arenas E, et al: Prediction of recurrent preeclampsia using first-trimester uterine artery Doppler. Am J Perinatol 31 (2):99, 2014 Dennis AT, Castro J, Carr e, et al: Haemodynamics in women with untreated pre-eclampsia. Anaesthesia 67(10):1105, 2012a

Dennis AT, Solnordal CB: Acute pulmonary oedema in pregnant women.

Anaesthesia 67(6):646, 2012b

De Paco e, Kametas N, Rencoret G, et al: Maternal cardiac output between 11 and 13 weeks of gestation in the prediction of preeclampsia and small for gestational age. Obstet Gynecol 111:292,n2008

De Snoo K: The prevention of eclampsia. Am J Obstet GynecoIn34:911, 1937 de Vries JI, van Pampus MG, Hague M: Low-molecular-weight heparin added to aspirin in the prevention of recurrent early-onset pre-eclampsia in women with inheritable thrombophilia: the FRUIT-RCT. J hromb Haemost 10(1):64, 2012

De Wolf F, De Wolf-Peeters e, Brosens I, et al: he human placental bed: electron microscopic study of trophoblastic invasion of spiral arteries. Am J Obstet Gynecoln137:58, 1980 DiFederico E, Genbacev 0, Fisher SJ: Preeclampsia is associated with widespread apoptosis of placental cytotrophoblasts within the uterine wall. m J PathoIn155:293, 1999 Drakeley AJ, Le Roux PA, Anthony J, et al: Acute renal failure complicating severe preeclampsia requiring admission to an obstetric intensive care unit. Am J Obstet Gynecol 186:253,n2002 Drassinower D, Friedman M, Levin H, et al: Does magnesium exposure afect neonatal resuscitation? Am J Obstet Gynecol 213:424.el, 2015 Duckworth S, Griin M, Seed PT, et al: Diagnostic biomarkers in women with suspected preeclampsia in a prospective multicenter study. Obstet Gynecol 128(2):245,n2016 Ducros A: Reversible cerebral vasoconstriction syndrome. Lancet Neurol 11(10):906,n2012 Duy CR, Odibo AO, Roehl A, et al: Efect of magnesium sulfate on fetal heart rate patterns in the second stage oflabor. Obstet GynecoIn119(6): 1129, 2012 Durr JA, Lindheimer MD: Control of volume and body tonicity. In Lindheimer MD, Roberts JM, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy, 2nd ed. Stamford, Appleton & Lange, 1999 Dyer A,Els I, Farbas J, et al: Prospective, randomized trial comparing general with spinal anesthesia for cesarean delivery in preeclamptic patients with a nonreassuring fetal heart trace. Anesthesiology 99:561,n2003 Easterling TR, Benedetti TJ, Schmucker Be, et al: Maternal hemodynamics in normal and preeclamptic pregnancies: a longitudinal study. Obstet Gynecol 76:1061, 1990 Eclampsia Trial Collaborative Group: Which anticonvulsant for women with eclampsia? Evidence from the collaborative eclampsia trial. Lancet 345:1455, 1995 Edlow JA, Caplan LR, O'Brien K, et al: Diagnosis of acute neurological emergencies in pregnant and post-partum women. Lancet Neurol 12(2): 175, 2013 Ehrenberg HM, Mercer BM: Abbreviated postpartum magnesium sulphate therapy for women with mild preeclampsia: a randomized controlled trial. Obstet Gynecol 108(4):833,n2006 Eichelberger Y, Baker Ml, Woodham PC, et al: Second-trimester maternal serum paraxanthine, CYP 1A2 activity, and the risk of severe preeclampsia. Obstet Gynecol 126(4):725,n2015 Erlebacher A: Immunology of the maternal-fetal interface. Annu Rev Immunol 31:387,n2013 Evans CS, Gooch L, Flotta 0, et al: Cardiovascular system during the postpartum state in women with a history of preeclampsia. Hypertension 58:57, 2011 Everett TR, Mahendru A, McEniery CM, et al: Raised uterine artery impedance is associated with increased maternal arterial stifness in the late second trimester. Placenta 33(7):572,n2012 Faas MM, Schuiling GA, Linton A, et al: Activation of peripheral leukocytes in rat pregnancy and experimental preeclampsia. Am J Obstet Gynecol 182:351,n2000

Facco FL, Parker CB, Reddy UM, et al: Association between sleep-disordered breathing and hypertensive disorders of pregnancy and gestational diabetes mellitus. Obstet GynecoIn129(1):31, 2017

Finnerty FA, Buchholz JH, Tuckman J: Evaluation of chlorothiazide (Diuril) in the toxemias of pregnancy. JAMA 166:141, 1958

Fisher S, Roberts JM: The placenta in normal pregnancy and preeclampsia. In Taylor RN, Roberts JM, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 2015

Fleischer A, Schulman H, Farmakides G, et al: Uterine artery Doppler velocimetry in pregnant women with hypertension. Am J Obstet Gynecol 154:806, 1986

Flowers CE, Grizzle JE, Easterling E, et al: Chlorothiazide as a prophylaxis against toxemia of pregnancy. A double-blind study. Am ] Obstet Gynecol 84:919, 1962

Fonseca JE, Mendez F, Catano e, et al: Dexamethasone treatment does not improve the outcome of women with HELLP syndrome: a doubleblind, placebo-controlled, randomized clinical trial. Am J Obstet Gynecol 193:1591, 2005

Forster JG, Peltonen S, Kaaja R, et al: Plasma exchange in severe postpartum HELLP syndrome. Acta Anaesthesiol Scand 46:955,n2002

Fugate JE, Rabinstein A: Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurol 14(9):914, 2015

Gallo OM, Wright 0, Casanova e, et al: Competing risks model in screening for preeclampsia by maternal factors and biomarkers at 19-24 weeks' gestation. Am J Obstet GynecoI214:619.el, 2016

Gant NF, Chand S, Worley RJ, et al: A clinical test useful for predicting the development of acute hypertension in pregnancy. Am J Obstet Gynecol 120:1, 1974

Ganzevoort W, Rep A, Bonsel G], et al: A randomized trial of plasma volume expansion in hypertensive disorders of pregnancy: influence on the pulsatile indices of the fetal umbilical artery and middle cerebral artery. m J Obstet Gynecol 192:233, 2005a

Ganzevoort W, Rep A, Bonsel GJ, et al: Plasma volume and blood pressure regulation in hypertensive pregnancy. J Hypertens 22: 1235, 2004

Ganzevoort W, Rep A, PERT A investigators, et al: A randomized controlled trial comparing two temporizing management strategies, one with and one without plasma volume expansion, for severe and early onset pre-eclampsia. BJOG 112:1337, 2005b

Gastrich MD, Gandhi SK, Pantazopoulos J, et al: Cardiovascular outcomes after preeclampsia or eclampsia complicated by myocardial infarction or stroke. Obstet GynecoIn120(4), 823, 2012

Gaugler-Senden IP, Huijssoon AG, Visser W, et al: Maternal and perinatal outcome of preeclampsia with an onset before 24 weeks' gestation. Audit in a tertiary referral center. Eur] Obstet Gynecol Reprod BioI 128:216, 2006

George IN, Charania RS: Evaluation of patients with microangiopathic hemolytic anemia and thrombocytopenia. Semin Thromb Hemost 39(2): 153, 2013

Gervasi MT, Chaiworapongsa T, Pacora P, et al: Phenotypic and metabolic characteristics of monocytes and granulocytes in preeclampsia. Am J Obstet Gynecol 185:792,n2001

Ghidini A, Locatelli A: Monitoring of fetal well-being: role of uterine artery Doppler. Semin Perinatol 32:258, 2008

Ghossein-Doha C, Peeters L, van Jeijster S, et al: Hypertension ater preeclampsia is preceded by changes in cardiac structures and function. Hypertension 62(2):382, 2013 Gillis EE, Mooney IN, Garrett MR, et al: Sildenafil treatment ameliorates the maternal syndrome of preeclampsia and rescues fetal growth in the Dahl salt-sensitive rat. Hypertension 67(3):647, 2016 Gilstrap Le, Cunningham FG, Whalley PJ: Management of pregnancyinduced hypertension in the nulliparous patient remote from term. Semin PerinatoIn2:73, 1978

Goel A, Maski MR, Bajracharya S, et al: Epidemiology and mechanisms of de novo and persistent hypertension in the postpartum period. Circulation 132(18):1726,n2015 Gortzak-Uzan L, Mezad 0, Smolin A: Increasing amniotic fluid magnesium concentrations with stable maternal serum levels. A prospective clinical trial. J Reprod Med 50:817, 2005 Graham NM, Gimovsky AC, Roman A, et al: Blood loss at cesarean delivery in women on magnesium sulfate for preeclampsia. J Matern Fetal Neonatal Med 29(11):1817,n2016 Groom K, McCowan L, MacKay L, et al: Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a history: a randomized trial. Am J Obstet Gynecol 216(3):296.e1, 2017 Groom M, North A, Stone PR, et al: Patterns of change in uterine artery Doppler studies between 20 and 24 weeks of gestation and pregnancy outcomes. Obstet Gynecol 113(2):332, 2009

Guirguis GF, Aziz MM, Boccia Liang C, et al: Is preeclampsia an independent predictor of diastolic dysfunction: a retrospective cohort study. Pregnancy Hypertens 5(4):359, 2015

Habli M, Eftekhari N, Wiebracht E, et al: Long-term maternal and subsequent pregnancy outcomes 5 years after hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. Am] Obstet GynecoI201(4):385.e1, 2009

Haddad B, Barton ]R, Livingston ]C, et al: Risk factors for adverse maternal outcomes among women with HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome. Am] Obstet Gynecol 183:444,n2000

Haddad B, Kayem G, Deis S, et al: Are perinatal and maternal outcomes dif ferent during expectant management of severe preeclampsia in the presence of intrauterine growth restriction? Am] Obstet Gynecol 196:237.e1, 2007

Haddad B, Winer N, Chitrit Y, et al: Enoxaparin and aspirin compared with aspirin alone to prevent placenta-mediated pregnancy complications. Obstet GynecoIn128(5):1053,n2016

Haggerty CL, Seifert ME, Tang G: Second trimester anti-angiogenic proteins and preeclampsia. Pregnancy Hypertens 2(2): 158, 2012

Hallak M, Berry SM, Madincea F, et al: Fetal serum and amniotic luid magnesium concentrations with maternal treatment. Obstet GynecoI81:185, 1993

Hallak M, Martinez-Poyer], Kruger ML, et al: he efect of magnesium sulfate on fetal heart rate parameters: a randomized, placebo-controlled trial. Am ] Obstet GynecoIn181:1122, 1999

Handor H, Daoudi R: Images in clinical medicine. Hypertensive retinopathy associated with preeclampsia. N Engl] Med 370(8):752,n2014

Hankins GO, Wendel GW]r, Cunningham FG, et al: Longitudinal evaluation of hemodynamic changes in eclampsia. Am] Obstet GynecoIn150:506, 1984 Harmon QE, Huang L, Umbach OM, et al: Risk of fetal death with pre eclampsia. Obstet GynecoIn125(3):628, 2015

Harskamp E, Zeeman GG: Preeclampsia: at risk for remote cardiovascular disease. Amn] Med Sci 334(4):291, 2007

Hauser A, Lacey OM, Knight MR: Hypertensive encephalopathy. Arch Neurol 45: 1078, 1988

Hauth ]C, Cunningham FG, Whalley P]: Management of pregnancy-induced hypertension in the nullipara. Obstet GynecoIn48:253, 1976

Head BB, Owen ], Vincent RD ]r, et al: A randomized trial of intrapartum analgesia in women with severe preeclampsia. Obstet Gynecol 99:452, 2002 Hecht ]L, Ordi ], Carrilho C, et al: he pathology of eclampsia: an autopsy series. Hypertens Pregnancy 36:259,n2017 Heilmann L, Rath W, Pollow K: Hemostatic abnormalities in patients with severe preeclampsia. Clin Appl Thromb Hemost 13: 285, 2007

Heller P], Scheider EP, Marx GF: Pharyngo-Iaryngeal edema as a presenting symptom in preeclampsia. Obstet Gynecol 62:523, 1983

Henderson ]T, Whitlock EP, O'Connor E, et al: Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med 160:695,n2014

Hermes W, Ket ]C, van Pampus MG, et al: Biochemical cardiovascular risk factors after hypertensive pregnancy disorders: a systematic review and metaanalysis. Obstet Gynecol Surv 67(12):793,n2012

Herraiz I, Escribano 0, Gomez-Arriaga PI, et al: Predictive value of sequential models of uterine artery Doppler in pregnancies at high risk for pre-eclampsia. Ultrasound Obstet Gynecol 40(1):68, 2012

Hertig AT: Vascular pathology in the hypertensive albuminuric toxemias of pregnancy. Clinics 4:602, 1945

Hibbard ]U, Shrof SG, Cunningham FG: Cardiovascular alterations in normal and preeclamptic pregnancy. In Taylor RN, Roberts ]M, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 2015

Hincheyn], Chaves C, Appignani B, et al: A reversible posterior leukoencephalopathy syndrome. N Engl] Med 334(8):494, 1996

Hirshberg A, Levine LD, Srinivas SK: Clinical factors associated with readmission for postpartum hypertension in women with pregnancy-related hypertension: a nested case control study. ] Perinatol 36(5):405, 2016

Hnat MD, Sibai BM, Caritis S, et al: Perinatal outcome in women with recurrent preeclampsia compared with women who develop preeclampsia as nulliparas. Am ] Obstet Gynecol 186:422, 2002

Hogg B, Hauth ]C, Caritis SN, et al: Safety of labor epidural anesthesia for women with severe hypertensive disease. Am ] Obstet Gynecol 181: 1096, 1999

Horsager R, Adams M, Richey S, et al: Outpatient management of mild pregnancy induced hypertension. Amn] Obstet Gynecol 172:383, 1995

Hunter SK, Martin M, Benda ]A, et al: Liver transplant after massive spontaneous hepatic rupture in pregnancy complicated by preeclampsia. Obstet Gynecol 85:819,n1995

Hupuczi P, Nagy B, Sziller I, et al: Characteristic laboratory changes in pregnancies complicated by HELLP syndrome. Hypertens Pregnancy 26:389, 2007 ]aatinen N, Ekholm E: Eclampsia in Finland: 2006 to 2010. Acta Obstet Gynecol Scand ,n2016 lana N, Dasgupta S, Das OK, et al: Experience of a low-dose magnesium sulfate regimen for the management of eclampsia over a decade. Int] Gynaecol Obstet 122(1):13,n2013 ]anzarik WG, Ehlers E, Ehmann R, et al: Dynamic cerebral autoregulation in pregnancy and the risk of preeclampsia. Hypertension 63: 161,n2014 ]askolka 0, Rernakaran R, Zinman B, et al: Fetal sex and maternal risk of pre-eclampsia/eclampsia: a systematic review and meta-analysis. B]OG 124(4):553,n2017 ]ayaballa M, Sood S, Alahakoon I, et al: Microalbuminuria is a predictor of adverse pregnancy outcomes including preeclampsia. Pregnancy Hypertens 5(4):303, 2015

Johnson LH, Mapp DC, Rouse 0]: Association of cord blood magnesium concentration and neonatal resuscitation.n] Pediatr 160(4):573,n2012

Kajantie E, Osmond C, Eriksson ]G: Gestational hypertension is associated with increased risk of type 2 diabetes in adult ofspring: the Helsinki Birth Cohort Study. Am] Obstet Gynecol 216(3):281.e 1, 2017

Karumanchi SA: Angiogenic factors in preeclampsia from diagnosis to therapy.

Hypertension 67:n1072, 2016a

Karumanchi SA, Granger ]P: Preeclampsia and pregnancy-related hypertensive disorders. Hypertension 67:238, 2016b

Karumanchi SA, Stillman IE, Lindheimer MD: Angiogenesis and preeclampsia. In Lindheimer MD, Roberts ]M, Cunningham FG (eds): Chesley's Hypertensive Disorders of Pregnancy, 3rd ed. New York, Elsevier, 2009

Kasawara KT, do Nascimento SL, Costa ML, et al: Exercise and physical activity in the prevention of pre-eclampsia: systematic review. Acta Obstet Gynecol Scand 91(10):1147,n2012

Kashanian M, Koohpayehzadeh], Sheikhansari N, et al: A comparison berween the rwo methods of magnesium sulfate administration for dutation of 12 versus 24 h after delivery in patients with severe preeclampsia. ] Matern Fetal Neonatal Med 29(14):2282, 2016

Katz L, de Amorim MM, Figueroa ]N, et al: Postpartum dexamethasone for women with hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome: a double-blind, placebo-controlled, randomized clinical trial. Am ] Obstet Gynecol 198:283.e 1, 2008

Keiser S, Owens M, Parrish M, et al: HELLP syndrome with and without eclampsia. Am] Perinatol 28(3):187, 2011 Kenny L, McCrae K, Cunningham FG: Platelets, coagulation, and the liver.

In Taylor RN, Roberts ]M, Cunningham FG (eds): Chesley's Hypertensive

Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 20n15

Khalil A, Akolekar R, Syngelaki A, et al: Maternal hemodynamics at 11-13 weeks' gestation and risk of pre-eclampsia. Ultrasound Obstet Gynecol 40(1):28,n2012

Khan KS, Wojdyla 0, Say L, et al: WHO analysis of causes of maternal death: a systematic review. Lancet 367: 1 066, 2006

Khodzhaeva ZS, Kogan YA, Shmakov RG, et al: Clinical and pathogenetic features of early-and late-onset preeclampsia. ] Matern Fetal Neonatal Med 29(18):2980,n2016

Kim MY, Buyon ]P, Guerra MM, et al: Angiogenic factor imbalance early in pregnancy predicts adverse outcomes in patients with lupus and antiphospholipid antibodies: results of the PROMISSE study. Am] Obstet Gynecol 214:108.e1,2016

Kleinrouweler CE, Wiegerinck MM, Ris-Stalpers C, et al: Accuracy of circulating placental growth factor, vascular endothelial growth factor, soluble fms-like tyrosine kinase 1 and soluble endoglin in the prediction of preeclampsia: a systematic review and meta-analysis. B]OG 8,2012

Knight M, UK Obstetric Surveillance System (UKOSS): Eclampsia in the United Kingdom 2005. B]OG 114:1072,2007

Knuist M, BOtlSei G], Zondervan HA, et al: Low sodium diet and pregnancyinduced hypertension: a multicentre randomized controlled trial. B]OG 105:430, 1998

Koopmans CM, Bijlenga D, Groen H, et al: Induction of labour versus expectant monitoring for gestational hypertension or mild pre-eclampsia after 36 weeks' gestation (HYPIT AT): a multicentre, open-label randomized controlled trial. Lancet 4(9694):979, 2009

Kozic ]R, Benton S], Hutcheon ]A, et al: Abnormal liver function tests as predictors of adverse maternal outcomes in women with preeclampsia. ] Obstet Gynaecol Can 33(10):995, 2011

Kraus D, Feng L, Heine RP, et al: Cigarette smoke-induced placental adrenomedullin expression and trophoblast cell invasion. Reprod Sci 21 (1):63, 2014

Kyle PM, Fielder ]N, Pullar B, et al: Comparison of methods to identiY signiicant proteinuria in pregnancy in the outpatient setting. B]OG 115:523, 2008

Labarrere CA, DiCarlo HL, Bammerlin E, et al: Failure of physiologic transformation of spiral arteries, endothelial and trophoblast cell activation, and acute atherosis in the basal plate of the placenta. Am ] Obstet Gynecol 216:287.el,n201

Lai ], Poon LC, Bakalis 5, et al: Systolic, diastolic and mean arterial pressure at 30-33 weeks in the prediction of preeclampsia. Fetal Diagn her 33(3): 173, 2013

Lam DS, Chan W: Images in clinical medicine. Choroidal ischemia in preeclampsia. N Engl] Med 344(10):739,n2001

Lam GK, Hopoate-Sitake M, Adair CD, et al: Digoxin antibody fragment, antigen binding (Fab), treatment of preeclampsia in women with endogenous digitalis-like factor: a secondary analysis of the DEEP trial. Am ] Obstet GynecoIn209(2):119.e1, 2013

Langenveld ], Ravelli AC], van Kaam AH, et al: Neonatal outcome of pregnancies complicated by hypertensive disorders berween 34 and 37 weeks of gestation: a 7 year retrospective analysis of national registry. Am ] Obstet GynecoIn205(6):540.e.1,n2011

Lara-Torre E, Lee MS, WolfMA, et al: Bilateral retinal occlusion progressing to long-lasting blindness in severe preeclampsia. Obstet Gynecol 100:940, 2002 Leduc L, Wheeler ]M, Kirshon B, et al: Coagulation proile in severe preeclampsia. Obstet Gynecol 79: 14, 1992

Lee SM, Romero R, Lee YJ, et al: Systemic inflammatory stimulation by microparticles derived from hypoxic trophoblast as a model for inflammatory response in preeclampsia. Am] Obstet GynecoIn207(4):337.e1, 2012

Leelang MM, Cnossen ]5, van der Post ]A, et al: Accuracy of ibronectin tests for the prediction of pre-eclampsia: a systematic review. Eurn] Obstet Gynecol Reprod Bioi 133(1):12, 2007

Leveno K], Alexander ]M, McIntire DD, et al: Does magnesium sulfate given for prevention of eclampsia afect the outcome of labor? Am ] Obstet Gynecol 178:707, 1998

Levine Rj, Hauth]e, Curet LB, et al: Trial of calcium to prevent preeclampsia.

N Engl J Med 337:69, 1997

Lewandowski A], Augustine D, Lamata P, et al: Preterm heart in adult life.

Cardiovascular magnetic resonance reveals distinct diferences in let ventricular mass, geometry, and function. Circulation 127(2):197,n2013

Lewis AR, Afroze SH, Wesley KB, et al: Pravastatin protects cytotrophoblasts from a hyperglycemia-induced preeclampsia phenotype. Abstract No. 879, Am] Obstet GynecoIn216:S502, 2017

Li H, Gudnason H, Olofsson P, et al: Increased uterine artery vascular impedance is related to adverse outcome of pregnancy but is present in only one-third of late third-trimester pre-eclampsia women. Ultrasound Obstet GynecoIn25:459,n2005

Lindheimer MD, Conrad K, Karumanchi SA: Renal physiology and disease in pregnancy. In Alpern Rj, Hebert SC (eds): Seldin and Giebisch's he Kidney: Physiology and Pathophysiology, 4th ed. New York, Elsevier, 2008a

Lindheimer MD, Taler 5], Cunningham FG: Hypertension in pregnancy [Invited Am Soc Hypertension position paper). ] Am Soc Hypertens 2:484, 2008b

Loisel DA, Billstrand C, Murray K, et al: he maternal HLA-G 1597 DC null mutation is associated with increased risk of pre-eclampsia and reduced HLA-G expression during pregnancy in African-American women. Mol Hum Reprod 19(3):144,n2013

Lopes van Balen VA, Spaan J], Cornelis T, et al: Prevalence of chronic kidney disease after preeclampsia. ] NephroIn30(3):403, 2017

L6pez-Llera M: Complicated eclampsia: fifteen years' experience in a referral medical center. Am ] Obstet Gynecol 142:28, 1982

Loureiro R, Leite Ce, Kahhale 5, et al: Difusion imaging may predict reversible brain lesions in eclampsia and severe preeclampsia: initial experience. Am] Obstet Gynecol 189: 1350, 2003

Louveau A, Smirnov I, Keyes T], et al: Structural and functional features of central nervous system lymphatic vessels. Nature 523:337,n2015

Lucas MJ, Leveno K], Cunningham FG: A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. N Engl J Med 333:201, 1995

Lucas MJ, Sharma 5, McIntire DD, et al: A randomized trial of the efects of epidural analgesia on pregnancy-induced hypertension. Am ] Obstet Gynecol 185:970, 2001

Ludmir], Vigil-De Gracia P, Mag-Pip (Magnesium postpartum in preeclampsia) study group: Is magnesium sulfate use of beneit postpartum? A randomized controlled trial. Abstract No.n4, Am ] Obstet Gynecol 216:53, 2017

Lut Fe, Gallery ED, Lindheimer MD: Normal and abnormal volume homeostasis. In Lindheimer MD, Roberts ]M, Cunningham FG (eds): Chesley's Hypertensive Disorders of Pregnancy, 3rd ed. New York, Elsevier, 2009

Lykke JA, Langhof-Roos J, Sibai BM, et al: Hypertensive pregnancy disorders and subsequent cardiovascular morbidity and type 2 diabetes mellitus in the mother. Hypertension 53:944, 2009a

Lykke ]A, Paidas M], Langhof-Roos J: Recurring complications in second pregnancy. Obstet GynecoIn113:1217, 2009b

Lynch TA, Dexter SC: Alcoholic pancreatitis masquerading as preeclampsia.

Obstet GynecoIn126(6):1276, 2015

Ma K, lin H, Hu R, et al: A proteomic analysis of placental trophoblastic cells in preeclampsia-eclampsia. Cell Biochem Biophys 69(2):247,n2014

Mabie WC, Gonzalez AR, Sibai BM, et al: A comparative trial of labetalol and hydralazine in the acute management of severe hypertension complicating pregnancy. Obstet Gynecol 70:328, 1987

Macdonald-Wallis C, Lawlor DA, Fraser A, et al: Blood pressure change in normotensive, gestational hypertensive, preeclamptic, and essential hypertensive pregnancies. Hypertension 59(6):1241, 2012

Macdonald-Wallis e, Silberwood R], de Stavola BL, et al: Antenatal blood pressure for prediction of preeclampsia, preterm birth, and small for gestational age babies: development and validation in rwo general population cohorts. BM] 351n:h5948, 2015

Mackay VA, Huda 55, Stewart FM, et al: Preeclampsia is associated with compromised maternal synthesis of long-chain polyunsaturated fatty acids, leading to ofspring deiciency. Hypertension 60(4):1078, 2012

Mackenzie M, Sandrim Ve, Carty DM, et al: Endothelial FOS expression and preeclampsia. BJOG 119(13):1564,2012

Madazli R, Budak E, Calay Z, et al: Correlation berween placental bed biopsy indings, vascular cell adhesion molecule and ibronectin levels in preeclampsia. B]OG 107:514,n2000

Magee LA, von Dadelszen P, Rey E, et al: Less-tight versus tight control of hypertension in pregnancy. N Engln] Med 372(5):407, 2015

Magpie Trial Collaboration Group: Do women with pre-eclampsia, and their babies, beneit from magnesium sulphate? he Magpie Trial: a randomised placebo-controlled trial. Lancet 359:1877,2002

Magpie Trial Follow-Up Collaborative Group: he Magpie Trial: a randomized trial comparing magnesium sulphate with placebo for pre-eclampsia. Outcome for women at 2 years. B]OG 1n14:300,n2007

Majander KK, Villa PM, Kivinen K, et al: A follow-up linkage study of Finnish pre-eclampsia families identiies a new fetal susceptibility locus on chromosome 18. Eur] Hum Genet 21(9):1024, 2013

Makrides M, Duley L, Olsen SF: Marine oil, and other prostaglandin precursor supplementation for pregnancy uncomplicated by pre-eclampsia or intrauterine growth restriction. Cochrane Database Syst Rev 3:CD003402, 2006

Manten GT, van der Hoek Y, Marko Sikkema], et al: The role of lipoprotein (a) in pregnancies complicated by pre-eclampsia. Med Hypotheses 64: 162, 2005

Martin IN ]r: Severe systolic hypertension and the search for safer motherhood.

Semin PerinatoIn40(2):119, 2016

Martin IN ]r, Bailey AP, Rehberg ]F, et al: Thrombotic thrombocytopenic purpura in 166 pregnancies: 1955-2006. Am] Obstet GynecoIn199(2), 98, 2008

Martinn]N ]r, Brewer ]M, Wallace K, et al: HELLP syndrome and composite major maternal morbidity: importance of Mississippi classiication System. ] Matern Fetal Neonatal Med 26(12):1201,n20n13 Martin]N ]r, Files ]C, Blake PG, et al: Postpartum plasma exchange for atypical preeclampsia-eclampsia as HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Am J Obstet Gynecol 172: 11 07, 1995 Martin ]N ] r, Owens MY, Keiser SO, et al: Standardized Mississippi protocol treatment of 190 patients with HELLP syndrome: slowing disease progression and preventing new major maternal morbidity. Hypertens Pregnancy 31(1):79,n2012 ]N Jr, higpen BO, Moore RC, et al: Stroke and severe preeclampsia and eclampsia: a paradigm shift focusing on systolic blood pressure. Obstet Gynecol 105(2):246,n2005 Masoudian P, Nasr A, de Nanassy J: Oocyte donation pregnancies and the risk of preeclampsia or gestation hypertension: a systematic review and metaanalysis. Amn] Obstet Gynecol 214(3):328, 2016 Matijevic R, Johnston T: In vivo assessment of failed trophoblastic invasion of the spiral arteries in pre-eclampsia. B]OG 106:78, 1999 Mattar F, Sibai BM: Eclampsia: VIII. Risk factors for maternal morbidity. Am ] Obstet Gynecol 182:307,2000 Mayama M, Uno K, Tano 5, et al: Incidence of posterior reversible encephalopathy syndrome in eclamptic and patients with preeclampsia with neurologic symptoms. Am] Obstet GynecoIn215(2):239.e1, 2016 Maynard 5, Epstein FH, Karumanchi SA: Preeclampsia and angiogenic imbalance. Annu Rev Med 59:61, 2008

Maynard SE, Min ]-Y, Merchan], et al: Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.n] Clin Invest 111(5):649, 2003 McCubbin JH, Sibai BM, Abdella TN, et al: Cardiopulmonary arrest due to acute maternal hypermagnesemia. Lancet 1: 1058, 1981 McKinney D, Boyd H, Langager A, et al: The impact of fetal growth restriction on latency in the setting of expectant management of preeclampsia. Am ] Obstet GynecoIn214(3):395.el, 2016

McMahon K, Karumanchi SA, Stillman IE, et al: Does soluble fms-like tyrosine kinase-1 regulate placental invasion? Insight from the invasive placenta. Am J Obstet Gynecol 1 0:66.e 1, 2014

Meher 5, Duely L: Rest during pregnancy for preventing pre-eclampsia and its complications in women with normal blood pressure. Cochrane Database Syst Rev 19:CD005939, 2006

Meher 5, Duley L, Hunter K, et al: Antiplatelet therapy before or after 16 weeks' gestation for preventing preeclampsia: an individual participant data meta-analysis. Am J Obstet Gynecol 216(2): 121, 2017

Melchiorre K, Sutherland G, Sharma R, et al: Mid-gestational maternal cardiovascular proile in preterm and term pre-eclampsia: a prospective study. BJOG 120(4):496,n2013

Melchiorre K, Sutherland G, Watt-Coote I, et al: Severe myocardial impairment and chamber dysfunction in preterm preeclampsia. Hypertens Pregnancy 31(4):454,n2012

Meldrum BS: Implications for neuroprotective treatments. Prog Brain Res 135:487, 2002

Melrose EB: Maternal deaths at King Edward VIII Hospital, Durban. A review of258 consecutive cases. 5 Mr Med J 65:161,n1984

Mignini LE, Latthe PM, Villar J, et al: Mapping the theories of preeclampsia: the role of homocysteine. Obstet Gynecoln105: 411, 2005

Milne F, Redman C, Walker J, et al: Assessing the onset of pre-eclampsia I the hospital day unit: summary of the pre-eclampsia guideline (PRECOG II). BMJ 339:b3129, 2009

Mone F, Mulcahy C, McParland M, et al: Should we recommend universal aspirin for all pregnant women? Am J Obstet GynecoIn216(2):141.e1, 2017

Morgan JL, Nelson DB, Roberts SW, et al: Association of baseline proteinuria and adverse outcomes in pregnant women with treat chronic hypertension. Obstet Gynecol 128(2):270,n2016

Morisaki H, Yamamoto 5, Morita Y, et al: Hypermagnesemia-induced cardiopulmonary arrest before induction of anesthesia for emergency cesarean section. J Clin Anesth 12(3):224, 2000

Morris E, McBride CA, Badger GJ, et al: Prepregnancy itness and risk of hypertensive disorders of pregnancy. Abstract No. 853, Am J Obstet Gynecol 216:5488, 2017

Morris RK, iley RO, Doug M, et al: Diagnostic accuracy of spot urinary protein and albumin to creatinine ratios for detection of signiicant proteinuria or adverse pregnancy outcome in patients with suspected pre-eclampsia: a systematic review and meta-analysis. BMJ 345:e4342, 2012

Moseman CP, Shelton 5: Permanent blindness as a complication of pregnancy induced hypertension. Obstet Gynecol 100:943,n2002

Mosimann B, Wagner M, Poon LC, et al: Maternal serum cytokines at 30-33 weeks in the prediction of preeclampsia. Prenat Diagn 33(9):823, 2013 Mostello 0, Catlin TK, Roman L, et al: Preeclampsia in the parous woman: who is at risk? Am J Obstet GynecoIn187:425, 2002

Myatt L, Brewer AS, Langdon G, et al: Attenuation of the vasoconstrictor efects of thromboxane and endothelin by nitric oxide in the human fetalplacental circulation. Am J Obstet Gynecol 166:224, 1992

Myatt L, Cliton R, Roberts J, et al: Can changes in angiogenic biomarkers between the irst and second trimesters of pregnancy predict development of pre-eclampsia in a low-risk nulliparous patient population? B]OG 120(10):1183,2013

Myatt L, Clifton RG, Roberts ]M, et al: First-trimester prediction of preeclampsia in nulliparous women at low risk. Obstet Gynecol 119(6):2012a

Myatt L, Clifton RG, Roberts JM, et al: The utility of uterine artery Doppler velocimetry in prediction of preeclampsia in a low-risk population. Obstet GynecoIn120(4):815,n2012b

Myers JE, Hart 5, Armstrong 5, et al: Evidence for multiple circulating factor in preeclampsia. Am] Obstet Gynecol 196(3):266.e1, 2007

Myers JE, T uyrten R, homas G, et al: Integrated proteomics pipeline yields novel biomarkers for predicting preeclampsia. Hypertension 61(6):1281, 2013

Napolitano R, Thilaganathan B: Mean, lowest, and highest pulsatility index of the uterine artery and adverse pregnancy outcome in twin pregnancies. Am J Obstet Gynecol 206(6):e8, 2012

National High Blood Pressure Education Program: Working group report on high blood pressure in pregnancy. Am J Obstet Gynecol 183:51, 2000

Ndaboine EM, Kihunrwa A, Rumanyika R, et al: Maternal and perinatal outcomes among eclamptic patients admitted to Bugando Medical Centre, Mwanza, Tanzania. Mr] Reprod Health 16(1):35,2012

Nelson DB, Bailey A, Khan A, et al: Liver injury in HELLP syndrome measured by difusion-weighted MR!. Abstract No. 965, Am ] Obstet Gynecol 216:5545,n2017

Nelson DB, Duraiswamy 5, McIntire DD, et al: Dose preeclampsia involve the pancreas? A report of original research. J Matern Fetal Neonatal Med 28(7):836,n2014a

Nelson DB, Yost NP, Cunningham FG: Acute fatty liver of pregnancy: clinical outcomes and expected duration of recovery. Am ] Obstet Gynecol 209(5):456.e1,n2013

Nelson DB, Ziadie MS, McIntire DD, et al: Placental pathology suggesting that preeclampsia is more than one disease. Am J Obstet Gynecol 210:66. e1,n2014b

Nelson KB, Grether JK: Can magnesium sulfate reduce the risk of cerebrl palsy in very low birthweight infants? Pediatrics 95:263, 1995

Newsome LR, Bramwell RS, Curling PE: Severe preeclampsia: hemodynamic efects oflumbar epidural anesthesia. Anesth Analg 65:31, 1986

Nguyen TM, Crowther CA, Wilkinson 0, et al: Magnesium sulfate for women at term for neuroprotection of the fetus. Cochrane Database Syst Rev 2:CD009395, 2013

Nilsson E, Ros HS, Cnattingius 5, et al: he importance of genetic and environmental efects for pre-eclampsia and gestational hypertension: a family study. BJOG 111:200,2004

Obeidat B, MacDougall J, Harding K: Plasma exchange in a woman with thrombotic thrombocytopenic purpura or severe pre-eclampsia. B]OG 109:961,n2002

O'Connor HD, Hehir MP, Kent EM, et al: Eclampsia: trends in incidence and outcomes over 30 years. Am J Perinatol 30(8):661,n2013

Odibo AO, Rada CC, Cahill AG, et l: First-trimester serum soluble fms-like yosine kinase-I, free vascular endothelial growth factor, placental growth factor and uterine artety Doppler in preeclampsia. J Perinatol2013 33(9):670, 2013

Oettle C, Hall D, Roux A, et al: Early onset severe pre-eclampsia: expectant management at a secondary hospital in close association with a tertiary institution. BJOG 112(1):84, 2005 0ian P, Maltau ]M, Noddleland H, et al: Transcapillary luid balance in preeclampsia. B]OG 93:235, 1986

Okusanya BO, Oladapo OT, Long Q, et al: Clinical pharmacokinetic properties of magnesium sulphate in women with preeclampsia and eclampsia. BJOG 123(3):356,n2016

Olafsdottir AS, Skuladottir GV, Thorsdottir I, et al: Relationship between high consumption of marine fatty acids in early pregnancy and hypertensive disorders in pregnancy. B]OG 113:301,n2006

Olsen RN, Woelkers 0, Dunsmoor-Su R, et al: Abnormal second-trimester serum analytes are more predictive of preterm eclampsia. Am J Obstet Gynecol 207:228.e1, 2012

Ong 55, Moore RJ, Warren AY, et al: Myometrial and placental artery reactivity alone cannot explain reduced placental perfusion in pre-eclampsia and intrauterine growth restriction. B]OG 110(10):909,2003

Orabona R, Sciatti E, Vizzard E, et al: Elastic properties of ascending aorta in women with previous pregnancy complicated by early-or late-onset preeclampsia. Ultrasound Obstet GynecoIn47(3):316, 2016

Orabona R, Vizzardi E, Sciatti E, et al: Insights into cardiac alterations after preeclampsia: an echocardiographic study. Ultrasound Obstet Gynecol 49(1):124,n2017

Palatnik A, Grobman WA, Miller ES: Is a history of preeclampsia associated with an increased risk of a small for gestational age infant in a future pregnancy? Am J Obstet GynecoI215(3):355.e1, 2016

Papanna R, Mann LK, Kouides RW, et al: Protein/creatinine ratio in preeclampsia: a systematic review. Obstet Gynecol 112: 135,n2008

Patrelli TS, DaI' asta A, Gizzo 5, et 1: Calcium supplementation and prevention of preeclampsia: a meta-analysis. J Matern Fetal Neonatal Med 25(12):2570, 2012

Pergialiotis V, Prodromidou A, Frountzas M, et al: Maternal cardiac troponin levels in preeclampsia: a systematic review. ] Matern Fetal Neonatal Med 29(20):3386,n2016

Phillips JK, Janowiak M, Badger GJ, et 1: Evidence for distinct preterm and term phenotypes of preeclampsia. J Matern Fetal Neonatal Med 23(7):622,n2010

Pickles J, Broughton Pipkin F, Symonds EM: A randomised placebo controlled trial of labetalol in the treatment of mild to moderate pregnancy induced hypertension. BJOG 99(12):964, 1992

Pisani-Conway , Simhan H: Does abnormal hemostasis as reflected by a thromboelastogram (TEG) correlate with preeclampsia disease severity? Abstract No. 621, Am] Obstet Gynecol 208(1 Suppl):S264, 2013

Podymow T, August P: Postpartum course of gestational hypertension and preeclampsia. Hypertens Pregnancy 29(3):294, 2010

Postma IR, Bouma A, Ankersmit IF, et al: Neurocognitive functioning following preeclampsia and eclampsia: a long-term follow-up study. Am J Obstet Gynecol 211(1):37.e1, 2014

Poston L, Briley L, Seed PT, et al: Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomized placebo-controlled trial. Lancet 367: 1145, 2006

Pourrat 0, Dorey M, Ragot 5, et al: High-dose methylprednisolone to prevent platelet decline in preeclampsia: a randomized controlled trial. Obstet Gynecol 128:153,n2016

Pritchard ]A: The use of magnesium ion in the management of eclamptogenic toxemias. Surg Gynecol Obstet 100:131, 1955

Pritchard ]A, Cunningham FG, Mason A: Coagulation changes in eclampsia: their frequency and pathogenesis. Am J Obstet GynecoIn124:855, 1976

Pritchard JA, Cunningham FG, Pritchard SA, et al: How often does maternal preeclampsia-eclampsia incite thrombocytopenia in the fetus? Obstet GynecoIn69:292, 1987

Pritchard JA, Cunningham FG, Pritchard SA: The Parkland Memorial Hospital protocol for treatment of eclampsia: evaluation of 245 cases. Am J Obstet GynecoIn148(7):951,n1984

Pritchard JA, Pritchard SA: Standardized treatment of 154 consecutive cases of eclampsia. m J Obstet GynecoIn123(5):543, 1975

Pritchard JA, Weisman R Jr, Ratnof OD, et al: Intravascular hemolysis, thrombocytopenia and other hematologic abnormalities associated with severe toxemia of pregnancy. N Engl J Med 250:87, 1954

Raab W, Schroeder G, Wagner R, et al: Vascular reactivity and electrolytes in normal and toxemic pregnancy. J Clin Endocrinol 16:1196, 1956

Ray A, Ray S: Epidural therapy for the treatment of severe pre-eclampsia in non labouring women. Cochrane Database Syst Rev 11: CD009540, 2017

Redman CW, Sargent IL, Taylor RN: Immunology of abnormal pregnancy and preeclampsia. In Taylor N, Roberts JM, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 2015a Redman CW, Staf AC: Preeclampsia, biomarkers, syncytiotrophoblast stress, and placental capacity. Am J Obstet Gynecol213(4 Suppl):S9.e1, 2015b

Redman CW, Tannetta DS, Dragovic A, et al: Review: does size matter? Placental debris and the pathophysiology of pre-eclampsia. Placenta 33(Suppl):S48,n2012

Reimer T, Rohrmann H, Stubert J, et al: Angiogenic factors and acute-phase proteins in serum samples of preeclampsia and HELLP syndrome patients: a matched-pair analysis. J Matern Fetal Neonatal Med 26(3):263, 2013

Rice MM, Landon MB, Varner MW, et al: Pregnancy-associated hypertension in glucose-intolerant pregnancy and subsequent metabolic syndrome. Obstet Gynecol 127(4): 71,n2016

Richards A, Graham DI, Bullock MRR: Clinicopathological study of neurological complications due to hypertensive disorders of pregnancy. J Neurol Neurosurg Psychiatty 51:416,n1988 Roberge A, Nicolaides K, Demers S, et al: he role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis. AmJ Obstet GynecoI216(2):110, 2017 Roberge S, Giguere Y, Villa P, et al: Early administration of low-dose aspirin for the prevention of severe and mild preeclampsia: a systematic review and meta-analysis. Am J PerinatoIn29(7):551, 2012 Roberts JM, Myatt L, Spong CY, et al: Vitamins C and E to prevent complications of pregnancy-associated hypertension. N Engl J Med 362(14):1282, 2010 Rodger A, Gris JC, de Vries JI, et al: Low-molecular-weight-heparin and recurrent placenta-mediated pregnancy complications: a meta-analysis of individual patient data from randomised controlled trials. Lancet 388(10060):2629,n2016 Roland C, Warshak CR, DeFranco EA: Success of labor induction for preeclampsia at preterm and term gestational ages. J PerinatoIn37(6):636, 20n17 Rolnik DL, Wright D, Poon Le, et al: Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med 377:613,n2017 Roos NM, Wiegman MJ, Jansonius NM, et al: Visual disturbance in (pre) eclampsia. Obstet Gynecol Surv 67(4):242,n2012 Royal College of Obstetricians and Gynaecologists: he management of severe pre-eclampsia. RCOG Guideline lOA: 1, 2006 Rumbold R, Crowther CA, Haslam RR: Vitamins C and E and the risks of preeclampsia and perinatal complications. N Engl J Med 354: 17, 2006

Sagsoz N, Kucukozkan T: The efect of treatment on endothelin-1 concentration and mean arterial pressure in preeclampsia and eclampsia. Hypertens Pregnancy 22:185,n2003 Saito Y, Tano Y: Retinal pigment epithelial lesions associated with choroidal ischemia in preeclampsia. Retina 18:103, 1998 Sakowicz A, Hejduk P, Pietrucha T, et al: Finding NEMO in preeclampsia. Am J Obstet GynecoIn214:538.e1, 2017 Salinger DH, MundIe S, Regi A, et al: Magnesium sulphate for prevention of eclampsia: are intramuscular and intravenous regimens equivalent? A population pharmacokinetic study. BJOG 120(7):894,n2013 Sanchez-Ramos L, Roeckner JT, Kaunitz M: Which agent most efectively prevents preeclampsia? A systematic review with multi-treatment comparison (network meta-analysis) of large multicenter randomized controlled trials. Abstract No. 883, Am J Obstet Gynecol 216:S504, 2017 Sansone M, Sarno L, Saccone G, et al: Risk of preeclampsia in human immunodeiciency virus-infected pregnant women. Obstet Gynecol 127(6): 1027,2016 Saucedo M, Deneux-haraux C, Bouvier-Colle MH, et al: Ten years of conidential inquiries into maternal deaths in France, 1998-2007. Obstet Gynecol 122(4):752,n2013 Scardo JA, Vermillion ST, Newman RB, et al: A randomized, double-blind, hemodynamic evaluation of nifedipine and labetalol in preeclamptic hypertensive emergencies. Am J Obstet Gynecol 181:862, 1999

Schendel DE, Berg Cj, Yeargin-Allsopp M, et al: Prenatal magnesium sulfate exposure and the risk for cerebral palsy or mental retardation among vety low birthweight children aged 3 to 5 years. JANiA 276:1805, 1996

Scholten RR, Hopman MT, Sweep FC, et al: Co-occurrence of cardiovascular and prothrombotic risk factors in women with a history of preeclampsia. Obstet GynecoIn121(1):97, 2013

Schutte JM, Schuitemaker NW, van Roosmalen J, et al: Substandard care in maternal mortality due to hypertensive disease in pregnancy in the Netherlands. BJOG 115(10):1322,n2008

Schwartz B, Feske SK, Polak JF, et al: Preeclampsia-eclampsia: clinical and neuroradiographic correlates and insights into the pathogenesis of hypertensive encephalopathy. Radiology 217:371,n2000

Sciscione AC, Ivester T, Largoza M, et al: Acute pulmonary edema in pregnancy. Obstet GynecoIn101:511, 2003

Sep S, Verbeek J, Spaanderman M, et al: Clinical diferences beween preeclampsia and the HELLP syndrome suggest diferent pathogeneses. Reprod Sci 16:176A, 2009

Sergis F, Maria Clara D, Galbriella F, et al: Prophylaxis of recurrent preeclampsia: low molecular weight heparin plus low-dose aspirin versus low-dose aspirin alone. Hypertension Pregnancy 25: 115, 2006

Shahabi A, Wilson ML, Lewinger JP, et al: Genetic admixture and risk of hypertensive disorders of pregnancy among Latinas in Los Angeles County. Epidemiology 24(2):285,n2013 Shahul S, Medvedofsky D, Wenger JB, et al: Antiangiogenic factors and myocardial dysfunction. Hypertension 67:1273,n2016

Shahul S, Tung A, Minhaj M, et al: Racial disparities in comorbidities, complications, and maternal and fetal outcomes in women with preeclampsia/ eclampsia. Hyperrens Pregnancy 34(4):506,n2015

Sharma KJ, Greene N, Kilpatrick SJ: Oralnlabetalol compared to oral nifedipine for postpartum hypertension: a randomized controlled trial. Hypertens Pregnancy 36(1):44,n2017 Shear RM, Rinfret D, Leduc L: Should we ofer expectant management in cases of severe preterm preeclampsia with fetal growth restriction? Am J Obstet Gynecol 192:1119,n2005

Sheehan HL, Lynch JB (eds): Cerebral lesions. In Pathology of Toxaemia of Pregnancy. Baltimore, Williams & Wilkins, 1973

Shekhar S, Gupta N, Kirubakaran R, et al: Oral nifedipine versus intravenous labetalol for severe hypertension during pregnancy: a systematic review and meta-analysis. BJOG 123(1):40,n2016 Sibai BM: Diagnosis and management of gestational hypertension and preeclampsia. Obstet Gynecol 102: 181, 2003

Sibai BM: Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count. Obstet Gynecoln103:981, 2004 Sibai BM: Diagnosis, prevention, and management of eclampsia. Obstet Gynecol 105:402,n2005

Sibai BM: Etiology and management of postpartum hypertension-preeclampsia. Am J Obstet Gynecol 206(6):470, 20n12 Sibai BM: Imitators of severe preeclampsia. Obstet Gynecol 109:956, 2007a Sibai BM, Barton JR, d S, et al: A randomized prospective comparison of nifedipine and bed rest versus bed rest alone in the management of preeclampsia remote from term. Am J Obstet Gynecol 167(1):879, 1992 Sibai BM, Barton JR: Expectant management of severe preeclampsia remote from term: patient selection, treatment and delivery indications. Am J Obstet GynecoIn196:514, 2007b Sibai BM, EI-Nazer A, Gonzalez-Ruiz A: Severe preeclampsia-eclampsia in young primigravid women: subsequent pregnancy outcome and remote prognosis. Am J Obstet Gynecol 155:1011, 1986 Sibai BM, Gonzalez AR, Mabie We, et al: A comparison of labetalol plus hospitalization versus hospitalization alone in the management of preeclampsia remote from term. Obstet Gynecol 70:323, 1987a Sibai BM, Mabie Be, Harvey Cj, et al: Pulmonary edema in severe preeclampsia-eclampsia: analysis of thirty-seven consecutive cases. Am J Obstet Gynecol 156:1174, 1987b Sibai BM, Mercer B, Sarinoglu C: Severe preeclampsia in the second trimester: recurrence risk and long-term prognosis. Am J Obstet Gynecol 165:1408, 1991 Sibai BM, Mercer BM, Schif E, et al: Aggressive versus expectant management of severe preeclampsia at 28 to 32 weeks' gestation: a randomized controlled trial. Am J Obstet Gynecol 171:818, 1994 Sibai BM, Paidas MJ, he PRESERVE Study Group: Randomized doubleblind placebo controlled evaluation of the safety and eicacy of recombinant antithrombin versus placebo in pre term preeclampsia. Abstract No. LB02, Am J Obstet Gynecol 216:S559, 2017 Sibai BM, Ramadan MK, Chari RS, et al: Pregnancies complicated by HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): subsequent pregnancy outcome and long-term prognosis. Am J Obstet Gynecol 2:125, 1995

Sibai BM, Spinnato ]A, Watson DL, et al: Eclampsia, 4. Neurological indings and future outcome. Am] Obstet Gynecol 152: 184, 1985

Sibai BM, Stella CL: Diagnosis and management of atypical preeclampsiaeclampsia. Amn] Obstet GynecoIn200:48n1.e1, 2009

Siepmann T, Boardman H, Bilderbeck A, et al: Long-term cerebral white and gray matter changes after preeclampsia. Neurology 88(13):1256, 2017

Silver RM, Myatt L, Hauth ]C, et al: Cell-free total and fetal DNA in irst trimester maternal serum and subsequent development of preeclampsia. Am ] PerinatoIn34(2):191, 2017

Smith ]M, Lowe F, Fullerton], et al: An integrative review of the side efects related to the use of magnesium sulfate for preeclampsia and eclampsia management. BMC Pregnancy Childbirth 13:34,n2013

Smyth RM, Spark P, Armstrong N, et al: Magpie Trial in the UK: methods and additional data for women and children at 2 years following pregnancy complicated by pre-eclampsia. BMC Pregnancy Childbirth 9:15, 2009

Society for Maternal-Fetal Medicine, Sibai BM: Evaluation and management of severe preeclampsia before 34 weeks' gestation. Am ] Obstet Gynecol 205(3):191,n2011

Somjen G, Hilmy M, Stephen CR: Failure to anesthetize human subjects by intravenous administration of magnesium sulfate. ] Pharmacol Exp Ther 154(3):652, 1966

Spaan]J, Ekhart T, Spaanderman ME, et al: Remote hemodynamics and renal function in formerly preeclamptic women. Obstet Gynecol 113:853,n2009 Spaann]J, Ekhart T, Spaanderman ME, et al: Renal function after preeclampsia: a longitudinal pilot study. Nephron Clin Pract 120(3):cl56, 2012a

Spaan ]J, Sep S], Lopes van Balen V, et al: Metabolic syndrome as a risk factor for hypertension ater preeclampsia. Obstet Gynecoln120(2 Pt 1):311, 2012b Spargo B, McCartney CP, Winemiller R: Glomerular capillary endotheliosis in toxemia of pregnancy. Arch Pathol 68:593, 1959

Spitz B, Magness RR, Cox SM: Low-dose aspirin. 1. Efect on angiotensin II pressor responses and blood prostaglandin concentrations in pregnant women sensitive to angiotensin II. Am] Obstet GynecoIn159(5):1035, 1988

Staf Ae, Braekke K, Johnsen GM, et al: Circulating concentration of soluble endoglin (CD 105) in fetal and maternal serum and in amniotic fluid in preeclampsia. Amn] Obstet Gynecol 6.e1,n2007

Staf AC, Sibai BM, Cunningham FG: Prevention of preeclampsia and eclampsia. In Taylor N, Roberts ]M, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 2015

Staines-Urias E, Paez Me, Doyle P, et al: Genetic association studies in preeclampsia: systematic meta-analyses and ield synopsis. Int ] Epidemiol 41(6):1764,n2012

Stekkinger E, Scholten RR, Heidema WM, et al: Recurrent preeclampsia in women with metabolic syndrome and low plasma volume: a retrospective cohort study. B]OG 122(13):1773,n2015

Stout M], Conner SN, Colditz GA, et al: he utility of 12-hour urine collection for the diagnosis of preeclampsia. Obstet Gynecol 126(4):731, 2015

Stout M], Scifres CM, Stamilio OM: Diagnostic utility of urine protein-tocreatinine ratio for identiYing proteinuria in pregnancy. ] Matern Fetal Neonatal Med 26(1):66,n2013

Strickland OM, Guzick OS, Cox K, et al: he relationship between abortion in the first pregnancy and the development of pregnancy-induced hypertension in the subsequent pregnancy. Am] Obstet Gynecol 154: 146, 1986

Sugulle M, Herse F, Hering L, et al: Cardiovascular biomarker midregional proatrial natriuretic peptide during and after preeclamptic pregnancies. Hypertension 59(3):395,n2012

Suzuki Y, Yamamoto T, Mabuchi Y, et al: Ultrastructural changes in omental resistance artery in women with preeclampsia. Am ] Obstet Gynecol 189:216,n2003

Swank M, Nageotte M, Hatield T: Necrotizing pancreatitis associated with severe preeclampsia. Obstet Gynecol 120(2 Pt 2):453,n2012

Szal SE, Croughan-Minibane MS, Kilpatrick S]: Efect of magnesium prophylaxis and preeclampsia on the duration of labor. Am ] Obstet Gynecol 180:1475, 1999

Tajik P, van der Tuuk K, Koopmans CM, et al: Should cervical favourability playna role in the decision for labour induction in gestational hypertension or mild preeclampsia at term? An exploratory analysis of the HYPIT AT trial. B]OG 119(9):1123,2012

Talledo OE, Chesley LC, Zuspan FP: Renin-angiotensin system in normal and toxemic pregnancies, 3. Diferential sensitivity to angiotensin II and norepinephrine in toxemia of pregnancy. Amn] Obstet Gynecol 100:218, 1968

Tan LK, de Swiet M: The management of postpartum hypertension. B]OG 109(7):733,n2002

Taufield PA, Ales L, Resnick LM, et al: Hypocalciuria in preeclampsia. N Engl] Med 316:715,n1987

Taylor N, Roberts ]M: Endothelial cell dysfunction. In Lindheimer MD, Roberts ]M, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy, 2nd ed. Stamford, CT, Appleton & Lange, 1999

Thadhani R, Hagmann H, Schaarschmidt W, et al: Removal of soluble fmslike tyrosine kinase-1 by dextran sulfate apheresis in preeclampsia. ] Am Soc NephroIn27(3):903,n2016

Thangaratinam S, Ismail KMK, Sharp S, et al: Accuracy of serum uric acid in predicting complications of pre-eclampsia: a systematic review. B]OG 113: 369, 2006

Theilen LH, Fraser A, Hollingshaus MS, et al: All-cause and cause-speciic mortality ater hypertensive disease of pregnancy. Obstet GynecoIn128(2):238, 2016

Thornton C, Dahlen H, Korda A, et al: The incidence of preeclampsia and eclampsia and associated maternal mortality in Australia from populationlinked datasets: 2000-2008. Am] Obstet 6.e1,n2013

Thurnau GR, Kemp DB, Jarvis A: Cerebrospinal fluid levels of magnesium in patients with preeclampsia after treatment with intravenous magnesium sulfate: a preliminary report. Am] Obstet Gynecol 157:1435, 1987

Trapani A ]r, Gonclaves LF, Trapani TF, et al: Perinatal and hemodynamic evaluation of sildenafil citrate for preeclampsia treatment. A randomized controlled trial. Obstet Gynecol 128:253,n2016

Triche EW, Uzun A, DeWan AT, et al: Bioinformatic approach to the genetics of preeclampsia. Obstet GynecoIn123(6):1155, 2014

Trommer BL, Homer 0, Mikhael MA: Cerebral vasospasm and eclampsia.

Stroke 19:326, 1988

Trudinger B], Cook CM: Doppler umbilical and uterine flow waveforms in severe pregnancy hypertension. B]OG 97:142,n1990

Tsai HM, Kuo E: From gestational hypertension and preeclampsia to atypical hemolytic uremic syndrome. Obstet GynecoIn127:907, 2016

Tsiakkas A, Mendez 0, Wright A, et al: Maternal serum soluble fms-like tyrosine kinase-1 at 12, 22, 32 and 36 weeks; gestation in screening for preeclampsia. Ultrasound Obstet GynecoIn47(4):478, 2016

Tudela CM, McIntire DO, Alexander ]M: Efect of maternal body mass index on serum magnesium levels given for seizure prophylaxis. Obstet Gynecol 121(2 Pt 1):314, 2013

Tufnell 0], Lilford R], Buchan PC, et al: Randomized controlled trial of day care for hypertension in pregnancy. Lancet 339:224, 1992

Tun C, Quinones ]N, Kurt A, et al: Comparison of 12-hour urine protein and protein:creatinine ratio with 24-hour urine protein for the diagnosis of preeclampsia. Am] Obstet Gynecol 207(3):233.e1, 2012

Turnbull DA, Wilkinson e, Gerard K, et al: Clinical, psychosocial, and economic efects of antenatal day care for three medical complications of pregnancy: a randomized controlled trial of 395 women. Lancet 363: 1104, 2004

Umans ]G, Abalos E: Cunningham FG: Antihypertensive treatment. In Taylor RN, Roberts ]M, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 2015

Urban G, Vergani P, Ghindini A, et al: State of the art: non-invasive ultrasound assessment of the uteroplacental circulation. Semin Perinatol31 (4),232,2007

Valensise H, Lo Presti 0, Gagliardi G, et al. Persistent maternal cardiac dysfunction after preeclampsia identifies patients at risk for recurrent preeclampsia. Hypertension 67(4):748, 2016

Valensise H, Vasapollo B, Gagliardi G, et al: Early and late preeclampsia: two diferent maternal hemodynamic states in the latent phase of the disease. Hypertension 52(5):873, 2008 van der Metwen]L, Hall DR, Wright C, et al: Are early and late preeclampsia distinct subclasses of the disease-what does the placenta reveal? Hypertens Pregnancy 29(4):2010 van Veen TR, Panerai RB, Haeri S, et al: Cerebral autoregulation in normal pregnancy and preeclampsia. Obstet Gynecol 122: 1064, 2013

Vatten L], Asvold BO, Eskild A: Angiogenic factors in maternal circulation and preeclampsia with or without fetal growth restriction. Acta Obstet Gynecol Scand 91(12):1388, 2012

Vaught A], Gavriilaki E, Hueppchen N, et al: Direct evidence of complement activation in HELLP syndrome: a link to atypical hemolytic uremic syndrome. Exp HematoIn44:390, 2016

Veena P, Lakshimdeepthi P, Raghavan SS: Furosemide in postpartum management of severe preeclampsia: a randomized controlled trial. Hypertens Preg 36:84,n2017

Ventura S], Martin ]A, Curtin Se, et al: Births: final data for 1998. Nad Vital Stat Rep 48(3):1,n2000

Vermillion ST, Scardo ]A, Newman RB, et al: A randomized, double-blind trial of oral nifedipine and intravenous labetalol in hypertensive emergencies of pregnancy. Amn] Obstet Gynecol 181:858, 1999

Vigil-De Gracia P, Ludmir ]. Perinatal and hemodynamic evaluation of sildenail citrate for preeclampsia treatment: a randomized controlled trial. Obstet Gynecol 128(5):1181,n2016

Vigil-De Gracia P, Ortega-Paz L: Pre-eclampsia/eclampsia and hepatic rupture.

Int] Gynaecol Obstet 118(3):186,n2012

Vigil-De Gracia P, Ortega-Paz L: Retinal detachment in association with pre-eclampsia, eclampsia, and HELLP syndrome. Int ] Gynaecol Obstet 114(3):223, 2011

Vigil-De Gracia P, Ruiz E, Lopez]e, et al: Management of severe hypertension in the postpartum period with intravenous hydralazine or labetalol: a randomized clinical trial. Hypertens Pregnancy 26(2): 163, 2007

Vigil-De Gracia P, Solis V, Ortega N: Ibuprofen versus acetaminophen as a postpartum analgesic for women with severe preeclampsia: randomized clinical study.] Matern Fetal Neonatal Med 30(11): 1279,n2017 Vigil-De Gracia P, Tejada OR, Minaca AC, et al: Expectant management of severe preeclampsia remote from term: the MEXPRE Latin Study, a randomized multicenter clinical trial. Am] Obstet Gynecol 209:425.el, 2013 Vikse BE, Irgens LM, Leivestad T, et al: Preeclampsia and the risk of end-stage renal disease. N Engl ] Med 359:800, 2008

Villa PM, Kajantie E, Raikkonen K, et al: Aspirin in the prevention of preeclampsia in high-risk women: a randomized placebo-controlled PREDO Trial and a meta-analysis of randomized trials. B]OG 120(1):64,n2013

Villar], Purwar M, Merialdi M, et al: World Health Organisation multicentre randomised trial of supplementation with vitamins C and E among pregnant women at high risk for pre-eclampsia in populations oflow nutritional status from developing countries. B]OG 116(6):780,n2009 Viteri OA, England ]A, Lash A, et al: Should non-steroidal anti-inlammatory drugs be avoided in puerperal hypertensive women? Abstract No. 49, Am] Obstet GynecoIn216:S34, 2017 Volhard F: Die doppelseitigen haematogenen Nierenerkrankungen. Berlin, Springer, 1918 von Dadelszen P, Firoz T, Donnay F, et al: Preeclampsia in low and middle income countries-health services lessons learned from the PRE-EMPT (PRE-eclampsia monitoring, prevention, and treatment) Project. ] Obstet Gynaecol Can 34(10):917,n2012 Wagner 5], Craici 1M, Grande ]P, et al: From placenta to podocyte: vascular and podocyte pathophysiology in preeclampsia. Clin Nephrol 78(3):241, 2012 Wallace DH, Leveno K], Cunningham FG, et al: Randomized comparison of general and regional anesthesia for cesarean delivery in pregnancies complicated by severe preeclampsia. Obstet Gynecol 86:1n93, 1995 Wallenburg He, Makovitz ]W, Dekker GA, et al: Low-dose aspirin prevents pregnancy-induced hypertension and preeclampsia in angiotensin-sensitive primigravidae. Lancet 327: 1, 1986 Walsh SW: Plasma from preeclamptic women stimulates transendothelial migration of neutrophils. Reprod Sci 16(3):320, 2009 Wang Le, Huang CY, Want HK, et al: Magnesium sulfate and nimesulide have synergistic efects on rescuing brain damage after transient focal ischemia.] Neurotrauma 29(7):1518,n2012 Wang Y, Gu Y, Granger ON, et al: Endothelial junctional protein redistribution and increased monolayer permeability in human umbilical vein endothelial cells isolated during preeclampsia. Am ] Obstet Gynecol 186:214, 2002 Ward K, Taylor RN: Genetic factors in the etiology of preeclampsia. In Taylor RN, Roberts ]M, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 2015 Wardhana MP, Dachlan EG, Dekker G: Pulmonary edema in preeclampsia: an Indonesian case-control study. ] Matern Fetal Neonatal Med March 1, 2017 [Epub ahead of printJ Watt-Morse ML, Caritis SN, Kridgen PL: Magnesium sulfate is a poor inhibitor of oxytocin-induced contractility in pregnant sheep. ] Matern Fetal Med 4:139, 1995 Weiner CP, hompson LP, Liu Z, et al: Endothelium derived relaxing factor and indomethacin-sensitive contracting factor alter arterial contractile responses to thromboxane during pregnancy. Am ] Obstet Gynecol 166: 1171,n1992 Weinstein L: Syndrome of hemolysis, elevated liver enzymes and low platelet count: a severe consequence of hypertension in pregnancy. Am ] Obstet GynecoIn142:159,n1982 White WM, Garrett AT, Craici 1M, et al: Persistent urinaty podocyte loss following preeclampsia may reflect subclinical renal injury. PLoS One 9(3):e92693,n2014 White M, Mielke MM, Araoz PA, et al: A history of preeclampsia is associated with a risk for coronary artery calcification 3 decades later. Amn] Obstet GynecoIn214(4)519.e1,n2016 Wicke C, Pereira PL, Neeser E, et al: Subcapsular liver hematoma in HELLP syndrome: evaluation of diagnostic and therapeutic options-a unicenter study. Am ] Obstet Gynecol 190: 1 06, 2004

Wide-Swensson DH, Ingemarsson I, Lunell NO, et al: Calcium channel blockade (isradipine) in treatment of hypertension in pregnancy: a randomized placebo-controlled study. Am] Obstet GynecoI173(1):872, 1995

Widmer M, Villar], Benigni A, et al: Mapping the theories of preeclampsia and the role of angiogenic factors. Obstet Gynecol' 109: 168, 2007

Wiegman M], de Groot]e, ]ansonius NM, et al: Long-term visual functioning after eclampsia. Obstet Gynecol 119(5):959,2012

Wikstrom AK, Stephansson 0, Cnattingius 5: Previous preeclampsia and risks of adverse outcomes in subsequent non preeclamptic pregnancies. Am ] Obstet GynecoI204(2):148.e1, 2011

Widin AG, Friedman SA, Sibai BA: The efect of magnesium sulfate therapy on the duration of labor in women with mild preeclampsia at term: a randomized, double-blind, placebo-controlled trial. Am] Obstet Gynecol 176:623, 1997

Worley LC, Hnat MD, Cunningham FG: Advanced extrauterine pregnancy: diagnostic and therapeutic challenges. Am] Obstet GynecoIn198(3):297.el, 2008

Yamada T, Obata-Yasuoka M, Hamadea H, et al: Isolated gestational proteinuria preceding the diagnosis of preeclampsia-an observational study. Acta Obstet Gynecol Scand 95(9):1048, 2016

Yang], Pearl M, DeLorenze GN, et al: Racial-ethnic diferences in midtrimester maternal serum levels of angiogenic and anti angiogenic factors. Am ] Obstet GynecoIn215:359.el, 2016

Yangn], Shangn], Zhang 5, et al: he role of renin-angiotensin-aldosterone system in preeclampsia: genetic polymorph isms and micro RNA. ] Mol Endocrinol 50(2):R53, 2013

Ye W, Shen L, Xiong Y, et al: Preeclampsia is associated with decreased methylation of the GNA12 promoter. Ann Hum Genet 80(1):7, 2016 Yefet E, Braester Y, Suleiman A, et al: he efect of magnesium sulfate at 1 gram versus 2 grams maintenance doses on serum magnesium concentrations and adverse efects profile in women with severe preeclampsia. [Abstract No. 884J Am] Obstet Cynecol 216:5504, 201

Yoshihara M, Mayama M, Ukai M, et al: Fulminant liver failure resulting from massive hepatic infarction associated with hemolysis, elevated liver enzymes, and low platelets syndrome.] Obstet Gynaecol Res 42(10):1375,n2016 Zachary 5, Rubeo ZS, ]ortani SA: The association of N-terminal pro-brain natriuretic peptide with severe preeclampsia, HELLP syndrome, and eclampsia Abstract No. 990, Am] Obstet Gynecol 216:5557,n201 Zeeman G, Alexander ]M, Vollaard E, et al: "Delta eclampsia"-a hypertensive encephalopathy of pregnancy in "normotensive" women. Abstract No. 479, Am] Obstet Gynecoln197(6 Suppl):S140, 2007

Zeeman GG, Alexander ]M, McIntire DO, et al: Homocysteine plasma concentration levels for the prediction of preeclampsia in women with chronic hypertension. Am] Obstet Gynecol 189:574,n2003

Zeeman GG, Cunningham FG, Pritchard ]A: he magnitude of hemoconcentration with eclampsia. Hypertens Pregnancy 28(2): 127, 2009 Zeeman GG, Fleckenstein ]L, Twickler OM, et al: Cerebral infarction in eclampsia. Am] Obstet Gynecol 190:714, 2004a

Zeeman GG, Hatab M, Twickler OM: Increased cerebral blood flow in preeclampsia with magnetic resonance imaging. Am ] Obstet Gynecol 191(4):1425,n2004b

Zeisler H, L1urba E, Chantraine F, et al: Predictive value of the sFlt-1:PIGF ration in women with suspected preeclampsia. N Engl] Med 374:l3, 2016a

Zeisler H, L1urba E, Chantraine F, et al: Soluble fms-like tyrosine kinase-1-toplacental growth factor ratio and time to delivery in women with suspected preeclampsia. Obstet Gynecol 128(2):261, 2016b

Zhou 5], Yelland L, McPhee A], et al: Fish-oil supplementation in pregnancy does not reduce the risk of gestational diabetes or preeclampsia. Am ] Clin Nutr 95(6):l378, 2012

Zhou Y, Damsky CH, Fisher 5]: Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. ] C1in Invest 99(9):2152, 1997

Zinaman M, Rubin ], Lindheimer MD: Serial plasma oncotic pressure levels and echoencephalography during and after delivery in severe preeclampsia. Lancet 1:1245,n1985

Zondervan HA, Oosting ], Smorenberg-Schoorl ME, et al: Maternal whole blood viscosity in pregnancy hypertension. Gynecol Obstet Invest 25:83, 1988

Zwart J], Richters A, Ory F, et al: Eclampsia in he Netherlands. Obstet Gynecol 112:820, 2008

GENERAL CONSIDERATIONS ......................755

UTERINE ATONY.................................758

UTERINE INVERSION.............................761

INJURIES TO THE BIRTH CANAL....................763 PUERPERAL HEMATOMAS........................764

UTERINE RUPTURE.............................. 765

PLACENTAL ABRUPTION..........................767

PLACENTA PREVIA. . . .. . . . . . . . . . . . . . . . . . . . . . .... 773 MORBIDLY ADHERENT PLACENTA..................777 OBSTETRICAL COAGULOPATHIES..................782 MANAGEMENT OF HEMORRHAGE..................787 ADJUNCTIVE SURGICAL PROCEDURES.............. 792

A profuse hemorrhage occurring prior to or shorty ater the birth of the child is always dangerous and not inrequenty a atal complication.

-J. Whitridge Williams (1903)

As in Williams' time, obstetrical hemorrhage continues along with hypertension and infection to be one part of the infamous "triad" of maternal death causes. It also is a leading reason for admission of pregnant women to intensive care units (Chantry, 2015; Crozier, 2011; De Greve, 2016; Guntupalli, 2015). Hemorrhage was a direct cause of 11r.4 percent of 5367 pregnancy-related maternal deaths from 2006 to 2013 in the United States (Creanga, 2015, 2017). Similarly, 16 percent of1102 maternal deaths recorded in the Nationwide Inpatient Sample were caused by hemorrhage (Kuriya, 2016). In developing countries, hemorrhage's contribution is even more striking, and it is the single most important cause of maternal death worldwide (Gofman, 2016; Oladapo, 2016; Thomas, 2016). Despite these numbers, a declining maternal mortality rate from hemorrhage in the United States has been a seminal achievement. But, as discussed in Chapter 1 (p. 5), it seems unlikely that deaths from hemorrhage have reached an irreducible minimum.

• Mechanisms of Normal Hemostasis

A major concept in understanding the pathophysiology and management of obstetrical hemorrhage is the mechanism by which hemostasis is achieved after normal delivery. Recall that near term an incredible amount of blood-at least 600 mLi min-flows through the intervillous space (Pates, 2010). his prodigious flow circulates through the spiral arteries, which average 120 in number. Also, recall that these vessels have no muscular layer because of their remodeling by trophoblasts, which creates a low-pressure system. With placental separation, these vessels at the implantation site are avulsed, and hemostasis is achieved first by myometrial contraction, which compresses this formidable number of large vessels. Compression is followed by clotting and obliteration of vessel lumens.

If, after delivery, the myometrium contracts vigorously, fatal hemorrhage from the placental implantation site is unlikely.

Importanty, an intact coagulation system is not necessary or postpartum hemostasis unless there are lacerations in the uterus, birth cana, or perineum. At the same time, however, fatal postpartum hemorrhage can result from uterine atony despite normal coagulation.

70 he blood volume of a pregnant D < 500 mL woman with normal pregnancy-induced hypervolemia usually rises by half, but individual increases range from 30 to 60

D 1000-1e500 mL percent, that is, 1500 ) • > 2500 mL average-sized woman (Pritchard, 1965).

) 40 The equation to calculate blood volume is shown in Table It is axiomatic ) ates, without any decrease in postpartum ..e hematocrit, blood loss at delivery that approaches the volume of blood that she added during pregnancy. Thus, if blood loss is less than the pregnancy-added vol ume, the hematocrit remains the same acutely and during the irst several days delivery delivery with hysterectomy postpartum. It then rises as nonpregnant

FIGURE 41-1 Blood loss associated with vaginal delivery, repeat cesarean delivery, and plasma volume normalizes during the repeat cesarean delivery plus hysterectomy. (Data from Pritchard, 1962.)

Traditionally, postpartum hemorrhage is defined as the loss of ::500 mL of blood after completion of the third stage of labor. This is problematic because almost half of all women delivered vaginally shed that amount of blood or more when losses are carefully measured (Pritchard, 1962). These results are depicted in Figure 41-1 and show further that approximately 5 percent of women delivering vaginally lose more than 1000 mL of blood. According to the American College of Obstetricians and Gynecologists (2017d), postpartum hemorrhage is deined as cumulative blood lossr> 1000 mL accompanied by signs and symptoms ofhypovolemia. And, almost a third of women undergoing cesarean delivery have blood loss that exceeds 1000 mL. These studies show that estimated blood loss is commony ony approximatey hafthe actual loss. Because of this, estimated blood loss in excess of "average" should alert the obstetrician to possible excessive bleeding. Whether quantiication of blood loss improves accuracy is controversial (Hamm, 2017; Toledo, 2007).

TABLE 41 -1. Calculation of Maternal Total Blood Volume next week or so. Whenever thepospartum hematocrit is lower than one obtained on admission or deivery, blood loss can be estimated as the sum of the calculated pregnancy-added volume plus 500 mL or each 3 volume percent decline ofthe hematocrit.

Excessive blood loss has been estimated by several methods. Sosa and colleagues (2009) used specially constructed drapes and reported that 10.8 percent of women had hemorrhage in excess of 500 mL with vaginal delivery, whereas 1.9 percent lost > 1000 mL. Compared with the indings of Figure 41-1, these estimates likely are too low. Tita and associates (2012) used a 6-volume percent drop in the postpartum hematocrit to define clinically signiicant blood loss with vaginal delivery. This decline easily signifies a > 1000-mL blood loss in the averaged-sized woman. hey documented this amount in a fourth ofwomen, which agrees with Figure 41-1.

Another marker used to estimate hemorrhage incidence is the transfusion rate. In the study by Tita just cited, more than 6 percent of women who delivered vaginally underwent blood transfusions. In a study of more than 66,000 women delivered at Parkland Hospital, 2.3 percent overall were given

Nonpregnant blood volumea: [Height (inches) x 50J + [Weight (pounds) x 25J = Blood volume (mL)

Pregnancy blood volume:

Average increase is 30 to 60 percent of calculated nonpregnant Increases across gestational age and plateaus at approximately 34 weeks

Usually larger with low normal-range hematocrit (-30) and smaller with high normal-range hematocrit (-40) Average increase is 40 to 80 percent with multifetal gestation

Average increase is less with preeclampsia-volumes vary inversely with severity

Postpartum blood volume with serious hemorrhage:

Assume acute return to nonpregnant total volume after fluid resuscitation Pregnancy hypervolemia cannot be restored postpartum aFormula arrived at by measuring blood volume and blood loss in more than 100 women using 51Cr-labeled erythrocytes. Data from Hernandez, 201n2.

blood transfusions for hypovolemia (Hernandez, 2012). Half 25 of these women had undergone cesarean delivery. Importantly, for those transfused, these investigators calculated blood loss to E average approximately 3500 mLl Finally, Green and coworkers (2016) reported that the incidence of massive tranfusion for

From the foregoing, it is apparent that significant blood loss � t postpartum hemorrhage was 23 per 100,000 births.

accompanies up to a fourth of vaginal deliveries. The amounts and proportions for cesarean delivery are much greater. And, � £ hemorrhage is underreported. For example, data from the

O.

postpartum hemorrhage incidences of only 2.0 and 2.6 per cent for two epochs in the United States (Berg, 2009). Similar incidences have been reported by others (Kramer, 2013; Mehrabadi, 2013; Patterson, 2014).

Numerous clinical circumstances raise the risks for obstetrical hemorrhage. he imposing list shown in Table 41-2 illustrates that hemorrhage can manifest at any time throughout pregnancy, delivery, and the puerperium. Thus, any description

TABLE 41 -2. Obstetrical Hemorrhage: Causes, Predisposing Factors, and Vulnerable Patients

Anesthesia or analgesia Halogenated agents Conduction analgesia with

Previous uterine atony Parity: primiparity, high parity

Acute fatty liver Anticoagulant treatment Congenital coagulopathies Amnionic fluid embolism Prolonged retention of

Cause of hemorrhage

FIGURE 41-2 Contributions to maternal death from various causes of obstetrical hemorrhage. Percentages are approximations because of different classification schemata used. DIC = nated intravascular coagulopathy. (Data from AI-Zirqi, 2008; Berg, 201o0; Creanga, 201o5; Zwart, 2008.) of obstetrical hemorrhage should include gestational age. Contributions to maternal death from some of these causes of are shown in Figure 41-2.

Obstetrical hemorrhage is traditionally classified as antepartumsuch as with placenta previa or placental abruption, or as pospartum-commonly caused by uterine atony or genital tract lacerations. In individual women, however, these terms are nonspeciic, and it is reasonable to speciy the cause and gestational age as descriptors.

to its cause. Many aspects of bleeding during the first half of pregnancy from abortion or ectopic pregnancy are covered in

Chapters 18 and 19. Discussions that follow concern pregnan cies with a viable-size fetus. In these cases, rapid assessment should always consider the deleterious etal fects ofmaternal hemorrhage.

During active labor, slight vaginal bleeding is common. This "bloody show" is the consequence of efacement and dilation of the cervix, with tearing of small vessels. Uterine bleeding above the cervix, however, is concerning. It may follow some separation of a placenta previa implanted in the immediate vicinity of the cervical canal, or it may be from a placental abruption or uterine tear. In some women, especially with a placenta previa, cervical varicosities may bleed (O'Brien, 2013). Rarely, there may be velamentous insertion of the umbilical cord, and the involved placental vessels may overlie the cevix-vasa previa. In this case, serious fetal hemorrhage follows laceration of these vessels at the time of membrane rupture (Swank, 2016).

N ear term in many women, the source of uterine bleeding is not identified, bleeding ceases, and no apparent anatomical cause is found at delivery. In most of these cases, bleeding likely originated from a slight marginal placental separation. Despite this, any pregnancy with antepartum bleeding remains at higher risk or an adverse outcome even though bleeding has stopped and placenta previa has been excluded sonographicaly.

Injuries to the Birth Canal

Bleeding after midpregnancy is associated with several adverse outcomes. he Canadian Perinatal Network described 806 women with hemorrhage between 22 and 28 weeks' gestation (Sabourin, 2012). Placental abruption (32 percent), previa (21 percent), and cervical bleeding (6.6 percent) were the most frequent causes identified. In a third, no cause was found. Of all women, 44 percent were delivered before 29 weeks' gestation. In more than 68,000 women in Scotland, the incidence of antepartum hemorrhage after the irst trimester was 11 percent (Bhandari, 2014). hese women were at signiicantly higher risk for preterm birth, labor induction, and postpartum hemorrhage.

In most cases, the source of postpartum hemorrhage can and should be determined. Frequent causes are uterine atony with placental site bleeding, genital tract trauma, or both. Postpartum hemorrhage is usually obvious. Important exceptions are unrecognized intrauterine and intravaginal blood accumulation and uterine rupture with intraperitoneal or retroperitoneal bleeding. Another consideration is an expanding vulvar or vaginal hematoma (p. 764). Initial evaluation attempts to diferentiate uterine atony from genital tract lacerations. For this, risk factors are sought, the lower genital tract is examined, and uterine tone is assessed. Atony is identiied by a boggy, soft uterus during bimanual examination and by expression of clots and hemorrhage during uterine massage.

Persistent bleeding despite a firm, well-contracted uterus suggests that hemorrhage most likely is from lacerations. Bright red blood further suggests arterial bleeding. To conirm that lacerations are a source of bleeding, carful inspection of the vagina, cervix, and uterus is essential. Sometimes bleeding may be caused by both atony and trauma, especially after forceps or vacuum-assisted vaginal delivery. Examination is easier if conduction analgesia was given. If there are no lower genital tract lacerations and the uterus is contracted, yet supracervical bleeding persists, then manual exploration of the uterus is done to exclude a uterine tear (Kaplanoglu, 2016). his also is completed routinely after internal podalic version, breech extraction, or successful vaginal birth after cesarean.

Late pospartum hemorrhage describes bleeding after the irst 24 hours. Found in up to 1 percent of women, it may be serious and is discussed in Chapter 37 (American College of Obstetricians and Gynecologists, 2017 d).

As noted, visual estimates are notoriously inaccurate, especially with excessive bleeding. Instead of sudden massive hemorrhage, postpartum bleeding is frequently steady. If atony persists, bleeding may appear to be only moderate at any given instant but may continue until serious hypovolemia develops. Bleeding from an episiotomy or a vaginal laceration can also appear to be only minimal to moderate. But, constant seepage can lead to enormous blood loss relatively quickl)r . In some cases, ater placental separation, blood may not escape vaginally but instead may collect within the uterine cavity, which can become distended by 1000 mL or more of blood. In others, postpartum uterine massage is applied to a roll of abdominal fat mistaken for the uterus.

All of these factors can lead to an underappreciation of the magnitude of hemorrhage over time. he efects of hemorrhage depend to a considerable degree on the maternal nonpregnant blood volume and the corresponding degree of pregnancyinduced hypervolemia. For this and other reasons, hypovolemia may not be recognized until very late. A treacherous eature of pospartum hemorrhage is the ailure of the pulse and blood pressure to undergo more than moderate alterations until large amounts of blood have been lost. The normotensive woman initially may actually become somewhat hypertensive from catecholamine release in response to hemorrhage. And importantly, women with preeclampsia may become "normotensive" despite remarkable hypovolemia.

Some gravidas may be particularly susceptible to hemorrhage because their blood volume expansion is less than expected. This situation is most commonly encountered in small womeneven those with normal pregnancy-induced hypervolemia. Women with severe preeclampsia or eclampsia are also more vulnerable to hemorrhage because they frequently do not have a normal blood volume accrual. Specifically, Zeeman and associates (2009) documented a mean increase above nonpregnant volume of only 10 percent in eclamptic women (Chap. 40, p. 718). A third example is the moderate-to-severe curtailing of pregnancy-induced volume expansion in women with chronic renal insuiciency (Chap. 53, p. 1034). When excessive hemorrhage is suspected in these high-risk women, cystalloid and blood are prompty administered or suspected hypovolemia.

The most frequent cause of obstetrical hemorrhage is failure of the uterus to contract suiciently after delivery and to arrest bleeding from vessels at the placental implantation site (p. 755). That said, some bleeding is inevitable during thirdstage labor as the placenta begins to separate. Blood from the implantation site may escape into the vagina immediately-the Duncan mechanism of placental separation, or it remains concealed behind the placenta and membranes until the placenta is delivered-the Schultze mechanism. After signs of placental separation, the uterus should be massaged if it is not contracted irmly, and placental descent is indicated by a slack umbilical cord. Importanty, separation and delivey of the placenta by cord traction, especialy when the uterus is atonic, may cause uterine inversion.

If heavy bleeding persists after delivery of the newborn and while the placenta remains partially or totally attached, then manual placental removal is indicated (Cummings, 2016; Frolova, 2016). For this, adequate analgesia is mandatory, and aseptic surgical technique should be used. As illustrated in

Figure 41-3, the fingertips of one hand, with fingers approxi mated, are insinuated between the uterine wall and placenta. A sweeping forward motion in this plane will peel the placenta of its uterine attachmenc. After its removal, trailing membranes are carefully teased free from the decidua using ring forceps as needed. Another method to clear membranes is to wipe out the uterine cavity with a gauze-wrapped hand. Most recommend

FIGURE 41 -3 Manual removal of placenta. A. One hand grasps the fundus. The other hand is inserted into the uterine cavity, and the fingers are swept from side to side as they are advanced. B. When the placenta has become detached, it is grasped and removed.

removal (World Health Organization, 2015).

he fundus is always palpated following placental delivery to conirm that the uterus is well contracted. If it is not irm, hemorrhage from atony (Hofmeyr, 2013). Simultaneously, 20 units of oxytocin in 1000 mL of crystalloid solution will of 200 m U / min. Higher concentrations are minimally more efective (Tita, 2012). Oxytocin is never given as an undiluted bolus dose because serious hypotension or cardiac arrhythmias can develop.

In many women with known risks, uterine atony can at least be anticipated well in advance of delivery. In one study, however, up to half of women with atony after cesarean deliveY had no risk factors (Rouse, 2006). The magnitude of risk for atony imposed by each of the factors shown in Table 41-2 varies considerably between reports. Primiparity and high parity are risk factors (Driessen, 2011). In one study, the incidence of postpartum hemorrhage rose from 0.3 percent in women of low parity to 1.9 percent with parity of four or greater. It was 2.7 percent with parity of seven or greater (Babinszki, 1999). The overdistended uterus is prone to hypotonia after delivery, and thus women with a large fetus, multiple fetuses, or hydramnios are at greater risk. Labor abnormalities predispose to atony and include hyper-or hypotonic labor. Similarly, labor induction or augmentation with either prostaglandins or oxytocin is more likely to be followed by atony (Driessen, 2011). he frequency of hemorrhage increases with prolongation of the third stage (Frolova, 2016). Finally, the woman who has had aprior postpartum hemorrhage is at risk for recurrence.

With immediate postpartum hemorrhage, careful inspection is done to exclude birth canal laceration. Because bleeding can be caused by retained placental fragments, inspection of the placenta after delivery should be routine. If a defect is seen, the uterus should be manually explored and the fragment removed. Occasionally, retention of a succenturiate lobe may cause postpartum hemorrhage (Chap. 6, p. 112). During examination for lacerations and causes of atony, the uterus is massaged and uterotonic agents are administered.

Several compounds can prompt the postpartum uterus to contract (Chap. 27, p. 527). One of these is routinely selected and given to prevent postpartum bleeding by ensuring uterine contractions. Nfost of these same agents are also used to treat uterine atony with bleeding. Moreover, because many trials combine results from atony prophylaxis and treatment, their evaluation is problematic. For example, oxytocin has been used for more than 70 years, and in most cases, it is infused intravenously or given intramuscularly after placental delivery. Neither route has been shown to be superior (Dagdeviren, 2016). his or other utero tonics given prophylactically will prevent most cases of uterine atony.

To treat uterine atony, ergot alkaloids have been used for centuries. If atony persists despite oxytocin and other preventive measures, ergot derivatives can be used for secondline treatment. Ergot preparations include methylergonovine (Methergine) and ergonovine, however, only methylergonovine is currently manufactured in the United States. Given parenterally, these drugs rapidly stimulate tetanic uterine contractions and act for approximately 45 minutes (Schimmer, 2011). A common regimen is 0.2 mg of either drug given intramuscularly. Methergine can be repeated at 2-to 4-hour intervals as needed. A caveat is that ergot agents, especialy given intravenousy, may cause dangerous hypertension, especialy in women with preeclampsia. Severe hypertension is also seen with concomitant use of protease inhibitors given for human immunodeiciency viral (HIV) infection. These adverse efects notwithstanding, it is speculative whether ergot derivatives ofer superior therapeutic efects compared with oxytocin.

In cases of atony refractory to one agent, an agent from a diferent group can be added. At least two randomized studies have addressed combined ergot-oxytocin regimens. In one, ergometrine plus oxytocin was compared with ergometrine alone to prevent postpartum hemorrhage (Koen, 2016). The overall need for transfusion was signiicantly lower with the combination regimen. Another comparable study reairmed these indings (�enti.irk, 2016).

During the past 40 years, other second-line agents for atony have included the E-and F-series prostaglandins. Carboprost tromethamine (Hemabate) is the 15-methyl derivative of prostaglandin F2a• It is approved for uterine atony treatment in a dose of 250 Lg (0.25 mg) given intramuscularly. This dose can be repeated if necessary at 15-to 90-minute intervals up to a maximum of eight doses. Observational data indicate an 88-percent success rate (Oleen, 1990). Carboprost causes side efects in approximately 20 percent of women. These include, in descending order of frequency, diarrhea, hypertension, vomiting, fever, flushing, and tachycardia. Another pharmacological efect is pulmonary airway and vascular constriction. hus, carboprost should not be used for asthmatic women and those with suspected amnionic fluid embolism (p. 785). We have occasionally encountered severe hypertension with carboprost given to women with preeclampsia. It has also been reported to cause arterial oxygen desaturation that averaged 10 percent (Hanins, 1988). Relative contraindications to carboprost include renal, liver, and cardiac disease (American College of Obstetricians and Gynecologists, 2017 d).

E-series prostaglandins can also prevent or treat atony.

Dinoprostone-prostaglandin E2-may be used of label and is given as a 20-mg suppository per rectum or per vaginum every 2 hours. It typically causes diarrhea, which is problematic for the rectal route, whereas vigorous vaginal bleeding may preclude its use per vaginum. Hypotension, which is commonly encountered with hemorrhage, is considered a contraindication by some. Intravenous prostaglandin E2-suprostone-is used in Europe, but it is not available in the United States (Schmitz, 2011).

Misoprostol-Cytotec-is a synthetic prostaglandin Ej analogue that is used for prevention and treatment of atony (AbdelAleem, 2001; Ugwu, 2016). Most studies have addressed prevention and have conflicting conclusions. In a Cochrane review, Mousa and associates (2014) reported no added benefits for misoprostol use compared with oxytocin or ergonovine for treatment. Derman and coworkers (2006) compared a 600-l-Lg oral dose given preventively at delivery against placebo. They found that the drug lowered the incidence of hemorrhage from 12 to 6 percent and that of severe hemorrhage from 1.2 to 0.2 percent. In another study, Gerstenfeld and Wing (2001) concluded that 400 ILg misoprostol administered rectally was not superior to intravenous oxytocin given to prevent postpartum hemorrhage. From a systematic review, Villar (2002) found that oxytocin and ergot preparations administered after delivery were more efective than misoprostol for prevention of postpartum hemorrhage (Chap. 27, p. 527). If misoprostol is used to treat atony, the American College of Obstetricians and Gynecologists (2017 d) recommends a dose of 600 to 1000 ILg rectally, orally, or sublingually.

Bleeding Unresponsive to Uterotonic Agents

If bleeding persists after initial measures for atony have been implemented, then the following management steps are performed immediately and simultaneously: 1.

Begin bimanual uterine compression, which is easily done and controls most cases of continuing hemorrhage (Fig. 41-4). This technique is not simply fundal massage. The posterior uterine wall is massaged by one hand on the abdomen, while the other hand is made into a fist and placed into the vagina. his fist kneads the anterior uterine wall through the anterior vaginal wall and the uterus is also compressed between the two hands.

2.

Immediately mobilize the emergent-care obstetrical team to the delivery room and call for whole blood or packed red cells.

3.

Request urgent help from the anesthesia team.

4.

Secure at least two large-bore intravenous catheters so that crystalloid with oxytocin can be continued simultaneously with blood products. Insert an indwelling Foley catheter for continuous urine output monitoring.

5.

Begin volume resuscitation with rapid intravenous infusion of crystalloid (p. 788).

6.

With sedation, analgesia, or anesthesia established and now with optimal exposure, once again manually explore the uterine cavity for retained placental fragments and for uterine abnormalities, including lacerations or rupture.

FIGURE 41-4 Bimanual compression for uterine atony. The uterus is positioned with the fist of one hand in the anterior fornix pushing against the anterior wall, which is held in place by the other hand on the abdomen. The abdominal hand is also used for uterine massage.

7.

Thoroughly inspect the cervix and vagina again for lacerations that may have escaped attention.

8.

If the woman is still unstable or if there is persistent hemorrhage, then blood transfusions are given (p. 788).

At this juncture, after causes other than atony have been excluded and after hypovolemia is reversed, several other measures are considered if bleeding continues. Their use depends on several factors such as parity, desire for sterilization, and experience with each method.

Balloon Tamponade. Uterine packing to treat refractory uterine atony fell from favor because of concerns regarding concealed bleeding and infection (Gilstrap, 2017). Newer techniques of balloon tamponade help alleviate some of these concerns (Sentilhes, 2016; Zelop, 201l). In one technique, the tip of a 24F to 30F Foley catheter with a 30-mL balloon is guided into the uterine cavity and illed with 60 to 80 mL of saline. The open tip permits continuous drainage of blood from the uterus. We have experienced balloon rupture when more than 50 mL was instilled into the balloon, thus a 34F Foley with a 60-ml balloon can be used. If bleeding subsides, the catheter is typically removed ater 12 to 24 hours. Similar devices for tamponade include SegstakenBlakemore, Rusch, and ebb balloons and condom catheters (Antony, 2017; Georgiou, 2009).

Enthusiasm has developed for specially constructed intrauterine balloons to treat hemorrhage from uterine atony and other causes. A Bakri Pospartum Baloon or BT-Cath may be inserted and inlated to tamponade the endometrial cavity and stop bleeding (Fig. 41-5). Insertion requires two or three team members. he irst performs abdominal sonography during the procedure. The second places the delated balloon into the uterus and stabilizes it. The third member instills luid to inlate the balloon, rapidly infusing at least 150 mL followed by further instillation over a few minutes for a total of 300 to 500 mL to arrest hemorrhage. It is reasonable to remove the balloon after approximately 12 hours (Einerson, 2017).

In prospective studies, nearly 150 women have been managed for postpartum hemorrhage with these uterine balloons

FIGURE 41 -5 Intrauterine Bakri balloon for postpartum hemorrhage.

(Gronvall, 2013; Kaya, 2016; Vintejoux, 2015). Perhaps a fourth of cases were caused by uterine atony. For all causes, the success rate was noted to be approximately 85 percent. Combinations of balloon tamponade and uterine compression sutures have also been described (Diemert, 2012; Yoong, 2012). Failures for all of these require various surgical methods including hysterectomy.

These include uterine compression sutures, pelvic vessel ligation, angiographic embolization, and hysterectomy. hese are discussed on page 792.

Puerperal inversion of the uterus is one of the classic hemorrhagic disasters encountered in obstetrics. Unless promptly recognized and managed appropriately, associated bleeding often is massive. Risk factors include alone or in combination: (1) fundal placental implantation, (2) uterine atony, (3) cord traction applied bore placental separation, and (4) abnormally adhered placentation such as with the accrete syndromes (p. 777).

Depending on which of these factors are contributory, the incidence and severity of uterine inversion varies. There is progressive severity of inversion as shown in Figure 41-6. The worst scenario is complete inversion with the uterus protruding from the birth canal (Fig. 41-7).

The incidence of uterine inversion ranges from 1 in 2000 to 1 in 20,000 vaginal deliveries (Coad, 2017; Ogah, 2011; Rana, 2009; Witteveen, 2013). Our experiences at Parkland Hospital comport with the higher 1 :2000 incidence. his is despite our policy of discouraging placental delivery by cord traction alone, and before certainty of its separation. It is unknown if active management o/third-stage labor with cord traction applied ostensiblyater signs of placental separation raises the likelihood of uterine inversion (Deneux-Tharaux, 2013; Gulmezoglu, 2012; Prick, 2013).

Immediate recognition of uterine inversion improves the chances of a quick resolution and good outcome (Furukawa, 20 15b). If initially unrecognized, continued hemorrhage likely

FIGURE 41-6 Progressive degrees of uterine inversion.

FIGURE 41 -9 Surgical anatomy of a completely inverted uterus viewed from above at laparotomy.

In some cases, the uterus will again invert almost immediately after repositioning. With this problem, uterine compression sutures can be used to prevent another inversion (Matsubara, 2009; Mondal, 2012). Occasionally, chronic puerperal uterine inversion may become apparent weeks after delivery.

Childbirth is invariably associated with trauma to the birth canal, which includes the uterus and cervix, vagina, and perineum. Injuries sustained during labor and delivery range from minor mucosal tears to lacerations that create life-threatening hemorrhage or hematomas.

According to the American College of Obstetricians and Gynecologists (2016b), up to 80 percent of women sustain some type of laceration at vaginal delivery. hese may lie proximally or distally along the lower genital tract.

First, small tears of the anterior vaginal wall near the urethra are relatively common. hey are often supericial with little to no bleeding, but they occasionally require sutures for hemostasis. Those large enough to require extensive repair are typically associated with short-term voiding diiculty, and an indwelling bladder catheter will obviate this.

Deeper perineal lacerations are usually accompanied by varying degrees of injury to the outer third of the vaginal vault. Some extend to involve the anal sphincter or varying depths of the vaginal walls. Repair of these perineal lacerations is detailed in Chapter 27 (p. 531).

Lacerations involving the middle or upper third of the vaginal vault usually are comorbid with injuries of the perineum or cervix. hese sometimes are missed unless inspection is thorough. Those that extend upward usually are longitudinal. They may follow spontaneous delivery but frequently result from injries sustained during operative vaginal delivery. Most niicant hemorrhage, which is controlled by suture repair. For this, efective analgesia or anesthesia, clear visualization, capable assistance, and suicient resuscitation of hypovolemia are man datory.

search for evidence of retroperitoneal hemorrhage or of perito neal perforation with hemorrhage. Also, intrauterine explora tion is considered to exclude uterine tears or rupture (Conrad, 2015). If peritoneal perforation or uterine rupture is strongly suspected, laparotomy is considered (Rai, 2010). As discussed later (p. 793), imaging and potential embolization may be suit able for large retroperitoneal hematomas.

Supericial lacerations of the cervix can be seen on close inspec tion in more than half of all vaginal deliveries. Most of these measure <0.5 cm and seldom require repair. Deeper lacera tions are less frequent, but even these may be unnoticed. Due to ascertainment bias, variable incidences are described. For example, with close inspection, the incidence of cervical lacera tions in the Consortium on Safe Labor database was 1 percent in nulliparas and 0.5 percent in multiparas (Landy, 2011). But, the overall incidence in a study of more than 81 ,000 Israeli women was only 0.16 percent (Melamed, 2009). Such lacera tions are more likely to be associated with vacuum-or forceps assisted vaginal delivery (Fong, 2014).

Cervical lacerations are not usually problematic unless they cause hemorrhage or extend to the vagina. Rarely, the cervix may be entirely or partially avulsed from the vagina in the anterior, posterior, or lateral fornices, an injury termed coporrhxis. Another rare injury is when the entire vaginal portion of the cervix is avulsed-annular or circular detachment. These injuries sometimes follow forceps deliveries performed through an incompletely dilated cervix with the blades applied over the cer vix. In some women, cervical tears reach into the lower uterine segment and involve the uterine artery and its major branches. They occasionally extend into the peritoneal cavity. More severe lacerations usually manifest as external hemorrhage or as a hematoma, however, they may occasionally be unsuspected. In the Israeli study just cited, almost 11 percent of women with a cervical laceration required blood transfusions (Melamed, 2009).

At times, the edematous anterior cervical lip is compressed berween the fetal head and maternal symphysis pubis. This usually is of little consequence and resolves spontaneously. Rarely, this causes severe ischemia, and the anterior lip may undergo necrosis and subsequently separate from the rest of the cervix.

As with vulvovaginal lacerations, cervical tears can be more fully appreciated with adequate exposure, which may be best attained with transfer to an operating room. An assistant applies irm downward pressure on the uterus, while the operator exerts gentle traction on the lips of the cervix with ring forceps. A second assistant can provide even better exposure with right-angle vaginal wall retractors or Breisky vaginal retractors. Use of suction devices can also aid viewing.

In general, cervical lacerations of 1 and even 2 cm are not repaired unless they are bleeding. Such tears heal rapidly and ultimately create an irregular, sometimes stellate appearing, external cervical os that indicates previous delivery.

FIGURE 41 -10 Repair of cervical laceration with appropriate surgical exposure. Continuous absorbable sutures are placed beginning at the upper angle of the laceration.

Deep cervical tears usually require surgical repair. When the laceration is limited to the cervix or even when it extends somewhat into the vaginal fornix, satisfactory results are obtained by suturing the cervix after bringing it into view as depicted in Figure 41-10. While cervical lacerations are repaired, any associated vaginal lacerations or an episiotomy may be tamponaded with gauze packs to arrest their bleeding. Because hemorrhage usually comes from the upper angle of the wound, the first suture using 2-0 chromic or polyglactin is placed in tissue above the angle. Subsequently, either interrupted or continuous locking sutures are serially placed outward toward the operator. If the uterus is involved and hemorrhage persists, some of the methods described later (p. 792) may be necessary to obtain hemostasis.

Pelvic hematomas can have several anatomical manifestations following childbirth. One classification is anatomical and describes vulvar, vulvovaginal, paravaginal, and retroperitoneal hematomas. Vulvar hematomas may involve the vestibular bulb or branches of the pudendal artery, which are the inferior rectal, perineal, and clitoral arteries (Fig.

Paravaginal hematomas may involve the descending branch of the uterine artery. In some cases, a torn vessel lies above the pelvic fascia, and a supralevator hematoma develops. These can extend into the upper portion of the vaginal canal and may almost occlude its lumen. Continued bleeding may dissect retroperitoneally to form a mass palpable above the inguinal ligament. In some cases, it may even dissect up behind the ascending colon to the hepatic flexure (Rai, 2010).

Risks for puerperal hematomas include vaginal or perineal laceration, episiotomy, or an operative delivery (Iskender, 2016). Any hematoma can also develop following stretch and rupture of a blood vessel without an associated laceration (Nelson, 2012). This may be especially true with forceps delivery. Occasionally, they are associated with an underlying coagulopathy (p. 782).

Perineal, vulvar, and paravaginal hematomas can develop rapidly and frequently cause excruciating pain (Fig. 41-12). A tense, tender swelling of varying size rapidly develops, encroaches on the vaginal lumen, and causes overlying skin or epithelium to become ecchymotic. A paravaginal hematoma may escape detection initially. However, symptoms of pelvic pressure, pain, or inability to void should prompt evaluation. Others may go undetected until other measures of hypovolemia become evident. When there is a supralevator extension, the hematoma extends upward in the paravaginal space and between the leaves of the broad ligament. The hematoma may escape detection until it can be felt on abdominal palpation or until hypovolemia develops. Imaging with sonography or computed tomographic scanning may be useful (Cichowski, 2017; Kawamura, 2014; Takeda, 2014).

Small hematomas often remained contained and show minimal expansion. In others, the tissues overlying an expanding hematoma may rupture from pressure necrosis. In some, profuse hemorrhage may follow, but in other cases, the hematoma drains in the form of large clots and old blood. In those that involve the paravaginal space and extend above the levator sling, retroperitoneal bleeding may be massive and occasionally fatal. Finally, we have encountered a few that rebled up to 2 weeks postpartum (Cunningham, 2017 a).

Vulvovaginal hematomas are managed according to their size, location, duration since delivery, and expansion. If bleeding ceases, then small-to moderate-sized hematomas may be treated expectantly until absorbed. But, if pain is severe or if the hematoma continues to enlarge, sutgical exploration is preferable. Blood loss with arge puerperal hematomas is neary always consideraby more than the clinical estimate. Hypovolemia is common, and transfusions are frequently required when surgical repair is necessary.

For repair, an incision is made at the point of maximal distention, blood and clots are evacuated, and bleeding points ligated. The cavity may then be obliterated with absorbable sutures. Often, no sites of bleeding are identified. Nonetheless, the evacuated hematoma cavity is surgically closed, and the vagina is packed for 12 to 24 hours. Supralevator hematomas are more diicult to treat. Although some can be evacuated by vulvar or vaginal incisions, laparotomy or interventional embolization, described next, is a consideration if bleeding continues.

Angiographic embolization has become popular for management of some puerperal hematomas. This is especially true

FIGURE 41 -7 Maternal death during home delivery caused by exsanguination from uterine inversion and a fundally implanted placenta accreta.

will prompt closer examination of the birth canal. Although complete inversion is usually evident, the partially inverted uterus can be mistaken for a uterine myoma, and sonography can aid diferentiation (Pan, 2015; Smulian, 2013). Many cases are associated with immediate life-threatening hemorrhage, and a fourth require blood replacement (eoad, 2017).

Once any degree of uterine inversion is recognized, several steps must be implemented urgently and simultaneously: 1.

Immediate assistance is summoned, including obstetrical and anesthesia personnel.

2.

Blood is brought to the delivery suite for potential use.

3.

he woman is evaluated for emergency general anesthesia.

Large-bore intravenous infusion systems are secured to begin rapid crystalloid infusion to treat hypovolemia while awaiting arrival of blood products.

4.

If the recently inverted uterus has not contracted and retracted completely and if the placenta has already separated, then the uterus may often be replaced simply by pushing up on the inverted fundus with the palm of the hand and ingers in the direction of the long axis of the vagina (Fig. 41-8). Some use two fingers rigidly extended to push the center of the fundus upward. Care is taken not to appy so much pressure as to peorate the uterus with the ingertips.

5.

If the placenta is still attached, then attempts are made to reposition the uterus with the placenta in situ. Many recommend a trial of an intravenously administered tocolytic drug such as terbutaline, magnesium sulfate, or nitroglycerin for uterine relaxation and repositioning (You, 2006). If these fail to provide suicient relaxation, then a rapidly acting halogenated inhalational agent is administered. After the uterus is replaced, the placenta is carefully manually removed.

6.

If uterine repositioning fails with the placenta attached, then it is peeled of and steady pressure with the fist, palm, or ingers is applied to the inverted fundus in an attempt to push it up into and through the dilated cervix as described in Step 4.

FIGURE 41-8 Incomplete uterine inversion repositioned by using the abdominal hand for palpation of the crater-like depression while simultaneously gently pushing the inverted fundus upward.

7. Once the uterus is restored to its normal coniguration, tocolysis is stopped. Oxytocin is then infused, and other utero tonics may be given as described for atony (p. 759). Meanwhile, the operator maintains the fundus in its normal anatomical position while applying bimanual compression to control further hemorrhage until the uterus is well contracted (see Fig. 41-4). The operator continues to monitor the uterus transvaginally for evidence of subsequent inversion. A Bakri balloon has been used to maintain the repositioned uterus (Haeri, 2015; Ida, 2015).

In most cases, the inverted uterus can be restored to its normal position by the techniques just described. Occasionally, manual replacement fails. One cause is a dense m) ometrial constriction ring. At this point, laparotomy is imperative. The anatomical coniguration found at surgery can be confusing as shown in

Figure 41-9. With agents given for tocolysis, a combined efort is made to reposition the uterus by simultaneously pushing upward from below and pulling upward from above. Application of atraumatic clamps to each round ligament and upward traction may be helpul-the Huntinton procedure. In some cases, placing a deep traction suture in the inverted fundus or grasping it with tissue forceps may be of aid. Either or both of these may be technically diicult. If a constriction ring still prohibits repositioning, a sagittal surgical cut-Haultain incisionis made posteriorly through the muscular ring to release it. he exposed fundus can then be reinverted (Sangwan, 2009). After uterine replacement, tocolytics are stopped, oxytocin and other utero to nics are given, and the uterine incision is repaired. Risks of separation of this posterior hysterotomy incision during subsequent pregnancy, labor, and delivery are unknown. Further illustration and discussion is found in Cunningham and

Gilstrapis Operative Obstetrics, 3rd edition (Zahn, 2017).

Clitoral crus Batholin gland , Bulbospongiosus m. A Colles fascia Ischioanal fossa hematoma c B Pudendal artery Vulvar hematoma branches Colles fascia cut edge Ischiocavenosus m. Dorsal atery of the clitoris Bulbospongiosus m. Perineal a. Superficial transvese perineal n. External anal sphinter n. Inferior rectal a. Levator ani m. --Gluteus maxinus m.

FIGURE 41-11 Schematic drawing showing types of puerperal hematomas. A. Coronal view showing a supralevator hematoma. B. Coronal view showing an anterior perineal triangle hematoma. C. Perineal view showing posterior perineal triangle anatomy and an ischioanal fossa hematoma. (Reproduced with permission from Cunningham FG: Genital tract lacerations and hematomas. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd edition. New York, McGraw-Hili Education, 201o7a.)

FIGURE 41-12 Let-sided anterior perineal triangle hematoma associated with a vaginal laceration following spontaneous delivery in a woman with consumptive coagulopathy from acute fatty liver of pregnancy.

for supralevator or retroperitoneal hematomas. Embolization can be used primarily, or more likely secondarily, if surgical attempts at hemostasis have failed or if the hematoma is difficult to access surgically (Distefano, 2013; Lee, 2012; Poujade, 2012). he use of a Bakri balloon for a paracervical hematoma has also been described (Gizzo, 2013; Gronvall, 2013). Finally, ultrasound-guided drainage of a recurrent supralevator hematoma has been reported (Mukhopadhyay, 2015) .

Uterine rupture frequently is catastrophic. It may be primay, deined as occurring in a previously intact or unscarred uterus, or may be seconday and associated with a preexisting incision, injury, or anomaly of the myometrium. Some of the etiologies associated with uterine rupture are presented in Table 41-3. Importantly, the contribution of each of these underlying causes has changed remarkably during the past 50 years. Speciically, before 1960, when the cesarean delivery rate was much

TABLE 41 -3. Some Causes of Uterine Rupture

Surgery involving the myometrium:

Myomectomy incision through or to the endometrium Deep cornual resection of interstitial fallopian tube Metroplasty

Coincidental uterine trauma:

Abortion with instrumentation-sharp or suction curette, sounds

Sharp or blunt trauma-assaults, accidents, bullets, knives

Congenital:

Before delivery:

Persistent, intense, spontaneous contractions Labor stimulation-oxytocin or prostaglandins Intraamnionic instillation-saline or prostaglandins Perforation by internal uterine pressure catheter External trauma-sharp or blunt

Uterine overdistention-hydramnios, multifetal pregnancy

During delivery:

Fetal anomaly distending lower segment Vigorous uterine pressure during delivery Difficult manual removal of placenta

Acquired:

Sacculation of entrapped retroverted uterus lower and women of great parity were numerous, primary uterine rupture predominated. As the incidence of cesarean delivery rose and especially as a subsequent trial oflabor in these women became prevalent through the 1990s, uterine rupture through the cesarean hysterotomy scar became the preeminent cause (Gibbins, 2015; Mone, 2016). However, concurrent with the diminished enthusiasm for a trial of labor in women with a prior cesarean delivery, incidence trends for the two types of rupture have again changed. In a study of 3942 cases of uterine rupture in more than 15 million women, approximately half were in women with a prior cesarean delivery (Yao, 2017). In 40 cases of rupture at Parkland Hospital from 2009 to 2016, 15 events (37 percent) were primary, and 25 (63 percent) were secondary (Happe, 2017).

Additional risks for rupture include other previous operations or manipulations that traumatize the myometrium. Examples are uterine curettage or perforation, endometrial ablation, myomectomy, or operative hysteroscopy (Kieser, 2002; Pelosi, 1997). In a study by Porreco and colleagues (2009), seven of21 women without a prior cesarean delivery had undergone prior uterine surgery.

In developed countries, the incidence of rupture is 1 in 4800 deliveries (Getahun, 2012). During a 40-year period in Norway, the uterine rupture rate rose significantly to about 1 in 1560 deliveries (Al-Zirqi, 2016). he frequency of primary rupture, however, approximates 1 in 10,000 to 15,000 births (Porreco, 2009). As discussed, one reason is a decreased incidence of women of great parity. Another is that excessive or inappropriate uterine stimulation with oxytocin-previously a frequent cause-has mostly disappeared. Maggio and associates (2014) found no association between the number of Montevideo units and secondary uterine rupture. In addition, in a recent analysis of three trials comparing high-versus low-dose oxytocin regimens, the rate of uterine rupture did not difer between groups (Budden, 2014). The rate of rupture is elevated with sequential induction of labor with prostaglandins and oxytocin (Al-Zirqi, 2017). At Parkland Hospital, we too have encountered primary uterine rupture in a disparate number of women in whom labor was induced with prostaglandin E1•

Blunt abdominal trauma can precipitate uterine rupture. Although the distended pregnant uterus is surprisingly resistant, pregnant women sustaining such trauma should be watched carefully for signs of a ruptured uterus (Chap. 47, p. 927). In one study of 13 cases of primary uterine rupture, trauma accounted for three cases (Miller, 1996). Other causes of traumatic rupture that are uncommon today are those due to internal podalic version and extraction, diicult forceps delivery, breech extraction, and unusual fetal enlargement such as with hydrocephaly.

Uncommon associations of rupture are uterine anomalies or multifetal pregnancy (Bankada, 2015; Tarney, 2013; Tola, 2014). Occasionally, focal inherent weakness in the myometrium predisposes to rupture. Examples include anatomical anomalies, leiomyomas, adenomyosis, choriocarcinoma, and connective-tissue defects such as Ehlers-Danlos syndrome (Arici, 2013; Nikolaou, 2013; Noh, 2013; Ramskill, 2014; Sun, 2016).

Rupture of the previously intact uterus during labor most often involves the thinned-out lower uterine segment. When the rent is in the immediate vicinity of the cervix, it frequently extends transversely or obliquely. When the rent forms in the portion of the uterus adjacent to the broad ligament, the tear

FIGURE 41-13 Supracervical hysterectomy specimen showing uterine rupture during spontaneous labor with a vertical tear at the left lateral edge of lower uterine segment.

is usually longitudinal. Although these tears develop primarily in the lower uterine segment, they can extend upward into the active segment or downward through the cervix and into the vagina (Fig. 41-13). In some cases, the bladder may also be lacerated. If the rupture is of suicient size, the uterine contents will usually escape into the peritoneal cavity. If the presenting fetal part is firmly engaged, however, then only a portion of the fetus may be extruded from the uterus. Fetal prognosis is largely dependent on the degree of placental separation and magnitude ;f !ii�tei!�l he!ii;iih�be �!d hypovolemia. In some cases, the overlying peritoneum remains intact, and this usually is accompanied by hemorrhage that extends into the broad ligament to cause a large retroperitoneal hematoma.

Following vaginal delivery in an unscarred uterus, we and others have occasionally encountered cases of an incomplete tear on the inside of the uterus that extends vertically into the active segment and is a source of profuse hemorrhage (Conrad, 2015). These tears are usually not visible from below but are found at the time of hysterectomy for intractable bleeding despite a contracted uterus. Hemorrhage with this type of tear can be torrential, and bleeding is usually not slowed until the uterine artery pedicles are clamped bilaterally.

The varied clinical presentations of uterine rupture and its management are discussed in detail in Chapter 31 (p. 598). In the most recent maternal mortality statistics from the Centers for Disease Control and Prevention, uterine rupture accounted for almost 10 percent of deaths caused by hemorrhage (Creanga, 2015, 2017). Maternal morbidity includes hysterectomy that may be necessary to control hemorrhage. Rates of perinatal mortality and morbidity, which may include severe neurological impairment, are also high (Gibbins, 2015; Porreco, 2009).

Maternal obesity comorbid with uterine rupture is associated with increased rates of adverse neonatal outcomes (Yao, 2017).

Separation of the placenta-either partially or totally-from its implantation site before delivery is described by the Latin term abruptio placentae. Literally translated, this refers to "rending asunder of the placenta," which denotes a sudden accident that is a clinical characteristic of most cases. In the purest sense, the cumbersome-and thus seldom used-term premature separation of the normaly implanted placenta is most descriptive because it excludes separation of a placenta previa.

Placental abruption is initiated by hemorrhage into the decidua basalis. he decidua then splits, leaving a thin layer adhered to the myometrium. Consequently, the process begins as a decidual hematoma and expands to cause separation and compression of the adjacent placenta. Inciting causes of many cases have been posited. he phenomenon of impaired tropho blastic invasion with subsequent atherosis is related in some cases of preeclampsia complicated by abruption (Brosens, 2011).

Inflammation or infection may be contributory (Mhatre, 2016;

Nath, 2007). Histological findings cannot be used to determine timing of the abruption (Chen, 2017).

Abruption likely begins with rupture of a decidual spi ral artery and then an expanding retroplacental hematoma.

In the early stages of placental abruption, clinical symptoms may be absent. Even with continued bleeding and placen tal separation, placental abruption can still be either total or partial (Fig. 41-14). With either, bleeding typically insinuates itself between the membranes and uterus, ultimately escaping through the cervix to cause external hemorrhage. Less often, the blood is retained between the detached placenta and the uterus, leading to concealed hemorrhage and delayed diagnosis. The delay translates into greater maternal and fetal hazards. Also with concealed hemorrhage, the likelihood of consumptive coagulopathy is elevated. This is because increased pressure within the intervillous space, caused by the expanding retroplacental clot, forces more placental thromboplastin into the maternal circulation (p. 784).

Nfost blood in the retroplacental hematoma in a nontraumatic placental abruption is maternal. his is because hemorrhage derives from separation within the maternal decidua, and placental villi are usually initially intact. In 78 women at Parkland Hospital with a nontraumatic placental abruption, fetal-tomaternal hemorrhage was documented in only 20 percent-and all of these had < 10 mL fetal blood loss (Stettler, 1992). Atkinson and colleagues (2015) identiied fetal cells in peripheral blood in only 4 percent of 68 women with a placental abruption.

When clinically suspected, an abruption is seen on a freshly delivered placenta as a circumscribed depression on the maternal surface. hese usually measure a few centimeters in diameter and are covered by dark, clotted blood. Because several minutes are required for these anatomical changes to materialize, a very recently separated placenta may appear totally normal at delivery. Our experiences are like those of fetal complications such as nonreassuring fetal status, growth restriction, or death; or neonatal outcomes that include death, preterm delivery, or growth restriction.

External trauma-usually from motor vehicle accidents or aggravated assault-can cause placental separation. he frequency of abruption originating from trauma varies. Kettel (1988) and Staford (1988) and their associates have appropriately stressed that abruption can stem from relatively minor trauma. he clinical presentation and consequences of these abruptions difer somewhat from spontaneous cases. For example, associated fetomaternal hemorrhage, while seldom clinically signiicant with most spontaneous abruptions, is more common with trauma because of concomitant placental tears or "fractures" (Chap. 47, p. 928). Fetal abruption with concealed hemorrhage. To the right is a partial abruption with blood a third of women with a traumatic abrup and clots dissecting between membranes and decidua to the internal cervical os and tion reported by Pearlman (1990). In eight

FIGURE 41-14 Schematic of placental abruption. Shown to left is a total placental bleeding that averaged 12 mL was noted in then externally into the vagina.

Benirschke and associates (2012) in that the "age" of the retroplacental clot cannot be determined exactly. In the example shown in Figure 41-15, a large dark clot is well formed, it has depressed the placental bulk, and it likely is at least several hours old.

Deining severity of placental abruption is problematic. We have considered abruption severe when the fetus dies, however, maternal and fetal complications can be serious even with a liveborn fetus. Ananth and coworkers (2016) have deined severe abruption as displaying one or more of the following: (1) maternal sequelae that include disseminated intravascular coagulation, shock, transfusion, hysterectomy, renal failure, or death; women cared for at Parkland Hospital, we

FIGURE 41-15 Partial placental abruption with a dark adherent clot.

found fetal-to-maternal hemorrhage of 80 to 100 mL in three of eight cases of traumatic placental abruption (Stettler, 1992). Importantly, in some cases of trauma, a nonreassuring fetal heart rate tracing may not be accompanied by other evidence of placental separation. A sinusoidal tracing is one example. Traumatic abruption is considered in more detail in Chapter 47 (p. 928).

Some cases of chronic placental separation begin early in pregnancy. Dugof and coworkers (2004) observed an association between some abnormally elevated maternal serum aneuploidy markers and subsequent abruption. Other have correlated irstand second-trimester bleeding with third-trimester placental abruption (Ananth, 2006; Weiss, 2004). In some cases of a chronic abruption, subsequent oligohydramnios developschronic abruption-oligohydramnios sequence-CAGS (Elliott, 1998). Even later in pregnancy, hemorrhage with retroplacental hematoma formation is occasionally arrested completely without delivery. hese women may have abnormally elevated serum levels of alpha-fetoprotein or placenta-specific RNAs as markers of the event (Miura, 2016; Ngai, 2012) .

he reported incidence of placental abruption varies because of diferent criteria used for diagnosis. hat said, its frequency averages 0.5 percent or 1 in 200 deliveries. From one database of almost 28 million births from 2006 through 2012, the incidence of placental abruption was nearly 1 percent (Ananth, 2016). From a cohort of more than 1.57 million births in the Netherlands, Ruiter and coworkers (2015) found the frequency was 0.22 percent-1 in 450. In more than 250,000 0.....) 5.

FIGURE 41-16 Frequency of placental abruption and placenta previa by maternal age at Parkland Hospital from 2000 through 2015.

deliveries at Parkland Hospital from 2000 through 2015, the incidence of placental abruption averaged 0.35 percent or 1 in 290 (Fig. 41-16).

he frequency ofplacental abruption has risen in this country, and most ofthis increase is in blackwomen (Ananth, 2005, 2016). At Parkland Hospital, however, the frequency ofsevere abruption has declined. This discrepancy may be explained in part by the variations in management ofearly-onset preeclampsia (Chap. 40, p. 728). Specifically, with placental abruption so extensive as to kill theetus, the incidence was 0.24 percent or 1 in 420 births from 1956 through 1967 (Pritchard, 1967). As the number of high-parity women giving birth declined along with improved availability of prenatal care and emergency transportation, the frequency of abruption causing fetal death dropped to 0.12 percent through 1989 in our obstetrical population. And, most recently through 2015, it declined to 0.05 percent or 1 in 2060.

Overall, perinatal outcomes are influenced by gestational age, and the frequency of placental abruption rises across the third trimester. As seen in Figure 41-17, more than half of the placental abruptions at Parkland Hospital developed at gestational ages ::37 weeks. Perinatal mortality and morbidity, however, are more common with earlier abruptions (Furukawa, 2015a). Ofother related factors, major fetal congenital anomalies have greater association with placental abruption (Riihimaki, 20l3).

Although the rates of fetal death have declined, the contribution of abruption as a cause of stillbirth remains prominent because other causes have also decreased. For example, since the early 1990s, 10 to 12 percent of all third-trimester stillbirths at Parkland Hospital have been the consequence of placental abruption. Others have documented high perinatal mortality rates caused by placental abruption. Salihu and colleagues (2005) analyzed more than 15 million singleton births between 1995 and 1998. The perinatal mortality rate associated with placental abruption was 11r9 per 1000 births compared with 8 per 1000 for the general obstetrical population.

22.7

FIGURE 41-17 Frequency of placental abruption by gestational age at Parkland Hospital.

Neonatal deaths are common following placental abruption.

At Parkland Hospital, 15 percent ofliveborn neonates died. Perinatal morbidity-oten severe-is also common in surviving newborns (Abdella, 1984). Studies by Matsuda and coworkers (2003, 2013) reported that 20 percent of survivors developed cerebrl palsy. These observations are similar to ours from Parkland Hospital. Notably, 20 percent ofliveborn neonates ofwomen with an abruption had severe acidemia, deined by a cord arterial blood pH <7.0 or base deficit of::12 mmollL. One review conirmed the associated risk for cerebral palsy (Downes, 2017). Even so, nanth and coworkers (2017) attribute adverse neurodevelopmental outcomes to be largely attributable to preterm delivery.

Several predisposing factors raise the risk for placental abruption, and some are listed in Table 41-4.Advancing matenalage is one, although data are conlicting regarding women of reat pariy

TABLE 41 -4. Risk Factors for Placental Abruption

Increased age and parity 1.3-2.3

Preeclampsia 2.1-4.0

Chronic hypertension 1n.8-3.0

Chorioamnionitis 3.0

Preterm ruptured membranes 2.4-4.9

Low birthweight 14.0

Cigarette smoking 1.4-1.9

Single umbilical artery 3.4

NA = not available.

Data from Ananth/ 1999a/b/ 2004/ 2007; Aviram/ 2015; Gutvirtz/ 2016; Morgan/ 2016; Nath/ 2007/ 2008; Ruiter/ 2015.

(Okby, 2017; Pritchard, 1991). ace or ethnicity also appears to be important. In almost 366,000 deliveries at Parkland Hospital, abruption severe enough to kill the fetus was most common in black and white women-1 in 200, less so in Asian women-1 in 300, and least common in Latin-American women-1 in 350 (Pritchard, 1991). Aomilial association was found in an analysis of a Norwegian population-based registry (Rasmussen, 2009). If a woman had a severe abruption, the risk for her sister was doubled.

Some form of hypertension is the most frequent condition associated with placental abruption. his includes gestational hypertension, preeclampsia, chronic hypertension, or a combination thereof. In a report by Pritchard and colleagues (1991) that described 408 women with placental abruption and fetal demise, hypertension was apparent in half once hypovolemia was corrected. Half of these latter women-a fourth of all 408-had chronic hypertension. Looked at another way, one Maternal-Fetal Medicine Units (MFMU) Network study found that 1.5 percent of pregnant women with chronic hypertension sufered placental abruption (Sibai, 1998). As discussed in Chapter 50 (p. 978), at Parkland Hospital, the frequency of placental abruption in treated chronically hypertensive women was almost 1 percent, which was threefold higher than the 0.3-percent baseline C..10rgan, 2016).

Chronic hypertension with superimposed preeclampsia or with fetal-growth restriction confers an even greater risk (Ananth, 2007). Even so, the severity of hypertension does not necessarily correlate with abruption incidence (Morgan, 2016; Zetterstrom, 2005). The long-term efects of these associations are apparent from the signiicantly elevated cardiovascular mortality risk in women with prior abruption, with or without chronic hypertension (DeRoo, 2016; Pariente, 2013). Observations from the Magpie Trial Collaborative Group suggest that women with preeclampsia, with or without chronic hypertension, given magnesium sulfate may have a reduced risk for abruption (Altman, 2002).

he abruption risk substantially rises when placental membranes rupture before term (American College of Obstetricians and Gynecologists, 2016a; Hackney, 2016). Major and colleagues (1995) reported that 5 percent of 756 women with ruptured membranes between 20 and 36 weeks' gestation developed an abruption. It was 17 percent with previable prematurely ruptured membranes (Kibel, 2016). he risk for abruption with preterm rupture is further increased with comorbid infection (Ananth, 2004). In these cases, inlammation and infection as well as preterm delivery may be primary causes leading to abruption (Nath, 2007, 2008).

Somewhat related, Aviram and coworkers (2015) found an eightfold higher abruption risk in pregnancies �34 weeks if hydramnios was comorbid. Abrupt uterine decompression during membrane rupture may be an inciting factor.

Many of the predisposing factors are chronic, and in these cases, placental abruption has a high recurrence rate. Pritchard and associates (1970) identiied a recurrence rate of 12 percentand half of these caused another fetal death. Furuhashi and colleagues (2002) reported a 22-percent recurrence rate-half recurred at a gestational age 1 to 3 weeks earlier than the first abruption. In the Dutch study mentioned previously, Ruiter and coworkers (2015) cited a recurrence risk of 5.8 percent. Looked at a second way, Tikkanen and associates (2006) found that of 114 parous women who experienced an abruption, 9 percent had a prior abruption. A third perspective is provided by a population-based study of 767,000 pregnancies reported by Rasmussen and Irgens (2009). They found a 6.5-fold higher risk for recurrence of a "mild" abruption and 11.5-fold risk for a "severe" abruption. For women who had two severe abruptions, the risk for a third was increased 50-fold.

Management of a pregnancy subsequent to an abruption is diicult because another separation may suddenly occur, even remote from term. In many of these recurrences, fetal wellbeing is almost always reassuring beforehand. hus, antepartum fetal testing is usually not predictive. Because term abruptions tend to be recurrent, Ruiter and coworkers (2015) recommend labor induction at 37 weeks. Our practice at Parkland Hospital is to induce labor at 38 weeks if other complications do not develop beforehand.

Cigarette smoking is linked to an elevated risk for abruption (vIisra, 1999; Naeye, 1980). Results of a metaanalysis of 1.6 million pregnancies included a twofold risk for abruption in smokers (Ananth, 1999b). This risk was five-to eightfold if smokers had chronic hypertension, severe preeclampsia, or both. Similar findings are reported by others (Hogberg, 2007; Kaminsky, 2007). Antepartum Vitamin C and E were reported to be protective for abruption in smokers (Abramovici, 2015).

Cocaine abuse is linked with an alarming frequency of placental abruption (Addis, 2001; Cressman, 2014). Bingol and colleagues (1987) described 50 women who abused cocaine during pregnancy-eight had a stillbirth caused by placental abruption.

Uterine leiomyomas, especially if located near the mucosal surface behind the placental implantation site, can predispose to placental abruption. This was reviewed recently by Ezzedine and Norwitz (2016).

Isolated single umbiical artey is associated with a 3.4-fold increased risk for placental abruption (Gutvirtz, 2016). Twins resulting from infertility treatments also carry greater risk (Okby, 2017). Subclinical hypothyroidism or high levels of antithyroid antibodies have been associated with a two-to threefold higher risk for abruption (Abbassi-Ghanavati, 2010; Casey, 2014; Maraka, 2016).

Women afected by some of the thrombophilias have higher associated rates of thromboembolic disorders during pregnancy. However, the link with placental abruption is less clear (American College of Obstetricians and Gynecologists, 2017 a,b). Lupus anticoagulant is associated with maternal floor infarction of the placenta but is less so with typical abruptions. No convincing evidence supports a role for thrombophilias and placental abruption.

Most women with a placental abruption have sudden-onset abdominal pain, vaginal bleeding, and uterine tenderness. In a prospective study, Hurd and colleagues (1983) reported that 78 percent with placental abruption had vaginal bleeding, 66 percent had uterine tenderness or back pain, and 60 percent had a nonreassuring fetal status. Other indings included fre quent contractions and persistent hypertonus. In a ifth of these women, preterm labor was diagnosed, and abruption was not suspected until fetal distress or death followed.

Importantly, the signs and symptoms of placental abruption can vary considerably. In some women, external bleeding can be profuse, yet placental separation may not be so extensive as to compromise the fetus. In others, there may be no external bleeding, but the placenta is suiciently sheared of that the fetus is dead-a concealed abruption. In one unusual case, a multiparous woman cared for at Parkland Hospital presented with a nosebleed. She had no abdominal or uterine pain, tenderness, or vaginal bleeding. Her fetus was dead, however, and her blood did not clot. he plasma ibrinogen level was 25 mg/dL. Labor was induced, and a total abruption was conirmed at delivery.

With severe placental abruption, the diagnosis generally is obvious. From the previous discussion, it follows that less severe, more common forms of abruption cannot always be recognized with certainty. hus, the diagnosis is one of exclusion. Unfortunately, no laboratory tests or other diagnostic methods accurately conirm lesser degrees of placental separation. Sonography has limited use because the placenta and fresh clots may have similar imaging characteristics. Glantz and Purnell (2002) reported only 24-percent sensitivity for sonography in 149 consecutive women with a suspected placental abruption.

Important, negative indings with sonographic examination do not exclude placental abruption. Conversely, magnetic resonance (MR) imaging is highly sensitive for placental abruption and should be considered if the diagnostic information would change management (Masselli, 2011).

With abruption, some degree of intravascular coagulation is almost universal. hus, elevated serum levels of D-dimers may be suggestive, but this has not been adequately tested. Preliminary data show that serum alpha-fetoprotein levels > 280 �g/L have a positive-predictive value of 97 percent (Ngai, 2012).

hus, in the woman with vaginal bleeding and a live fetus, it is often necessary to exclude placenta previa and other causes of bleeding by clinical and sonographic evaluation. It has long been taught-perhaps with some justiication-that painful uterine bleeding signiies placental abruption, whereas painless uterine bleeding is indicative of placenta previa. he diferential diagnosis is usually not this straightforward, and labor accompanying previa may cause pain suggestive of placental abruption. On the other hand, pain from abruption may mimic normal labor, or it may be painless, especially with a posterior placenta. At times, the cause of the vaginal bleeding remains obscure even after delivery.

Placental abruption is one of several notable obstetrical entities that may be complicated by massive and sometimes torrential hemorrhage. Hypovolemic shock is caused by maternal blood loss. In an earlier report from Parkland Hospital, Pritchard and Brekken (1967) described 141 women with abruption so severe as to kill the fetus. Blood loss in these women often amounted to at least half of their pregnant blood volume. Importantly, massive blood loss and shock can develop with a concealed abruption. Prompt treatment of hypotension with crystalloid and blood infusion is essential, and resuscitation steps are described later (p. 788).

onic fluid embolism-led to the initial recognition of di brination syndrome. his syndrome is currently referred to as lation, which later is described more broadly on page 782.

is intravascular activation of clotting. Abruption is the most common cause of clinically profound consumptive coagulop athy in obstetrics-and indeed, probably in all of medicine (Cunningham, 2015).

An important consequence of intravascular coagulation is the activation of plasminogen to plasmin, which lyses ibrin microemboli to maintain microcirculatory patency. With placental abruption severe enough to kill the fetus, there are always pathological levels of ibrinogen-ibrin degradation products and D-dimers in maternal serum (Erez, 2015). heir quantiication is not clinically useful. In a third of women with an abruption severe enough to kill the fetus, the plasma ibrinogen level will be < 150 mg/ dL. hese levels are dependent on the maternal preabruption ibrinogen level, and thus higher levels are "protective" (Cunningham, 2015; Wang, 2016). Clinically signiicant low levels may cause troublesome surgical bleeding. Levels of several other coagulation factors are also variably decreased. In addition, thrombocytopenia, sometimes profound, may accompany severe hypoibrinogenemia initially and becomes common after repeated blood transfusions.

Consumptive coagulopathy is more likely with a concealed abruption because intrauterine pressure is higher. his forces more thromboplastin into the large veins draining the implantation site. With a partial abruption and a live fetus, severe coagulation defects are less common. Our experience has been that if serious coagulopathy develops, it is usually evident by the time abruption symptoms appear.

At the time of cesarean delivery, it is not uncommon to ind widespread extravasation of blood into the uterine musculature and beneath the serosa (Fig. 41-18). It is named after Couvelaire, who in the early 1900s termed it uteroplacental apoplexy. hese myometrial hemorrhages seldom cause uterine atony, and alone they are not an indication for hysterectomy. Efusions of blood are also seen beneath the tubal serosa, between the leaves of the broad ligaments, in the substance of the ovaries, and free in the peritoneal cavity.

FIGURE 41-18 Couvelaire uterus from total placental abruption ater cesarean delivery. Blood markedly infiltrates the myometrium to reach the serosa, especially at the cornua. The small serosaloleio myoma seen on the lower anterior uterine surface is an incidental finding. (Used with permission from Dr. Angela Fields Walker.)

Acute kidney injury AI) is a general term describing renal dysfunction from many causes (Chap. 53, p. 1036). Delayed or incomplete treatment of hypovolemia with severe placental abruption can be one. However, even with abruption complicated by severe disseminated intravascular coagulation, prompt and vigorous treatment of hemorrhage with blood and crystalloid solution usually prevents clinically signiicant renal dysfunction. The risk for renal injury with abruption is magnified when preeclampsia coexists (Alexander, 2015; Drakeley, 2002). Most cases of AKI are reversible and not so severe as to require dialysis. Generally, long-term outcomes are good (Arazi, 2015). That said, irreversible acute cortical necrosis encountered in pregnancy can be associated with abruption (Gopalakrishnan, 2015).

Rarely, pituitary failure-Sheehan syndrome-follows severe intrapartum or early postpartum hemorrhage. Described in Chapter 58 (1133), the exact pathogenesis is not well understood, especially because endocrine abnormalities are infrequent even in women who sufer catastrophic hemorrhage (Matsuwaki, 2014; Robalo, 2012).

Treatment of the woman with a placental abruption varies depending on her clinical condition, gestational age, and the amount of associated hemorrhage. With a living viable-aged fetus, and with vaginal delivery not imminent, emergency cesarean delivery is chosen by most. In some women, fetal compromise will be evident as shown in Figure 41-19. When evaluating fetal status, sonographic conirmation of fetal heart activity may be necessary because sometimes an electrode applied directly to a dead fetus will provide misleading information by recording the maternal heart rate. If the fetus has died or if it is not considered suiciently mature to live outside the uterus, then

FIGURE 41-19 Placental abruption with fetal compromise. Lower panel: Uterine hypertonus with a baseline pressure of 20 to 25 mm Hg and frequent contractions peaking at approximately 75 mm Hg. Upper panel: The fetal heart rate demonstrates baseline bradycardia with repetitive late decelerations.

vaginal delivery is preferable. In either case, prompt and intensive resuscitation with blood plus crystalloid is begun to replace blood lost from retroplacental and external hemorrhage. hese measures are lifesaving for the mother and hopefully for her fetus. If the diagnosis of abruption is uncertain and the fetus is alive and without evidence of compromise, then close observation may be warranted provided that immediate intervention is available. Colon and coworkers (2016) performed a randomized trial and found no beneits to magnesium sulfate tocolysis given to women with a preterm "nonsevere" abruption at 24 to 34 weeks' gestation.

The compromised fetus is usually best served by cesarean delivery, and the speed of response is an important factor in perinatal outcomes. Kayani and coworkers (2003) studied this relationship in 33 singleton pregnancies with a clinically overt placental abruption and fetal bradycardia. Of the 22 neurologically intact survivors, 15 were delivered within a 20-minute decision-to-delivery interval. However, eight of 11 infants who died or developed cerebral palsy were delivered with intervals > 20 minutes.

A major hazard to cesarean delivery is imposed by clinically signiicant consumptive coagulopathy. Preparations include plans for blood and component replacement and assessment of coagulation-especially fibrinogen levels.

If the fetus has died, then vaginal delivery is usually preferred. As reviewed earlier, hemostasis at the placental implantation site depends primarily on myometrial contraction and not blood coagulability. Thus, after vaginal delivery, uterotonic agents and uterine massage are used to stimulate myometrial contractions. Uterine muscle ibers compress placental site vessels and prompt hemostasis even if coagulation is defective.

In some instances, vaginal delivery may not be preferable, even with a dead fetus. One example is brisk hemorrhage that cannot be successfully managed by vigorous blood replacement. Others are the myriad obstetrical complications that prohibit vaginal delivery in general. hese are listed in Table 30-1 (p. 568).

In some women with extensive placental abruption, labor tends to be rapid because the uterus is usually persistently hypertonic. This can magniy fetal compromise. In some cases, baseline intraamnionic pressures reach 50 mm Hg or higher, and with contractions, pressures may attain levels exceeding 100 mm Hg. Overall, however, irst-and second-stage labor do not appear to be shortened (Downes, 2016).

Early amniotomy has long been championed in the manage ment of placental abruption. his ostensibly achieves better spi ral artery compression to diminish implantation site bleeding and reduce thromboplastin infusion into the maternal vascular system. Although evidence supporting this theY is lacking, membrane ruprure may hasten delivery. However, if the fetus is small, the intact sac may be more eicient in promoting cervical dilation. If rhythmic uterine contractions are not superimposed on baseline hypertonus, then oxytocin is given in standard doses. No data indicate that oxytocin augments thromboplas tin escape into the maternal circulation to worsen coagulopathy (Clark, 1995; Pritchard, 1967). In light of hypertonus associ ated with abruption, misoprostol may be a less favored induc tion agent due to its association with uterine tachysystole.

In the past, some had set arbitrary time limits to permit vaginal delivery. Instead, experiences illustrate that maternal outcome depends on the diligence with which adequate luid and blood replacement therapy are pursued rather than on the interval to delivery. Observations from Parkland Hospital described by Pritchard and Brekken (1967) are similar to those from the University of Virginia reported by Brame and associates (1968). Specifically, women with severe abruption who were transfused during 18 hours or more before delivery had similar outcomes to those in whom delivery was accomplished sooner.

Expectant Management with a Preterm Fetus

If possible, delaying delivery may benefit an immature fetus. Bond and colleagues (1989) expectantly managed 43 women with placental abruption before 35 weeks' gestation, and 31 of them were given tocolytic therapy. he mean interval-todelivery for all 43 was approximately 12 days. Cesarean delivery was performed in 75 percent, and there were no stillbirths. As discussed earlier, women with a very early abruption may develop chronic abruption-oligohydramnios sequence. In one report, Elliott and coworkers (1998) described four women with an abruption at a mean gestational age of 20 weeks who developed oligohydramnios and delivered at an average gestational age of 28 weeks. In a description of 256 women with an abruption at <28 weeks' gestation, Sabourin and colleagues (2012) reported that a mean of 1.6 weeks was gained. Of the group, 65 percent were delivered <29 weeks, and half of all women underwent emergent cesarean delivery.

Unfortunately, even continuous fetal heart rate monitoring does not guarantee universally good outcomes. For example, a normal tracing may precede sudden further separation with instant fetal compromise. In some of these, if the separation is suicient, the fetus will die before it can be delivered. Tocolysis is advocated by some for suspected abruption if the fetus does not display compromise. Some investigators have observed that tocolysis improved outcomes in a highly selected cohort of women with preterm pregnancies (Bond, 1989; Combs, 1992; Sholl, 1987). In another study, Towers and coworkers (1999) administered magnesium sulfate, terbutaline, or both to 95 of 131 women with abruption diagnosed before 36 weeks. The perinatal mortality rate was 5 percent in both groups with or without tocolysis. Similar results were reported from a randomized trial (Colon, 2016). We are of the opinion that suspected placental abruption contraindicates use of tocolytic agents.

The Latin previa means going bore-and in this sense, the placenta goes before the fetus into the birth canal. In obstetrics, placenta previa describes a placenta that is implanted somewhere in the lower uterine segment, either over or very near the internal cervical os. Because these anatomical relationships cannot always be precisely deined, and because they frequently change across pregnancy, terminology can sometimes be confusing.

Beginning with the use of sonography in obstetrics, the term placental migration was coined to describe the apparent movement of the placenta away from the internal os (King, 1973). Obviously, the placenta does not move per se, and the mechanism of apparent movement is not completely understood. To begin with, migration is clearly a misnomer, because decidual invasion anchors chorionic villi at the cervical os.

Explanations of placental migration are likely additive.

First, apparent movement of the low-lying placenta relative to the internal os is related to the imprecision of two-dimensional sonography. Second, as pregnancy progresses, growth of the lower and upper uterine segments difers. With greater blood low in the upper uterus, placental growth is more likely directed toward the fundus-trophotropism. Many of those placentas that "migrate" most likely never were circumferentially implanted with true villous invasion that reached the internal cervical os. Importanty, a low-ying placenta or placenta previa is less likey to "migrate JJ if there is a prior cesarean delivey scar.

he frequency of placental migration has been quantiied. Sanderson and Milton (1991) studied 4300 women at midpregnancy and found that 12 percent had a low-lying placenta. Of placentas not covering the internal os, previa did not persist, and none subsequently had placental hemorrhage. Conversely, approximately 40 percent of placentas that covered the os at midpregnancy continued to do so until delivery. Thus, placentas that lie close to but not over the internal os up to the early third trimester are unlikely to persist as a previa by term (Heller, 2014; Parrott, 2015). However, other evidence from Bohrer and associates (2012) showed that a second-trimester low-lying placenta was associated with antepartum admission for hemorrhage and increased blood loss at delivery.

The likelihood that placenta previa persists after being identiied sonographically at given epochs before 28 weeks' gestation is shown in Figure 41-20. For twin pregnancies, similar findings are reported until 23 weeks, after which the previa persistence rate is much higher (Kohari, 2012). Staford and coworkers

FIGURE 41 -21 Placenta previa showing that copious hemorrhage could be anticipated with any cervical dilatation.

• Previa, prior CD ) • Previa, no prior CD � • 1-5 mm,prior CD )S 75 • 1-5 mm,no prior CD

FIGURE 41-20 Likelihood of persistence of placenta previa or low-lying placenta 1 to 5 mm from the internal os at delivery. These are shown as a function of sonographic diagnosis at three pregnancy epochs. CD = cesarean delivery. (Data from Oyelese, 2006.) (2010), but not Trudell and colleagues (2013), found that a previa and a third-trimester cervical length <30 mm elevated the risks for hemorrhage, uterine activity, and preterm birth. Friszer and associates (2013) showed that women admitted for bleeding had a greater chance of delivery in the subsequent 7 days when the cervical length was <25 mm, although Trudell (2013) again did not confirm this.

Terminology for placenta previa has evolved, and from a Fetal Imaging Workshop sponsored by the National Institutes of Health (NIH), the following classiication was recommended: • Placenta previa-the internal os is covered partially or completely by placenta (Figs. 41-21 and 41-22). In the past, these were further classiied as either total or partial previa.

FIGURE 41-22 On speculum examination, placenta is visible protruding through the cervical os. (Used with permission from Dr. Maureen E. Flowers.) • Low-ying placenta-implantation in the lower uterine segment is such that the placental edge does not cover the internal os but lies within a 2-cm wide perimeter around the os. A previously used term, marginal previa, described a placenta that was at the edge of the internal os but did not overlie it (Reddy, 2014).

Clearly, the classification of some cases of previa will depend on cervical dilation at the time of assessment (Dashe, 2013; Reddy, 2014). For example, a low-lying placenta at 2-cm dilation may become a partial placenta previa at 4-cm dilation because the cervix has opened to expose the placental edge. Conversely, a placenta previa that appears to be total before cervical dilation may become partial at 4-cm dilation because the cervical opening now extends beyond the edge of the placenta. Digital papation in an attempt to ascertain these changing relations between the placental edge and intenal os as the cervix dilates usualy causes severe hemorrhage!

With any degree of placenta previa, a certain amount of spontaneous placental separation is inevitable during lower uterine segment remodeling and cervical dilation. Although this frequently causes bleeding, and thus technically constitutes a placental abruption, this term is usually not applied in these instances.

Somewhat but not always related is vasa previa, in which fetal vessels course through membranes and present at the cervical os (Catanzarite, 2016). Vasa previa was recently reviewed by the Society for Maternal-Fetal Medicine (2015) and is discussed in Chapter 6 (p. 118).

he incidence of placenta previa has risen during past 30 years. Reported incidences average 0.3 percent or 1 case per 300 to 400 deliveries. he frequency at Parkland Hospital from 1988 through 2003 for nearly 250,000 births was 2.6 per 1000. For the 2004 to 2015 epoch, it rose to 3.8 per 1000. Similar frequencies have been reported from Austria, Finland, and

Israel (Kollmann, 2016; Raisanen, 2014; Rosenberg, 2011).

Several demographic factors may contribute to this higher risk for placenta previa. First, maternal age raises the frequency of placenta previa (Biro, 2012; Roberts, 2012). In the First-and

Second-Trimester E val uation of Risk (FASTER) trial, which included more than 36,000 women, the frequency of previa was 0.5 percent for women <35 years compared with 1.1 percent in those :35 years (Cleary-Goldman, 2005). At Parkland Hospital, this incidence difered from a low rate of approximately 0.65 per 1000 births for women ; 19 years to almost 10 per 1000 births for women older than 35 (see Fig. 41-16).

Multpariy also elevates the risk for previa (Raisanen, 2014).

Obviously, the efects of advancing maternal age and parity are confounding. Still, Babinszki and colleagues (1999) reported that the 2.2-percent incidence in women with parity of five or greater was significantly higher than that of women with lower parity.

he interpregnancy interval does not afect this rate (Fox, 2015).

Cigarette smoking increases the relative risk of placenta previa at least twofold (Usta, 2005). It has been postulated that carbon monoxide hypoxemia causes compensatory placental hypertrophy and more surface area. Smoking may also be related to decidual vasculopathy. Last, uterine leiomyomas are a risk factor for previa Oenabi, 2017).

Several clinical characteristics also raise previa risks. Foremost, women with one or more prior cesarean deliveries are at greater risk for subsequent placental disorders that include placenta previa, abruption, or morbidly adherent placenta (Gibbins, 2018; Klar, 2014). The cumulative risks for placenta previa that accrue with the increasing number of cesarean deliveries are extraordinary. The risk rises even further if there was a prior prelabor cesarean delivery (Downes, 2015). In one MFMU Network study of 30,132 women undergoing cesarean delivery, the incidence was 1.3 percent for those with only one prior cesarean delivery, but it was 3.4 percent if there were six or more prior cesareans (Silver, 2006). In a retrospective cohort of nearly 400,000 women who were delivered of two consecutive singletons, those with a cesarean delivery for the first pregnancy had a 1.6-fold greater risk for previa in the second pregnancy (Gurol-Urganci, 2011). hese same investigators reported a 1.5-fold higher risk from six similar population-based cohort studies. The likelihood of previa is increased more than eightfold in women with parity greater than four and who have more than four prior cesarean deliveries (Gesteland, 2004; Gilliam, 2002).

Importantly, women with a prior uterine incision and placenta previa have an elevated likelihood that cesarean hysterectomy will be necessary because of an associated morbidly adherent placenta (Wei, 2014). In one study, 6 percent of women with a primary cesarean delivery for previa required a hysterectomy. his rate was 25 percent for women with a previa undergoing repeat cesarean delivery (Frederiksen, 1999).

Maternal serum aphaetoprotein (MSAFP) levels, if abnormally elevated for otherwise unexplained reasons during prenatal screening, raise the risk for previa and a host of other abnormalities. Moreover, women with a previa and comorbid MSAFP level :2.0 multiples of the median (MoM) at 16 weeks' preterm birth (Chap. 14, p. 283).

Last, assisted reproductive technoloy AR) used for concep tion elevates previa risks. Some of this association may derive from overlapping efects. For example, older women comprise a signiicant portion of ART patients (Luke, 2017). In addition, multifetal gestation is a well-known risk of both in vitro fertil ization and previa. However, even adjusting for these overlap ping elements, ART is still associated with higher previa rates (Romundstad, 2006).

Painless bleeding is the most characteristic event with placenta previa. Bleeding usually does not develop until near the end of the second trimester or later, but it can begin even before mid pregnancy. And undoubtedly, some late abortions are caused by an abnormally located placenta. Bleeding from a previa usu in a woman who has had an uneventful prenatal course. his so-called sentinel bleed is rarely so profuse as to prove fatal. Usu ally it ceases, only to recur. However, in perhaps 10 percent of women, particularly those with a placenta implanted near but not over the cervical os, there is no bleeding until labor onset.

Bleeding at this time varies from slight to profuse, and it may clinically mimic placental abruption.

A speciic sequence of events leads to bleeding in cases in which the placenta is located over the internal os. First, the uterine body remodels to form the lower uterine segment. With this, the internal os dilates, and some of the implanted placenta inevitably separates. Bleeding that ensues is augmented by the inherent inability of myometrial fibers in the lower uterine segment to contract and thereby constrict torn vessels. Similarly, bleeding from this lower segment implantation site also frequently continues ater placentl delivery. Last, there may be lacerations in the friable cervix and lower segment. These may be especially problematic following manual removal of a somewhat adhered placenta.

Morbidy adherent placentas are a frequent and serious complication associated with placenta previa. Described later (p. 777), this abnormally firm placental attachment derives in part from poorly developed decidua that lines the lower uterine segment. Biswas and coworkers (1999) performed placental bed biopsies in 50 women with a previa and in 50 control women. Trophoblastic giant-cell iniltration of spiral arterioles-rather than endovascular trophoblast cells-was found in half of previa specimens. In contrast, only 20 percent of biopsies from normally implanted placentas had these changes. In another study of 514 cases of previa, abnormal placental attachment was identiied in 7 percent (Frederiksen, 1999). As discussed, previa overlying a prior cesarean incision conveys a particularly high risk for morbidly adherent placenta.

Coagulation dects are rare complications of placenta previa, even when implantation site separation is extensive (Cunningham, 2015). Placental thromboplastin, which incites the intravascular coagulation seen with placental abruption, is presumed to readily escape through the cervical canal rather than be forced into the maternal circulation. he paucity of large myometrial veins in this area may also be protective.

Whenever there is uterine bleeding after midpregnancy, placenta previa or abruption are always considered. In the Canadian Perinatal Network study discussed earlier (p. 758), placenta previa accounted for 21 percent of women admitted from 22 to 28 weeks' gestation with vaginal bleeding (Sabourin, 2012). Previa should not be excluded until sonographic evaluation has clearly proved its absence. If sonography is not readily available, diagnosis by clinical examination is done using the double set-up technique because it requires that a inger be passed through the cervix and the placenta palpated. A digital examination should not be performed unless delivery is planned. A cervical digital examination is done with the woman in an operating room and with preparations or immediate cesarean delivey. Even the gentlest examination can cause torrential hemorrhage. Fortunately, double set-up examination is rarely necessary because placental location can almost always be ascertained sonographically.

Quick and accurate localization can be accomplished using standard sonographic techniques (American Institute of Ultrasound in Medicine, 2013). his is usually done with transabdominal sonography. If the placenta clearly overlies the cervix or if it lies away from the lower uterine segment, the examination has excellent sensitivity and negative-predictive value (Olive, 2006; Quant, 2014). Obese women may have limitations of visualization of the lower uterine segment. Also, a full bladder may artiicially elongate the cervix and compress the lower uterine segment to give the impression that the placenta overlies the cervix. If placental location remains in question, then transvaginal sonography is the most accurate method of assessment (Fig. 41-23). It is safe, even when there is bleeding.

Accuracy depends on the sonographic technique used. In a comprehensive study, the internal os was visualized in all cases with transvaginal sonography but in only 30 percent with transabdominal sonography (Farine, 1988). As discussed, according to the Fetal Imaging Workshop, if the placental edge is <2 cm from the internal os, but not covering it, the placenta is considered low lying (Reddy, 2014). In the absence of any other indication, sonography need not be frequently repeated simply to document placental position. At Parkland, women with a placenta previa identiied at 18 to 22 weeks' gestation with a prior cesarean delivery are evaluated again at 28 weeks and those without at 32 weeks. Restriction of activity is not necessary unless a previa persists beyond 28 weeks or if clinical findings such as bleeding or contractions develop before this time. At 32 weeks' gestation, if the placental edge is still <2 cm from the os, then transvaginal sonography is repeated at 36 weeks.

Using MR imaging, several investigators have reported excellent results in visualizing placental abnormalities. hat said, it is unlikely that this technique will replace sonography for routine evaluation anytime soon. However, MR imaging has proved useful for evaluation of morbidly adherent placenta (p. 780).

Women with a placenta previa are managed based on their individual clinical circumstances. Three prominent factors include fetal age and maturity, labor, and bleeding severity. In one study of 214 women with a previa, 43 percent had an emergency delivery, and half of these were preterm (Ruiter, 2015). But, if the fetus is immature and active bleeding subsides, close observation in an obstetrical unit is indicated. Data are sparse regarding tocolytic administration for uterine contractions. Although robust randomized trials are lacking, Bose and colleagues (201r1) recommend that if tocolytics are given, they be limited to 48 hours of administration. We categorically recommend against their use in this setting.

Ater bleeding has ceased for approximately 2 days and the fetus is judged to be healthy, a woman can usually be discharged home with instructions for "pelvic rest." Importantly, the woman and her family must ully appreciate the possibility of recurrent bleeding and be prepared for immediate transport back to the hospital. In other cases, prolonged hospitalization may be ideal.

FIGURE 41 -23 Placenta previa. A. In this transvaginal image at 34 weeks' gestation, the anterior placenta completely covers the internal cervical os outlined by arrows. B.This transvaginal image at 34 weeks' gestation depicts a posterior placenta (arrow) that just reaches the level of the internal cervical os. (Reproduced with permission from Cunningham FG: Placenta previa and morbidly adherent placenta. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd edition. New York, McGraw-Hili Education,o201o7b.) he frequency of emergency delivery in women with pla centa previa ranges from 25 to 40 percent (Gibbins, 2018;

Kassir, 2017). But, in properly selected patients, long-term inpatient care does not appear to add beneits compared with outpatient management (Neilson, 2003). In one random ized study of 53 women who had a bleeding previa at 24 to 36 weeks' gestation, maternal or fetal morbidity rates did not difer between management method (Wing, 1996). Of all study women, 60 percent had recurrent bleeding, and half eventually required expeditious cesarean delivery.

For women who are near term and who are not bleeding, plns re made for scheduled cesarean delivery. Timing balances fetal immaturity risks against antepartum hemorrhage. One NIH workshop suggested elective delivery at 36 to 37 completed weeks' gestation (Spong, 2011). he Society for Maternal-Fetal Medicine (2017) recommends delivery between 34 and 37 weeks. At Park land Hospital, we usually perform elective cesarean delivery at 38 weeks. With a suspected morbidly adherent placenta, delivery is recommended at 34 to 35 completed weeks by the NIH workshop (p. 781). Our practice is to schedule delivery at 36 completed weeks.

Practically all women with placenta previa undergo cesarean delivery. Many surgeons recommend a vertical laparotomy incision to provide rapid entry in cases with torrential bleeding or operating space if hysterectomy is required. As discussed, cesarean delivery is emergently performed in more than half because of hemorrhage, for which about a fourth require blood transfusion (Boyle, 2009; Sabourin, 2012). Although a low transverse hysterotomy is usually possible, this may cause fetal bleeding if the placenta is implanted anteriorly and the placenta is incised. In such cases, fetal delivery should be expeditious (Silver, 2015a). A vertical uterine incision may be preferable in some instances. In either case, even when the incision extends through the placenta, maternal or fetal outcomes are rarely compromised.

Following placental removal, the placenta site may bleed uncontrollably due to poorly contracted smooth muscle, which is characteristic of the lower uterine segment. If hemostasis at the placental implantation site cannot be obtained by adequate uterotonic administration and pressure, it can be oversewn with O-chromic sutures. Cho and associates (1991) described interrupted O-chromic sutures at I-em intervals to form a circle around the bleeding portion of the lower segment to control hemorrhage. Others have reported success with compression sutures that traversed and compressed the anterior and posterior uterine wall (Kayem, 2011; Penotti, 2012).

Of other methods, Bakri or Foley balloon tamponade used alone or coupled with compression sutures has been described (Albayrak, 2011; Diemert, 2012; Kumru, 2013). Law and coworkers (2010) successfully used a hemostatic gel. Other surgical options are bilateral uterine or internal iliac artery ligation, illustrated later (p. 792). Finally, pelvic artery embolization has also gained acceptance.

If these more conservative methods fail and bleeding is brisk, hysterectomy is necessary. Placenta previa-especially with an abnormally adherent placenta-currently is the most frequent and other institutions Qakobsson, 2015; Wong, 2011). When there is no associated accrete syndrome, the reported incidence of hysterectomy is 2 percent (Gibbins, 2018).

hus, it is not possible to accurately estimate the efect on the hysterectomy rate from previa alone without considering the associated accrete syndromes. Again, or women whose pla centa previa is implanted anteriory at the site of a prior uterine incision, the likelihood of an associated morbidy adherent placenta and need or hysterectomy is increased. In a study of 318 peri partum hysterectomies performed in the United Kingdom, 40 percent were done for abnormal placentation (Knight, 2007).

Similar results were reported for 211 hysterectomies from the

Nordic Obstetric Surveillance Study Qakobsson, 2015). At

Parkland Hospital, 44 percent of cesarean hysterectomies were placenta (Wortman, 2015). The technique for peripartum hys terectomy is described in Chapter 30 (p. 580).

ute substantively to maternal morbidity and mortality rates. he maternal mortality ratio is increased approximately threefold for women with a placenta previa (Gibbins, 2018; Oyelese, 2006).

In another report of 5367 maternal deaths in the United States from 2006 to 2013, placenta previa alone accounted for nearly 3 percent of deaths from hemorrhage (Creanga, 2015, 2017).

The report from the Consortium on Safe Labor emphasizes the ongoing perinatal morbidity with placenta previa (Lai, 2012). Preterm delivery continues to be a major cause of perinatal death (N0rgaard, 2012). In deliveries with placenta previa in the United States in 1997, the neonatal mortality rate was threefold higher than that in unafected pregnancies and stemmed primarily from preterm delivery (Salihu, 2003). Ananth and colleagues (2003) reported a comparably elevated risk of neonatal death even for fetuses who delivered at term. This is at least partially related to the fetal anomaly rate, which is two-to threefold higher in pregnancies with placenta previa (Crane, 1999).

The association of fetal-growth restriction with placenta previa is likely minimal ter controlling for gestational age. In a populationbased cohort of more than 500,000 singleton births, Ananth and associates (2001) found that most low-birthweight newborns associated with placenta previa resulted from preterm birth. Harper and coworkers (2010) reported similar indings from a cohort of nearly 58,000 women. In contrast, at least two studies reported a greater risk for fetal-growth restriction (iisanen, 2014; Weiner, 2016).

The term morbidy adherent placenta describes aberrant placentation characterized by abnormally implanted, invasive, or adhered placenta. We also refer to these disorders collectively as accrete syndromes and use these terms interchangeably. Derivation of accrete comes from the Latin ac-+ crescere-to adhere or become attached to (Benirschke, 2012).

In the accrete syndromes, abnormal placental adherence to the myometrium stems in part from partial or total absence of the decidua basalis and imperfect development of the ibrinoid or Nitabuch layer, described in Chapter 5 (p. 86). If the decidual spongy layer is lacking either partially or totally, then the physiological line of cleavage is absent, and some or all cotyledons are densely anchored. Microscopically, placental villi attach to smooth muscle ibers rather than to decidual cells. This decidual deiciency then prevents normal placental separation after delivery. he surface area of the implantation site involved and the depth of trophoblastic tissue ingrowth are variable between women, but all afected placentas can potentially cause signiicant hemorrhage.

Substantiated data now suggest that accrete syndromes are not solely caused by this anatomical layer deficiency (Duzyj, 2017; T antbirojn, 2008). Indeed, the cytotrophoblasts may control decidual invasion through factors such as angiogenesis (Duzyj, 2015; Goh, 2016; Wehrum, 2011). Also, accrete syndrome tissue specimens show "hyperinvasiveness" (Pri-Paz, 2012) . Myometrial ibers attached to the basal plate in an antecedent pregnancy are predictive markers for a subsequent

FIGURE 41-24 Morbidly adherent placentas: A. Placenta accreta. B. Placenta increta. C. Placenta percreta.

placenta accreta (Linn, 2015; Nliller, 2016). his implies an antecedent "constitutional endometrial defect" in most cases. The greater risk conveyed by previous surgical uterine trauma may be partially explained by an enhanced vulnerability to trophoblast invasion (Garmi, 2012; Gill, 2015; Jauniaux, 2017).

his association with prior trauma is reinforced by the close relationship between cesarean-scar pregnancy (CSP) and later development of placenta accreta in the same pregnancy. Indeed, accruing evidence suggests that CSP and accrete syndromes lie on a spectrum and that CSP is a precursor, as both share the same histopathology (Happe, 2018; Timor-Tritsch, 2014). CSP frequency has been reported to approximate 1 in 2000 pregnancies (Berhie, 2015; Rotas, 2006). Described in Chapter 19 (p. 381), early rupture and hemorrhage are not uncommon with CSP, and women often elect pregnancy-terminating interventions to avoid these (Michaels, 2015; Timor-Tritsch, 2015).

Variants of the morbidly adherent placenta are classified by the depth of trophoblastic growth (Figs. 41-24 and 41-25).

FIGURE 41-25 Varying degrees of myometrial invasion with the accrete syndromes. Incisions begin on the serosal surface and extend through to the placenta. A. In this case, the myometrium (M) shows minimal invasion by the placenta (P). S = uterine serosa. B. A greater degree of myometrial invasion is seen here. C. In this example, the placenta (backets) extends to the serosal edge, held by the surgeon's hand. No myometrium remains at this site. (Reproduced with permission from Dr. C. Edward Wells in Cunningham FG: Placenta previa and morbidly adherent placenta. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd edition. New York, McGraw-Hili Education, 2017b.)

Placenta accreta indicates that villi are attached to the myome trium. With placenta in creta , villi actually invade the myome trium, and placenta percreta defines villi that penetrate through the myometrium and to or through the serosa (Bailit, 2015;

Silver, 20 15a). In clinical practice, these three variants are encountered in an approximate ratio of 80:15:5, respectively (Wong, 2008). In all three varieties, abnormal adherence may involve all lobules-total placenta accreta. If all or part of a single lobule is abnormally attached, it is described as a ocal placenta accreta. Histological diagnosis cannot be made from the placenta alone, and myometrial samples are necessary for confirmation (Benirschke, 2012) .

he frequency of accrete syndromes was 1 in 20,000 births almost 100 years ago (McKeogh, 1951). As late as 1971, Hell man and Pritchard in the 14th edition of Williams Obstetrics described accreta to be the subject of case reports. Since then, the incidence has grown remarkably in direct relationship to the rising cesarean delivery rate. For example, incidence was 1 in 2500 births in the 1980s, but it was 1 per 731 births in the report from the MFMU Network comprising 115,502 women (Bailit, 2015). And a Canadian study of more than 570,000 births found an incidence of 1 in 700 deliveries (Mehrabadi, 2015). In the Nationwide Inpatient Sample, the prevalence of accreta was 3.7 per 1000 births-1 per 270 (Mogos, 2016).

This rising frequency has made accrete syndromes one of the most formidable problems in obstetrics. In one review of 5367 pregnancy-related maternal deaths in the United States from 2006 to 2013, 13 percent were due to hemorrhage caused by accrete syndromes (Creanga, 2015, 2017). In addition, they are a leading cause of hemorrhage and emergency peripartum hysterectomy (Awan, 2011; Eller, 2011; Rossi, 2010). The American College of Obstetricians and Gynecologists (2017 c) and the Society for Maternal-Fetal Medicine (2010) have taken the lead to address and optimize management.

In subsequent pregnancies following placenta accreta, recurrence risks are high. Women in whom hysterectomy is avoided have an estimated 20-percent incidence of recurrence (Cunningham, 2016; Roeca, 2017). In addition, some evidence shows that these women have greater risks for previa, uterine rupture, and hysterectomy (Eshkoli, 2013).

hese are similar in many aspects to those for placenta previa (p. 774). That said, the two most important risk factors are an associated previa, a prior cesarean delivery, and more likely a combination of the two (Kia', 2014). A classical hysterotomy incision has a higher risk for a subsequent accrete placenta (Gyami-Bannerman, 2012). In fact, almost half of women with a prior cesarean delivery had myometrial fibers seen microscopically adhered to the placenta (Hardardottir, 1996; Miller, 2016). An associated previa confers an even higher risk. his is shown in Figure 41-26, and the astonishing increase in frequency of associated accrete syndromes is apparent with a concomitant previa.

FIGURE 41-26 Frequency of morbidly adherent placenta in women with 1 to 5 prior cesarean deliveries (CDs) now with a previa. (Data from Silver, 2006.)

Dysfunctional decidual formation also may follow any other type of myometrial trauma such as curettage or endometrial ablation (Benirschke, 2012; Gill, 2015). Even without a prior hysterotomy, coexisting placenta previa is additive to frequency, and in one study, 10 percent ofsuch women with a previa had an associated accrete syndrome. A shorter cervical length with placenta accrete syndromes did not confer a greater risk for preterm delivery (Rae, 2017).

Another risk marker became apparent with widespread use of MSAFP and human chorionic gonadotropin (hCG) screening for neural-tube defects and aneuploidies. In one study of more than 9300 women screened at 14 to 22 weeks' gestation, the risk for accrete syndromes was eightfold higher with MSAFP levels >2.5 110M, and it was increased fourfold with maternal serum free �-hCG levels >2.5 MoM (Hung, 1999).

In cases offirst-and second-trimester accrete syndromes, there is usually hemorrhage that is the consequence ofcoexisting placenta previa. Such bleeding will typically prompt evaluation and management. In some women who do not have an associated previa, accreta may not be identiied until third-stage labor when an adhered placenta is encountered. Unfortunately, imaging modalities are less than perfect to identiy all of these placentas early.

Ideally, sonography is used for antepartum identiication of abnormal placental ingrowth (Chantraine, 2013; Jauniaux, 2016; Reddy, 2014; Tam Tam, 2012). Happe and colleagues (2018) found that first-trimester measurement of the smallest myometrial thickness can be used to predict the necessity for peripartum hysterectomy with an accrete syndrome. Other indings include loss of the normal hypoechoic retroplacental zone between the placenta and uterus, placental vascular lacunae, and placental bulging into the posterior bladder wall (Fig. 41-27). Using these criteria, Warshak and associates (2006) calculated the following values: sensitivity of 77 percent; specificity of 96 percent; positive-predictive creta shows mUltiple and massive placental "lakes" or "lacunae". (Reproduced with permission from Dr. Martha Rac in Cunningham FG: Placenta previa and morbidly adherent placenta. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd edition. New York, McGraw-Hili Education, 201o7b.) value of 98 percent. Similar values are cited by the American College ofObstetricians and Gynecologists (2017c) and others (Chalubinski, 2013; Elhawary, 2013; Maher, 2013).

Despite these findings, some investigators report less spectacular results with sonography aauniaux, 2016; Primo, 2014). Bowman and colleagues (2014)r.described the sensitivity of sonography to be 54 percent; specificity, 88 percent; positivepredictive value, 82 percent; negative-predictive value, 65 percent; and accuracy, 65 percent. Location afects sonographic accuracy. In one study, the detection rate was 90 percent for anterior placenta accreta compared with 50 percent for posterior wall ones (Pilloni, 2016). Nageotte (2014) concluded that identiication of the morbidly adherent placenta with sonography should be interpreted along with clinical and operative indings.

Better results have been reported by some using threedimensional (3-D) sonography and power Doppler (Collins, 2015; Doyle, 2015). We too have found that the addition of Doppler color low mapping is highly predictive ofmyometrial invasion (Fig. 41-28). This is suspected if the distance between the uterine serosa-bladder wall interface and the retroplacental vessels measures < 1 mm and if there are large intraplacental lacunae (Rae, 2015a; Twicler, 2000). Similarly, Cali and associates (2013) reported that hypervascularity of the uterine serosa-bladder wall interface had the highest positive-and negative-predictive values for placenta percreta.

MR imaging can be added to outline anatomy and to identiy invasion of adjacent structures, including possible ureteral involvement (Chalubinski, 2013; Reddy, 2014). Although gadolinium is usually not added during pregnancy, this contrast may enhance images (Millischer, 2017). Lax and coworkers (2007) described three MR imaging findings that suggest accreta: uterine bulging, heterogeneous signal intensity within the placenta indicative of lacunae, and dark intraplacental bands on T2-weighted imaging. Some recommend use of MR imaging if sonography results are inconclusive or there is a posterior previa (American College of Obstetricians and Gynecologists, 2017c; Silver, 2015a).

FIGURE 41-28 Transvaginal sonogram of placental invasion with a morbidly adherent placenta. Retroplacental vessels (white arrows) invade the myometrium and obscure the bladder-serosal interface. Abnormal intraplacental venous lakes (black arrowheads) are commonly seen in this setting.

Preoperative assessment ideally begins once a possible accrete syndrome is recognized antenatally (Fitzpatrick, 2014; Sentilhes, 2013). A major decision concerns the timing of and the ideal aciliy or delivey. Considerations include appropriate surgical, anesthesia, intensive care, and blood banking capabilities. n obstetrical surgeon or gynecological oncologist and surgical, urological, and interventional radiological consultants should be available (Brennan, 2015; Shamshirsaz, 2015). he American College of Obstetricians and Gynecologists (2017c) and the Society for Maternal-Fetal Medicine (2010) recommend planned delivery in a tertiary-care facility. In some of these, specially designed teams have been assembled and are on call (AI-Khan, 2014; Erfani, 2017a; Smulian, 2017; Walker, 2013).

Silver and colleagues (2015b) have provided criteria for accreta centers of excellence. Shown in Table 41-5 are some

TABLE 41-5. Criteria for Consideration of Delivery in an Accrete Center of Excellence

Placenta previa with abnormal ultrasound appearance

Placenta previa with ::3 prior cesarean deliveries

Inability to adequately evaluate or exclude placenta accreta

Any other reason to suspect morbidly adherent placenta

Reproduced with permission from Silver, 201Sb.

criteria to consider transfer to a higher level-of-care facility. Women who refuse blood or its derivatives pose especially diicult management dilemmas (Barth, 201r1). If possible, delivery is best scheduled for peak availability of all resources and team members. Even so, a third of cases require unscheduled delivery, and contingency plans should be ready (Pettit, 2017) .

Timing of Delivery maternal consequences of emergency cesarean delivety (Stephen son, 2016). The American College of Obstetricians and Gynecolo gists (2017 c) recommends individualization of delivery timing. It fetal lung maturity testing ater 34 completed weeks (Robinson, 2010). he Society for Maternal-Fetal Medicine (2017) recom mends delivery between 34 and 37 weeks. Two recent surveys weeks or later (Esako, 2012; Wright, 2013). At Parkland Hos pital, we generally schedule these procedures ater 36 completed weeks but are prepared also to manage them in nonelective situ ations (Rac, 2015b). Perlman and colleagues (2017) recommend individualization based on speciic risk criteria.

In some cases, placenta accrete syndrome is not recognized until laparotomy. If there are inadequate resources to surgically manage the percreta, and if the woman is stable and not bleed ing, then the fetus is not delivered, the abdominal incision is closed, and she is transferred to a tertiary-care facility .

In cases that may involve one or both ureters, catheterization may aid in dissection or identification and repair of injury. Some, but not all, advocate preoperative ureteral catheterization (Eller, 2011; Society for Maternal-Fetal Medicine, 2010; Tam Tam, 2012).

Balloon-tipped intraarterial catheters to mitigate blood loss and thereby enhance surgical visibility have also gained supporters. Catheters are advanced preoperatively into the internal iliac arteries, and then after delivery, they are inflated to occlude pelvic blood low (Ballas, 2012; Desai, 2012). Alternatively, the catheters can be used to deliver occluding emboli to bleeding arterial sites. Others have concluded that these procedures ofer borderline eicacy and have serious risks (Salim, 2015; Sentilhes, 2009). Complications have included thromboses of the common and left iliac arteries (Bishop, 2011). At this time, the American College of Obstetricians and Gynecologists (2017 c) concludes that a irm recommendation cannot be made for or against intraarterial catheter use. Similarly, there are no obvious benefits to internal artery ligation (Eller, 2011; Po, 2012).

Before commencing with delivery, the risk of hysterectomy to prevent exsanguination should be estimated. Some of these abnormal placentations, especially if partial, may be amenable to placental delivery with hemostatic suture placement. Conirmation of a percreta or increta almost always mandates hysterectomy. Because the scope of invasion may not be apparent before delivery of the fetus, we complete many dissection steps early. This also minimizes blood loss during potentially tedious dissection after hysterotomy. Thus, we usually attempt to create a wide bladder flap bore making the hysterotomy incision (Cunningham, 2017b). The round ligaments are divided, and the lateral edges of the peritoneal relection are dissected downward. If possible, these incisions are extended to encircle the entire placental implantation site that visibly occupies the prevesical space and posterior bladder wall. Following this, a classical hysterotomy or transverse fundal incision is made to avoid the placenta (Kotsuji, 2013).

Ater etal delivery, the extent of placental invasion is assessed without attempts at manual placental removal. In a report from the United Kingdom, attempts for partial or total placental removal prior to hysterectomy were associated with twice as much blood loss (Fitzpatrick, 2014). Generally speaking, with obvious percreta or increta, hysterectomy is usually the best course, and the placenta is left in situ (Eller, 2011). With more extensive placental ingrowth, there may be little or no bleeding until manual placental removal is attempted. Unless there is spontaneous separation with bleeding that mandates emergency hysterectomy, the operation begins after full assessment is made. With bleeding, successful treatment depends on immediate blood replacement therapy and other measures that can include uterine or internal iliac artery ligation, balloon occlusion, or embolization.

he group at Baylor College of .Medicine has described a modified radical hysterectomy for surgical management of the morbidly adherent placenta (Shamshirsaz, 2015). For a description of this technique, refer to Cunningham and Gilstrap s Operative Obstetrics (Yeomans, 2017). At Parkland Hospital, we have had cases in which a traditional radical hysterectomy was necessary to excise all abnormally implanted placenta.

Occasionally, it may be possible to trim the umbilical cord, repair the hysterotomy incision, leave the placenta in situ, and not pursue hysterectomy. This option may be used for women in whom abnormal placentation was not suspected before cesarean delivery and in whom uterine closure stops bleeding. After this, she can be transferred to a higher-level facility for definitive management. Another consideration is the woman with a strong desire for fertility and who has received extensive counseling.

Conservative management was reviewed by Perez-Delboy (2014) and Fox (2015) and their colleagues. In some of these cases, the placenta spontaneously resorbed between 1 and 12 months with a mean of6 months. Numerous complications can occur and include sepsis, disseminated intravascular coagulation, pulmonary embolism, and arteriovenous malformation (Fox, 2015; Judy, 2015; Roach, 2015).

In some of these women, a subsequent hysterectomyeither planned or prompted by bleeding or infection-is performed days to weeks postpartum when blood loss might be lessened (l-Khan, 2014; Sentilhes, 2009). In one study, only 21 percent of such women ultimately required hysterectomy (Bretelle, 2007). In other reports, however, up to 60 percent eventually required emergency hysterectomy (Clausen, 2013; Pather, 2014). Evidence that treatment with methotrexate aids resorption is lacking. Last, for women in whom the placenta is left in situ, serial serum �-hCG measurements are not informative, and serial sonographic or MR imaging is recommended (Timmermans, 2007; Worley, 2008).

At this time, we agree with the American College of Obstetricians and Gynecologists (2017 c) that leaving the placenta in situ is seldom indicated. Exceptions are for temporization to permit transfer to a higher level of care.

In sum, these syndromes can have disastrous outcomes for both mother and fetus. Although the depth of placental invasion does not correspond with perinatal outcome, it is of paramount maternal significance (Seet, 2012). Shown in Table 41-6 are outcomes from reports of women from tertiary-care hospitals and in whom the diagnosis of morbidly adherent placenta was made preoperatively. Despite these advantages, a litany of complications included hemorrhage, urinary tract injury, intensive care unit admission, and secondary surgical procedures. Some of these reports chronicle outcomes in a second cohort of women in whom care was not given at a tertiary-care facility or in whom the diagnosis of percreta was not made until delivery, or both. In these cohorts, morbidity was higher, and there was one maternal death.

The terms consumptive coagulopathy, deibrination syndrome, or disseminated intravascular coagulation (DIC) are often used interchangeably, but there is an important distinction in these terms. An event related to actual consumption of pro coagulants within the intravascular tree results in a consumptive coagulopathy. In contrast, massive loss of procoagulants from hemorrhage results in a dilutional coagulopathy. Semantics aside, the clinicopathological coagulation disturbances with consumptive coagulopathy culminate in a systemic intravascular activation that completely disrupts natural hemostasis. As a result, an inefective balance of natural anticoagulant mechanisms leads to widespread fibrin deposition that can cause multiorgan failure (Levi, 2013).

Because of the many deinitions and variable severity, citing an accurate incidence for consumptive coagulopathy in pregnant women is problematic, but it ranges from 0.03 to 0.35 percent (Erez, 2014; Rattray, 2012). For example, some degree of significant coagulopathy is found in virtually all cases of placental abruption and amnionic fluid embolism. Other instances in which frequently occurring but less recognized degrees of coagulation activation can be found include sepsis, thrombotic microangiopathies, acute kidney injury, acute fatty liver, severe preeclampsia, and hemolysis, elevated liver enzyme levels, low platelet count (HELLP) syndrome (Cunningham, 2015). he overall contribution of each of these obstetrical disorders also varies depending on the population studied (Erez, 2015).

JOutcomes shown as mean ± 1 SO; median (range). hOata from Warshak, 2010. (Data from Eller, 201n1n.

dOata from Walker, 2013.

eOata from AI-Khan, 2014. fData from Erfani, 2017b; Shamshirsaz, 2015.

FFP = fresh-frozen plasma; ICU = intensive care unit; LOS = length of stay; NS = not stated; RBC = red blood cells.

When consumptive coagulopathy is severe, the likelihood of and ibrinogen-ibrin degradation products, which includes maternal and perinatal morbidity and mortality is increased. In D-dimers. long with lower concentrations of anticoagulant one study of 49 cases, antecedent causes included those listed protein S, hypercoagulability, and decreased ibrinolysis, there above, and 59 percent received blood transfusions, 18 percent is augmented-yet compensated-intravascular coagulation underwent hysterectomy, 6 percent were dialyzed, and three that may function to maintain the utero placental interface. mothers died (Rattray, 2012). he perinatal mortality rate was 30 percent. Callaghan and associates (2012) reviewed data from • Activation of Normal Coagulation the Nationwide Inpatient Sample and found a rising prevalence Instead of the "waterfall" sequential activation of clotting, a curofDIC from 1998 to 2009. And, from 2010 to 2011, DIC was rent theory proposes that tissue factor-an integral membrane the second most common severe maternal morbidity indicator glycoprotein-serves as the principal initiator of coagulation(Creanga, 2014). Notably, DIC was associated with nearly a (Levi, 2010b). Coagulation then moves forward but incorpofourth of maternal deaths during this study period. Despite these rates a feedback loop. To begin, tissue factor forms complexesstatistics, consumptive coagulopathy as the sole cause of maternal with factor VII/VIla to activate factors IX and X. Tissue factor death is relatively uncommon and accounts for only 0.2 percent is found in highly vascularized organs such as the brain, lungs, of pregnancy-related deaths in the United States (Creanga, 2015).

(Kuczynski, 2002; 0sterud, 2006; Uszynski, 2001).

Tissue factor-factor VIla complexes ultimately generate During normal pregnancy, extensive changes in coagulation activated factor X (Xa) to initiate clotting. Subsequently, the and fibrinolysis develop to create a procoagulant state. Some previously labeled "intrinsic" pathway amplifies this process. of these include appreciable increases in the plasma concentraSpecifically, the initial thrombin produced directly activates tions of factors I (fibrinogen), VII, VIII, IX, and X. A partial factor XI by providing a feedback amplification loop. This list of these normal values is found in the Appendix (p. 1256). primary role of tissue factor-factor VIla complex in coaguAt the same time, plasminogen levels rise considerably, but lation and consequent ampliication loop of thrombin is levels of plasminogen activator inhibitor-1 and 2 (PAI-1 and depicted in Figure 41-29 (Rapaport, 1995). he end result PAI-2) also grow. hus, plasmin activiy usually declines until of this ampliied coagulation process is fibrin formation. This after delivery (Hale, 2012; Hui, 2012). he mean platelet count is then counterbalanced by the ibrinolytic system, in which drops by 10 percent during pregnancy, and platelet activation is plasminogen is activated. As shown in Figure 41-29, even enhanced (Kenny, 2015). this process is tied initially to tissue factor. he inal result is

The net results of these changes include greater levels production of fibrinogen/fibrin degradation products, which of fibrinopeptide A, �-thromboglobulin, platelet factor 4, include D-dimers.

Plasminogen ---�,

FIGURE 41 -29 Schematic of coagulation pathway. FSP = fibrin split products; PAl = plasminogen activator inhibitor;TFPI = tissue factor pathway inhibitor.

Activation of Pathological Coagulation he initiation of DIC begins with the release of tissue factor by pathological entities. Tissue factor is released by subendothelial tissue and stimulated monocytes, which in turn provoke release of cytokines from the endothelium. With generalized endothelial activation, difuse activation of coagulation follows. his pathological cycle ofcoagulation and ibrinolysis becomes clinically important when coagulation factors and platelets are suiciently depleted to create consumptive coagulopathy.

Several obstetrical syndromes can trigger consumptive coagulopathy. The best known and most common is placental abruption with its significant release of thromboplastin. Another is embolization of amnionic luid and debris into the maternl circulation. This causes activation of factor X by abundant mucin found in fetal squames. Other causes include endotoxins from gram-negative bacteriaand exotoxins from gram-positive bacteria.

Bioassay is an excellent method to detect or suspect clinically signiicant coagulopathy. Excessive bleeding at sites of modest trauma characterizes defective hemostasis. Examples include persistent bleeding from venipuncture sites, nicks from shaving the perineum or abdomen, trauma from bladder catheterization, and spontaneous bleeding from the gums, nose, or gastrointestinal tract. Purpura or petechiae at pressure sites such as sphygmomanometer cufs or tourniquets suggest signiicant thrombocytopenia. Any surgical procedure provides the ultimate bioassay and elicits generalized oozing from abdominal wall layers, the retroperitoneal space, the episiotomy, or incisions and dissections for cesarean delivery or hysterectomy.

Ofaboratory tests, ibrinogen, fibrin, and degradation product leves can be informative. In late pregnancy, plasma fibrinogen levels typicallyhave risen to 300 to 600 mg/dL. Even with severe consumptive coagulopathy, levels may sometimes be suiciently high to protect against clinically signiicant hypofibrinogenemia. For example, deibrination caused by a placental abruption might lower an initial fibrinogen level of 600 mg/dL to 250 mg/dL. Although this would indicate massive ibrinogen consumption, levels are still adequate to promote clinical coagulationusually about 150 mg/dL. If serious hypoibrinogenemia-less than 50 mg/dL-is present, the clot formed from whole blood in a glass tube may initially be sot but not necessarily remarkably reduced in volume. Then, over the next half hour or so, as platelet-induced clot retraction develops, the clot becomes quite small. When many ofthe erythrocytes are extruded, the volume ofliquid in the tube clearlyexceeds that ofclot.

As depicted in Figure 41-29, fibrinolysis cleaves ibrin and ibrinogen into various fibrin degradation products that are detected by several sensitive assays. There are many fragment types, and monoclonal antibodies in assay kits usually measure D-dimers speciic for that assay. These values are always abnormally high with clinically significant consumptive coagulopathy. At least in obstetrical disorders, quantiication has not been correlated with outcomes. Examples of the magnitude of ibrin split product elevations in various obstetrical coagulopathies is shown in Figure 41-30.

Thrombocytopenia is likely if petechiae are abundant or if clotted blood fails to retract within an hour or so. Conirmation is provided by a low platelet count. Ifsevere preeclampsia syndrome is comorbid, there may also be qualitative platelet dysfunction (Chap. 40, p. 719).

are standard coagulation tests. Prolongation may stem from very 256 ... .

j .� ):l0 " 128 ..,.., j ..

.S ::•64 ... • .

32 . .

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8 ..

FIGURE 41 -30 Quantification offibrin-split products in various obstetrical syndromes that cause disseminated intravascular coagulation. AFLP = Acute fatty liver of pregnancy; HELLP = hemolysis, elevated liver enzyme levels, low platelet count. (Reproduced with permission from Cunningham FG, Nelson DB: Disseminated intravascular coagulation syndromes in obstetrics. Obstet Gynecol. 2015 Nov;126(5):999-101o1.) low fibrinogen concentrations, from appreciably reduced levels of the procoagulants needed to generate thrombin, or from large amounts of circulating fibrinogen-ibrin degradation products.

Thromboelastomety and thromboelastography are point-of care tests used as adjuncts to conventional laboratory studies (Abdul-Kadir, 2014). Their current role may serve to guide blood product replacement, discussed later (p. 791).

Using many of these tests, several organizations have attempted to establish a more uniform deinition of DIC. One is the International Society on Thrombosis and Haemostasis (ISTH) scoring system. The score is used ony ater a condition known to cause intravascular coagulation is identiied and is calculated using a combination of laboratory tests. Composite

ISTH-DIC scores <5 suggest nonovert DIC, whereas scores �5 are compatible with overt DIC. Other than one report of acute fatty liver of pregnancy, this scoring system has not been applied widely in obstetrics (Nelson, 2014).

To halt ongoing deibrination, prompt identiication and removal of the inciting source of the coagulopathy is a priority. With surgical incisions or extensive lacerations accompanied by severe hemorrhage, rapid replacement of procoagulants is usually indicated. Vigorous restoration and maintenance of the circulation to treat hypovolemia cannot be overemphasized. Adequate perfusion restores hepatic and endothelial synthesis of procoagulants and permits prompt removal of activated coagulation factors, ibrin, and ibrin degradation products by the reticuloendothelial system.

Aside from these fundamental steps, few other agents have proven soundly efective. Although seemingly counterintuitive, unfractionated heparin had been recommended but has now been abandoned. Other examples include use of antiibrinolytic agents-either tranexamic acid or epsilon-aminocaproic acid (micar) (American College of Obstetricians and Gynecologists, 2017 d; Pacheco, 2017). Currently, use of these two agents is not recommended because the ibrinolytic system is necessary for dissolution of widespread ibrin thromboses caused by generalized intravascular coagulation (Hunt, 2014). Discussed later (p. 790), recombinant factor VIla (rFVIIa) has been used to help control severe obstetrical hemorrhage from other causes. However, current clinical evidence is insuicient to make irm recommendations on its administration for obstetrical coagulopathies.

Placental abruption is the most common cause of severe consumptive coagulopathy in obstetrics and is discussed more fully on page 767. Typical quantiied levels of ibrin-split products with abruption are shown in Figure 41-30. With preeclampsia, eclampsia, and HELLP syndrome, endothelial activation is a hallmark and is discussed in Chapter 40 (p. 715). In general, the clinical severity of preeclampsia is directly correlated with thrombocytopenia and ibrinogen-ibrin degradation products (Kenny, 2015; Levi, 2010b). As shown in Figure 41-30, intravascular coagulation is seldom severe enough to be clinically worrisome (Pritchard, 1976).

Consumptive coagulopathy associated with prolonged reten tion of a dead fetus is unusual today because fetal death can be easily conirmed and there are highly efective methods for labor induction. With singleton pregnancies, if the dead fetus is unde livered, most women enter spontaneous labor within 2 weeks.

Gross disruption of maternal coagulation rarely develops before 4 weeks (Pritchard, 1959, 1973). After 1 month, however, almost a fourth will develop consumptive coagulopathy.

in a multifetal pregnancy in which one fetus dies while the other survives (Chescheir, 1988; Landy, 1989). his situation is uncommon, and in one study of 22 such pregnancies, none developed a coagulopathy (Petersen, 1999). Most cases are seen in monochorionic twins with shared circulations, which are described in Chapter 45 (p. 877).

he classic triad of abrupt hemodynamic and respiratory compromise along with DIC underpins its diagnosis (Clark, 2016). Most reports describe a frequency of 1 in 40,000 to 1 in 50,000 (Clark, 2014; Knight, 2010; Kramer, 2012). The case-fatality rate in all of these studies ranges from 11 to 43 percent. From another perspective, amnionic fluid embolism was the cause of 5 to 15 percent of all pregnancy-related deaths in the United States and Canada (Berg, 2003, 2010; Creanga, 2015; Kramer, 2012).

Predisposing conditions are rapid labor, meconium-stained luid, and tears into uterine and other large pelvic veins that permit an exchange of luids between the maternal and fetal compartment (Society for Maternal-Fetal Medicine, 2016). Other commonly cited risks include older maternal age; postterm pregnancy; labor induction or augmentation; eclampsia; cesarean, forceps, or vacuum delivery; placental abruption or previa; and hydramnios (Knight, 2010, 2012; Kramer, 2012). The association of uterine hypertonus appears to be the fectrather than the cause because uterine blood low ceases when intrauterine pressures exceed 35 to 40 mm Hg. Thus, a hypertonic contraction would be the least likely circumstance for amnionic luid and other debris to enter uterine veins (Clark, 1985). For this reason, hypertonus from oxytocin is not implicated.

Diagnosis. Proposed criteria for diagnosis of amnionic luid embolism are shown in Table 41-7. he classic example is dramatic, and a woman in the late stages of labor or immediately postpartum begins gasping for air. Seizures or cardiorespiratory arrest rapidly follows accompanied by massive hemorrhage from consumptive coagulopathy. Clinical manifestations are variable. For example, we and others have managed several women in whom otherwise uncomplicated vaginal or cesarean delivery was followed by severe acute consumptive coagulopathy without overt cardiorespiratory diiculties. In those women, consumptive coagulopathy appears to be the orme ruste of amnionic luid embolism (Kramer, 2012; Porter, 1996).

Because of this clinical variability, other sources of acute cardiac or respiratory failure should be considered. These include myocardial infarction, pulmonary or air embolism, high spinal blockade, eclampsia, and anaphylactic shock. In some cases, the temporal relationship of events aids diagnosis. Unortunatey, no

FIGURE 41 -31 Fatal amnionic fluid embolism. A.Autopsy

TABLE 41 -7. Diagnostic Criteria for Amnionic Fluid Embolism

Abrupt onset of cardiorespiratory arrest, or both hypotension and respiratory compromise.

Documentation of overt disseminated intravascular coagulation. Coagulopathy must be detected prior to loss of sufficient blood to cause dilutional or shock-related consumptive coagulopathy.

Clinical onset during labor or within 30 minutes of placental delivery. No fever �38°C.

Adapted from Clark, 201n6.

specic diagnostic laboratoy test conirms or refutes the diagnosis Management. The initial period of systemic and pulmonary of amnionic luid embolism, and it remains a clinical diagnosis. hypertension with amnionic fluid embolism is transient. Thus, Importantly, women sufering from excessive blood loss and immediate high-quality cardiopulmonary resuscitation and resulting coagulopathy may be misdiagnosed with amnionic advanced cardiac life support must be initiated without delay fluid embolism, when the true culprit is unrecognized or under(Society for Maternal-Fetal 1edicine, 2016). These are disappreciated hemorrhage (Clark, 2016). In either event, a woman cussed in detail in Chapter 47 (p. 931). with cardiopulmonary compromise should receive immediate If resuscitation is successful, hemodynamic instability is resuscitation (Society for Maternal-Fetal Medicine, 2016). common in survivors. Both fever and hyperoxia will worsen ischemia-reperfusion injury to the brain, and thus both are Pathophysiology.

The mechanism of injury from amnionic avoided. A suitable goal for temperature is 36°C and for mean luid embolism has evolved. Early theories proposed that amniarterial pressure is 65 mm Hg (Society for Maternal-Fetal onic fluid and debris entered maternal circulation and obstructed pulmonary artery flow, which led to hypoxia, right heart failure, and death. However, during normal delivery, amnionic fluid commonly enters the maternal circulation through venous channels at the placental implantation site or from small lacerations. Accordingly, squames, fetal cells, and trophoblasts can oten be identiied in maternal peripheral blood at delivery (Clark, 1986; Lee, 1986). And, infused amnionic luid is generally innocuous, even in large amounts (Adamsons, 1971; Stolte, 1967).

Current explanations describe disruption of the maternal-fetal interface, which allows material from the fetal compartment to enter maternal circulation. This leads to abnormal activation of proinflammatory mediator systems, similar to the systemic inflammatory response syndrome (SIRS), and causes initial, transient pulmonary vasoconstriction and hypertension. Acute right ventricular failure is then followed by hemodynamic collapse from right ventricular infarction coupled with interventricular 300A Platelets x 103/lL septum displacement to the let and ultimately decreased let sided cardiac output. This right and now let ventricular dysfunc250 tion is followed by cardiogenic pulmonary edema and systemic hypotension. Concurrently in this process, acute respiratory fail ure with severe hypoxemia from shunting develops. Notably, the resulting multiorgan dysfunction is an interrelated process, with both the cardiac and pulmonary systems afecting each other. Women who survive beyond these first phases invariably have the third component of the classic triad-a consumptive coagulopathy. Similar to the coagulation process described earlier, the material from the fetal compartment containing tissue 50 factor activates factor VII. This leads to the development of DIC (see Fig. 41-29).

In those who succumb, postmortem histopathological ind1100 1200 ings may be obvious (Fig. 41-31). However, detection of such B Time(hours) material may require special stains, and even then, debris may not be seen. In one study, fetal elements were detected in 75 findings of fetal squames (arrows) packed into a small pulmonary percent of autopsies and in 50 percent of specimens prepared artery. B. Results of coagulation studies from the same woman from concentrated buy coat aspirates taken antemortem from with abruptly decreased fibrinogen levels and platelets and a pulmonary artery catheter (Clark, 1995). simultaneously increased fibrin split products.

Medicine, 2016). Additional supportive care measures such as intubation are usually necessary. During the phase of right ventricular failure, inotropic agents such as dobutamine may improve right heart output, and later systemic hypotension should be treated with vasopressors such as norepinephrine.

Excess fluid administration is discouraged due to risks of wors ening dilation of an already engorged right ventricle, which of the inteventricular septum.

lapse or during the ensuing phases of injly, a coagulopathy develops in most cases from activation of factor VII and X. This may be exacerbated by ongoing hemorrhage. A common source of obstetrical bleeding is uterine atony. herefore, immediate evaluation of coagulation parameters is prudent with concur rent clinical management of bleeding.

Clinical Outcomes. Most reports describe dismal outcomes with amnionic fluid embolism. his is likely influenced by underdiagnosis and reporting biases that favor the most severe cases with the highest mortality rates. Several reports are illustrative. From a California database of 1.1 million deliveries, the mortality rate with amnionic fluid embolism was 60 percent (Gilbert, 1999). In a report of34 mothers from China, 90 percent died (Weiwen, 2000). Death can be amazingly rapid, and 12 of the 34 died within 30 minutes. he mortality rate was somewhat better in the largest study from Canada. Of 120 women with an amnionic luid embolism, only a fourth died. Survivors commonly have profound neurological impairment. Clark (1995) observed that only 8 percent of women who lived despite cardiac arrest survived neurologically intact. Overall, prognosis appears to be more associated with disease severity and the attendant cardiac arrest than with any speciic treatment modality (Clark, 2014).

As perhaps expected, perinatal outcomes are also poor and are inversely related to the maternal cardiac arrest-to-delivery interval. Even so, neonatal survival rate is 70 percent, but unfortunately, up to half of survivors sufer residual neurological impairment. In the Canadian study, 28 percent of infants were considered to be asphyxiated at birth (Kramer, 2012).

Various infections that are accompanied by endo-or exotoxin release can lead to sepsis syndrome. Although a feature of this syndrome includes activation of coagulation, seldom does sepsis alone cause massive procoagulant consumption. Escherichia coli bacteremia is frequently seen with antepartum pyelonephritis and puerperal infections, however, accompanying consumptive coagulopathy is usually not severe. Some notable exceptions are septicemia associated with puerperal infection or septic abortion caused by exoroxins released from infecting organisms such as group A Streptococcus pyogenes, Staphylococcus aureus, or Clostridium peringens, C sordelii, or C noyi (Herrera, 2016). Treatment of sepsis syndrome and septic shock is discussed in Chapter 47 (p. 921).

his severe-often lethal-form of consumptive coagulopathy is caused by micro thrombi in small blood vessels leading to skin necrosis and sometimes vasculitis. Debridement of large areas of skin over the extremities and buttocks frequently requires treatment in a burn unit. Purpura fulminans usually complicates sepsis in women with heterozygous protein C deiciencies and low protein C serum levels (Levi, 2010b). Note that homozygous protein C or S deiciency results in fatal neonatal purpurafulminans (Chap. 52, p. 1007).

Septic abortion-especially associated with the organisms just discussed-can incite coagulation and worsen hemorrhage, especially with midtrimester abortions. Indeed, sepsis syn 25 percent of abortion-related deaths (Saraiya, 1999). In the past, especially with illegal abortions, infections with C perin gens were a frequent cause of intense intravascular hemolysis at

Parkland Hospital (Pritchard, 1971). More recently, however, septic abortions from infection with C sordelii have emerged as important causes (Chap. 18, p. 351).

cular coagulation even in the absence of sepsis. Ben-Ami and associates (2012) described a 1.6-percent incidence in 1249 evacuation. Two thirds were done for fetal demise, which may have been contributory to coagulopathy. Another source of intense coagulation is from instillation of hypertonic solutions to efect mid trimester abortions. These are not commonly used currently for pregnancy terminations. he mechanism is thought to initiate coagulation by thromboplastin release into maternal circulation from the placenta, fetus, and decidua by the necrobiotic efect of hypertonic solutions (Burkman, 1977).

Recognition of obstetrical hemorrhage severity is crucial to its management. Visual estimation of blood loss, especially when excessive, is notoriously inaccurate, and true blood loss is often two to three times the clinical estimate. Consider also that in obstetrics, part and sometimes even all of the lost blood may be concealed. Estimation is further complicated in that peripartum hemorrhage also includes the pregnancy-induced augmented blood volume. After pregnancy hypevolemia is lost at delivery, blood loss can be estimated by calculating 500 mL loss for each 3 volume percent drop in hematocrit. he hematocrit nadir depends on the speed of resuscitation with intravenous crystalloids. ith acute blood loss, the real-time hematocrit is at its maximum whenever measured in the delivey, operating, or recovey room.

A prudent rule is that any time blood loss is considered more than average, then the hematocrit is determined and plans are made for close observation for potential physiological deterioration. Urine output measured hourly is one of the most important "vital signs." Unless diuretic agents are given-and these are seldom indicated with active bleeding-accuratey measured urine low relects renal pefusion, which in turn rlects pefusion of other vital organs. Urine low of at least 30 mL, and preferably :50 mL per hour, should be maintained.

Shock from hemorrhage evolves through several stages. Early in the course of massive bleeding, mean arterial pressure, stroke volume, cardiac output, central venous pressure, and pulmonary capillary wedge pressure decline. Increases in arteriovenous oxygen content diference relect a relative rise in tissue oxygen extraction, although overall oxygen consumption falls.

Blood low to capillary beds in various organs is controlled by arterioles. These are resistance vessels that are partially controlled by the central nervous system. However, approximately 70 percent of total blood volume is contained in venules which are passive resistance vessels controlled by humoral factors. Catecholamine release during hemorrhage prompts greater venular tone, which provides an auto transfusion from this capacitance reservoir (Barber, 1999). his is accompanied by compensatory rises in heart rate, systemic and pulmonary vascular resistance, and myocardial contractility. In addition, cardiac output and blood volume are redistributed from the efect of selective, centrally mediated arteriolar constriction or relaxation-autoregulation. hus, although perfusion to the kidneys, splanchnic beds, muscles, skin, and uterus is diminished, relatively more blood flow is diverted to the heart, brain, and adrenal glands.

When the blood volume deicit exceeds approximately 25 percent, compensatory mechanisms usually are inadequate to maintain cardiac output and blood pressure. Importantly, additional small losses of blood will now cause rapid clinical deterioration. Following an initial augmented total oxygen extraction by maternal tissue, maldistribution of blood flow results in local tissue hypoxia and metabolic acidosis. This creates a vicious cycle of vasoconstriction, organ ischemia, and cellular death.

Another important clinical efect of hemorrhage is activation of lymphocytes and monocytes, which in turn causes endothelial cell activation and platelet aggregation. These promote release of vasoactive mediators that occlude small vessels and further impair microcirculatory perfusion. Other common obstetrical syndromes-preeclampsia and sepsis-also lead to loss of capillary endothelial integrity, additional loss of intravascular volume into the extracellular space, and platelet aggregation. These then can incite DIC.

he pathophysiological events just described create important but often overlooked extracellular luid and electrolyte shifts involved in both the genesis and successful treatment of hypovolemic shock. hese include changes in the cellular transport of various ions such as sodium and water into skeletal muscle as well as potassium loss. Replacement of extracellular luid and intravascular volume are both necessary. Survival is enhanced in acute hemorrhagic shock if blood plus cystalloid solution is given compared with blood tranusions alone.

Whenever excessive blood loss is suspected in a pregnant woman, steps are simultaneously taken to identiy the bleeding source and to begin resuscitation. If she is undelivered, restoration of blood volume is beneficial to mother and fetus, and it also prepares for emergent delivery. If she is postpartum, it is essential to immediately identiy uterine atony, retained placental fragments, or genital tract lacerations. At least one and preferably more large-bore intravenous infusion systems are established promptly with rapid administration of crystalloid solutions, while blood is made available. An operating room is readied, and a surgical and anesthesia team are assembled immediately. Specific management of hemorrhage is further dependent on its etiology.

It cannot be overemphasized that treatment of serious hemorrhage demands prompt and adequate reilling of the intravascular compartment with crystalloid solutions. These rapidly equilibrate into the extravascular space, and only 20 percent of crystalloid remains intravascularly in critically ill patients after 1 hour (Zuckerbraun, 2010). Because of this, initial luid is infused in a volume two to three times the estimated blood loss.

Resuscitation of hypovolemic shock with colloid versus crystalloid solutions has been debated. In a Cochrane review of resuscitation of nonpregnant critically ill patients, Perel and coworkers (2013) found equivalent benefits but concluded that colloid solutions were more expensive. Similar results were found in the Saline versus Albumin Fluid Evaluation (SAFE) randomized trial of almost 7000 nonpregnant patients (Finfer, 2004). We concur with Zuckerbraun and colleagues (2010) that acute volume resuscitation is preferably done with crystalloid and blood.

The hematocrit level or hemoglobin concentration that mandates blood transfusion is controversial. Cardiac output does not substantively drop until the hemoglobin concentration falls to approximately 7 g/dL or hematocrit of 20 volume percent. At this level, several organizations recommend consideration for red cell transfusions (Carson, 2017). Also, Military Combat Trauma Units in Iraq used a target hematocrit of 21 volume percent (Barbieri, 2007). In general, with ongoing obstetrical hemorrhage, we recommend rapid blood infusion when the hematocrit is <25 volume percent. This decision is dependent on whether the fetus has been delivered; surgery is imminent or ongoing operative blood loss is expected; or acute hypoxia, vascular collapse, or other factors are present.

Scant clinical data elucidate these issues. In a study from the Canadian Critical Care Trials Group, nonpregnant patients were randomly assigned to restrictive red cell transfusions to maintain hemoglobin concentrationr>7 gl dL or to liberal transfusions to maintain the hemoglobin level at 10 to 12 gl dL. he 30-day mortality rate was similar-19 versus 23 percent in the restrictive versus liberal groups, respectively (Hebert, 1999). Transfusion therapy in nonpregnant patients with septic shock had similar mortality rates when 7 g/dL was compared with 9 gl dL as targets for transfusions (Holst, 2014). he number of units transused in a given woman to reach a target hematocrit depends on her body mass and on expectations of additional blood loss.

Contents and efects of transfusion of various blood components are shown in Table 41-8. Compatible whole blood is ideal

TABLE 41 -8. Blood Products Commonly Transfused in Obstetrical Hemorrhage

Whole blood About 500 mL; Hct RBCs, plasma, 600-700 mg Restores blood volume and �40 percent fibrinogen, no platelets fibrinogen, increases Hct

Packed RBCs 250-300 mL; RBCs, minimal fibrinogen, no Increases Hct 3-4 volume percent

Fresh-frozen About 250 mL; 30-minute Colloid, 600-700 mg fibrinogen, no Restores circulating volume and plasma (FFP) thaw platelets fibrinogen 3-4 g will increase �Cryoprecipitate About 15 mL, frozen One unit �200 mg fibrinogen, 15-20 units or other clotting factors, no platelets baseline fibrinogen 150 mg/dL Platelets About 50 mL, stored at One unit raises platelet count about 6-10 units transfused: single-donor room temperature 5000/�L; single-donor apheresis bag preferable to raise platelets

Hct = hematocrit; RBCs = red blood cells.

or treatment of hypovolemia rom catastrophic hemorrhage. It has a shelf life of 40 days, and 70 percent of the transfused red cells function for at least 24 hours following transfusion. One unit raises the hematocrit by 3 to 4 volume percent. Important for obstetrical hemorrhage, whole blood replaces many coagulation factors in obstetrics-especially fibrinogen-and its plasma treats hypovolemia. A collateral derivative is that women with severe hemorrhage are resuscitated with fewer blood donor exposures than with packed red cells and components (Shaz, 2009).

Evidence supports the preferable use of whole blood for massive hemorrhage, including our experiences at Parkland Hospital (Alexander, 2009; Hernandez, 2012). Of more than 66,000 deliveries, women with obstetrical hemorrhage treated with whole blood had signiicantly lower incidences of renal failure, acute respiratory distress syndrome, pulmonary edema, hypoibrinogenemia, intensive care unit admissions, and maternal death compared with those given packed red cells and component therapy. Freshly donated whole blood has also been used successfully for life-threatening massive hemorrhage at combat support hospitals (Murdock, 2014; Stubbs, 2016).

In most institutions today, however, whole blood is rarely available. hus, most women with obstetrical hemorrhage and ongoing massive blood loss are given packed red cells and crystalloid. In these instances, no data support a 1: 1 plasma: red cell transfusion ratio. As subsequently discussed, many institutions use massive tranfusion protocols designed to anticipate all facets of massive obstetrical hemorrhage. These "recipes" commonly contain a combination of red cells, plasma, cryoprecipitate, and platelets (Cunningham, 2015; Pacheco, 2011; Shields, 201l).

Several studies have assessed plasma:red cell ratio with massive transfusion protocols used in civilian trauma units and military combat hospitals (Borgman, 2007; Gonzalez, 2007; Hardin, 2014; Johansson, 2007). Patients undergoing massive transfusion-deined as 10 or more units of blood-had much higher survival rates as the ratio of plasma to red cell units neared 1: 1.4, that is, one unit of plasma given for each 1.4 units of packed red cells. By way of contrast, the highest mortality group had a ratio of 1 :8. Most of these studies ound that component replacement is rarey necessay with acute replacement of 5 to 10 units of packed red cels.

F rom the foregoing, when red cell replacement exceeds five units or so, evaluation of platelet count, clotting studies, and plasma fibrinogen concentration is reasonable. In the woman with obstetrical hemorrhage, the platelet count should be maintained > 50,000/�L by the infusion of platelet concentrates. A fibrinogen level < 150 mg/dL or a suiciently prolonged PT or PTT in a woman with surgical bleeding is an indication for replacement. Fresh-frozen plasma is administered in doses of 10 to 15 mLlkg, or alternatively, cryoprecipitate is infused (see Table 41-8).

A major drawback of treatment for massive hemorrhage with crystalloid solutions and packed red blood cells is depletion of platelets and clotting factors. his can lead to a dilutional coagulopathy that is clinically indistinguishable from DIe (Hossain, 2013). Thrombocytopenia is the most frequent coagulation defect found with blood loss and multiple transfusions (Counts, 19 9). In addition, packed red cells have only very small amounts of soluble clotting factors, and stored whole blood is deicient in platelets and in factors V, VIII, and XI. As discussed, massive replacement with red cells only and without factor replacement can also cause hypoibrinogenemia and prolongation of the PT and PTT. Because many causes of obstetrical hemorrhage also cause consumptive coagulopathy, the distinction between dilutional and consumptive coagulopathy can be confusing. Fortunately, treatment for both is similar.

A blood type and antibody screen should be performed for any woman at significant risk for hemorrhage. Screening involves mixing maternal serum with standard reagent red cells that carry antigens to which most of the common clinically signiicant antibodies react. Crossmatching involves the use of actual donor erythrocytes rather than the standardized red cells. This process is eicient, and only 0.03 to 0.07 percent of patients identiied as having no antibodies are subsequently found to have antibodies (Boral, 1979). Importanty, administration of screened blood rarey results in adverse clinical sequelae.

One unit of packed erythrocytes is derived from one unit of whole blood to have a hematocrit of 55 to 80 volume percent. One unit will increase the hematocrit by 3 to 4 volume percent.

With surgical delivery or with lacerations, platelet transfusions are considered with ongoing obstetrical hemorrhage when the platelet count falls below 50,000/�L (Kenny, 2015). In the nonsurgical patient, bleeding is rarely encountered if the platelet count is 10,000/�L or higher (Murphy, 2010). The preferable source of platelets is one "bag" obtained by single-donor apheresis. This contains the equivalent of six units from six individual donors. Depending on maternal size, each single-donor apheresis six-unit bag raises the platelet count by approximately 20,000/�L (Schlicter, 2010). If these bags are not available, then individual-donor platelet units are used, and six to eight such units are generally transfused one at a time.

Importantly, the donor plasma in platelet units must be compatible with recipient erythrocytes. Further, because some red blood cells are invariably transfused along with the platelets, only units from D-negative donors should be given to D-negative recipients. If it is necessary to give these, however, adverse sequelae are unlikely (Lin, 2002).

This component is prepared by separating plasma from whole blood and then freezing it. Approximately 30 minutes are required for frozen plasma to thaw. It is a source of all stable and labile clotting factors, including fibrinogen. Thus, it is often used for treatment of women with consumptive or dilutional coagulopathy. Plasma is not appropriate or use as a volume expander in the absence of speciic clotting actor deiciencies. It should be considered in a bleeding woman with a fibrinogen level < 150 mg/dL or with an abnormal PT or PTT.

An alternative to frozen plasma is liquid plasma (LQP). This never-frozen plasma is stored at 1 to 6°C for up to 26 days, and in vitro, it appears to be superior to thawed plasma (Matijevic, 2013),.

Each unit of cryoprecipitate is prepared from one unit of fresh-frozen plasma. Each 10-to 15-mL unit contains at least 200 mg of fibrinogen along with factor VIII:C, factor VIII:von Willebrand factor, factor XIII, and ibronectin (American Association of Blood Banks, 2014). It is usually given as a "pool" or "bag" using an aliquot of ibrinogen concentrate taken from 8 to 120 donors. Cryoprecipitate is an ideal source of ibrinogen when levels are dangerously low and there is oozing from surgical incisions. Another alternative is virus-inactivated ibrinogen concentrate. Each gram of this raises the plasma fibrinogen level approximately 40 mg/ dL (Ahmed, 2012; Kikuchi, 2013).

This synthetic vitamin K-dependent protein is available as NovoSeven. It binds to exposed tissue factor at the site of injury to generate thrombin that activates platelets and the coagulation cascade. Since its introduction, rFVIla has been used to help control hemorrhage from surgery, trauma, and obstetrical causes (Goodnough, 2016; Murakami, 2015). Most Level I trauma centers include it in their massive transfusion protocols, and it is included in the one used at Parkland Hospital. Importantly, rFVIIa will not be efective if the plasma fibrinogen level is <50 mg/dL or the platelet count is <30,000/�L.

One major concern with rFVIla use is arterial-and to a lesser degree venous-thrombosis. In a review of 35 randomized trials with nearly 4500 subjects, arterial thromboembolism developed in 55 percent (Levi, 2010a). A second concern is that it was found to be only marginally efective (Pacheco, 2011).

This antiibrinolytic drug has been used for traumatic and obstetrical hemorrhage. Tranexamic acid inhibits clot lysis to help forestall bleeding by preventing plasmin from degrading ibrin. Its use has been associated with a higher incidence of renal cortical necrosis (F rimat, 2016). The evidence supporting its use as an adjunct in obstetrical hemorrhage is limited, and its routine use for prophylaxis is not recommended American College of Obstetricians and Gynecologists, 2017 d; Pacheco, 2017).

These function to speed blood product delivery to the bedside or operating room, which permits product infusion early in the resuscitation process. he rationale is to prevent adverse efects of aggressive resuscitation solely with crystalloid and packed red blood cells. That said, it is not necessary to activate massive transfusions until at least four to ive units of red cells have been given within 2 hours or so. Once activated, red cells, plasma, platelets, and fibrinogen are given by protocol in amounts shown in Table 41-9. Some protocols include rFVIIa and others include tranexamic acid.

As expected, studies attesting to the superiority for survival with massive transfusion protocols are limited. Most

TABLE 41-9. Parkland Hospital Obstetrical Massive Transfusion Protocol

No. 5 Units 3 Units 6-pack 1 Unit 2 mg rVlla = recombinant activated factor VII (NovoSeven).

reports describe nonpregnant Normal coagulation trauma victims, but some obser vational studies address obstetrical hemorrhage (Green, 2016; 60 60 Pacheco, 2016). More data with 40 40 use of these protocols is needed. 20 20 rotational thromboelastometry (ROTEM) are point-of-care tests 10 20 30 40 50 min 10 20 30 40 50 min that assess coagulation in whole A EXTEM B FIBTEM blood during massive transfu

FIGURE 41-32 TEG/ROTEM based viscoelastic assays of coagulation profiles in a pregnant sions. These tests work by ana woman. A. EXTEM clot profile: CT = clotting time; A5-20 = clot amplified at 5, 10, 15,o20 min;

MCF = maximum clot firmness. B. FIBTEM clot profile showing excellent fibrin-based clot qualbreakdown in a whole blood samity. (Reproduced with permission from Solomon C, Collis RE, Collins PW: Haemostatic monitorple from a given patient. Testing ing during postpartum haemorrhage and implications for management, Br J Anaesth. 201o2 produces a proile of coagulation Dec;1o09(6):851-863.) dynamics, and displayed values indicate the speed and quality of clot formation (Fig. 41-32). hese assays provide information regarding time to clot formation, clot strength, and fibrinolysis. Currently, they guide blood product replacement in trauma, liver transplant, and cardiac surgery patients. Studies of TEG and ROTEM techniques in pregnant women have conirmed the hypercoagulable state of pregnancy and provide reference ranges for use in this population (Butwick, 2015; de Lange, 2014; Solomon, 2012).

Although these point-of-care tests appear promising, they also have several limitations. For example, they cannot be used to detect disorders of primary hemostasis (Solomon, 2012). Additionally, these tests cannot diagnose coagulopathies stemming from platelet dysfunction or anti platelet drugs. A major drawback is the risk of misinterpretation when tests are used by inadequately trained personnel. Further study is necessary before these tests are widely applied for treatment of obstetrical hemorrhage.

Several agents can be used to control persistent surgical oozing. These were recently reviewed by Miller and colleagues (2015). Other than for cesarean hysterectomy, these are seldom used in obstetrical hemorrhage.

Preoperative patient phlebotomy and autologous blood storage for transfusion has been disappointing. Exceptions are women with a rare blood type or with unusual antibodies. Most have concluded that autologous transfusions are not cost efective (Etchason, 1995; Pacheco, 2011, 2013).

Intraoperative blood salvage with reinfusion is considered to be a safe intervention in obstetrical patients. As discussed in Chapter 30 (p. 569), this practice may be helpful for women declining transfusion. Prior concern centered on amnionic fluid contamination and embolism (Dhariwal, 2014; Goucher, 2015; Pacheco, 2011). A recent randomized trial involving 3028 women compared routine cell salvage use against routine care, in which salvage was employed only for bleeding indications. he rate of nonautologous donor blood transfusion was reduced in the cell salvage group-2.5 versus 3.5 percent, but this was not a signiicant diference (han, 2017). Similar to prior reports, no cases of amnionic luid embolism were reported.

Of serious known risks, transfusion of an incompatible blood component may result in acute hemolysis. If severe, this can cause DIC, acute kidney injury, and death. Preventable errors responsible for most of such reactions frequently include mislabeling of a specimen or incorrectly transfusing a patient not slated for those products. The rate of such errors in the United States is estimated to be 1 in 14,000 units, but these events are likely underreported (Lerner, 2010). A transfusion reaction is characterized by fever, hypotension, tachycardia, dyspnea, chest or back pain, lushing, severe anxiety, and hemoglobinuria. Immediate supportive measures include stopping the transfusion, treating hypotension and hyperkalemia, provoking diuresis, and alkalinizing the urine.

Transfusion-related acute lung injury (TAIl) is the most common cause of transfusion-related mortality. The syndrome is characterized by severe dyspnea, hypoxia, and noncardiogenic pulmonary edema that develop within 6 hours of transfusion (Peters, 2015). TRALI is estimated to complicate at least 1 in 12,000 transfusions (Carson, 2017). Although the pathogenesis is incompletely understood, injury to the pulmonary capillaries may arise from anti-human leukocyte antigen (HA) and neutrophil (HNA) antibodies in donor plasma (Lerner, 2010). A delayed form ofTRALI has been reported to begin 6 to 72 hours following transfusion (Marik, 2008). Management is supportive and may include mechanical ventilation (Chap. 47, p. 919).

Bacterial inection from transfusion of a contaminated blood component is unusual because organism growth is discouraged by refrigeration. The most often implicated contaminants of red cells include Yersinia, Pseudomonas, Serratia, Acinetobacter, and Escherichia species. The more important risk is from bacterial contamination of platelets, which are stored at room temperature. Current estimates are that 1 in 1000 to 2000 platelet units are contaminated. Death from transfusion-related sepsis is 1 per 17,000 for single-donor platelets and 1 per 61,000 for apheresis-donor packs (Lerner, 2010).

iral inection risks from transfusion have been curtailed. he risk of HIV or hepatitis C virus infection in screened blood is estimated to be 1 case per 1 to 2 million units transfused (Carson, 2017; Stramer, 2004). The risk for HIV-2 infection is less. Other viral infections include hepatitis B transmission, which is estimated to be < 1 per 100,000 transused units Qackson, 2003). Because of its high prevalence, cytomegalovirus-infected leukocytes are often transfused. hus, precautions are taken for immunosuppressed recipients, keeping in mind that this includes the fetus.

Also, risks for transmitting West Nile virus, human T -lymphotropic virus type I, parvovirus B 19, and toxoplasmosis are slight (American Association of Blood Banks, 2013;

Foroutan-Rad, 2016). Finally, Zika virus has emerged as another relevant transfusion-transmitted infection (Motta, 2016). The Food and Drug Administration (2016) revised recommendations for collection of all whole blood components to include testing for Zika virus. This practice has been airmed by the Centers for Disease Control and Prevention (2016).

Several invasive procedures can help arrest postpartum hemorrhage. A report from the Agency for Healthcare Research and Quality concluded that most studies addressing these methods are of poor quality (Likis, 2015). In one study of 6660 women with postpartum hemorrhage, 4.4 percent underwent an invasive procedure, and 1.1 percent had a hysterectomy (Kayem, 2016). he failure rate of conservative measures was 15 percent in surgical and embolization procedures.

The technique for unilateral or bilateral uterine artery ligation is used primarily for lacerations at the lateral part of a h) ster otomy incision (Fig. 41-33). In our experiences, this procedure is less helpful for hemorrhage from uterine atony.

his surgical technique uses a no. 2 chromic suture to compress the anterior and posterior uterine walls together (B-Lynch, 1997). Because they give the appearance of suspenders, they are also called braces (Fig. 41-34). Several modiications of the B-Lynch technique have been described (Cho, 2000; Hayman, 2002; Matsubara, 2013; Nelson, 2007). Indications vary for its application, and this will afect the success rate. For example, B-Lynch (2005) cited 948 cases with only seven failures. Conversely, Kayem and associates (2011) described 211 women who had an overall failure rate of 25 percent, which did not difer between B-Lynch sutures and their modiications. In another series, the failure rate was 20 percent (Kaya, 2016). From their review, Sathe and coworkers (2016) reached similar conclusions.

FIGURE 41-33 Uterine artery ligation. The suture goes through the lateral uterine wall anteriorly, curves around posteriorly, then re-enters anteriorly. When tied, it encompasses the uterine artery.

Some unique complications can rarely follow compression sutures (Matsubara, 2013). Most involve variations of uterine ischemic necrosis with peritonitis (Gottlieb, 2008; Joshi, 2004; Ochoa, 2002; Treloar, 2006). In one case, total uterine necrosis followed B-Lynch sutures that were placed in combination with bilateral ligation of uterine, uteroovarian, and round ligament arteries (Friederich, 2007). In most cases, subsequent pregnancies are uneventful if compression sutures are used (n, 2013). A few women, however, with B-Lynch or Cho sutures developed uterine wall defects (Akoury, 2008). Another longterm complication is uterine cavity synechiae (Alouini, 2011; Ibrahim, 2013; Poujade, 2011).

For years, ligation of one or both internal iliac arteries has been used to reduce pelvic hemorrhage. Drawbacks are that the procedure may be technically diicult and is only successful half of the time (American College of Obstetricians and Gynecologists, 2017d). It is not particularly helpful for abating hemorrhage with postpartum atony (Clark, 1985).

For ligation, adequate exposure is obtained by opening the peritoneum over the common iliac artery and dissecting down to the bifurcation of the external and internal iliac arteries (Fig. 41-35). Branches distal to the external iliac arteries are palpated to veriY pulsations at or below the inguinal area. ligation of the internal iliac artery 5 cm distal to the common iliac bifurcation will usually avoid the posterior division branches (Bleich, 2007). The areolar sheath of the artery is incised longitudinally, and a right-angle clamp is carefully passed just beneath the artery from lateral to medial. Care must be taken not to perforate contiguous large veins, especially the internal

FIGURE 41-34 Uterine compression suture or "brace." The B-Lynch suture technique is illustrated from an anterior view of the uterus in Figures A, B, and 0 and a posterior view in Figure C. The numbers denote the sequential path of the suture and are shown in more than one figure. Step 1. Beginning below the incision, the needle pierces the lower uterine segment to enter the uterine cavity. Step 2. The needle exits the cavity above the incision. The suture then loops up and around the fundus to the posterior uterine surface. Step 3. The needle pierces the posterior uterine wall to reenter the uterine cavity. The suture then traverses to the opposite side within the cavity. Step 4. The needle exits the uterine cavity through the posterior uterine wall. From the back of the uterus, the suture loops up and around the fundus to the front of the uterus. Step 5. The needle pierces the myometrium above the incision to reenter the uterine cavity. Step 6. The needle exits below the incision and the sutures at points 1 and 6 are tied below the incision. The hysterotomy incision is then closed in the usual fashion.

iliac vein. Suture-usually nonabsorbable-is passed under the artery with a clamp, and the vessel is then securely ligated.

he most important mechanism of action with internal iliac artery ligation is an 85-percent reduction in pulse pressure in those arteries distal to the ligation (Burchell, 1968). his converts an arterial pressure system into one with pressures approaching those in the venous circulation. his creates vessels more amenable to hemostasis via pressure and clot formation.

Even bilateral internal iliac artery ligation does not appear to interfere with subsequent reproduction. Nizard and colleagues (2003) reported follow-up in 17 women who had bilateral artery ligation. From a total of 21 pregnancies, 13 were normal, three ended with miscarriage, three were terminated, and two were ectopic.

This modality is now used for many causes of intractable hemorrhage when surgical access is diicult. In more than 500 women reported, embolization was 90-percent efective (Gronvall, 2014; Lee, 2012; Poujade, 2012; Zhang, 2015). After his review, Rouse (2013) concluded that embolization can be used to arrest refractory postpartum hemorrhage. Other reports have been less enthusiastic. Fertility is not impaired, and many subsequent successful pregnancies have been reported (Chauleur, 2008; Fiori, 2009; Kolomeyevskaya, 2009). An important caveat or these procedures is that women with hemodynamic instabiliy related to active bleeding should not be removed rom the operating room.

FIGURE 41 -35 Ligation of the right internal iliac artery. Unembalmed cadaveric dissection shows the right-angle clamp passing underneath the anterior division of the internal iliac artery just distal to its posterior division. (Used with permission from Dr. Marlene Corton.)

Complications of embolization are relatively uncommon but can be severe. Case reports detail instances of iatrogenic iliac artery rupture, uterine ischemic necrosis, and uterine infection (Gronvall, 2014; Katakam, 2009; Nakash, 2012). Finally, l-hunyan and coworkers (2012) described a woman with massive buttock necrosis and paraplegia following bilateral internal iliac artery embolization.

In a few instances, massive blood loss and diicult surgical dissection is anticipated. The use of balloon-tipped catheters preoperatively inserted into the iliac or uterine arteries was described earlier in management of placenta accrete syndromes (p. 781).

For significant bleeding refractory to suture or topical hemostats, pelvic packing with gauze and termination of the operation may be considered. Rolls of gauze are packed to provide constant local pressure. This may serve as a temporizing step prior to interventional embolization. In other cases, packing alone may be left for 24 to 48 hours. If the patient is stable and bleeding appears to have stopped, packing is removed.

The umbrela orparachute pack uses a similar concept (Logothetopulos, 1926). Although seldom used today, it can be lifesaving if all other measures have failed, especially in low-resource areas (Dildy, 2006; Howard, 2002). The pack is constructed of a sturdy sterile plastic bag that is illed with gauze rolls that are unwound and knotted together. Suicient rolls are used to provide enough volume to fill the pelvis. he pack is introduced transabdominally with the stalk exiting the vagina. Mild traction is applied by tying the stalk to a I-liter fluid bag, which is hung over the foot of the bed. The umbrella pack is removed vaginally after 24 hours.

Abbassi-Ghanavati M, Casey BM, Spong CY, et al: Pregnancy outcomes in women with thyroid peroxidase antibodies. Obstet Gynecol 116:381, 2010 Abdel-Aleem H, El-Nashar I, Abdel-Aleem A: Management of severe post partum hemorrhage with misoprostol. Int] Gynaecol Obstet 2:75, 2001 Abdella TN, Sibai BM, Haysn]M ]r, et al: Perinatal outcome in abruptio placentae. Obstet Gynecol 63:365, 1984

Abdul-Kadir R, McLintock C, Ducloy AS, et al: Evaluation and management of postpartum hemorrhage: consensus from an international expert panel. Transfusion 54(7): 1756, 2014

Abramovici A, Gandley E, Clifton RG, et al: Prenatal Vitamin C and E supplementation in smokers is associated with reduced placental abruption and preterm birth: a secondary analysis. B]OG 122(13):1740,n2015

Adamsons K, Mueller-Heubach E, Myers RE: he innocuousness of amniotic fluid infusion in the pregnant rhesus monkey. Am ] Obstet Gynecol 109:977, 1971

Addis A, Moretti ME, Ahmed Syed F, et al: Fetal efects of cocaine: an updated meta-analysis. Reprod Toxicol 15:341, 2001

Ahmed S, Harrity C, Johnson S, et al: The eicacy of ibrinogen concentrate compared with cryoprecipitate in major obstetric haemorrhage-an observational study. Transfus Med 22(5):344,n2012

Akoury H, Sherman C: Uterine wall partial thickness necrosis following combined B-Lynch and Cho square sutures for the treatment of primary postpartum hemorrhage. ] Obstet Gynaecol Can 30:421, 2008

Al-Khan A, Gupta V, Illsley NP, et al: Maternal and fetal outcomes in placenta accreta after institution of team-managed care. Reprod Sci 21(6):761,n2014

Al-hunyan A, Al-Meshal 0, Al-Hussainan H, et al: Buttock necrosis and paraplegia after bilateral internal iliac artery embolization for postpartum hemorrhage. Obstet Gynecol 120(2 Pt 2):468,n2012

Altman 0, Carro Ii G, Duley L, et al: Do women with preeclampsia, and their babies, beneit from magnesium sulphate? he Magpie Trial: a randomised placebo-controlled trial. Lancet 359: 1877, 2002

Al-Zirqi I, Daltveit AK, Forsen L, et al: Risk factors for complete uterine rupture. Am] Obstet GynecoIn216(2):165.e1, 2017

Al-Zirqi 1, Vangen S, Forsen L, et al: Prevalence and risk factors of severe obstetric haemorrhage. BJOG 115:1265,n2008

Al-Zirqi L, Stray-Pedersen B, Forsen L, et al: Uterine rupture: trends over 40 years. BJOG 123(5):780,n2016

Albayrak M, Ozdemir I, Koc 0, et al: Post-partum haemorrhage from the lower uterine segment secondary to placenta previa/accreta: successful conservative management with Foley balloon tamponade. Aust N Z ] Obstet Gynaecol 51(4):377, 2011

Alexander JM, Cunningham FG: Management. In Taylor RN, RobertS JM, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 2015

Alexander JM, Sarode R, McIntire DO, et l: Use of whole blood in the management of hypovolemia due to obstetric hemorrhage. Obstet GynecoIn1n13:1320, 2009

Alouini S, Coly S, Megier P, Lemaire B, et al: Multiple square sutures for postpartum hemorrhage: results and hysteroscopic assessment. Am ] Obstet Gynecol 205(4):335, 2011

American Association of Blood Banks: Circular of information for the use of human blood and blood components. 2014. Available at: https:llwww.fda. gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatolyinformation/guidances/blood/ucm364593.pdf. Accessed July 31,n2017

American Association of Blood Banks: Human parvovirus B19. 2013. Available at: https:l/www.aabb.orgltm/eid/Documents/Human-Parvovirus-B 19. pdf. Accessed] uly 31, 2017

American College of Obstetricians and Gynecologists: Premature rupture of membranes. Practice Bulletin No. 172, January 2016a

American College of Obstetricians and Gynecologists: Prevention and management of obstetric lacerations at vaginal delivery. Practice Bulletin No. 165, July 2016b

American College of Obstetricians and Gynecologists: Antiphospholipid syndrome. Practice Bulletin No. 132, December 2012, Reairmed 2017a

American College of Obstetricians and Gynecologists: Inherited thrombophilias in pregnancy. Practice Bulletin No. 138, September 2013, Reairmed 2017b American College of Obstetricians and Gynecologists: Placenta accreta. Com mittee Opinion No. 529, July 2012, Reairmed 201

American College of Obstetricians and Gynecologists: Postpartum hemorrhage. Practice Bulletin No. 183, Ocrober 2006, Reairmed 2017 d

American Institute of Ultrasound in Medicine: ALUM practice guideline for the performance of obstetric ultrasound examinations. J Ultrasound Med 32(6):1063,n2013

An GH, Ryu HM, Kim My, et al: Outcomes of subsequent pregnancies after uterine compression sutures for postpartum hemorrhage. Obstet Gynecol 122(3):565,n2013

Ananth CV, Berkowitz GS, Sayitz DA, et al: Placental abruption and adverse perinatal outcomes. JAMA 282:1646, 1999a

Ananth CV, Demissie K, Smulian JC, et al: Relationship among placenta previa, fetal growth restriction, and preterm delivery: a population-based study. Obstet Gynecol 98:299,n2001

Ananth CV, Friedman AM, Lavery JA, et al: Neurodevelopmental outcomes in children in relation ro placental abruption. BjOG 124(3):463,n2017 Ananth CV, Getahun 0, Peltier MR, et al: Placental abruption in term and preterm gestations. Obstet Gynecol 107:785, 2006

Ananth CV, LavelY JA, Vintzileos AM, et al: Severe placental abruption: clinical deinition and associations with maternal complications. Am J Obstet GynecoIn214(2):272.el,n2016

Ananth CV, Oyelese Y, Srinivas N, et al: Preterm premature rupture of membranes, intrauterine infection, and oligohydramnios: risk facrors for placental abruption. Obstet Gynecol 104: 71, 2004

Ananth CV, Oyelesc Y, Yeo L, et al: Placental abruption in the United States, 1979 through 2001: temporal trends and potential determinants. Am J Obstet Gynecol 192(1):191,n2005

Ananth CV, Peltier MR, Kinzler L, et al: Chronic hypertension and risk of placental abruption: is the association modiied by ischemic placental disease? Am J Obstet Gynecol 197:273.e1, 2007

Ananth CV, Smulian JC, Vintzileos M: Incidence of placental abruption in relation ro cigarette smoking and hypertensive disorders during pregnancy: a meta-analysis of observational studies. Obstet Gynecol 93:622, 1999b

Ananth CV, Smulian JC, Vintzileos AM: The efect of placenta previa on neonatal morraliry: a population-based study in the United States, J 989 through 1997. Am J Obstet Gynecol 188:1299,n2003

Anrony KM, Racusin DA, Belfort MA, et al: Under pressure: intraluminal illing pressures of postpartum hemorrhage tamponade balloons. AJP Rep 7(2):e86, 2017

Arazi ES, Kessous R, Shoham-Vardi I, et al: Is there an association between a hisrory of placental abruption and long-term matenal renal complications? J Matern Fetal Neonatal Med 28(14):1641, 2015

Arici V, Corbetta R, Fossati G, et al: Acute irst onset of Ehlers-Danlos syndrome type 4 with spontaneous rupture of posterior tibial artery pseudoaneurysm. Vascular 21(1):43,n2013

Atkinson AL, Sanrolaya-Forgas J, Matta P, et al: The sensitivity of the K1eihauer-Betke test for placental abruption. J Obstet Gynaecol 35(2): 139, 2015

Aviram A, Salzer L, Hiersch L, et al: Association of isolated polyhydramnios at or beyond 34 weeks of gestation and pregnancy outcome. Obstet Gynecol 125(4):825,n2015

Awan N, Bennett MJ, Walters WA: Emergency peripartum hysterectomy: a 10-year review at the Royal Hospital for Women, Sydney. Aust N Z J Obstet Gynaecol 51(3):210,n2011 B-Lynch C: Partial ischemic necrosis of the uterus following a uterine brace compression suture. BJOG 112: 126, 2005 B-Lynch CB, Coker A, Laval AH, et al: he B-Lynch surgical technique for control of massive postpartum hemorrhage: an alternative ro hysterectomy? Five cases reported. BJOG 104:372, 1997

Babinszki A, Kerenyi T, Torok 0, et al: Perinatal outcome in grand and greatgrand multiparity: efects of parity on obstetric risk factors. Am J Obstet Gynecol 181 :669, 1999

Bailit JL, Grobman WA, Rice MM, et al: Morbidly adherent placenta treatments and outcomes. Obstet GynecoIn125(3):683, 2015

Ballas J, Hull AD, Saenz, et al: Preoperative intravascular balloon catheters and surgical outcomes in pregnancies complicated by placenta accreta: a management paradox. Am J Obstet Gynecol 207(3):216.el, 2012

Bankada V, Purra P, Ningappa AM, et al: A rare case of bilateral broad ligament haemaroma in twin pregnancy. J C1in Diagn Res 9(10):QD03, 2015

Barber A, Shires GT III, Shires GT: Shock. In Schwartz SI, Shires GT, Spencer FC, et al (eds): Principles of Surgery, 7th ed. New York, McGraw-Hili, 1999

Barbieri RL: Control of massive hemorrhage: lessons from Iraq reach the U.S. labor and delivery suite. OBG Management 19:8,n200

Barth WH Jr, Kwolek q, Abrams JL, et al: Case records of the MassachusettS General Hospital. Case 23-2011. A 40-year-old pregnant woman with placenta accreta who declined blood products. N Engl J Med 365(4):359, 201n1

Ben-Ami I, Fuchs N, Schneider 0, et al: Coagulopathy associated with dilation and evacuation for second-trimester abortion. Acta Obstet Gynecol Scand 91 (1): 10,n2012

Benirschke K, Burton, Baergen RN: Pathology of the Human Placenta, 6th ed.

New York, Springer, 2012, p 204

Berg q, Callaghan WM, Syverson C, et al: Pregnancy-related mortaliry in the United States, 1998-2005. Obstet GynecoIn1l6(6):1302, 2010

Berg q, Chang J, Callaghan WM, et al: Pregnancy-related mortaliry in the United States, 1991-1997. Obstet Gynecol 101:289,n2003

Berg CJ, MacKay AP, Qin C, et al: Overview of maternal morbidity during hospitalizations for labor and delivery in the United States. 1993-1997 and 2001-2005. Obstet GynecoIn113(5):1075, 2009

Berhie SH, Molina RL, Davis MR, et al: Laparoscopic hysterectomy for -week cesarean delivery scar implantation pregnancy. Am J Obstet Gynecol 212:247.el, 2015

Bhandari S, Raja EA, Shetty A, et al: Maternal and perinatal consequences of antepartum haemorrhage of unknown origin. BJOG 121(1):44,n2014 Bingol N, Fuchs M, Diaz V, et al: Terarogenicity of cocaine in humans.

J rediatr 110:93, 1987

Biro A, Davey A, Carolan M, et al: Advanced matenal age and obstetric morbidity for women giving birth in Vicroria, Australia: a population-based study. Aust N ZJ Obstet GynaecoI52(3):229, 2012

Bishop S, Butler K, Monaghan S, et al: Multiple complications following the use of prophylactic internal iliac artery balloon catheterization in a patient with placenta percreta. Int J Obstet Anesth 20(1):70, 2011

Biswas R, Sawhney H, Dass R, et al: Hisropathological study of placental bed biopsy in placenta previa. Acta Obstet Gynecol Scand 78: 3, 1999

Bleich AT, Rahn DO, Wieslander CK, et al: Posterior division of the internal iliac artery: anaromic variations and clinical applications. Am J Obstet Gynecol 197:658.el, 2007

Bohrer J, Goh W, Hirai C, et al: Obstetrical outcomes in patients with lowlying placenta in the second trimester. Abstract No. 129, Am J Obstet Gynecol 206(1):S69, 2012

Bond AL, Edersheim TG, Curry L, et al: Expectant management of abruptio placentae before 35 weeks' gestation. m J Perinarol 6:121,n1989

Boral LI, Hill SS, Apollon q, et al: he type and antibody screen, revisited.

Am J C1in Pathol 71:578, 1979

Borgman MA, Spinella PC, Perkins JC, et al: he ratio of blood products transfused afects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma 63:805, 2007

Bose DA, Assel BG, Hill JB, et al: Maintenance tocolytics for preterm symptomatic placenta previa: a review. Am J Perinatol 28(1):45, 2011

Bowman ZS, Eller AG, Kennedy M, et al: Accuracy of ultrasound for the prediction of placenta accreta. Am J Obstet Gynecol 211 (2): 1n.e1, 2014 Boyle RK, Waters BA, O'Rourke PK: Blood transusion for caesarean delivery complicated by placenta praevia. Aust N Z J Obstet Gynaecol 49(6):627, 2009 Brame RG, Harbert GM Jr, McGaughey HS Jr, et al: Maternal risk in abruption. Obstet Gynecol 31 :224, 1968

Brennan OJ, Schulze B, Chetty N, et al: Surgical management of abnormally invasive placenta: a retrospective cohort study demonstrating the beneits of a standardized operative approach. Acta Obstet Gynecol Scand 94(12):1380, 2015

Bretelle f, Courbiere B, Mazouni C, et al: Management of placenta accreta: morbidity and outcome. Eur J Obstet Gynecol Reprod Bioi 133(1):34,2007

Brosens I, Pijnenborg R, Vercruysse L, et al: The "great obstetrical syndromes" are associated with disorders of deep placentation. Am J Obstet Gynecol 204(3): 193, 2011

Budden A, Chen LJ, Henry A: High-dose versus low-dose oxytocin infusion regimens for induction of labour at term. Cochrane Database Syst Rev 1 0:CD00970 1, 2014

Burchell RC: Physiology of internal iliac artery ligation. J Obstet Gynaecol Br Commonw 75:642, 1968

Burkman RT, Bell WR, Atienza MF, et al: Coagulopathy with midtrimester induced abortion: association with hyperosmolar urea administration. Am J Obstet Gynecol 127:533, 197

Butwick AJ, Goodnough LT: Transfusion and coagulation management in major obstetric hemorrhage. Curr Opin Anesthesiol 28:275, 2015

Cali G, Biambanco L, Puccio G, et al: Morbidly adherent placenta: evaluation of ultrasound diagnostic criteria and diferentiation of placenta accreta from percreta. Ultrasound Obstet Gynecol 41 (4) :406, 2013

Callaghan WM, Creanga AA, Kuklina EV: Severe maternal morbidity among delivelY and postpartum hospitalizations in the United States. Obstet Gynecol 120(5):1029, 2012

Carson ]L, Triulzi 0], Ness PM: Indications for and adverse efects of red-cell transfusion. N Engl] Med 377:13, 201

Casey B, de Veciana M: Thyroid screening in pregnancy. Am] Obstet Gynecol 211:351,n2014

Catanzarite V, Cousins L, Daneshmand S, et al: Prenatally diagnosed vasa previa. A single-institution series of 96 cases. Obstet Gynecol 128(5):1153, 2016

Centers for Disease Control and Prevention: Zika and blood transfusions. 2016.

Available at: https:/ Iww.cdc.govlzika/transmission/blood-transfusion.html. Accessed March 3, 2017

Chalubinski K, Pils S, Klein K, et al: Prenatal sonography can predict the degree of placental invasion. Ultrasound Obstet Gynecol 42(5):518, 2013

Chantraine F, Braun T, Gonser M, et al: Prenatal diagnosis of abnormally invasive placenta reduces maternal peripartum hemorrhage and morbidity. Acta Obstet Gynecol Scand 92(4):439,n2013

Chantry AA, Deneux-Tharaux C, Bonnet MP, et al: Pregnancy-related ICU admissions in France: trends in rate and severity, 2006-2009. Crit Care Med 43: 8,n2015

Chauleur C, Fanget C, Tourne G, et al: Serious primary post-partum hemorrhage, arterial embolization and future fertility: a retrospective study of 46 cases. Hum Reprod 23:1553, 2008

Chen AL, Goldfarb IT, Scourtas AO, et al: he histologic evolution of revealed, acute abruptions. Hum Pathol 67: ,n201

Chescheir NC, Seeds ]W: Spontaneous resolution of hypo fibrin ogenemi a associated with death of a twin in utero: a case report. Am ] Obstet Gynecol 159:1183, 1988

Cho ]H, ]un HS, Lee CN: Haemostatic suturing technique or uterine bleeding during cesarean delivery. Obstet Gynaecol 96: 129, 2000

Cho ]Y, Kim S], Cha Y, et l: Interrupted circular suture: bleeding control during cesarean delivery in placenta previa accreta. Obstet Gynecol 78:876, 1991 Cichowski S, Rogers RG: Managing complications of perineal lacerations. Contemp Ob/Gyn 62:22, 2017

Clark SL Amniotic luid embolism. Obstet Gynecol 123:337,n2014

Clark SL, Hankins GDV, Dudley DA, et al: Amniotic luid embolism: analysis of the National Registry. Am] Obstet GynecoIn172:1158, 1995

Clark SL, Pavlova Z, Greenspoonn], et al: Squamous cells in the maternal pulmonary circulation. Am ] Obstet Gynecol 154: 104, 1986

Clark SL, Phelan ]P, Yeh SY: Hypogastric artery ligation for obstetric hemorrhage. Obstet Gynecol 66:353, 1985

Clark SL, Romero R, Dildy GA, et al: Proposed diagnostic criteria for the case definition of amniotic luid embolism in research studies. Amn] Obstet Gynecol October, 2016

Clausen C, Stensballe], Albrechtsen CK, et al: Balloon occlusion of the internal iliac arteries in the multidisciplinary management of placenta percreta. Acta Obstet Gynecol Scand 92(4):386, 2013

Cleary-Goldman ], Malone FD, Vidaver ], et al: Impact of maternal age on obstetric outcome. Obstet Gynecol 105:983,n2005

Coad S, Dahlgren L, Hutcheson ]A: Risk and consequences of puerperal uterine inversion in the United States, 2004-2013. Amn] Obstet Gynecol ,201

Collins SL, Stevenson GN, AI-Khan A, et al: Three-dimensional power Doppler ultrasonography for diagnosing abnormally invasive placenta and quantiying the risk. Obstet GynecoIn126(3):645, 2015

Colon I, Berletti M, Garabedian M], et al: Randomized, double-blinded trial of magnesium sulfate tocolysis versus intravenous normal saline for preterm nonsevere placental abruption. Am] Perinatol 33(7):696, 2016

Combs CA, Nyberg DA, Mack A, et al: Expectant management after 5Onographic diagnosis of placental abruption. Am] Perinatol 9: 170, 1992 Conrad LB, Groome K], Black DR: Management of persistent postpartum hemorrhage caused by inner myometrial lacerations. Obstet Gynecol 126(2):266,n2015

Counts RB, Haisch C, Simon TL, et al: Hemostasis in massively transfused trauma patients. Ann Surg 190:91, 1979

Crane ]M, Van Den Hof MC, Dodds L, et al: Neonatal outcomes with placenta previa. Obstet Gynecol 93:541, 1999

Creanga A, Bateman BT, Kuklina EV, et al: Racial and ethnic disparities in severe maternal morbidity: a multistate analysis, 2008-2010. Amn] Obstet GynecoIn21O(5):435.e.1,n2014

Creanga A, Berg C], Syverson C, et al: Pregnancy-related mortality in the United States, 2006-2010. Obstet Gynecol 125(1):5,n2015

Creanga A, Syverson C, Seed K, et al: Pregnancy-related mortality in the United States, 2011-2013. Obstet GynecoIn130:366, 2017

Cressman M, Natekar A, Kim E, et al: Cocaine abuse during pregnancy. ] Obstet Gynaecol Can 36(7):628, 2014

Crozier TM, Wallace EM: Obstetric admissions to an integrated general intensive care unit in a quaternary maternal facility. Aust N Z] Obstet Gynaecol 51(3):233,n2011

Cummings K, Doherty DA, Magann EF, et al: Timing of manual placenta removal to prevent postpartum hemorrhage: is it time to act? ] Matern Fetal Neonatal Med 29(24):3930,n2016

Cunningham FG: Genital tract lacerations and hematomas. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hill Education, 2017a

Cunningham FG: Placenta previa and morbidly adherent placenta. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education,n20n17b

Cunningham FG, Nelson DB: Disseminated intravascular coagulation syndromes in obstetrics. Obstet Gynecol 126(5):999,n2015

Cunningham KM, Anwar A, Lindow SW: The recurrence risk of placenta accreta following uterine conserving management. ] Neonatal Perinatal Med 8(4):293,n2016

Dagdeviren H, Cengiz H, Heydarova U, et al: Intramuscular versus intravenous prophylactic oxytocin for postpartum hemorrhage after vaginal delivery: a randomized controlled study. Arch Gynecol Obstet 294(5):911, 2016

Dashe ]S: Toward consistent terminology of placental location. Semin PerinatoIn37(5):375,n2013

De Greve M, Van Mieghem T, Van Den Berghe G, et al: Obstetric admissions to the intensive care unit in a tertiary hospital. Gynecol Obstet Invest 81(4):315,n2016 de Lange NM, van Rheenen-Flach LE, Lance MD, et al: Peri-partum reference ranges for ROTEM thromboelastography. Br] Anesth 112:852,n2014

Deneux-Tharaux C, Sentilhes L, Maillard F, et al: Efect of routine controlled cord traction as part of the active management of the third stage of labour on postpartum hemorrhage: multicentre randomized controlled trial (TRACOR). BM] 346:fl541, 2013

Derman RJ, Kodkany BS, Gaudar SS, et al: Oral misoprostol in preventing postpartum haemorrhage in resource-poor communities: a randomized controlled trial. Lancet 368: 1248, 2006

DeRoo L, Skjaervan R, Wilcox A, et al: Placental abruption and long-term maternal cardiovascular disease mortality: a population-based registry study in Norway and Sweden. Eur] EpidemioI31(5):501, 2016

Desai N, Tam HT, Fleischer A: Prophylactic arterial catheterization may improve operative morbidity in suspected placenta accreta and reduce the need for hysterectomy. Amn] Obstet Gynecol 206(1):S44, 2012

Dhariwal SK, Khan KS, Allard S, et al: Does current evidence support the use of intraoperative cell salvage in reducing the need for blood transfusion in caesarean section? Curr Opin Obstet GynecoIn26(6):425, 2014 Diemert A, Ortmeyer G, Hollwitz B, et al: The combination of intrauterine balloon tamponade and the B-Lynch procedure for the treatment of severe postpartum hemorrhage. Am] Obstet GynecoI206(1):65.e1, 2012 Dildy GA, Scott AR, Safer CS: An efective pressure pack for severe pelvic hemorrhage. Obstet Gynecol 108(5):1222,n2006

Distefano M, Casarella L, moroso S, et al: Selective arterial embolization as a first-line treatment for postpartum hematomas. Obstet Gynecol 121 (2 Pt 2 Suppl):443, 2013

Downes KL, Grantz L, Shenassa ED: Maternal, labor, delivery, and perinatal outcomes associated with placental abruption: a systematic review. Am ] PerinatoIn34:935,n2017 Downes L, Hinkle SN, Sjaarda A, et al: Previous prelabor or intrapartum cesarean delivery and risk of placenta previa. Am ] Obstet Gynecol 212(5):669.e1,n2015

Downes LK, Shenassa ED, Grantz L: Duration of labor associated with placental abruption. Abstract No. 692, Am] Obstet GynecoIn214(l):S365, 2016 Doyle N, Pullenn], Holliday N, et al: 3D ultrasound: the best view of placenta accreta. Abstract No. 108, Am] Obstet GynecoI212(1):S72, 2015

Drakeley AJ, Le Roux PA, Anthonyn], et al: Acute renal failure complicating severe preeclampsia requiring admission to an obstetric intensive care unit. Am] Obstet Gynecol 186:253, 2002

Driessen M, Bouvier-Colle MH, Dupont C, et al: Postpartum hemorrhage resulting from uterine atony after vaginal delivery. Factors associated with severity. Obstet GynecoIn117(1):21, 2011

Dugof L, Hobbins ]C, Malone FD, et al: First trimester maternal serum PAPPA and free-beta subunit human chorionic gonadotropin concentrations and nuchal translucency are associated with obstetric complications: a population-based screening study (The FASTER Trial). Amn] Obstet Gynecol 191:1446, 2004

Duzyj CM, Barishansky S, Khan S, et al: Evidence of active wound remodeling at the site of trophoblast invasion in placenta accreta. Abstract No. 147, Am ] Obstet Gynecol 216:S99, 201 Duzyj CM, Buhimschi IA, Motawea H, et al: The invasive phenotype of placenta accreta extravillous trophoblasts associates with loss of E-cadherin. Placenta 36(6):645,n2015

Einerson BD, Son M, Schneider P, et al: The association between intrauterine balloon tamponade duration and postpartum hemorrhage outcomes. Am J Obstet GynecoIn216:300.el, 2017

Elhawary TM, Dabees NL, YoussefA:Diagnostic value of ultrasonography and magnetic resonance imaging in pregnant women at risk for placenta accreta. J Matern Fetal Neonatal Med 26(14): 1443, 2013

Eller AG, Bennett A, Sharshiner M, et al: Maternal morbidity in cases of placenta accreta managed by a multidisciplinary care team compared with standard obstetric care. Obstet Gynecol 117(2 Pt 1):331, 2011

Elliott JP, Gilpin B, Strong TH Jr, et al: Chronic abruption-oligohydramnios sequence. J Reprod Med 43:418, 1998

Erez 0, Mastrolia SA, Thachil J: Disseminated intravascular coagulation in pregnancy: insights in pathophysiology, diagnosis and management. Am J Obstet GynecoIn213(4):452, 20n15

Erez 0, Novack L, Beer-Weisel R, et al: DIC score in pregnant women-a population based modification of the International Society on Thrombosis and Hemostasis score. PLoS One 9:e93240, 2014

Erfani H, Fox A, Bateni ZH, et al: Morbidly adherent placenta-comparison of characteristics and outcomes between scheduled and unscheduled deliveries managed within a single, multidisciplinary team-based referral center. Abstract No. 724, Am J Obstet GynecoIn21n6:S422, 2017a

Erfani H, Fox A, Bateni ZH, et al: Multidisciplinary team learning in management of morbidly adherent placenta-outcome improvements over time. Abstract No. 865, Am J Obstet Gynecol 216:5494, 2017b

Esakof TF, Handler SJ, Granados JM, et al: PAMUS: placenta accreta management across the United States. J Matern Fetal Neonatal Med 25:761, 20n12

Eshkoli T, Weintraub AY, Sergienko R, et al: Placenta accreta: risk factors, perinatal outcomes, and consequences for subsequent births. Am J Obstet Gynecol 208(3):219.e1, 2013

Etchason J, Petz L, Keeler E, et al: The cost efectiveness of preoperative autologous blood donations. N Engl J Med 332:719, 1995

Ezzedine D, Norwitz ER: Are women with uterine fibroids at increased risk for adverse pregnancy outcome? C1in Obstet Gynecol 59(1):119, 2016

Farine D, Fox HE, Jakobson 5, et al: Vaginal ultrasound for diagnosis of placenta previa. Am J Obstet Gynecol 159:566, 1988

Finfer 5, Bellomo R, Boyce N, et al: A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 350:2247, 2004

Fiori 0, Deux JF, Kambale JC, et al: Impact of pelvic arterial embolization for intractable postpartum hemorrhage on fertility. Am J Obstet Gynecol 200:384.e1,n2009

Fitzpatrick K, Sellers 5, Spark P, et al: he management and outcomes of placenta accreta, increta, and percreta in the UK: a population-based descriptive study. BJOG 121(1):62,n2014

Food and Drug Administration: Revised recommendation for reducing the risk ofZika virus transmission by blood and blood components. 2016. Available at: https:llwww. fda.govl downloads/BiologicsBloodVaccineslGuidanceComplianceRegulatorylnformation/Guidances/Blood/UCM5n18213. pdf. Accessed March 3, 2017

Fong A, Wu E, Pan D, et al: Temporal trends and morbidities of vacuum, forceps, and combined use of both. J Matern Fetal Neonatal Med 27(8):1886, 2014

Foroutan-Rad M, Majidan H, Dalvand 5, et al: Toxoplasmosis in blood donors: a systematic review and meta-analysis. Transfus Med Rev 30(3):116,n2016

Fox K, Shamshirsaz A, Salman ian B, et al: Is interpregnancy interval a predictor of severity of invasion in morbidly adherent placenta? Abstract No. 821, Am J Obstet GynecoIn212(1):S395, 2015

Frederiksen MC, Glassenberg R, Stika CS: Placenta previa: a 22-year analysis.

Am J Obstet GynecoIn180:1432, 1999

Friederich L, Roman H, Marpeau L: A dangerous development. Am J Obstet Gynecol 196:92, 2007

Frimat M, Decambron M, Lebas C, et al: Renal cortical necrosis in postpartum hemorrhage: a case series. Am J Kidney Dis 68(1):50,2016 Friszer 5, Le Ray C, Tort J, et al: Symptomatic placenta praevia: short cervix at admission is a predictive factor for delivery within 7 days. Abstract No. 158, Am J Obstet Gynecol 208(1):578,n2013

Frolova AI, Stout MJ, Tuuli MG, et al: Duration of the third stage oflabor and risk of postpartum hemorrhage. Obstet GynecoIn127(5):951, 2016 Furuhashi M, Kurauchi 0, Suganuma N: Pregnancy following placental abruption. Arch Gynecol Obstet 267:n11n,n2002

Furukawa 5, Doi K, Furuta K, et al: he efect of placental abruption on the outcome of extremely premature infants. J Matern Fetal Neonatal Med 28(6):705,n2015a

Furukawa 5, Sameshima H: The importance of the monitoring of resuscitation with blood transfusion for uterine inversion in obstetrical hemorrhage. Obstet Gynecol Int 2015:269156, 2015b

Garmi G, Samlim R: Epidemiology, etiology, diagnosis, and management of placenta accreta. Obstet Gynecol Int 2012:873929,n2012

Georgiou C: Balloon tamponade in the management of postpartum haemorrhage: a review. BJOG 116(6):748,2009

Gerstenfeld TS, Wing DA: Rectal misoprostol versus intravenous oxytocin for the prevention of postpartum hemorrhage after vaginal delivery. Am J Obstet Gynecol 185:878, 2001

Gesteland K, Oshiro B, Henry E, et al: Rates of placenta previa and placental abruption in women delivered only vaginally or only by cesarean section. Abstract No. 403, J Soc Gynecol Invest 11:208A, 2004

Getahun BS, Yeshi MM, Roberts DJ: Case records of the Massachusetts General Hospital: case 34-2012: a 27-year old woman in Ethiopia with severe pain, bleeding, and shock during labor. N Engl J Med 367(19):1839, 2012

Gibbins KJ, Einerson BD, Varner MW, et al: Placenta previa and maternal hemorrhagic morbidity. J Matern Fetal Neonatal Med 31(4):494,n2018

Gibbins KJ, Weber T, Holmgren CM, et al: Maternal and fetal morbidity associated with uterine rupture of the unscarred uterus. Am J Obstet Gynecol 213(3):382.e1,n2015

Gilbert WM, Danielsen B: Amniotic luid embolism: decreased mortality in a population-based study. Obstet Gynecol 93:973, 1999

Gill A, Baldwin E, Lessard-Anderson C, et al: Septic abortion with placenta accreta in pregnancy after endometrial ablation. Obstet Gynecol 125(4):822,n2015

Gilliam M, Rosenberg D, Davis F: he likelihood of placenta previa with greater number of cesarean deliveries and higher parity. Obstet Gynecol 99:976, 2002

Gilstrap LC III: Management of postpartum hemorrhage. In Yeomans ER, Hofman BL, Gilstrap LC, et al (eds): Cunningham and Gilstrap's Operative Obstetrics. New York, McGraw-Hill Education, 2017

Gizzo 5, Saccardi C, Paztrelli TS, et al: Bakri balloon in vaginal-perineal hematomas complicating vaginal delivery: a new therapeutic approach. J Low Genit Tract Dis 17:125,n2013

Glantz C, Purnell L: Clinical utility of sonography in the diagnosis and treatment of placental abruption. J Ultrasound Med 21 :837, 2002

Gofman D, Nathan L, Chazotte C: Obstetric hemorrhage: a global review.

Semin PerinatoIn40(2):96, 2016

Goh WA, Zalud I: Placenta accreta: diagnosis, management and the molecular biology of the morbidly adherent placenta. J Matern Fetal Neonatal Med 29(11):1795,n2016

Gonzalez EA, Moore FA, Holcomb JB, et al: Fresh frozen plasma should be given earlier to patients requiring massive transfusion. J Trauma 62: 1n12, 2007 Goodnough LT, Levy JH: he judicious use of recombinant factor VIla. Semin

Thromb Hemost 42(2):125,n2016

Gopalakrishnan N, Dhanapriya J, Muthkumar P, et al: Acute kidney injury in pregnancy-a single center experience. Ren Fail 37(9):1476, 2015

Gottlieb AG, Pandipati S, Davis M, et al: Uterine necrosis. A complication of uterine compression sutures. Obstet Gynecol 112:429,n2008

Goucher H, Wong CA, Patel SK, et al: Cell salvage in obstetrics. Anesth Analg 121(2):465,n2015

Green L, Knight M, Seeney FM, et al: The epidemiology and outcomes of women with postpartum haemorrhage requiring massive transfusion with eight or more units of red cells: a national cross-sectional study. BJOG 123(13):2164, 20n16

Gronvall M, Tikkanen M, Metsatahti M, et al: Pelvic arterial embolization in severe obstetric hemorrhage. Acta Obstet Gynecol Scand 93(7):716, 2014

Gronvall M, Tikkanen M, Tallberg E: Use of Bakri balloon tamponade in the treatment of postpartum hemorrhage: a series of 50 cases from a tertiary teaching hospital. Acta Obstet Gynecol Scand 92(4):433, 2013

Giilmezoglu M, Lumbiganon P, Landoulsi S, et al: Active management of the third stage of labor with and without controlled cord traction: a randomized, controlled, non-inferiority trial. Lancet 379(9827):1721, 2012

Guntupalli KK, Hall N, Karnad DR, et al: Critical illness in pregnancy: part I: an approach to a pregnant patient in the lCU and common obstetric disor ders. Chest 148(4):1093,n2015

Gurol-Urganci I, Cromwell DA, Edozien LC, et al: Risk of placenta previa in second birth after first birth cesarean section. BMC Pregnancy Childbirth 11:95,n201n1

Gutvirtz G, Walfisch A, Beharier 0, et al: Isolated single umbilical artery is an independent risk factor for perinatal mortality and adverse outcomes in term neonates. Arch Gynecol Obstet, 294(5):931, 2016

Gyami-Bannerman C, Gilbert S, Landon MB, et al: Risk of uterine rupture and placenta accreta with prior uterine surgery outside of the lower segment. Obstet GynecoIn120(6):1332, 2012

Hackney DN, Kuo K, Petersen RJ, et al: Determinants of the competing outcomes of intrauterine infection, abruption, or spontaneous preterm birth after preterm premature rupture of membranes. J Matern Fetal Neonatal Med 29(2):258,n2016

Haeri S, Rais S, Monks B: Intrauterine tamponade balloon use in the treatment of uterine inversion. BM] Case Rep January 6, 2015

Hale SA, Sobel B, Benvenuto A, et al: Coagulation and ibrinolytic system protein proiles in women with normal pregnancies and pregnancies complicated by hypertension. Pregnancy Hypertens 2(2):152, 2012

Hamm RF, Wang EY, O'Rourke K, et al: Implementation of quantitative blood loss does not improve prediction of hemoglobin drop in deliveries with average blood loss. Abstract No. 454, Amn] Obstet Gynecol ,n2017

Hankins GO, Berryman GK, Scott RT ]r, et al: Maternal arterial desaturation with 15-methyl prostaglandin F2 alpha for uterine atony. Obstet Gynecol 72:367, 1988

Happe SK, Rac MW, Moschos E, et al: Prospective assessment of morbidly adherent placenta with irst trimester ultrasound. Presented at the 38th Annual Meeting of the Society for Maternal-Fetal Medicine, January 29February 3, 2018

Happe SK, Yule CS, Wells EC: Outcomes in pregnancies complicated by uterine rupture. Unpublished data, 201 Hardardottir H, Borgida AF, Sanders MM, et al: Histologic myometrial ibers adherent to the placenta: impact of method of placental removal. Am ] Obstet Gynecol 174:358, 1996 Hardin MO, Ritchie ]0, Aden ]K, et al: Plasma-to-red cell ratio and mechanism of injury in massively transfused combat casualties. Mil Med 179(1):92,n2014 Harper LM, Odibo AO, Macones GA, et al: Efect of placenta previa on fetal growth. Am] Obstet GynecoIn203(4):330.e1, 2010 Hayman RG, Arulkumaran S, Steer P]: Uterine compression sutures: surgical management of postpartum hemorrhage. Obstet Gynecol 99:502, 2002 Hebert PC: Anemia and red cell transfusion in critical care. Transfusion Requirements in Critical Care Investigators and the Canadian Critical Care Trials Group. Minerva Anestesiol 65(5)293, 1999 Heller HT, Mullen M, Gordon RW, et al: Outcomes of pregnancies with a low-lying placenta diagnosed on second-trimester sonography. ] Ultrasound Med 33(4):691, 2014 Hellman LM, Pritchard ]A (eds): Placenta previa. In Williams Obstetrics, 14th ed. New York, Appleton Century Crofts, 1971 Hernandez ]S, Alexander ]M, Sarode R, et al: Calculated blood loss in severe obstetric hemorrhage and its relation to body mass index. Am ] Perinatol 29(7):557,n2012 Herrera C, Meehan R, Poddutori V, et al: Maternal deaths due to Clostridium novyi in an injection drug user. Obstet Gynecol 128:876,n2016 Hofmeyr G], Abdel-Aleem H, Abdel-Aleem A: Uterine massage for preventing postpartum haemorrhage. Cochrane Database Syst Rev 7:CD006431, 2013 Hogberg V, Rasmussen S, Irgens L: The efect of smoking and hypertensive disorders on abruptio placentae in Norway 1999-2002. Acta Obstet Gynecol Scand 86:304, 2007 Holst LB, Haase N, Wetterslev], et al: Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl] Med 371(15):1381, 2014 Hossain N, Paidas M]: Disseminated intravascular coagulation. Semin Perinatol 37(4):257, 2013 Howard R], Straughnn]M ]r, Huh K, et al: Pelvic umbrella pack for refractory obstetric hemorrhage secondary to posterior uterine rupture. Obstet Gynecol 100(5 Pt 2):1061, 2002 Hui C, Lili M, Libin C, et al: Changes in coagulation and hemodynamics during pregnancy: a prospective longitudinal study of 58 cases. Arch Gynecol Obstet 285(5):1231,n2012 Hung TH, Shau Y, Hsieh CC, et al: Risk factors for placenta accreta. Obstet Gynecol 93:545, 1999 Hunt BJ: Bleeding and coagulopathies in critical care. N Engl] Med 370:847, 2014 Hurd W, Miodovnik M, Hertzberg V, et al: Selective management of abruptio placentae: a prospective study. Obstet Gynecol 61 :467, 1983 Ibrahim Ml, Raafat TA, Ellaithy MI, et al: Risk of postpartum uterine synechiae following uterine compression suturing during postpartum haemorrhage. Aust N Z] Obstet Gynecol 53(1):37, 2013 Ida A, Ito K, Kubota Y, et al: Successful reduction of acute puerperal uterine inversion with the use of a Bakri postpartum balloon. Case Rep Obstet GynecoIn2015:424891,n2015 Iskender C, Topcu HO, Timur H, et al: Evaluation of risk factors in women with puerperal genital hematomas. ] Matern Fetal Neonatal Med 29(9):1435,n2016

Jackson BR, Busch MP, Stramer SL, et al: he cost-efectiveness of NAT for HIV, HCV, and HBV in whole-blood donations. Transfusion 43:721, 2003 ]akobsson M, Tapper M, Colmorn LB, et al: Emergency peripartum hysterectomy: results from the prospective Nordic Obstetric Surveillance Study (NOSS). Acta Obstet Gynecol Scand 94(7):745, 2015 ]auniaux E, Collins S, Burton G]: Placenta accreta spectrum: pathophysiology and evidence-based anatomy for prenatal ultrasound imaging. Am ] Obstet Gynecol ] une 24, 2017 [Epub ahead of print] ]auniaux E, Collins SL, ]urkovic 0, et al: Accreta placentation: a systematic review of prenatal ultrasound imaging and grading of villous invasiveness. Am] Obstet GynecoIn215(6):712, 2016 ]enabi E, Fereidooni B: The uterine leiomyoma and placenta previa: a meta-analysis. ] Matern Fetal Neonatal Med November 21,2017 [Epub ahead of print] ] ohansson PI, Stensballe ], Rosenberg I, et al: Proactive administration of platelets and plasma for patients with a ruptured abdominal aortic aneurysm: evaluating a change in transfusion practice. Transfusion 47:593, 2007

Joshi VM, Shrivastava M: Partial ischemic necrosis of the uterus following a uterine brace compression suture. B]OG III :279, 2004

Judy AE, Lyell 0], Druzin ML, et al: Disseminated intravascular coagulation complicating the conservative management of placenta percreta. Obstet Gynecol 126(5):1016,n2015 Kaminsky LM, Ananth CV, Prasad V, et al: he influence of matenal cigarette smoking on placental pathology in pregnancies complicated by abruption. An1] Obstet Gynecol 197:275.e1, 2007 Kaplanoglu M, Kaplanoglu 0, Bulbul M, et al: Inner myometrial laceration-an unusual presentation of antepartum and postpartum hemorrhage: case reports and review of the literature.] Matern Fetal Neonatal Med 29(16):2621,2016 Kassir E, Fox A, Efani H, et al: Placenta previa without morbidly adherent placentation: comparison of characteristics berween scheduled and unscheduled (emergency) deliveries in a tertiary center. Abstract 26, Am ] Obstet Gynecol 216:S423, 2017 Katakam N, Vitthala S, Sasson S, et al: Complications and failure of uterine artery embolization for intractable postpartum haemorrhage. B]OG 116(6):863,n2009 Kawamura Y, Kondoh E, Hamanishi ], et al: Treatment decision-making for postpartum hemorrhage using dynamic contrast-enhanced computed tomography.n] Obstet Gynaecol Res ,n2014 Kaya B, Guralp 0, Tuten A, et al: Which uterine sparing technique should be used for uterine atony during cesarean section? The Bakri balloon or the B-Lynch suture? Arch Gynecol Obstet 294(3):511,n2016 Kayani SI, Walkinshaw SA, Preston C: Pregnancy outcome in severe placental abruption. B]OG 110:679,n2003 Kayem G, Dupont C, Bouvier-Colle MH, et al: Invasive therapies for primary postpartum haemorrhage: a population-based study in France. B]OG 123(4):598,n2016 Kayem G, Kurinczuk ]], Alirevic A, et al: Uterine compression sutures for the man· agement of severe postpartum hemorrhage. Obstet GynecoInI17(l):14, 2011 Kenny L, McCrae K, Cunningham FG: Platelets, coagulation, and the liver. In Taylor R, Roberts ]M, Cunningham FG (eds): Chesley's Hypertension in Pregnancy, 4th ed. Amsterdam, Academic Press, 2015 Kettel LM, Branch OW, Scott ]R: Occult placental abruption after maternal trauma. Obstet Gynecol 71:449, 1988 Khan K, Moor P, Wilson M], et al: Cell salvage during caesarean section: a randomised controlled trial (The SALVO Trial). Abstract No. LBOl, Amn] Obstet GynecoIn216:S559, 2017 Kibel M, Asztalos E, Barrettn], et al: Outcomes of pregnancies complicated by preterm premature rupture of membranes berween 20 and 24 weeks of gestation. Obstet Gynecol 128:313,n2016 Kieser KE, Baskett TF: A 10-year population-based study of uterine rupture. Obstet Gynecol 100:749,2002

Kikuchi M, Itakura A, Miki A, et al: Fibrinogen concentrate substitution therapy for obstetric hemorrhage complicated by coagulopathy. ] Obstet Gynaecol Res 0,n2013 King DL: Placental migration demonstrated by ultrasonography. Radiology 109:167, 1973 Klar M, Michels KB: Cesarean section and placental disorders in subsequent pregnancies-a meta-analysis.n] Perinat Med 42(5):571,n2014 Knight , Berg C, Brocklehurst P, et al: Amniotic luid embolism incidence, risk factors and outcomes: a review and recommendations. BMC Pregnancy Childbirth 12:7,n2012 Knight M, Tufnell 0, Brocklehurst P, et al: Incidence and risk factors for amniotic-fluid embolism. Obstet Gynecol 115(5):910,n2010 Knight M, UKOSS: Peripartum hysterectomy in the UK: management and outcomes of the associated haemorrhage. B]OG 114:1380,n2007 Koen S, Synman LC, Pattinson RC, et al: A randomised controlled trial comparing oxytocin and oxytocin +ergotamine for prevention of postpartum hemorrhage at caesarean section. S Afr Med] 106:55,2016 Kohari KS, Roman AS, Fox NS, et al: Persistence of placenta previa in rwin gestations based on gestational age at sonographic detection. ] Ultrasound Med 31(7):985,n2012 Kollmann M, Gaulhofer], Lang U, et al: Placenta previa: incidence, risk factors and outcome.n] Maten Fetal Neonatal Med 29(9):1395, 2016 Kolomeyevskaya NV, Tanyi ]L, Coleman NM, et al: Balloon tamponade of hemorrhage after uterine curettage for gestational trophoblastic disease. Obstet Gynecol 113:557,2009

Kotsuji F, Nishihima K, Kurokawa T, et al: Transverse uterine fundal incision for placenta praeyia with accreta, involving the entire anterior uterine wall: a case series. B]OG 120(9):1144,n2013

Kramer MS, Berg C, Abenhaim H, et 1: Incidence, risk factors, and temporal trends in severe postpartum hemorrhage. Am] Obstet GynecoI209(5):449.el, 2013 Kramer MS, Rouleau ], Liu 5, et al: Amniotic fluid embolism: incidence, risk factors, and impact on perinatal outcomes. B]OG 4,n2012

KUCZYI1Skin], Uszynski W, Zekanowska E, et al: Tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in the placenta and myometrium. Eur ] Obstet Gynecol Reprod Bioi 105: 15, 2002

Kumru P, Demirci 0, Erdogdu E, et al: The Bakri balloon for the management of postpartum hemorrhage in cases with placenta previa. Eurn] Obstet Gynecol Reprod Bioi (2):167,n2013

Kuriya A, Piedimonte 5, Spence AR, et al: Incidence and causes of matenal mortality in the USA.n] Obstet Gynaecol Res 42(6):661,n2016

Lai ], Caughey AB, Qidwai GI, et al: Neonatal outcomes in women with sonographically identiied uterine leiomyomata. ] Matern Fetal Neonatal Med 25(6):710,n2012

Landy H], Laughon K, Bailit ]L, et al: Characteristics associated with severe perineal and cervical lacerations during vaginal delivery. Obstet Gynecol 117(3):627,n2011

Landy H], Weingold AB: Management of a multiple gestation complicated by an antepartum fetal demise. Obstet Gynecol Surv 44:171,n1989

Law L W, Chor CM, Leung TY: Use of hemostatic gel in postpartum hemorrhage due to placenta previa. Obstet GynecoInI16(SuppI2):528, 2010

Lax A, Prince MR, Mennitt W,et a1: The value of speciic MRI features in the evaluation of suspected placental invasion. Magn Reson Imaging 25:87, 200

Lee HY, Shin ]H, Kim ], et a1: Primaty postpartum hemorrhage: outcome of pelvic arterial embolization in 251 patients at a single institution. Radiology 264(3):903,n2012

Lee W, Ginsburg A, Cotton DB, et al: Squamous and trophoblastic cells in the maternal pulmonaty circulation identiied by invasive hemodynamic monitoring during the peripartum period. Amn] Obstet Gynecol 155:999, 1986

Lerner NB, Refaai MA, Blumberg N: Red cell transfusion. In Kaushansky K, Lichtman M, Beutler K, et al (eds): Williams Hematology, 8th ed. New York, McGraw-Hill, 2010, p 2287

Levi M: Pathogenesis and management of peripartum coagulopathic calamities (disseminated intravascular coagulation and amniotic luid embolism). hromb Res 131(Supplnl):S32, 2013

Levi M, Levy ]H, Andersen HF, et al: Safety of recombinant activated factor VII in randomized clinical trials. N Engl] Med 363(19):1791, 2010a

Levi M, Seligsohn U: Disseminated intravascular coagulation. In Kaushansky K, Lichtman M, Beutler K, et al (eds): Williams Hematology, 8th ed. New York, McGraw-Hill, 2010b

Likis FE, Sathe NA, Morgans AK, et al: Management of postpartum hemorrhage.

Agency for Healthcare Research and Quality (US) Report No. 15-EHCOI3

EF, April 2015

Lin Y, Callum ]L, Coovadia AS, et al: Transfusion of ABO-nonidentical platelets is not associated with adverse clinical outcomes in cardiovascular surgery patients. Transfusion 42: 1 66, 2002

Linn RL, Miller ES, Lim G, et al: Adherent basal plate myometrial ibers in the delivered placenta as a risk factor for development of subsequent placenta accreta. Placenta 36(12):1419, 2015

Logothetopulos K: Eine absolut sichere Blutstillungsmethode bei vaginalen und abdominalen gynakologischen Operationen. Zentralbl Gynakol 50:3202, 1926

Luke B, Gopal 0, Cabral H, et al: Pregnancy, birth, and infant outcomes by matenal fertility status: the Massachusetts Outcomes Study of Assisted Reproductive Technology. Am ] Obstet Gynecol 217(3):327.el-327, 2017

Maggio L, Forbes ], Carey LL, et a1: Association of Montevideo units with uterine rupture in women undergoing a trial of labor. ] Reprod Med 59(910):464,n2014

Maher MA, Abdelaziz A, Bazeed MF: Diagnostic accuracy of ultrasound and MRI in the prenatal diagnosis of placenta accreta. Acta Obstet Gynecol Scand ,2013

Major CA, deVeciana M, Lewis OF, et al: Preterm premature rupture of membranes and abruptio placentae: is there an association between these pregnancy complications? Am ] Obstet Gynecol 1 2:672, 1995

Maraka 5, Ospina NM, O'Keefe DT, et al: Subclinical hypothyroidism in pregnancy: a systematic review and meta-analysis. Thyroid 26(4):580, 2016 Marik PE, Corwin HL: Acute lung injuty following blood transfusion: expanding the deinition. Crit Care Med 36(1n1):3080, 2008

Masselli G, Brunelli R, Di Tola M, et al: MR imaging in the evaluation of placental abruption: correlation with sonographic indings. Radiology 259(1):222,n2011

Matijevic N, Wang W, Cotton BA, et al: Better hemostatic proiles of neverfrozen liquid plasma compared with thawed fresh frozen plasma. ] Trauma Acute Care Surg 74(1):84,n2013

Matsubara 5, Yano H, Ohkuchi A, et al: Uterine compression suture for postpartum hemorrhage: an overview. Acta Obstet Gynecol Scand 92(4):378, 2013

Matsubara 5, Yano H, Taneichi A, et al: Uterine compression suture against impending recurrence of uterine inversion immediately after laparotomy positioning.n] Obstet Gynaecol Res 35(4):819, 2009

Matsuda Y, Maeda T, Kouno 5: Comparison of neonatal outcome including cerebral palsy between abruptio placentae and placenta previa. Eur] Obstet Gynecol Reprod Bioi 106:125, 2003

Matsuda Y, Ogawa M, Konno], et al: Prediction of fetal acidemia in placental abruption. BMC Pregnancy Childbirth 13:156,n2013

Matsuwaki T, Khan KN, Inoue T, et al: Evaluation of obstetrical factors related to Sheehan syndrome.n] Obstet Gynaecol Res 40(1):46, 2014

McKeogh RP, D'Errico E: Placental accreta: clinical manifestations and conservative management. N Engl] Med 245:159,n1951

Mehrabadi A, Hutcheon ], Lee L, et al: Epidemiological investigation of a temporal increase in atonic postpartum haemorrhage: a population-base retrospective cohort study. B]OG 120(7):853,n2013

Mehrabadi A, Hutcheon ]A, Liu 5, et al: Contribution of placenta accreta to the incidence of postpartum hemorrhage and severe postpartum hemorrhage. Obstet Gynecol 125(4):814,n2015

Melamed N, Ben-Haroush A, Chen R, Kaplan B, et al: Intrapartum cervical lacerations: characteristics, risk factors, and efects on subsequent pregnancies. Am] Obstet Gynecol 200(4):388.el, 2009

Mhatre MV, Potter ]A, Lockwood C], et al: hrombin augments LPS-induced human endometrial endothelial cell inlammation via PARKI activation. Am] Rcprod Immunol 76(1):29, 2016

Michaels AY, Washburn EE, Pocius KD, et al: Outcome of cesarean scar pregnancies diagnosed sonographically in the irst trimester. ] Ultrasound Med 34(4):595,n2015

Miller DA, Paul RH: Rupture of the unscarred uterus. Am ] Obstet Gynecol 174:345, 1996

Miller DT, Roque OM, Santin AD: Use ofMonsel solution to treat obstetrical hemorrhage: a review and comparison to other topical hemostatic agents. Am] Obstet Gynecol 212(6):725, 2015

Miller ES, Linn L, Ernst LM: Does the presence of placental basal plate myometrial ibers in a prior pregnancy improve prediction of placenta accreta? B]OG 123(13):2140,n2016

Millischer AE, Solomon L], Porcher R, et al: Magnetic resonance imaging for abnormally invasive placenta: the added value of intravenous gadolinium injection. B]OG 124(1):88,n2017

Misra DP, Ananth CV: Risk factor proiles of placental abruption in first and second pregnancies: heterogeneous etiologies. ] Clin Epidemiol 52:453, 1999

Miura K, Higashijima A, Murakami Y, et al: Circulating levels of pregnancyassociated, placenta-speciic microRNAs in pregnant women with placental abruption. Reprod Sci June 13, 2016 [Epub ahead of print]

Mogos MF, Salemi ]L, Ashley M, et al: Recent trends in placenta accreta in the United States and its impact on maternal-fetal morbidity and healthcare-associated costs, 1998-20 11n. Ultrasound Obstet Gynecol 29(7): 1077,n2016

Mondal PC, Ghosh 0, Santra 0, et al: Role of Hayman technique and its modiication in recurrent puerperal uterine inversion. ] Obstet Gynaecol Res 38(2):438, 2012

Mone F, Elsayed 5, McAulife FM, et al: Uterine rupture-when, why and emerging trends in an Irish population. Abstract No. 433, Am ] Obstet Gynecol 214(1):5238, 2016

Morgan ]L, Nelson DB, Roberts SW, et al: he impact of baseline proteinuria in pregnant women with treated chronic hypertension. Obstet Gynecol 128:270,n2016

Motta I], Spencer BR, Cordeiro da Silva SG, et al: Evidence for transmission of Zika virus by platelet transfusion. N Engl ] Med 5(11): 1101, 20n16

Mousa HA, Blum], Abou EI Senoun G, et al: Treatment for primary postpartum haemorrhage. Cochrane Database Syst Rev 2:CD003249, 2014

Mukhopadhyay 0, Jennings PE, Banerjee vf, et a1: Ultrasound-guided drainage of supralevator hematoma in a hemodynamically stable patient. Obstet GynecoIn126(6):1188,n2015

Murakami M, Kobayashi T, Kubo T, et al: Experience with recombinant activated factor VII for severe postpartum hemorrhage in Japan, investigated by Perinatology Committee, Japan Society of Obstetrics and Gynecology. ] Obstet Gynaecol Res 41(8):1161,n2015 \lurdock AD, Berseus 0, Hervig T8 et al: Whole blood: the future of traumatic hemorrhagic shock resuscitation. Shock 41n(Supp 1):62,n2014

Murphy M, Vassallo R: Preservation and clinical use of platelets. In Kaushansky K, Lichtman M, Beutler K, et al (eds): Williams Hematology, 8th ed. New York, McGraw-Hill, 2010

Naeye L: Abruptio placentae and placenta previa: frequency, perinatal mortality, and cigarette smoking. Obstet Gynecol 55:701, 1980

Nageotte MP: Always be vigilant for placenta accreta. m J Obstet Gynecol 211(2):87,n2014

Nakash A, Tuck S, Davies N: Uterine sepsis with uterine artery embolisation in the management of obstetric bleeding. J Obstet Gynecol 32(1):26, 2012

Nath CA, Ananth CV, DeMarco C, et al: Low birthweight in relation to placental abruption and maternal thrombophilia status. Am J Obstet Gynecol 198:293.el, 2008

Nath CA, Ananth CV, Smulian JC, et al: Histologic evidence of inflammation and risk of placental abruption. Am J Obstet Gynecol 197:319.e1, 2007 Neilson JP: Interventions for suspected placenta praevia. Cochrane Database

Syst Rev 2:CDOO 1998, 2003

Nelson DB, Yost NP, Cunningham FG: Acute fatty liver of pregnancy: clinical outcomes and expected durations of recovery. Am J Obstet Gynecol 209(5):456.e1,n2013

Nelson DB, Yost NP, Cunningham FG: Hemostatic dysfunction with acute fatty liver of pregnancy. Obstet GynecoIn124:40, 2014

Nelson EL, Parker AN, Dudley OJ: Spontaneous vulvar hematoma during pregnancy: a case report. J Reprod Med 57(1-2):74, 2012 Nelson L, O'Brien JM: he uterine sandwich for persistent uterine atony: combining the B-Lynch compression suture and an intrauterine Bakri balloon. Am J Obstet Gynecol 196(5):e9, 2007 Ngai I, Bernstein , Chazotte C, et al: Maternal serum alpha fetoprotein (MSAFP) and placental abruption. Abstract No. 122, m J Obstet Gynecol 206(1):S66,n2012 Nikolaou M, Kourea HP, Antonopoulos K, et al: Spontaneous uterine rupture in a primigravid woman in the early third trimester attributed to adenomyosis: a case report and review of literature. J Obstet Gynaecol Res 39(3):727, 2013 Nizard J, Barrinque L, Ftydman R, et al: Fertility and pregnancy outcomes following hypogastric artery ligation for severe post-partum haemorrhage. Hum Reprod 18:844, 2003 Noh J], Park CH, Jo MH, et al: Rupture of an unscarred uterus in a woman with long-term steroid treatment for systemic lupus erythematosus. Obstet Gynecol 122(2 Pt 2):472,n2013 N0rgaard LN, Pinborg A, Lidegaard 0, et al: A Danish national cohort study on neonatal outcome in singleton pregnancies with placenta previa. Acta Obstet Gynecol Scand 91 (5): 546, 2012 O'Brien B, Smoleneic J: Cervical varicosities and placenta praevia. Aust N Z J Obstet Gynaecol 53(5):451, 2013 Ochoa M, Allaire AD, Stitely ML: Pyometria after hemostatic square suture technique. Obstet Gynecol 99:506, 2002 Ogah K, Munjuluri N: Complete uterine inversion after vaginal delivery. J Obstet GynaecoIn31(3):265, 2011 Okby R, Atawaz A, Wainstock T, et al: Placental abruption in twin pregnancies, risk factors and perinatal outcomes. Abstract No. 978, Am J Obstet GynecoIn216:S551,n2017 Oladapo OT, Adetoro 00, Ekele BA, et al: When getting there is not enough: a nationwide cross-sectional study of 998 maternal deaths and 1451 near-misses in public tertiary hospitals in a low-income country. BJOG 123(6):928,2016 Oleen MA, Mariano JP: Controlling refractory atonic postpartum hemorrhage with Hemabate sterile solution. Am J Obstet GynecoIn162:205, 1990 Olive EC, Roberts CL, Nassar N, et al: Test characteristics of placental location screening by transabdominal ultrasound at 18-20 weeks. Ultrasound Obstet Gynecol 28(7):944, 2006 0sterud B, Bjorklid E: Sources of tissue factor. Semin Thromb Hemost 32(1):11,n2006 Oyelese Y, Smulian JC: Placenta previa, placenta accreta, and vasa previa. Obstet Gynecoln107:927, 2006 Pacheco LD, Hankins GV, Saad AF, et al: Tranexamic acid for the management of obstetric hemorrhage. Obstet Gynecol 130:765,n2017 Pacheco LD, Saade GR, Costantine MM, et al: An update on the use of massive transfusion protocols in obstetrics. m J Obstet Gynecoln214(3):340, 2016 Pacheco LD, Saade GR, Constantine MM, et al: he role of massive transfusion protocols in obstetrics. m J PerinatoI30(1):1, 2013 Pacheco LD, Saade GR, Gei F,et al: Cutting-edge advances in the medical management of obstetrical hemorrhage. m J Obstet GynecoI205(6):526, 2011 Pan J, Zhou L, Huang A, et al: Sonographic diagnosis of complete uterine inversion: an unusual case. Clin Exp Obstet GynecoIn42(2):240, 2015 Pariente G, Shoham-Vardi I, Kessous R, et al: Placental abruption as a marker for long term cardiovascular mortality: a follow-up period of more than a decade. m J Obstet GynecoI208(1):S62, 2013

Parrott J, Holland M: Second trimester marginal previa: is follow-up necessaty?

Abstract No. 653, m J Obstet GynecoI212(1):S322, 2015

Pates JA, Hatab MR, .McIntire DO, et al: Determining uterine blood flow in pregnancy with magnetic resonance imaging. Magn Reson Imaging 28(4): 507, 2010

Pather S, Strockyj S, Richards A, et al: Maternal outcome after conservative management of placenta percreta at caesarean section: a report of three cases and a review of the literature. Aust N Z J Obstet Gynaecol 54(1):84, 2014

Patterson JA, Roberts CL, Bowen JR, et al: Blood transfusions during pregnancy, birth, and the postnatal period. Obstet GynecoI123(1):126, 2014 Pearlman MD, Tintinalli JE, Lorenz RP: A prospective controlled study of out come after trauma during pregnancy. m J Obstet Gynecol 162: 1502, 1990

Pelosi MA III, Pelosi A: Spontaneous uterine rupture at thirty-three weeks subsequent to previous superficialnlaparoscopic myomectomy. m J Obstet Gynecoln1 7:n1547, 1997

Penotti M, Vercellini P, Bolis G: Compressive suture of the lower uterine segment for the treatment of postpartum hemorrhage due to complete placenta previa: a preliminary study. Gynecol Obstet Invest 73(4):314,n2012

Perel P, Roberts I, Ker K: Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev 2:CD000567, 2013 Perez-Delboy A, Wright JD: Surgical management of placenta accreta: to leave or remove the placenta? BJOG 121:163,n2014

Perlman NC, Little SE, homas A, et al: Patient selection for later delivery timing with suspected previa-accreta. Acta Obstet Gynecol Scand 96(8): 1021, 2017

Peters I, Van Stein 0, Vlaar AP: Antibody-mediated transfusion-related acute lung injury: from discovery to prevention. Br J Haematol 170(5):59 ,2015

Petersen IR, Nyholm HC: Multiple pregnancies with single intrauterine demise. Description of twenty-eight pregnancies. Acta Obstet Gynecol Scand 78:202, 1999

Pettit E, Stephenson ML, Truong N, et al: Maternal and neonatal outcomes among scheduled versus unscheduled deliveries in women with prenatally diagnosed, pathologically proven placenta accreta. J Matern Fetal Neonatal Med November 5, 201 [Epub ahead of print]

Pilloni E, Alemanno MG, Gaglioti P, et al: Accuracy of ultrasound in antenatal diagnosis of placental attachment disorders. Ultrasound Obstet Gynecol 47(3):302,n2016

Po LK, Simons ME, Levinsky ES: Concealed postpartum hemorrhage treated with transcatheter arteril embolization. Obstet Gynecoln120(2 Pt 2):461,2012 Porreco P, Clark SL, Belfort A,et al: The changing specter of uterine rup ture. m J Obstet Gynecol 200(3):269.el, 2009

Porter TF, Clark SL, Dildy GA, et al: Isolated disseminated intravascular coagulation and amniotic fluid embolism. Am J Obstet GynecoIn174:486, 1996

Poujade 0, Grossetti A, Mougel L, et al: Risk of synechiae following uterine compression sutures in the management of major postpartum haemorrhage. BJOG 118(4):433,2011

Poujade 0, Zappa M, Letendre I, et al: Predictive factors for failure of pelvic arterial embolization for postpartum hemorrhage. Int J Gynaecol Obstet 117(2):119,n2012

Pri-Paz S, Devine PC, Miller RS, et al: Cesarean hysterectomy requiring emergent thoracotomy: a case report of a complication of placenta percreta requiring a multidisciplinary efort. J Reprod Med 57(1-2):58, 2012

Prick BW, Vos A, Hop WC, et al: he current state of active third stage management to prevent postpartum hemorrhage: a cross-sectional study. Acta Obstet Gynecol Scand 92(11): 1277,n2013

Primo LF, Arbogast K, Digiacomo T, et al: Placenta accreta: can we forecast its arrival? Obstet Gynecol 123(Suppl 1):166S, 2014

Pritchard JA: Changes in the blood volume during pregnancy and delivery.

Anesthesiology 26:393, 1965

Pritchard JA: Fetal death in utero. Obstet Gynecol 14:573, 1959

Pritchard JA: Haematological problems associated with delivery, placental abruption, retained dead fetus, and amniotic fluid embolism. Clin Haematol 2:563, 1973

PritchardJA, Baldwin M1, Dickey JC, et al: Blood volume changes in pregnancy and the puerperium, 2. Red blood cell loss and changes in apparent blood volume during and following vaginal delivery, cesarean section, and cesarean section plus total hysterectomy. m J Obstet Gynecol 84: 1271, 1962

Pritchard JA, Brekken L: Clinical and laboratory studies on severe abruptio placentae. Am J Obstet GynecoIn97:681, 1967

Pritchard JA, Cunningham FG, Mason A: Coagulation changes in eclampsia: their frequency and pathogenesis. m J Obstet GynecoIn124:855, 1976 Pritchard JA, Cunningham FG, Pritchard SA, et al: On reducing the frequency of severe abruptio placentae. m J Obstet GynecoIn165:1345, 1991

Pritchard JA, Mason R, Corley M, et al: Genesis of severe placental abruption. m J Obstet Gynecol 108:22, 1970

Pritchard JA, Whalley PJ: Abortion complicated by Clostridium perfringens infection. Am J Obstet Gynecol 111 :484, 1971

Quant HS, Friedman M, Wang E, et al: Transabdominal sonography s a screening test for second-trimester placenta previa. Obstet GynecoIn13(3):628, 2014 Rac MW, Dashe ]5, Wells CE, et al: Ultrasound predictors of placental inva sion: the Placenta Accreta Index. Am ] Obstet Gynecol 212:343, 2015a Rac MW, Mcintire DO, Wells CE, et al: Cervical length in patients at risk for placental accreta.n] Ultrasound Med ):1431,n2017

Rac MW, Wells CE, Twicker OM, et al: Placenta accreta and vaginal bleeding according to gestational age at delivery. Obstet GynecoIn125(4):808, 2015b Ran], Muppala H: Retroperitoneal haematomas in obstetrics: literature review.

Arch Gynecol Obstet 281(3):435,n2010

Raisanen 5, Kancherla V, Kramer MR, et al: Placenta previa and the risk of delivering a small-for-gestational-age newborn. Obstet Gynecol 124(2 Pt 1):285,n2014

Ramskill N, Hameed A, Beebeejaun Y: Spontaneous rupture of uterine leiomyoma during labor. BM] Case Rep 2014:pii: bcr2014204364, 2014 Rana A, Patel PS: Complete uterine inversion: an unusual yet crucial sono graphic diagnosis.] Ultrasound Med 28(12):1719,n2009

Rapaport 51, Rao LV: he tissue factor pathway: how it has become a "prima ballerina." Thromb Haemost 74:7, 1995

Rasmussen 5, Irgens LM: Occurrence of placental abruption in relatives. B]OG 116:693,n2009

Rattray DO, O'Connell CM, Baskett TF: Acute disseminated intravascular coagulation in obstetrics: a tertiary centre population review (1980 to 2009). ] Obstet Gynaecol Can 34(4):341, 2012

Reddy UM, Abuhamad Z, Levine 0, et al: Fetal imaging: executive summary of a joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Institute of Ultrasound in Medicine, American College of Obstetricians and Gynecologists, American College of Radiology, Society for Pediatric Radiology, and Society of Radiologists in Ultrasound Fetal Imaging Workshop. Obstet GynecoIn123(5):1070, 2014

Riihimaki 0, Metsaranta M, Ritvanen A, et al: Increased prevalence of major congenital anomalies in births with placental abruption. Obstet Gynecol 122(2 Pt 1):268,n2013

Roach MK, homassee MS: Acquired uterine arteriovenous malformation and retained placenta increta. Obstet Gynecol 126(3):642, 2015

Robalo R, Pedroso C, Agapito A, et al: Acute Sheehan's syndrome presenting as central diabetes insipidus. BM] Case Rep Online Nov 6, 2012

RobertS CL, A1gert CS, Warrendorf], et al: Trends and recurrence of placenta previa: a population-based study. Aust N Z ] Obstet Gynaecol 52(5):483, 2012

Robinson q, Villers MS, Johnson DO, et al: Timing of elective repeat cesarean delivery at term and neonatal outcomes: a cost analysis. Am ] Obstet GynecoIn202(6):632,n2010

Roeca C, Little SE, Carusi 0: Pathologically-diagnosed accreta and hemorrhagic morbidity in a subsequent pregnancy. Obstet Gynecol 129(2):321,2017

Romundstad LB, Romundstad PR, Sunde A, et al: Increased risk of placenta previa in pregnancies following IVFIICSI; a comparison of ART and nonART pregnancies in the same mother. Hum Reprod 21 (9):2353,n2006

Rosenberg T, Pariente G, Sergienko R, et al: Critical analysis of risk factors and outcome of placenta previa. Arch Gynecol Obstet 284(1):47, 201n1

Rossi AC, Lee RH, Chmait RH: Emergency postpartum hysterectomy for uncontrolled postpartum bleeding: a systematic review. Obstet Gynecol 115(3):637,n2010

Rotas A, Haberman 5, Luvgur M: Cesarean scar ectopic pregnancies: etiology, diagnosis, and management. Obstet :1373,n2006

Rouse 0]: Epidemiological investigation of a temporal increase in atonic postpartum haemorrhage: a population-based retrospective cohort study. Obstet Gynecol 122(3):693,n2013

Rouse 0], MacPherson C, Landon M, et al: Blood transfusion and cesarean delivery. Obstet Gynecol 108:891, 2006

Ruiter L, Ravelli AC, de Graaf 1M, et al: Incidence and recurrence rate of placental abruption: a longitudinal linked national cohort study in the Netherlands. Am] Obstet GynecoI213(4):573.e1, 2015

Sabourin ]N, Lee T, Magee A, et al: Indications for, timing of, and modes of delivery in a national cohort of women admitted with antepartum hemorrhage at 22+0 to 28+6 weeks' gestation.] Obstet Gynaecol Can 34(11): 1043,2012

Salihu HM, Bekan B, A1iyu MH, et al: Perinatal mortality associated with abruptio placenta in singletons and multiples. Am] Obstet Gynecoln193: 198, 2005 Salihu HM, Li Q, Rouse 0], et al: Placenta previa: neonatal death after live births in the United States. Am] Obstet GynecoIn188:1305, 2003

Salim R, Chulski A, Romano 5, et al: Precesarean prophylactic balloon catheters for suspected placenta accreta: a randomized controlled trial. Obstet GynecoIn126(5):1022,n2015

Sanderson DA, Milton P]D: he efectiveness of ultrasound screening at 18-20 weeks gestational age for predication of placenta previa. ] Obstet Gynaecol 11:320, 1991

Sangwan N, Nanda 5, Singhal 5, et al: Puerperal uterine inversion associated with unicornuate uterus. Arch Gynecol Obstet 280(4):625, 2009

Saraiya M, Green CA, Berg C], et al: Spontaneous abortion-related deaths among women in the United States-1981-1991. Obstet GynecoI94:172, 1999

Sathe NA, Likis FE, Young ]L, et al: Procedures and uterine-sparing surgeries for managing postpartum hemorrhage: a systematic review. Obstet Gynecol Surv 71(2):99,n2016

Schimmer BP, Parker KL: Contraception and pharmacotherapy of obstetrical and gynecological disorders. In Brunton LL, Chabner BA, Knollmann BC (eds): Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12th ed. New York, McGraw-Hill, 2011

Schlicter 5], Kaufman M, Assmann SF, et al: Dose of prophylactic platelet transfusions and prevention of hemorrhage. N Engl] Med 362(7):600, 2010

Schmitz T, Tararbit K, Dupont C, et al: Prostaglandin E2 analogue sulprostone for treatment of atonic postpartum hemorrhage. Obstet Gynecol 118(Pt 2):257,n2011

Seet EL, Kay HH, Wu 5, et al: Placenta accreta: depth of invasion and neonatal outcomes.n] Matern Fetal Neonatal Med 25(10):2042,n2012

Sentilhes L, Goinet F, Kayem G: Management of placenta accreta. Acta Obstet Gynecol Scand 92(10):1125, 2013

Sentilhes L, Gromez A, Clavier E, et al: Predictors offailed pelvic arterial embolization for severe postpartum hemorrhage. Obstet Gynecol 113:992,n2009 Sentilhes L, Medot B, Madar H, et al: Postpartum hemorrhage: prevention and treatment. Expert Rev Hematol 9(11): 1043,2016 �entiirk 5, Kagtitci M, Balik G, et al: he efect of the combined use of methylergonovine and oxytocin during caesarean section in the prevention of postpartum haemorrhage. Basic Clin Pharmacol Toxicol 118:338,n2016

Shamshirsaz A, Fox A, Salman ian B, et al: Maternal morbidity in patients with morbidly adherent placenta treated with and without a standardized multidisciplinary approach. Am] Obstet Gynecol 212:218.el, 2015

Shaz BH, Dente C], Harris RS, et al: Transfusion management of trauma patients. Anesth Analg 108: 1760, 2009

Shields LE, Smalarz K, Reigee L, et al: Comprehensive maternal hemorrhage protocols improve patient safety and reduce utilization of blood products. Am] Obstet GynecoIn205:368.el, 2011

Sholl ]5: Abruptio placentae: clinical management in nonacute cases. Am ] Obstet Gynecol 156:40, 198

Sibai BM, Lindheimer M, Hauthn], et al: Risk factors for preeclampsia, abruptio placentae, and adverse neonatal outcomes among women with chronic hypertension. N Engl] Med 339:667, 1998

Silver RM: Abnormal placentation: placenta previa, vasa previa, and placenta accreta. Obstet GynecoIn126(3):654, 2015a

Silver M, Fox A, Barton ]R, et al: Center of excellence for placenta accreta.

Am] Obstet Gynecol, May 2015b

Silver RM, Landon MB, Rouse 0], et al: Maternal morbidity associated with multiple repeat cesarean deliveries. Obstet Gynecol : 1226, 2006 Smuliann]C, DeFulvio ]0, Diven L, et al: Sonographic indings in acute uterine inversion.n] Clin Ultrasound 41(7):453,n2013

Smulian ]C, Pascual AL, Hesham H, et al: Invasive placental disease: the impact of a multidisciplinary team approach to management. ] Matern Fetal Neonatal Med 30(12):1423, 2017

Society for Maternal-Fetal Medicine, Belfort MA: Placenta accreta. Am ] Obstet GynecoIn203(5):430, 2010

Society for Maternal-Fetal Medicine, Gyamn-Bannerman C: Management of bleeding in the late preterm period. Consult Series No. 44. Am ] Obstet Gynecol October 25, 2017 [Epub ahead of print]

Society for Maternal-Fetal Medicine, Pacheco LK, Saade G, et al: Amniotic luid embolism; diagnosis and management. Am ] Obstet Gynecol 215(2):B16, 2016

Society for Maternal-Fetal Medicine, Sinkey RG, Odibo AO, et al: Diagnosis and management of vasa previa. Am] Obstet Gynecol 213(5):615, 2015

Society of horacic Surgeons: 2011 update to the Society of horacic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg 91 (3):944, 2011

Solomon C, Collis E, Collins PW: Haemostatic monitoring during postpartum haemorrhage and implications for management. Br ] Anesth 109(6): 851,n2012

Sosa CG, A1thabe F, Belizan ]M, et al: Risk factors for postpartum hemorrhage in vaginal deliveries in a Latin-American population. Obstet Gynecol 113(6):1313,n2009

Spong CY, Mercer BM, D'A1ton M, et al: Timing of indicated late-preterm and early-term birth. Obstet Gynecol 118(2 Pt 1):323, 2011

Staford lA, Dashe ]5, Shivvers SA, et al: Ultrasonographic cervical length and risk of hemorrhage in pregnancies with placenta previa. Obstet Gynecol 116(3):595,n2010

Staford PA, Biddinger PW, Zumwalt E: Lethal intrauterine fetal trauma. Am ] Obstet GynecoIn159:485, 1988

Stephenson ML, Pettit E, Henry DE, et al: Complicated accreta: comparison of matenal and neonatal outcomes. Abstract No. 623, Amn] Obstet Gynecol 214:S332, 2016

Stettler RW, Lutich A, Pritchard ]A, et al: Traumatic placental abruption: a separation from traditional thought. Presented at the American College of Obstetricians and Gynecologists Annual Clinical Meeting, April 27, 1992

Stolte L, van Kessel H, Seelen ], et al: Failure to produce the syndrome of amniotic luid embolism by infusion of amniotic luid and meconium into monkeys. m] Obstet Gynecol 98:694, 1967

Stramer SL, Glynn SA, Kleinman SH, et al: Detection of HIV-I and HCV infections among antibody-negative blood donors by nucleic acid-ampliication testing. N Engln] Med 351n:760,n2004

Stubbs ]R, Zielinski MD, Jenkins D: he state of the science of whole blood: lessons learned at Mayo Clinic. Transfusion 56(Suppl 2):SI73, 2016

Sun ]N, Zhang BL, Yu HY, et al: Spontaneous uterine ruptute due to placenta percreta during pregnancy. Am] Emerg Med 34(9):1918.el, 2016

Swank ML, Garite T], Maurel K, et al: Vasa previa: diagnosis and management. Am] Obstet Gynecol 215(2):223.el, 2016

Takeda A, Koike W, Imoto S, et al: Three-dimensional computerized tomographic angiography for diagnosis and management of intractable postpartum hemorrhage. Eur] Obstet Gynecol Reprod Bioi 176: 1 04, 2014

Tam Tam KB, Dozier ], Martin ]N ]r: Approaches to reduce urinary tract injury during management of placenta accreta, increta, and percreta: a systematic review. ] Maternal Fetal Neonatal Med 25(4):329,n2012

Tantbirojn P, Crum CP, Parast MM: Pathophysiology of placenta accreta: the role of decidua and extravillous trophoblast. Placenta 29(7):639, 2008 Tarney CM, Whitecar P, Sewell M, et al: Rupture of an unscarred uterus in a quadruplet pregnancy. Obstet Gynecoln121(2 Pt 2 Supplnl):483, 2013

Thomas S, Meadows ], McQueen A: Access to cesarean section will reduce maternal mortality in low-income countries: a mathematic model. Worldn] Surg 40(7):1537,n2016

Tikkanen M, Nuutila M, Hiilesmaa V, et al: Prep regnancy risk factors for placental abruption. Acta Obstet Gynecol Scand 85:40, 2006 Timmermans S, van Hof AC, Duvekot J]: Conservative management of abnormally invasive placentation. Obstet Gynecol Surv 62:529, 2007

Timor-Tritsch IE, Khatib N, Monteagudo A, et al: Cesarean scar pregnancies: experience of 60 cases.n] Ultrasound Med 34(4):601, 2015

Timor-Tritsch IE, Monteagudo A, Cali G, et al: Cesarean scar pregnancy is a precursor of morbidly adherent placenta. Ultrasound Obstet Gynecol 44(3):346,n2014

Tita AT, Szychowski ]M, Rouse D], et al: Higher-dose oxytocin and hemorrhage after vaginal delivery. Obstet Gynecol 119(2 Pt 1):293,n2012

Tola EN: First trimester spontaneous uterine rupture in a young woman with uterine anomaly. Case Rep Obstet Gynecol 2014:967386, 2014

Toledo P, McCarthy R], Hewlett B], et al: The accuracy of blood loss estimation after simulated vaginal delivety. Anesth Analg 105: 1736, 2007

Towers CV, Pircon A, Heppard M: Is tocolysis safe in the management of third-trimester bleeding? Am ] Obstet Gynecol 180: 1572, 1999 Treloar E], Anderson RS, Andrews HG, et at: Uterine necrosis following B-Lynch suture for primary postpartum haemorrhage. B]OG 113:486,2006

Trudell A, Stout M, Cahill A, et al: Second trimester cervical length and persistence of placental previa in the third trimester. Abstract No. 91, Presented at the 33rd Annual Meeting of the Society for Maternal-Fetl Medicine, February 11-16, 2013

T wielder D M, Lucas M], Balis AB, et al: Color low mapping for myometrial invasion in women with a prior cesarean deliveY. ] Matern Fetal Med 9:330, 2000 Ugwu lA, Oluwasola T A, Enabor 00, et al: Randomized controlled trial comparing 200�g and 400�g sublingual misoprostol for prevention of primary postpartum hemorrhage. Int] Gynaecol Obstet 133(2):173, 2016 Usta 1M, Hobeika EM, Abu Musa A, et al: Placenta previa-accreta: risk factors and complications. Am] Obstet Gynecol 193:1045,n2005 Uszynski M, Zekanowska E, Uszynski W, et al: Tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in amniotic luid and blood plasma: implications for the mechanism of amniotic luid embolism. Eurn] Obstet Gynecol Reprod Bioi 95:163, 2001

Villar], Gi.ilmezoglu AM, Hofmeyr G], et al: Systematic review of randomized controlled trials of misoprostol to prevent postpartum hemorrhage. Obstet Gynecolnl00:1301,n2002

Vintejoux E, Ulrich D, Mousty E, et al: Success factors for Bakri balloon usage secondary to uterine atony: a retrospective, multicenter study. Aust N Z ] Obstet Gynaecol 55(6):572, 2015 Walker MG, Allent L, Windrim RC, et al: Multidisciplinary management of invasive placenta previa.n] Obstet Gynaecol Can 35(5):417, 2013

Wang L, Matsunaga S, Mikami Y, et al: Pre-delivery ibrinogen predicts adverse maternal or neonatal outcomes in patients with placental abruption. ] Obstet Gynaecol Res 42(7):796, 2016

Warshak CR, Eskander R, Hull AD, et al: Accuracy of ultrasonography and magnetic resonance imaging in the diagnosis of placenta accreta. Obstet Gynecol 108(3 Pt 1):573, 2006

Warshak CR, Ramos GA, Eskander R, et al: Efect of predelivery diagnosis in 99 consecutive cases of placenta accreta. Obstet Gynecol 115(1):65,n2010

Wehrum M], Buhimschi lA, Salaia C, et al: Accreta complicating complete placenta previa is characterized by reduced systemic levels of vascular endothelial growth factor and by epithelial-to-mesenchymal transition of the invasive trophoblast. Am] Obstet Gynecol 204(5):411.el, 2011

Wei Q, Zhang W, Chen M, et al: Peripartum hysterectomy in 38 hospitals in China: a population-based study. Arch Gynecol Obstet 289(3):549, 2014 Weiner E, Miremberg H, Grinstein E, et at: The efect of placenta previa on fetal growth and pregnancy outcome in correlation with placental pathology.n] Perinatol 36(12):1073, 2016 Weiss ]L, Malone FO, Vidaver ], et al: Threatened abortion: a risk factor for poor pregnancy outcome, a population-based screening study. Amn] Obstet Gynecol 190: 45,n2004 Weiwen Y: Study of the diagnosis and management of amniotic luid embolism: 38 cases of analysis. Obstet Gynecol 95:385, 2000 Wing OA, Paul RH, Millar LK: Management of the symptomatic placenta previa: a randomized, controlled trial of inpatient versus outpatient expectant management. Am] Obstet Gynecol 174:305, 1996

Witteveen T, van Stralen G, Zwart], et al: Puerperal uterine inversion in the Netherlands: a nationwide cohort study. Acta Obstet Gynecol Scand 92(3):334, 2013 Wong HS, Cheung K, Zuccollon], et al: Evaluation of sonographic diagnostic criteria for placenta accreta.n] C1in Ultrasound 36(9):551,n2008

Wong Y: Emergency peripartum hysterecwmy: a 10-year review in a tertiary obstetric hospital. N Z Med] 124(1345):34,2011

World Health Organization: WHO recommendations for prevention and treatment of maternal peripartum infections. Geneva, WHO, 2015

Worley KC, Hnat MO, Cunningham FG: Advanced extrauterine pregnancy: diagnostic and therapeutic challenges. Am] Obstet GynecoIn198:297.e 1, 2008

Wortman A, Schaefer S, Wilson K, et al: Maternal morbidity associated with placenta previa with and without placental invasion. Abstract No. 601, Am ] Obstet GynecoI212(1):S299, 2015

Wright ]0, Silver RM, Bonanno C, et al: Practice patterns and knowledge of obstetricians and gynecologists regarding placenta accreta. ] Matern Fetal Neonatal Med 26(16):1n602,n2013

Yao R, Goetziner KR, Crimmins SO, et al: Association of maternal obesity with matenal and neonatal outcomes in cases of uterine rupture. Obstet Gynecol 129:683,n2017

Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 2017

Yoong W, Ridout A, Memtsa M, et al: Application of uterine compression suture in association with intrauterine balloon tamponade ("uterine sandwich") for postpartum hemorrhage. Acta Obstet Gynecol Scand 91(1):147, 2012

You B, Zahn CM: Postpartum hemorrhage: abnormally adherent placenta, uterine inversion, and puerperal hematomas. Clin Obstet Gynecol 49: 184, 2006 Zahn C, Timofeev J: Uterine inversion. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 2017 Zeeman GG, Cunningham FG, Pritchard]A: The magnitude of hem ocone entration with eclampsia. Hypertens Pregnancy 28(2):1n27,n2009

Zelop CM: Postpartum hemorrhage. Becoming more evidence-based. Obstet Gynecoln11 (1):3,n201n1 Zetterstrom K, Lindeberg SN, Haglund B, et al: Maternal complications in women with chronic hypertension: a population-based cohort study. Acta Obstet Gynecol Scand 84:419, 2005 Zhang E, Liu L, Owen R: Pelvic artery embolization in the management of obstetrical hemorrhage: predictive factors for clinical outcomes. Cardiovasc Intervent Radiol 38(6):1477, 2015 Zuckerbraun BS, Peitzman AB, Billiar TR: Shock. In Brunicardi FC, Andersen OK, Billiar TR, et al (eds): Schwartz's Principles of Surgery, 9th ed. New York, McGraw-Hill, 20LO Zwart J], Richters ]M, OY F, et al: Severe maternal morbidity during pregnancy, delivery and puerperium in the Netherlands: a nationwide population-based study of 371 ,000 pregnancies. B]OG 115:842, 2008

It is generaly admitted that there exists in the medulla a centre or uterine contractions, which can be stimulated by an excess of carbon dioxide in the bloo, by anaemia and the presence of various toxic substances; and it seems highy probable that the requency of premature labour in cases of renal insuiciency and eclampsia may be due to the action of metabolic poisons upon the centre.

-J. Whitridge Williams (1903)

In this textbook's first edition, very little was mentioned regarding preterm birth. Indeed, preterm birth was not incorporated as a stand-alone topic until the 13th edition in 1966. And, this content totaled only three sentences that cited use ofisoxsuprine as a tocolytic agent. In contrast, present-day research now produces more than 3000 articles published annually. Data derive from study of animal models, translational research, clinical trials, and genetic investigations. Despite eforts, elucidating the biology of human parturition and the subsequent eforts to prevent preterm birth remain elusive (Martin, 2017).

Low birthweight deines neonates who are born too small. Preterm or premature birth describes neonates who are born too early. With respect to gestational age, a newborn may be preterm, term, or postterm. With respect to size, a newborn may be normally grown and appropriate or gestational age; undersized, thus, smaL or gestational age; or overgrown and consequently, large or gestational age. Small for gestational age categorizes newborns whose birthweight is <10th percentile for gestational age. Other frequently used terms have included etal-growth restriction or intrauterine growth restriction. he term large for gestational age describes newborns whose birthweight is > 90th percentile for gestational age. The term appropriate or gestational age designates newborns whose weight is between the 10th and 90th percentiles.

Thus, neonates born before term can be small or large for gestational age, but still preterm by deinition. Low birthweight refers to neonates weighing 1500 to 2500 g; vey low birthweight are those between 1000 and 1500 g; and extremey low birthweight refers to those between 500 and 1000 g.

Before the 15th edition of this textbook, apreterm orpremature newborn was deined by a birthweight <2500 g. With that edition, preterm neonates were considered to be those delivered before 37 completed weeks, that is, <366r weeks (Pritchard, 1976). This definition, which has now been in use for more than 40 years, was first promulgated in 1976 by the World Health Organization (WHO) and the International Federation

FIGURE 42-1 Percentage of preterm births in the United States according to method of assessment of gestational age. LMP = date of last normal menses. (Adapted with permission from Martin JA, Osterman MJ, Kirmeyer SE, et al: Measuring gestational age in vital statistics data: transitioning to the obstetric estimate. Natl Vital

TABLE 42-1 . Infant Mortality Rates in the United States in 201e3

No. (%) (per 1000 births)

Total infants 3,932,1n81 (1n00) 23,446 (6)

Gestational age: <34 weeks 133,503 (3) 13,284 (100) 34-36 weeks 313,858 (8) 2268 (7) <37 weeks 447,361 (1n1) 15,552 (35) 37-38 weeks 974,162 (25) before 39 weeks (Spong, 2011). An unintended consequence of this health-care strategy has been a rise in stillbirth rates in the United States. One concern is that the rule may be misapplied to gestations with true medical indications for early delivery (Hill, 2017; Nicholson, 2016). Spong (2016) has emphasized the need to perform necessary obstetrical interventions when indicated.

39-41 weeks 2,291,468 (58) 4218 (2) ::42 weeks 215,510 (5) 515 (2)

Data from Matthews, 2015.

of Gynecology and Obstetrics (FIGO). The definition derived from a statistical analysis of gestational age distribution at birth (Steer, 2005). Importantly, the denotation lacks a specific functional basis and should be clearly distinguished from the concept ofprematuriy. Prematurity represents incomplete development of various organ systems at birth. For example, the lungs are particularly afected, leading to the respiratory distress syndrome (RDS) (Chap. 34, p. 636).

In 2013 in the United States, 23,446 infants died in their first year oflife, and a third ofinfants died from preterm-related causes (Matthews, 2015). Gestational age at deliveryand the risk of neonatal morbidity and mortality are inversely related (Frey, 2016). Namely, neonates born in the early-preterm period make up the smallest proportion of births, but these infants experience disproportionately higher rates of prematurity-related complications (Table 42-1).

Beginning in 2005, in recognition that neonates born between 34°/7 weeks and 366/7 weeks experience morbidities and mortality characteristic of premature newborns, preterm births were subdivided. Those before 336/ weeks are labeled earypreterm, and those occurring between 34 and 36 completed weeks are late preterm. Indeed, compared with births at weeks through 40617 weeks, these late-preterm infants experience morbidities that are also associated with prematurity (Spong, 2013). Recently, this concepthas expanded to births 37°/7 weeks through 386/ weeks, which are now defined as eary term, and those 39°/7 weeks through weeks, which are deined as term.

his revised terminology has led some to redefine a short gestation as those <39°/ weeks. By doing so, more than a third of live births in the United States in 2015 would be defined as having a shortened period of gestation (Martin, 2017). One implication is that only 65 percent of births in the United States occurred during the optimal 39 to 41 weeks' gestation. This emphasizes the realization that fetal maturation in humans is a continuum that is completed later in human pregnancy than previously appreciated. As a result, adverse neonatal sequelae from neonatal immaturity with elective delivery before 39 completed weeks are appreciable (Reddy, 2009; Tita, 2009).

This knowledge resulted in the development and application ofthe "39-week rule" to deter nonmedically indicated deliveries In the United States, the preterm birth rate rose slightly from 9.57 percent in 2014 to 9.63 percent for 2015 (Martin, 2017). This marks the irst rise in this percentage since 2007. Although concerning, some argue that the drop in preterm birth rates from 2007 to 2014 reflected systematic bias associated with changes in obstetrical dating (Frey, 2016).

Speciically, beginningwith the 2014 data year, the National Vital Statistics Reports from the National Center for Health Statistics transitioned to a new standard for estimating newborn gestational age for birth certificate completion (Martin, 2015). The new measure-obstetrical estimate of gestational age at delivery-replaced calculations based on the date of the last normal menses (Chap. 44, p. 846). As shown in Figure 42-1, these measures difer and do not provide equivalent absolute numerical comparisons ofpreterm birth rates. For example, the 2015 obstetrical estimate-based preterm birth rate was 9.6 percent compared with the last menstrual period-based rate of 11.3 percent (Martin, 2017). hus, current national data are now not directy comparable to previousy reported rates ofpreterm birth due to diering gestational age caculation methodologies. he national data are now reported starting with year 2007, which coincides with the year that this information became available.

12.68

J..,

Stat Rep. 2015 Jun 1 ;64(5):1-20.) tem data showed that the overall reduction of preterm birth before 2014 was in part due to the changes in maternal age dis tribution. Speciically, teen birth rates declined. This translated into a drop in preterm birth rates over the same epoch and could explain the lower infant mortality rates (Callaghan, 2017).

One disturbing aspect of preterm birth rate trends in the United States is persistent racial and ethnic disparities. Rates of pre term birth among black women are markedly elevated above those for white and Hispanic women in every year recorded (Martin, 2017). Moreover, rates of births before 32 completed weeks in black women are higher than those in white and Hispanic women combined. Some investigators attribute this disparity to socioeconomic circumstances (Collins, 2007; Leveno, 2009). Internationally, the rates of preterm birth in the United States are also higher compared with those in other industrialized countries (Ananth, 2009; Delnord, 2017; Martin, 2017).

Newborns born before 37 weeks sufer various morbidities, largely due to organ system immaturity (Table 42-2). hat said, remarkable strides have been made in neonatal survival for those born preterm. his is especially true for neonates born after 28 weeks. In a study of more than 18,000 newborns weighing between 400 and 1500 g or aged between 22 and 32 weeks' gestation, survival rates were analyzed as a function of both birthweight and gestational age (Fanarof, 2007). Mter achieving a birthweight of : 1000 g or a gestational age of 28 weeks for females, or 30 weeks for males, survival rates reach 95 percent.

• Threshold of Viability

Births once considered to be "abortuses" because the fetus weighed <500 g are now classified as live births. In the United

States in 2014, 5863 live births <500 g were recorded (Martin, 2017). For those newborns delivered before 33 weeks' gesta tion, perinatal and neonatal care has advanced tremendously.

As a result, the threshold of viability, which is the lower limit of fetal maturation compatible with extrauterine survival, has been reassessed. Currently, the threshold of viability lies between 20 and 26 weeks' gestation.

Neonates born in this periviable period have been described as fragile and vulnerable because of their immature organ systems. Many of these are described in Chapter 34 (p. 639) and include brain injury from hypoxic-ischemic injury and sepsis. In this setting, hypoxia and sepsis start a cascade of events that lead to brain hemorrhage, to white-matter injury that causes periventricular leukomalacia, and to poor subsequent brain growth eventuating in neurodevelopmental impairment. Associated morbidities include intellectual disability, cerebral palsy, blindness, seizures, and spastic quadriparesis that can result in the need for a lifetime of medical care (Annas, 2004). Because active brain development normally occurs throughout the second and third trimesters, those born <25 weeks are believed to be especially vulnerable to brain injury.

To clariY obstetrical care of these fetuses, the Society for Maternal-Fetal Medicine, the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD), the American Academy of Pediatrics, and the American College of Obstetricians and Gynecologists convened a joint workshop in 2013 (Raju, 2014). he executive summary statement from this meeting served as the underpinnings for an Obstetric Care Consensus document from the American College of Obstetricians and Gynecologists (2017 e).

TABLE 42-2. Major Short-and Long-Term Problems in Very-Low-Birthweight Infants

Respiratory distress syndrome, air leak, bronchopulmonary dysplasia, apnea of prematurity Hyperbilirubinemia, feeding intolerance, necrotizing enterocolitis, growth failure

Hospital-acquired infection, immune deficiency, perinatal infection

Intraventricular hemorrhage, periventricular leukomalacia, hydrocephalus Retinopathy of prematurity

Hypotension, patent ductus arteriosus, pulmonary hypertension

Water and electrolyte imbalance, acid-base disturbances

Iatrogenic anemia, need for frequent transfusions, anemia of prematurity

Hypoglycemia, transiently low thyroxine levels, cortisol deficiency

Bronchopulmonary dysplasia, reactive airway disease, asthma

Failure to thrive, short-bowel syndrome, cholestasis

Respiratory syncytial virus infection, bronchiolitis

Cerebral palsy, hydrocephalus, cerebral atrophy, neurodevelopmental delay, hearing loss Blindness, retinal detachment, myopia, strabismus

Pulmonary hypertension, hypertension in adulthood

Impaired glucose regulation, increased insulin

Data from Eichenwald, 2008.

TABLE 42-3. Outcomes at 2V2 Years Corrected Age 80 by Gestational Age at Birth in Sweden, 2004-2007 )o 40 • Ishii (2013) .D • Stoll (2010) Outcome 22 23 24 25 26 Total o (no.)

Survived to 10 53 67 82 85 70

FIGURE 42-2 Neonatal survival rates according to condition at birth and gestational age. Ishii (201o3) data curve reflects liveborn survival rates; Stoll (201o0) curve reflects liveborn survival rates; Mild 40 19 33 29 34 31 Rysavy (2015) curve reflects overall survival rates. Moderate 20 30 21 17 10 16 • %of infants who died • %of infants who survived with he Obstetric Care Consensus summary provides a review of outcomes for those born in the periviable period. Delivery before 23 weeks typically results in death, and survival rates approximate only 5 percent (Fig. 42-2). Among those that live, morbidity is nearly universal. Notably, the authors highlight the wide variation in practices regarding active resuscitation and suggest that these variations may explain the difering perinatal outcomes among diferent institutions. An important caveat, however, is ascertainment bias. For example, the mean survival rate is 45 percent if the denominator is all live births compared with 72 percent if the denominator is only newborns admitted to neonatal intensive care (Guillen, 2011). Another source of bias is use of multicenter datasets with considerable diferences in obstetrical and early neonatal interventions, particularly at 22 and 23 weeks' gestation (Stoll, 2010).

To evaluate contemporaneous outcomes of neonates born at 22 to 24 weeks, the NICHD Neonatal Research Network reported both survival and neurodevelopmental outcomes assessed across consecutive birth-year epochs of 2000 to 2003, 2004 to 2007, and 2008 to 2011 in infants aged 18 to 22 months (Younge, 2017). The percentage of infants who survived rose signiicantly from 30 percent in 2000 to 2003 to 36 percent in 2008 to 2011r. he percentage of infants who survived without neurodevelopmental impairment also significantly grew from 16 percent to 20 percent during the same time period (Fig. 42-3). Although rates of survival without neurodevelopmental impairment increased over time among infants born at 23 and apercentage with disability at 2V2 years corrected age. The overall rate of disabilities includes performance on the

Bayley III assessments, mental development delay, cerebral palsy. and visual and hearing disabilities.

Data from Serenius F, I allen K, Blennow M, et al: infants at 2.5 years after active perinatal care in Sweden,

JAMA 201 3 May 1;309( 1 7): '181n0-1n820.

24 weeks, only 1 percent of infants born at 22 weeks survived without neurodevelopmental impairment (Younge, 2017).

Somewhat similar results were published from Sweden (Serenius, 2013). his report details a national populationbased prospective study of all neonates born before 27 weeks. Shown in Table 42-3 are the survival and disability rates for 707 Swedish infants born alive from 22 to 26 weeks' gestation between 2004 and 2007 in Sweden. Compared with rates in the United States, rates of survival without neurodevelopmental impairment were higher in the Swedish cohort for infants born at 24 weeks during 2004 to 2007.

he Obstetric Care Consensus document also addresses management options based on the clinical characteristics of a given pregnancy. Nonmodiiable factors are fetal gender, weight, and plurality. Potentially modifiable antepartum and intrapartum factors include the location of delivery, intent to intervene

FIGURE 42-3 Mortality and neurodevelopmental outcomes at 18 to 22 months of corrected age by birth epoch in neonates born at 22 to 24 weeks. (Data from Younge N, Goldstein RF, Bann eM, et al: Survival and neurodevelopmental outcomes among periviable infants, N Engl J Med. 2017 Feb 16;376(7):617-628.)

EFM = electronic fetal monitoring; GBS = group B streptococcus; PPROM = preterm premature rupture of membranes. Data from the American College of Obstetricians and Gynecologists, 2017e; Raju, 2014.

by cesarean delivery or labor induction, and administration of antenatal corticosteroids and magnesium sulfate. Postnatal management addresses the initiation or withdrawal of intensive care after birth. Areas of general guidance were then reviewed for each week of gestation (Table 42-4).

Mode of delivery represents another dilemma because cesarean delivery at the threshold of viability is controversial. For example, if the fetus-neonate is perceived to be too immature for aggressive support, then cesarean delivery for common indications such as breech presentation or nonreassuring fetal heart rate patterns might be preempted. Moreover, observational studies have failed to document a benefit of cesarean delivery for the sole indication of periviability (Alirevic, 2013).

In a study of 2906 singletons between 24°17 and weeks eligible for attempted vaginal birth, 84 percent of cephalic presenting fetuses were delivered vaginally (Reddy, 2012). Neonatal mortality rates did not difer compared with those associated with planned cesarean delivery. For breech presentations, however, relative risk for mortality was threefold higher with attempted vaginal delivery. In another study, Werner and colleagues (2013) analyzed 20,231 newborns delivered at 24 to 34 weeks. Cesarean delivery did not protect against poor outcomes such as neonatal death, intraventricular hemorrhage, seizures, respiratory distress, and subdural hemorrhage. From these indings, the Obstetric Care Consensus proposes that cesarean delivery be considered for fetal indications at 23°(; to weeks. However, before 22 weeks, this route is reserved only for maternal indications.

It is diicult to summarize the current practices of obstetrical care in the management of the periviable pregnancy given its rapid evolution. For example, since January 2016, the American College of Obstetricians and Gynecologists has penned three iterations of its Practice Bulletin "Management of Preterm Labor," and three versions of the "Obstetric Care Consensus" document have been published since November 2015. In this uncertain environment, individualized, patientcentered care with a multidisciplinary team remain as bedrock for the clinician.

While we do not have the answers, we describe our strategies from Parkland Hospital as one approach to management. Our policies were developed in conjunction with the Division of Neonatal Medicine. Importantly, the decision not to perform cesarean delivery does not necessarily imply that care for the fetus is discounted. Neonatologists are consulted before delivery, and a trilateral discussion of survival and morbidity rates ensues with the woman and her family. A neonatologist attends each delivery and determines subsequent management.

In our institution, traditional fetal indications for cesarean delivery are practiced in women at 25°/7 weeks or beyond. Cesarean delivery is not ofered for fetal indications before 24°/7 weeks. At 240r weeks, cesarean delivery is not ofered unless fetal weight is estimated at 750 g or greater. Aggressive obstetrical management is practiced in cases of growth restriction, wherein gestational age is used to guide management rather than fetal size.

Neonates born between 34 and 36 weeks account for more than 70 percent of all preterm births (Fig. 42-4). This group has been the fastest rising proportion of singleton preterm births in the United States (Raju, 2006). Nationally, the late-preterm 32-33 weeks (12.1%) 34-36 weeks (71e.3%) (late preterm)

FIGURE 42-4 Distribution of preterm births by gestational age in the United States in 201o5. (Data from Martin JA, Hamilton BE, Osterman MJ: Births: final data for 2015. Natl Vital Stat Rep 66(1):1, 2017.)

Spontaneous rupture ofPlacental abruption, 1 % membranes Placenta previa, 1 % 35%

Fetalcomplications, 2%

Other, 3%

FIGURE 42-5 Obstetrical complications associated with 21,771 late-preterm births at Parkland Hospital. (Data from Mcintire DO, Leveno J: Neonatal mortality and morbidity rates in later preterm births compared with births at term, Obstet Gynecol. 2008 Jan;loll (1 ):35-41o.) birth rate rose from 6.82 percent to 6.87 percent from 2014 to 2015 (Martin, 2017).

To estimate the risks associated with late-preterm births, investigators analyzed neonatal mortality and morbidity rates at 34, 35, and 36 weeks compared with those of births at term between 1988 and 2005 at Parkland Hospital (McIntire, 2008). Approximately 3 percent of all births during the study period were between 24 and 32 weeks, and 9 percent were during the late-preterm weeks. hus, and similar to the national rates, late-preterm births accounted for three fourths of all preterm births. Approximately 80 percent of these resulted from 1.6 1.5a 1.4 1.2 1.0 0.8 0.6 0.4 0.2

FIGURE 42-6 Neonatal death rates at Parkland Hospital from 34 to 40 weeks' gestation in singleton infants without malformations. ap <0.001 compared with 39 weeks as the referent. bp = 0.02 compared with 39 weeks as the referent. (Reproduced with permission from Mcintire DO, Leveno J: Neonatal mortality and morbidity rates in later preterm births compared with births at term, Obstet Gynecol. 2008 Jan;lolol (1 ):35-41.) idiopathic spontaneous preterm labor or prematurely ruptured membranes (Fig. 42-5). Other obstetrical complications were implicated in the remaining 20 percent of cases. Rates of morbidity and mortality were greater in these late-preterm newborns compared with rates in term ones (Table 42-5 and Fig. 42-6). Similarly, T omashek (2017) also reported higher neonatal mortality rates for late-preterm newborns. Rates of

TABLE 42-5. Neonatal Morbidity Rates at Parkland Hospital in Live Births Delivered Late Preterm Compared with 39 Weeks

Grades 1,2

Grades 3,r4 Sepsis

One or more of the above aData presented as n (%).

bp <.001 compared with 39 weeks referent. cp <.05 compared with 39 weeks referent. Reproduced with permission from Mcintire DO, Leveno IJ: Neonatal mortality and morbidity rates in later preterm births compared with births at term, Obstet Gynecol. 2008 Jan;lnll (1 ):35-41r.

adverse neurodevelopment outcomes are also increased in these late-preterm infants (Petrini, 2009).

Taken together, these findings suggest that a health-care focus on prematurity should include these late-pre term births.

Moreover, approximately 80 percent of afected women begin labor spontaneously-similar to births before 34 weeks-and attempts to interrupt preterm labor have been insuicient (Institute of Medicine, 2007). Because of this, a national strat egy aimed at prevention of late-preterm births is unlikely to provide discernible benefit without new developments in the prevention and management of preterm labor. In the mean time, the American College of Obstetricians and Gynecolo for delivery exists.

Four direct causes for preterm births in the United States include: (1) spontaneous unexplained preterm labor with intact membranes, (2) idiopathic preterm premature rupture of membranes (PPROM), (3) delivery for maternal or fetal indications, and (4) twins and higher-order multi fetal births. Of all preterm births, 30 to 35 percent are indicated, 40 to 45 percent are due to spontaneous preterm labor, and 30 to 35 percent follow preterm membrane rupture (Goldenberg, 2008). Indeed, much of the increase in the singleton preterm birth rate in the United States is explained by rising numbers of indicated preterm births (Ananth, 2005). Last, more than one of every two twins and more than nine of every ten triplets are born preterm or with low birthweight in the United States (Chap. 45, p. 873) (Martin, 2017).

Reasons for preterm birth have multiple, often interacting, antecedents and contributing factors (Esplin, 2016). This is particularly true for PPROM and spontaneous preterm labor.

Analogous to other complex disease processes, multiple coexistent genetic alterations and environmental factors may lead to preterm birth (Esplin, 2005; Velez, 2008; Ward, 2008). For example, inherited mutations in genes regulating collagen assembly may predispose to cervical insuiciency or prematurely ruptured membranes (Anum, 2009; Wang, 2006; Warren, 2007). And, whole blood gene expression and proteonomic biomarkers are now being used to help identiy predictors of preterm birth (Cantonwine, 2016; Heng, 2016).

For both clinical and research purposes, pregnancies with spontaneous preterm labor yet intact fetal membranes must be distinguished from those complicated by preterm prematurely ruptured membranes. Even so, those with spontaneous preterm labor do not constitute a homogeneous group. Among the more common associated findings are multi fetal pregnancy, intrauterine infection, bleeding, placental infarction, premature cervical dilation, cervical insuiciency, hydramnios, uterine fundal abnormalities, and fetal anomalies. Severe maternal illness from infections, autoimmune diseases, and gestational hypertension also raises preterm labor risks.

Despite their diversity, these processes culminate in a common end point-premature cervical dilation and efacement and premature activation of uterine contractions. Importantly, the actual process of preterm labor should be considered a final step stemming from progressive or acute changes that could be initiated days or even weeks before labor onset. Indeed, many forms of spontaneous preterm labor that result from premature initiation of phase 2 of parturition may be viewed in this light (Chap. 21, p. 408). Although the end result in preterm birth is the same as at term with cervical ripening and myometrial activation, recent studies in animal models support the idea that preterm birth is not always an acceleration of the normal process. Diverse pathways to instigate parturition exist and are dependent on the etiology of preterm birth. Four major causes include uterine distention, maternal-fetal stress, premature cervical changes, and infection.

Multifetal pregnancy and hydramnios are well-recognized risks for preterm birth. Early uterine distention likely acts to initiate expression of contraction-associated proteins (CAPs) in the myometrium. he CAP genes that are influenced by stretch include those coding for gap-junction proteins such as connexin 43, for oxytocin receptors, and for prostaglandin synthase (Korita, 2002; Lyall, 2002; Sooranna, 2004). More recent reports suggest that levels of gastrin-releasing pep tides (GRPs) are increased with stretch to promote myometrial contractility. GRP antagonists can inhibit uterine contractility (Tattershell, 2012). Also, a stretch-induced potassium channel-TREK-1is up regulated during gestation and downregulated in labor. his suggests a potential role in uterine relaxation during pregnancy (Buxton, 2010).

Excessive uterine stretch also leads to early activation of the placental-fetal endocrine cascade shown in Figure 21-10 (p. 410). The resultant early rise in maternal corticotropinreleasing hormone and estrogen levels can further enhance the expression of myometrial CAP genes (Warren, 1990; Wolfe, 1988). Finally, the influence of uterine stretch should be considered with regard to the cervix. Prematurely increased stretch and endocrine activity may initiate events that shift the timing of uterine activation, including premature cervical ripening.

Stress is deined as a condition or adverse circumstance that disturbs the normal physiological or psychological functioning of an individual. Examples of stressors are nutrient restriction, obesity, infection, and diabetes. Psychological duress can include racial discrimination, childhood stress, depression, or posttraumatic stress syndrome (Gillespie, 2017; Goldstein, 2017; Shaw, 2017). A quantitative measure of "stress" is difficult. Yet, considerable evidence shows a correlation between some degree of maternal stress and adverse birth outcomes that include stillbirth, preterm birth, and abnormal fetal development (Hobel, 2003; Ruiz, 2003). Factors that activate this cascade likely are broad and inluence the stress response.

One potential mechanism for stress-induced preterm birth is premature activation of the placental-adrenal endocrine axis. One trigger may be elevations in cortisol from maternal psychological stress (Lockwood, 1999; Petraglia, 2010; Wadhwa, 2001). Activation of this axis yields rising maternal serum levels of placentalderived corticotropin-releasing hormone (CRH). This raises adult and fetal adrenal steroid hormone production and promotes early loss of uterine quiescence (Fig. 21-10, p. 410).

If preterm delivery is associated with early activation of the fetal adrenal-placental endocrine axis, maternal estrogen levels would likely be prematurely elevated. Indeed, an early rise in serum estriol concentrations is noted in women with subsequent preterm labor (Heine, 2000; McGregor, 1995). Physiologically, this premature rise in estrogen levels may alter myometrial quiescence and accelerate cervical ripening.

Another mechanism by which stress may translate to preterm birth is premature cellular senescence. As part of normal physiology, aging of fetal and decidual cells precipitates the release of uterotonic signals for uterine activation at term (Menon, 20 14a). Animal studies supported by correlative studies in women demonstrate that accelerated senescence of the decidua results in preterm birth (Cha, 2013; Hirota, 2010). In addition, premature cellular senescence may contribute to PPROM (Menon, 2016).

In most cases, premature cervical remodeling precedes premature labor onset. In some instances, cervical dysfunction of either the epithelia or stromal extracellular matrix is the underlying cause. For example, an intact cervical epithelial barrier is critical to prevent ascending infection. Disruption of this barrier, such as that in mice lacking the glycosaminoglycan hyaluronan, predisposes mice to ascending infection and preterm birth (Akgul, 2014). Interestingly, the enhanced risk of preterm birth from group B streptococcal colonization may be in part due to the bacteria's ability to secrete hyaluronidase. his enzyme degrades hyaluronic acid in the cervicovaginal epithelia to aid bacterial ascension (V ornhagen, 2017).

Second, the mechanical competence of the cervix can be reduced. For example, genetic mutations in components of collagen and elastic fibers or proteins required for their assembly are risk factors for cervical insuiciency, PPROM, and preterm birth (Anum, 2009; Nallasamy, 2017; Pyeritz, 2000).

A patent female reproductive tract, although essential for conception and delivery, is theoretically problematic during phase 1 of parturition. Bacteria can gain access to intrauterine tissues through: (1) transplacental transfer of maternal systemic infection, (2) retrograde flow of infection into the peritoneal cavity via the fallopian tubes, or (3) ascending infection with bacteria from the vagina and cervix. Because the lower pole of the fetal membrane-decidual junction is contiguous with the cervical canal oriice, this anatomical arrangement provides a passageway for microorganisms. Ascending infection is considered to be the most common entry route. Ascending microorganisms colonize the cervix, decidua, and possibly the membranes, where they then may enter the amnionic sac.

Intraamnionic infection as a primary cause of preterm labor in pregnancies with intact membranes accounts for 25 to 40 percent of preterm births (Goncalves, 2002; lams, 1987). In some instances, histological evidence of inflammation is found in the fetal membranes, decidua, or umbilical cord. Other cases are deemed "subclinical." Current data suggest that microbial invasion of the reproductive tract is suicient to induce infection-mediated preterm birth. ffected women are more likely to develop clinical chorioamnionitis and PPROM compared with women with sterile cultures. Moreover, their neonates are also more likely to have perinatal complications that include RDS, intraventricular hemorrhage, and necrotizing enterocolitis (Hitti, 2001). Although the clinical course is more severe when intraamnionic infection is obvious, inlammation in the absence of detectable intraamnionic microorganismstermed sterile intraamnionic inlammation-is also a risk factor for an inlammatory response, described in the next section (Lee, 2007, 2008; Romero, 2014). In sum, the earlier the onset of preterm labor, the greater the likelihood of underlying infection (Goldenberg, 2000; Goncalves, 2002; Watts, 1992).

he incidence of culture-positive amnionic luid collected by amniocentesis during spontaneous term labor is similar to that with preterm labor (Gomez, 1994; Romero, 1993). It has been suggested that at term, amnionic luid is iniltrated by bacteria as a consequence oflabor, whereas in preterm pregnancies, bacteria represent an inciting cause of labor. hus, fetal infection, as deined by bacteria detected within the amnionic luid, has both difering etiologies and consequences.

Despite these observations, considerable data associate chorioamnionitis with preterm labor (Goldenberg, 2002; Ustiin, 2001). With chorioamnionitis, microbes may invade maternal tissue only and not amnionic fluid. Despite this, endotoxins can stimulate amnionic cells to secrete cytokines that enter amnionic luid. his scenario may serve to explain the apparently contradictory observations concerning an association between amnionic luid cytokines and preterm labor in cases in which microbes are not detected in the amnionic luid.

Inflammatory Responses. Inlammatory responses drive the pathogenesis of infection-induced preterm labor. lipopolysaccharide (LPS) or other toxins elaborated by bacteria are recognized by pattern-recognition receptors such as toll-like receptors (Janssens, 2003). hese receptors are present on mononuclear phagocytes, decidual cells, cervical epithelia, and trophoblasts (Chuang, 2000; Gonzalez, 2007; Holmlund, 2002). Loss of specific toll-like receptors results in delayed parturition in mouse models (Montalbano, 2013). Instead, activation of tolllike receptors induces a signaling cascade that activates production of chemokines such as interleukin 8 (IL-8) and cytokines such as IL-13. Activation also recruits immune cells into the reproductive tract. Cytokines are produced by immune cells and by cells within the cervix, decidua, membranes, or fetus itsel.

LPS-induced production ofIL-13 in turn promotes a series of responses that include: (1) increased synthesis of others, that is, IL-6, IL-8, and tumor-necrosis factor alpha (TNF-.); (2) proliferation, activation, and migration of leukocytes; (3) modiications in extracellular matrix proteins; and (4) mitogenic and cytotoxic efects such as fever and acute-phase response (EI-Bastawissi, 2000). Also, in many tissues, including myometrium, decidua, and amnion, IL-1 3 promotes prostaglandin formation that induces cervical ripening and loss of myometrial quiescence (Casey, 1990; Challis, 2002; Keelan, 2003). he importance of prostaglandins to infection-mediated pre term birth is supported by the observation that prostaglandin inhibi tors can reduce the rate of LPS-induced preterm birth in both the mouse and nonhuman primate (Gravett, 2007; Timmons, 2014). Inhibition of cyclooxygenase-2 prevents inlammation mediated preterm labor in the mouse. And, immunomodula intraamnionic infection in a nonhuman primate model.

Proteases such as matrix metalloproteinases (MMPs) are also induced by IL-1 3 and function to break down extracel lular matrix components such as collagen or elastic ibers. This disrupts the structural integrity of fetal membranes and the cer vix. Current evidence from animal and human studies suggests that many aspects of infection-mediated preterm birth difer from pathways that regulate term parturition (Hamilton, 2012; Holt, 2011; Shynlova, 2013a,b; Timmons, 2014).

Origin of Cytokines. Uterine cytokines are likely important for preterm labor. For example, it appears that cytokines produced side, whereas cytokines produced in the membranes or in cells within the amnionic fluid will not be transferred to maternal tissues. he transfer of cytokines such as IL-1 3 from decidua across the membranes into amnionic luid, however, appears to be severely limited. Additionally, the human myometrium expresses chemokine receptors that decline during labor (Hua, 2013).

he requirement of leukocytes for initiation of term labor in women remains inconclusive. In general, resident and invading leukocytes produce the bulk of cytokines in cases of inlammation resulting from infection. Indeed, with infection, leukocytesmainly neutrophils, macrophages, and T lymphocytes-iniltrate the cervix, lower uterine segment, fundus, and membranes at the time of labor. Invading leukocytes and certain parenchymal cells produce cytokines and appear to be the primary source of myometrial cytokines (Young, 2002). By contrast, in the decidua, both stromal cells and leukocytes likely contribute. In the cervix, glandular and surface epithelial cells appear to produce cytokines.

he presence of cytokines in amnionic fluid and their association with preterm labor is well documented. But, their exact cellular origin-with or without recoverable microorganismsis not well deined. Amnionic fluid cytokines are most likely secreted by mononuclear phagocytes or neutrophils activated and recruited into the amnionic luid. Thus, the amount of amnionic luid IL-1 3 would be determined by the number of leukocytes recruited, their activational status, or the efect of amnionic fluid constituents on their IL-1 3 secretion rate.

Vaginal Microbiota. Factors that predispose to ascending infection and then preterm birth are a key focus of ongoing basic research. \1ucosal immunity and barrier function of the cervicovaginal epithelia, the microbiota composition in the vaginal tract, and their interplay are a major topic (Smith, 2017). From animal studies, mucosal immunity of the lower reproductive tract can be disrupted by viral infection with a subsequent enhanced susceptibility to ascending bacterial infection (Racicot, 2013, 2017). Along with the ability of the cervico vaginal epithelia to respond to environmental insults, the com position of the microbe ecosystem in the vaginal tract may also determine susceptibility to ascending infection.

that the nonpregnant vaginal tract hosts a complex microbial community (Gajer, 2012; White, 201l). Also described in

Chapter 65 (p. 1245), these community state types can difer widely among women who are all healthy. And, the vaginal microbiome changes during normal pregnancy (Aagaard, 2012;

Stout, 2017). Namely, the diversity and richness of microbe populations are reduced during pregnancy and become more stable. Compared with nonpregnant controls, Lactobacillus species show an enhanced dominance. Some but not all stud ies report an increased population of certain microbes-for example, Gardnerella vaginalis and Ureaplasma ureayticumqi in women with preterm birth (Donders, 2009; Nelson, 2014).

However, diferences in populations of pregnant women stud ied, in deinitions of preterm birth, and in data analysis may complicate interpretation of these data.

Some speciic microorganisms are detected more frequently than others in amnionic fluid of women with preterm labor (Gerber, 2003; Hillier, 1988; Yoon, 1998). hese include G vaginalis, Fusobacterium species, Mycoplasma hominis, and U ureayticum. Their identification was interpreted by some as presumptive evidence that speciic microorganisms are more commonly involved as pathogens in the induction of preterm labor. Another interpretation, however, is that given direct access to the membranes after cervical dilation, selected micro organisms, such as fusobacteria, are more capable of burrowing through these exposed tissues and will do so. Fusobacteria are found in the vaginal luid of only 9 percent of women but in 28 percent of positive amnionic luid cultures from pregnancies with preterm labor and intact membranes (Chaim, 1992).

• Preterm Premature Rupture of Membranes his term deines spontaneous rupture of the fetal membranes before 37 completed weeks and before labor onset (American College of Obstetricians and Gynecologists, 20 16d). Such rupture likely has various causes, but intrauterine infection, oxidative stress-induced DNA damage, and premature cellular senescence are major predisposing events (Dutta, 2016; Gomez, 1997; Mercer, 2003). Associated risk factors include lower socioeconomic status, body mass index < 19.8, nutritional deiciencies, and cigarette smoking. Women with PPROM carry an enhanced risk for recurrence during a subsequent pregnancy (Bloom, 2001). Despite these known risk factors, none is identified in most cases of pre term rupture.

Increased apoptosis or necroptosis of membrane cellular components and greater levels of specific proteases in membranes and amnionic luid are related to PPROM. Most tensile strength of the membranes is provided by the amnionic extracellular matrix and interstitial amnionic collagens that are produced in mesenchymal cells (Casey, 1996). Thus, collagen degradation has been a focus of research. he MMP family is involved with normal tissue remodeling and particularly with collagen degradation. Some members are found in higher concentrations in amnionic luid from pregnancies with PPROM (Maymon, 2000; Park, 2003; Romero, 2002). MMP activity is in part regulated by tissue inhibitors of matrix metalloproteinases-TI\1Ps. Several of these inhibitors are found in lower concentrations in amnionic fluid from women with ruptured membranes. Elevated MMP levels found at a time when protease inhibitor expression declines urther supports that their expression alters amnionic tensile strength.

Studies of amniochorion explants show greater MMP expression following treatment with certain cytokines (Fortunato, 1999a,b, 2002). With membrane rupture, thrombin activity rises, which activates MMPs and prostaglandin synthesis. Studies by Mogami (2013) provide a mechanism b) which bacterial endotoxin or TNF-. elicits release of fetal fibronectin (FN) by amnion epithelial cells. The FN then binds toll-like receptor 4 in the amnion mesenchymal cells to activate signaling cascades. hese result in augmented prostaglandin E (PGEJ synthesis and elevated activity of MJlIPs. Higher prostaglandin levels promote cervical ripening and uterine contractions. Greater MMP concentrations allow collagen breakdown in the fetal membranes resulting in premature rupture.

In pregnancies with PPROM, the amnion exhibits a higher degree of cell death and more apoptosis markers than that in term amnion (Arechavaleta-Velasco, 2002; Fortunato, 2003). In vitro studies indicate that apoptosis is likely regulated by bacterial endotoxin, IL-13, and TNF-.. In addition, oxidative stress initiated by events other than infection can induce DNA damage, premature senescence, and subsequent inflammation and proteolysis that leads to PPROM (Menon, 2014a,b). Last, there are proteins involved in the synthesis of mature crosslinked collagen or matrix proteins that bind collagen and thereby promote tensile strength. These proteins are altered in membranes with premature rupture (Wang, 2006).

Several studies have investigated the incidence of infectioninduced PPROM. Bacterial cultures of amnionic luid support a role for infection in a significant proportion. One review of 18 studies and almost 1500 women with PPROM found that bacteria were isolated from amnionic fluid in a third of cases (Goncalves, 2002). Accordingly, some have given antimicrobial treatment to women in spontaneous preterm labor with intact membranes, however, results have been disappointing as discussed later on page 825 (Kenyon, 2008b).

The inflammatory response that leads to membrane weakening and mediators of this process are currently areas of research. One goal is to identiy early risk markers for PPROM.

Twins and higher-order multifetal births account for approximately 3 percent of neonates born in the United States (Martin, 2017). Preterm delivery continues to be the major cause of the excessive perinatal morbidity and mortality with multifetal pregnancies. The efects of uterine stretch discussed on page 809 are obvious. Many of these interrelationships are discussed in Chapter 45 (p. 885).

Several genetic and environmental factors afect the frequency of preterm labor. Of these, threatened abortion in early pregnancy is associated with higher rates of later adverse outcomes. Weiss (2004) reported outcomes with vaginal bleeding at 6 to 13 weeks' gestation in nearly 14,000 women. Both light and heavy bleeding were associated with subsequent preterm labor, placental abruption, and pregnancy loss before 24 weeks.

Birth defects in the fetus may also predispose to preterm birth. In a secondary analysis of data from the First-and Second-Trimester Evaluation of Risk (FASTER) Trial, birth defects were associated with preterm birth and low birthweight neonates (Dolan, 2007).

Cigarette smoking, inadequate maternal weight gain, and illicit drug use afect the incidence and outcome of low-birthweight neonates (Chap. 44, p. 849). Extremes of maternal weight-both underweight and obese mothers-have an enhanced risk of preterm birth (Cnattingius, 2013; Girsen, 2016). Other maternal factors implicated include young or advanced maternal age, poverty, short stature, and vitamin C deficiency (Casanueva, 2005; Gielchinsy, 2002; Kramer, 1995; Leveno, 2009; Meis, 1995).

As discussed on page 809, psychological factors such as depression, anxiety, and chronic stress are associated with preterm birth (Hofman, 2016; Venkatesh, 2016). In one review of more than 50 studies, Donovan and coworkers (2016) found a signiicant link between low birthweight and preterm birth in women injured by physical abuse (Chap. 47, p. 925).

Studies of work and physical activity related to preterm birth have yielded conlicting results (Goldenberg, 2008). Some evidence suggests that working long hours and hard physical labor are probably linked to a higher risk of preterm birth (Luke, 1995). However, aerobic exercise in normal-weight women with uncomplicated singleton pregnancies appears to be safe and not associated with preterm birth (American College of Obstetricians and Gynecologists, 2017d; Di Mascio, 2016). One metaanalysis of physical activity found that leisure-time physical activity was associated with a reduced risk of preterm birth (Aune, 2017).

he recurrent, familial, and racial nature of preterm birth suggests that genetics may playra causal role. Accumulating literature on genetic variants buttresses this concept (Gibson, 2007; Hampton, 2006; Macones, 2004; Velez, 2009). Several such studies have also implicated immunoregulatory genes in potentiating chorioamnionitis in cases of preterm delivery due to infection (Varner, 2005).

Gum inflammation is a chronic anaerobic inflammation that afects as many as 50 percent of pregnant women in the United

States (Goepfert, 2004). Vergnes and Sixou (2007) performed a metaanalysis of 17 studies and concluded that periodontal disease was signiicantly associated with preterm birth. To better study this relationship, Michalowicz (2006) randomly assigned 813 pregnant women between 13 and 17 weeks' gestation who had periodontal disease to treatment during pregnancy or postpartum. Treatment during pregnancy improved periodontal disease and was safe. However, treatment failed to significantly alter preterm birth rates. his position was reafirmed by a joint workshop of the European Federation of Periodontology and the American Academy of Periodontology (Sanz, 2013).

he intervals between pregnancies are linked with adverse perinatal outcomes. In a metaanalysis, intervals < 18 months and > 59 months were associated with greater risks for both preterm birth and small-for-gestational age newborns (Conde-Agudelo, 2006). he causal efect of short interpregnancy intervals, however, has been questioned (Ball, 2014).

he most important risk factor for preterm labor is a prior preterm delivery. Data from nearly 16,000 women delivered at Parkland Hospital are instructive. Namely, the recurrent preterm delivery risk for women with a preterm first delivery was threefold greater than that of women whose first neonate was born at term. More than a third of women whose irst two newborns were preterm subsequently delivered a third preterm newborn. Most-70 percent-of the recurrent births in this study occurred within 2 weeks of the gestational age of the prior preterm delivery. he causes of prior preterm delivery also recurred. Although women with prior preterm births are clearly at risk for recurrence, they represented only 10 percent of the total preterm births in this study. Expressed another way, 90 percent of the preterm births at Parkland Hospital could not be predicted based on a history of preterm birth. Laughon and associates (2014) confirmed the importance of prior spontaneous preterm birth. Notably, these investigators also found that prior indicated preterm birth was strongly associated with subsequent spontaneous preterm birth. Variations in the deinition of spontaneous and indicated used may explain this association.

Ultimately, risk of recurrent preterm birth is influenced by three factors: the frequency of prior preterm deliveries, severity as measured by gestational age, and the order in which the prior preterm delivery occurred (McManemy, 2007). That is, an individual woman's risk for recurrent preterm birth is inluenced by her past number and sequence of preterm and term births. For example, a risk of recurrent preterm birth for a gravida 3 para 2 woman with a prior preterm birth followed by a term birth difers from a woman with a prior term birth followed by preterm birth. Thus, the inluence of reproductive history has a profound prognostic significance for risk of recurrence. Moreover, this may also inluence the supposed benefit attributed to various interventions described later.

As discussed on page 810, a link between some cases of preterm birth and infection seems irrefutable (Goldenberg, 2008). In several studies, antimicrobial treatment has been given to prevent preterm labor thought to be due to microbial invasion. These strategies especially targeted Mycoplasma species. Morency and colleagues (2007) performed a metaanalysis of 61 articles and suggested that antimicrobials given in the second trimester may prevent subsequent preterm birth. Andrews and associates (2006) reported results of a randomized trial in which they gave a course of azithromycin plus metronidazole every 4 months to 241 nonpregnant women whose last pregnancy resulted in spontaneous delivery before 34 weeks. Approximately 80 percent of the women with subsequent pregnancies had received study drug within 6 months of their subsequent conception. Such interconceptional antimicrobial treatment did not reduce the rate of recurrent preterm birth. Using a subgroup analysis of these same women, Tita and coworkers (2007) concluded that such use of antimicrobials may be harmful. In another randomized study, 2661 women received placebo or metronidazole plus erythromycin between 20 and 24 weeks' gestation followed by ampicillin plus metronidazole during labor (Goldenberg, 2006). his antimicrobial regimen did not reduce the rate of preterm birth or that of histological chorioamnionitis. At this time, antibiotic prophylaxis to prevent preterm birth is not recommended in women with preterm labor and intact membranes (Flenady,r2013).

In this condition, normal, hydrogen peroxide-producing, lactobacillus-predominant vaginal flora is replaced with anaerobes (Hillier, 1995; Nugent, 1991). Its diagnosis and management are discussed in Chapter 65 (p. 1245). Using Gram staining, relative concentrations of the bacterial morphotypes characteristic of bacterial vaginosis are determined and graded by the Nugent score or assessed clinically with Amsel criteria.

Bacterial vaginosis has been associated with spontaneous abortion, preterm labor, PPROM, chorioamnionitis, and amnionic fluid infection (Hillier, 1995; Kurki, 1992; Leitich, 2003a,b). Environmental factors appear to be important in bacterial vaginosis development. Exposure to chronic stress, ethnic diferences, and frequent or recent douching are associated with higher rates of the condition (Culhane, 2002; Ness, 2002). A gene-environment interaction has also been described (Macones, 2004). Women with bacterial vaginosis and a susceptible TNF-a genotype had a ninefold increased incidence of preterm birth.

From all of these studies, adverse vaginal flora seems associated with spontaneous preterm birth. Unfortunately, to date, screening and treatment have not prevented preterm birth. These are discussed further in Chapter 65 (p. 1246). Indeed, microbial resistance or antimicrobial-induced change in the vaginal flora results from regimens intended to eliminate bacterial vaginosis (Beigi, 2004; Carey, 2005).

Early diferentiation between true and false labor is diicultespecially before demonstrable cervical efacement and dilation. Uterine activity alone can be misleading because of Braxton Hicks contractions. These irregular, nonrhythmical contractions can cause considerable confusion in the diagnosis of true labor. Not infrequently, women who deliver before term have uterine activity that is attributed to Braxton Hicks contractions that prompt an incorrect diagnosis of false labor. Accordingly, the American College of Obstetricians and Gynecologists (2016b) defines preterm labor to be regular contractions before 37 weeks that are associated with cervical change.

In addition to contractions, pelvic pressure, menstrual-like cramps, watery vaginal discharge, and lower back pain have been empirically associated with impending preterm birth. Such complaints are thought by some to be common in normal pregnancy and are therefore often minimized by patients and obstetrical care providers.

he importance of these symptoms as a harbinger of labor has been emphasized by some but not all investigators (lams, 1990; Kragt, 1990). lams and coworkers (1994) found that the signs and symptoms signaling preterm labor, including uterine contractions, appeared only within 24 hours of preterm labor.

Chao (2011) prospectively studied 843 women with a singleton fetus who presented to Parkland Hospital with preterm labor symptoms between 24°/7 and 336/7 weeks, intact membranes, and cervical dilation <2 em. hose whose cervix remained <2 em were sent home with a diagnosis of false preterm labor. When analyzed against the general obstetrical population, women sent home had a similar rate of birth before 34 weeks-2 versus 1 percent. However, these women did have significantly higher rates of birth between 34 and 36 weeks-5 percent compared with 2 percent. Women with cervical dilation of 1 em at discharge were signiicantly more likely to deliver before 34 weeks compared with women without cervical dilation-5 percent versus 1 percent. Importantly, almost 90 percent of the I-em group delivered within 21 days of the initial presentation.

Researchers have evaluated asymptomatic cervical changes that may predict preterm labor. Asymptomatic cervical dilation after midpregnancy is suspected to be a risk factor for preterm delivery, although some clinicians consider it to be a normal anatomical variant. Moreover, study results have suggested that parity alone is not suicient to explain cervical dilation discovered early in the third trimester.

Cook (1996) longitudinally evaluated cervical status with transvaginal sonography between 18 and 30 weeks in nulliparas and multiparas who all subsequently gave birth at term. Cervical length and diameter were identical in both groups throughout these critical weeks. In a study from Parkland Hospital, routine digital cervical examinations were performed between 26 and 30 weeks in 185 asymptomatic women. Approximately 25 percent of women whose cervix was dilated 2 or 3 em delivered before 34 weeks (Leveno, 1986a). Other investigators have verified cervical dilation as a predictor of increased preterm delivery risk (Copper, 1995) .

Although women with dilation and efacement in the third trimester are at greater risk for preterm birth, detection does not necessarily improve pregnancy outcome. Buekens and associates (1994) randomly assigned 2719 women to undergo routine cervical examinations at each prenatal visit and compared them with 2721 women in whom serial examinations were not performed. Knowledge of antenatal cervical dilation did not afect any pregnancy outcome related to preterm birth or the frequency of interventions for preterm labor. The investigators also reported that cervical examinations were not related to PPROM. hus, it seems that prenatal cervical examinations in asymptomatic women are neither beneficial nor harmful.

An external tocodynamometer belted around the abdomen and connected to an electronic waist recorder allows a woman to ambulate while uterine activity is recorded. Results are transmitted via telephone daily. Women are educated concerning signs and symptoms of preterm labor, and clinicians are kept apprised of their progress. The 1985 approval of this monitor by the Food and Drug Administration (FDA) prompted its widespread clinical use. Subsequently, it was proven that the use of this expensive and time-consuming system does not reduce preterm birth rates (Collaborative Home Uterine Monitoring Study Group, 1995; lams, 2002; Urquhart, 2017). Despite improvements in technology with the internet and cellular telephones, use of such monitoring is discouraged (merican College of Obstetricians and Gynecologists, 20 16c).

his glycoprotein is produced in 20 diferent molecular forms by various cell types, including hepatocytes, fibroblasts, endothelial cells, and fetal amnion cells. Present in high concentrations in maternal blood and amnionic luid, fFN is thought to function in intercellular adhesion during implantation and in maintenance of placental adherence to uterine decidua (Leeson, 1996). Detected in cervicovaginal secretions in women who have normal pregnancies with intact membranes at term, fFN appears to reflect stromal remodeling of the cervix before labor.

Lockwood (1991) reported that FN detection in cervicovaginal secretions before membrane rupture was a possible marker for impending preterm labor. Qualitative and quantitative FN levels are measured using enzyme-linked immunosorbent assays, and values exceeding 50 ng/mL are considered positive. Sample contamination by amnionic luid and maternal blood should be avoided. Interventional studies based on the use of FN screening in asymptomatic women have not demonstrated improved perinatal outcomes (Andrews, 2003; Esplin, 2017; Grobman, 2004). The American College of Obstetricians and Gynecologists (2016c) does not recommend screening with FN tests. Its use in conjunction with cervical length measurement is discussed next.

are associated with increased rates of preterm birth (lams, 1996). he technique to measure cervical length with sonog raphy is described in Chapter 10 (p. 189). When performed by trained operators, cervical length analysis using transvagi nal sonography is safe, highly reproducible, and more sensitive lege of Obstetricians and Gynecologists, 20 16c). The Society for the performance of proper cervical length measurement.

obtain speciic training in the acquisition and interpretation of cervical length imaging through accreditation programs.

Transvaginal cervical sonography is not afected by maternal obesity, cervix position, or shadowing from the fetal presenting part. Because of the inability to easily distinguish the lower uterine segment from the cervix in early gestation, transvaginal cervical length assessment is typically performed ater 16 weeks' gestation.

Such interrogation is currently limited to singleton gestations and not recommended for multifetal gestations outside of research tri als (American College of Obstetricians and Gynecologists, 2016c).

Indications for cervical length measurement are somewhat controversial. For those women with a history of prior spontaneous preterm birth, the Society for Maternal-Fetal Medicine (20 16b) recommends transvaginal cervical length screening. But, the American College of Obstetricians and Gynecologists (2016c) only recommends consideration of screening for this indication. In women with singleton pregnancies but without a history of prior preterm birth, the Society for Maternal-Fetal Medicine (20 16b) views cervical length screening as reasonable yet acknowledges that this remains an area of debate.

A irst concern with screening surrounds the eicacy of interventions to improve perinatal outcomes once cervical length screening has isolated at-risk gravidas. Of interventions, cervical cerclage and administration of vaginal progesterone have both been evaluated. Vaginal progesterone for this indication is discussed on page 817. For prophylactic cerclage in women with prior preterm births and shortened cervices, many studies have failed to show superior primary outcomes. But, piecemeal subgroup analyses from the trials have been subsequently used as the basis for recommendations in current practice guidelines regarding cervical length assessment and consideration for cerclage placement. A second concern is the accuracy and utility of the screening test, especially in low-risk women, who represent most of the population with preterm birth (p. 813).

To address this issue in low-risk women, Esplin and colleagues (2017) prospectively studied 9410 nulliparas with singleton pregnancies. Universal screening of sonographically measured cervical length and quantitative measurement of vaginal fFN levels were evaluated as predictors of women who would spontaneously deliver before 37 weeks. hese measures had poor predictive performance as a screening test. In fact, all screening modalities had relative low sensitivity and low positive-predictive values. Based on these indings, routine use of these screening tests in this low-risk population is not recommended. Bloom and Leveno (2017) subsequently critiqued the use of transvaginal cervicalrlength screening in low-risk women and the promulgation of consensus guidelines. As described in Chapter 1 (p. 7), they highlighted the staggering costs encumbering the health-care system in the United States as a result of such strategies.

Prevention of preterm birth remains an elusive goal. Still, may be achievable.

Of options, cerclage placement may be used to prevent pre term birth in at least three circumstances. First, the procedure may beneit women who have a history of recurrent midtrimester losses and who are diagnosed with cervical insuiciency. A second instance is the woman identiied during sonographic examination to have a short cervix. The third indication is a "rescue" cerclage, done emergently when cervical incompetence is recognized in women with threatened preterm labor.

As is the case for virtually all obstetrical conditions, an accurate history is critical for management decisions. For recurrent abortion from cervical incompetence, historical clues are outlined in Chapter 18 (p. 354). For women with a short cervix incidentally detected by sonography, the beneit of cerclage placement appears directly related to whether the woman has a history of prior preterm birth. In those without a prior preterm birth, cerclage for a sonographically detected short cervix alone ofers no advantage. To and associates (2004) screened 47,123 women and randomly assigned the 253 women with cervices < 15 mm, with or without a history of preterm birth, to cerclage or no cerclage. he frequency of preterm delivery before 33 weeks did not difer signiicantly. In contrast, women with a sonographically diagnosed short cervix and a history of preterm birth may beneit. Owen and colleagues (2009) randomly assigned 302 women with prior preterm birth and with a short cervix-deined as length <25 mm-to cerclage or no procedure. The primary study outcome was not supported by the intervention. However, women with a cervical length < 15 mm delivered before 35 weeks signiicantly less oten following cerclage compared with women with no cerclage-30 versus 65 percent. his study suggested that recurrent preterm birth could be prevented in a subset of women with asymptomatic singleton gestations with both previous pre term birth and short cervical length.

These findings prompted a reassessment by Berghella and coworkers (201r1), who performed a metaanalysis using individual patient data (Fig. 42-7). he primary outcomes from the included trials did not support cerclage placement. However, these investigators concluded that cerclage signiicantly prevented preterm birth and improved composite perinatal mortality and morbidity in women with prior spontaneous preterm birth, singleton gestation, and cervical length <25 mm.

One caveat in the interpretation of this cerclage data is the inluence of obstetrical history. For example, all of the trials comprising the metaanalysis included preterm birth as early as 16 to 17 weeks' gestation. Deining these early second trimester losses as preterm births, rather than cervical incompetence, is problematic. Thus, it is diicult to distinguish whether these women were treated in the context of cervical incompetence or of preterm labor at 16 weeks. Nonetheless, based on these

Risk Ratio StudyorSubgroup M-H, Fixed, 95% CI 0.01 0.1 10 100

FIGURE 42-7 Cerclage versus no cerclage for prevention of recur rent preterm birth in women with a cervical length <25 mm. Forest plot analysis of composite perinatal mortality and morbidity. CI = confidence index. (Adapted with permission from Berghella V, Rafael TJ, Szychowski JM, et al: Cerclage for short cervix on ultrasonography in women with singleton gestations and previous preterm birth: a meta-analysis, Obstet Gynecol 117(3):663,2011.) indings, the American College of Obstetricians and Gynecologists (2016c) concluded that in women with a singleton pregnancy, prior spontaneous preterm birth before 34 weeks, cervical length <25 mm, and gestational age <24 weeks, cerclage placement may be considered.

• Prophylaxis with Progestogen Compounds

In most mammals, progesterone withdrawal is considered to be a parturition-triggering event. During human parturition, however, maternal, fetal, and amnionic fluid progesterone levels remain elevated. It has been proposed that human parturition involves functional progesterone withdrawal mediated by decreased activity of progesterone receptors (Chap. 21, p. 401). It follows conceptually that the administration of progesterone may block preterm labor. This hypothesis has stimulated several studies of both 17 -alpha hydroxyprogesterone caproate (17OHP-C) and vaginally administered progesterone in women with varying risks for preterm birth.

At present, the reported benefits of either of these progestogen therapies are limited to women with singleton pregnancies. Progesterone prophylaxis speciically in multifetal gestations has not lowered preterm birth rates (Caritis, 2009; Rouse, 2007). Accordingly, both the American College of Obstetricians and Gynecologists (2016c) and the Society for Maternal-Fetal Medicine (2017 a) approve the use of progestogen therapy for prevention of preterm birth in select women with singleton pregnancies. Criteria are a history of prior preterm birth or no prior preterm birth but a sonographically identified short cervix.

17 -OHP-C is a synthetic progestogen, and the first and only drug approved by the FDA for prevention of recurrent preterm birth. The approval in 2011 was supported by a study by the Maternal-Fetal Medicine Units (MFNIU) Network (Meis, 2003). In this trial, 463 women with a prior preterm birth were randomly assigned to receive weekly intramuscular injections of inert oil or 17-0HP-C from 16 through 36 weeks' gestation. They reported a significantly reduced recurrence of preterm birth in 36 percent of women receiving 17-0HP-C compared with 55 percent of those given placebo.

This MFMU study has been challenged because of the unexpectedly high preterm delivery rate in the placebo arm (Romero, 2013). One explanation for this high rate in the placebo group was asymmetry in the risks of recurrence. Indeed, 41 percent of the control group had ::2 prior preterm births compared with only 28 percent in the 17-0HP-C group. Another concern was that the injection dosage of 17-0HP-C, which was 250 mg weekly, was empirically chosen (Caritis, 2014). Only later reports described the pharmacokinetics of 17-0HP-C (Caritis, 2012). Nonetheless, the Society for Maternal-Fetal Medicine (2017a) recently reairmed the use of 17-0HP-C, rather than vaginal progesterone, for prevention of recurrent preterm birth.

Sharma and associates (2008) reported that the metabolism of 17-0HP-C was predominantly mediated by the CYP3A enzymatic system. Thus, other agents that induce or inhibit this enzymatic system as well as hepatic impairment may alter drug levels. They also showed that 17-0 HP -C is not converted after administration to the primary progesterone metabolite, 17a-hydroxyprogesterone. The relative binding ainity of 17-0 HP -C to progesterone receptors approximates only 30 percent of that by progesterone (Attardi, 2007). Because synthetic 17-0HP-C is not converted to a naturally occurring progestogen and is not superior to progesterone in eliciting a hormonal response via the classic steroid-receptor mediated pathway, alternative pathways are now being considered to explain its eicacy (Manuck, 2011).

Caritis and colleagues (2012) examined 61 women receiving 17-0HP-C therapy and found that the hlf-life was relatively long (median 16.2 days). Pharmacokinetic parameters were ffected by maternal body habitus and varied widely between subjects. In addition, 17 -OHP-C crossed the placental barrier and was detectible in cord plasma 44 days ater the last maternal injection (Caritis, 2012). Despite this, evidence to date suggests that 17-0HP-C is safe for the fetus. No abnormalities, including abnormal genitlia, were found in a 48-month follow-up study of infants exposed in the 2003 MFMU Network trial (Northen, 2007).

here are special concerns involving 17-0HP-C and subsequent price-gouging claims (Cohen, 2011; Romero, 2013). In 2011, the FDA gave temporary approval to V Pharmaceutical to market 17 -OHP-C under the brand name Makena. Because regulations prohibited compounding, there was no competitor for this relatively inexpensive drug, and Makena was priced at $1500 per injection. This caused widespread concern because the cumulative cost of Makena would be more than $30,000 per pregnancy.

Use of 17-0HP-C at Parkland Hospital

A program for implementation of 17-0HP-C was incorporated at Parkland Hospital in 2012. Given the concerns above,

Preterm Birth 81.7

TABLE 42-6. Prior Obstetrical History of 430 Women with Births ;35 weeks and Recurrence Rates After 17-0HP-C at Parkland Hospital

Prior Birth <35 Weeks Recurrence Ratea No. No. Rate p valueb

Overall 16.8% 430 106 25% 1.0

Para 1 18% 141 44 31 % 1.0

Para 2:

Only 2nd birth :;35 weeks 17% 48 20 42% 0.49 11 21 % 0.84

Only 1 st birth :;35 weeks Para 3+: 11 % 5% 0.18

All :;35 weeks 45% 12 44% 0.56

Other sequences of :;35 weeks 12% 123 17 14% 0.78 aRecurrence rate is derived from the Parkland obstetrical population for 1988-201n1 prior to introduction of 17-0HP-C.

bp values are one-sided.

Reproduced with permission from Nelson, 2017.

a local compounding pharmacy provided 250-mg, single-dose From the foregoing studies, evidence to support the use of vials of 17-0HP-C in sesame oil at a cost of $25 per dose. 17-0HP-C to prevent recurrent preterm birth is problematic Nelson and colleagues (2017) recently reported their indings (Young, 2017). he mechanism of action remains unknown, from this program in a prospective study of 430 women given and the pharmacological properties have yet to be established. compounded 17-0HP-C. Use of 17-0HP-C was inefective Evidence of clinical efectiveness has yet to be replicated. A confor prevention of recurrent preterm birth at 35 weeks or less dition of the FDA approval for 17-0HP-C was that a conircompared with a historical cohort from Parkland. As shown matory multicenter, double-blind randomized controlled trial in Table 42-6, 17-0HP-C did not signiicantly reduce the be conducted with a preferred primary end point of delivery rates of recurrent preterm birth regardless of prior preterm <35 weeks. This international trial-PRO LONG-is currently birth number or sequence. Moreover, plasma concentrations of underway with scheduled completion in 2018 and with an esti17-0HP-C were not diferent at 24 weeks or 32 weeks between mated enrollment of 1707 participants (PROLONG, 2014). women delivered :;35 weeks and those delivered later. Interestingly, levels were consistent with those previously reported using castor oil as a vehicle (Caritis, 2014). Last, the gestational age interval at which preterm birth recurred did not difer after use of 17-0HP-C. A side efect of 17-0HP-C was a signifiThree randomized trials are at the center of whether progestocant increase in the rate of gestational diabetes. Taken together, gen therapy should be used in women without prior preterm 17 -0 HP -C use was inefective to prevent recurrent preterm births. hese trials, shown in Table 42-7, hinge on sonographbirth and was associated with a significant side efect. ically determined cervical length. In the irst trial, Fonseca and

TABLE 42-7. Randomized Trials of Progestogen Compounds Given Prophylactically to Prevent Preterm Labor

Fonseca (2007) n = 250; 5% nulliparous, 10% <15 mm Progesterone, 200-mg Delivery <34 weeks: twins, 15% prior PTB; 8 hospitals: vaginal capsules daily 19% vs 34%, P = .02

UK, Greece, Brazil, Chile

Hassan (201l) n = 465; singletons only; 55% 10-20 mm Progesterone, 90-mg Delivery <33 weeks: 9% nulliparous; 13% prior PTB; vaginal gel daily vs 16%, p = .02

Grobman (2012) n = 657; singletons only; nulliparous <30nmm 17-0HP-C, 250 mg 1M Delivery <37 weeks: only; 14 centers across US weekly 25% vs 24%, p = NS

Determined sonographically.

17-0HP-C = 17-hydroxyprogesterone caproate; 1M = intramuscularly; NS = nonsignificant; PTB = preterm birth; UK = United Kingdom; US = United States.

colleagues (2007) randomly assigned 250 women with short cervices measuringr:;15 mm identified during routine prenatal care. Women were given nightly 200-mg micronized progesterone vaginal capsules or placebo from 24 to 34 weeks' gestation. Spontaneous delivery <34 weeks was significantly reduced by progesterone therapy. Importantly, this trial included not only nulliparas but also those with twins or prior pre term birth.

In the second trial, Hassan and coworkers (2011) randomly assigned 465 women with a short cervix-IO to 20 mm-to vaginal progesterone gel, 90 mg daily, or placebo. his trial also included nulliparas and women with prior preterm births.

From these studies, the FDA rejected progesterone gel for use because the results did not meet the level of statistical significance required to show eicacy in the subjects recruited in the United States. According to Likis and colleagues (2012), the heterogeneity of these first two studies that included women with varied indications for progestogen treatment, combined with the fact that outcomes were not reported by risk factors such as nulliparity, made it impossible to interpret the eicacy of progesterone for speciic indications.

The third study randomly assigned administration of 17 -0 HP -C intramuscular injection or placebo between 16 and 223/7 weeks to nulliparas with a singleton gestation and a cervical length < 30 mm detected sonographically (Table 42-8) (Grobman, 2012). Treatment with 17-0HP-C given weekly did not reduce the frequency of preterm birth before 37 weeks. Regardless of cervical length, 17-0 HP -C was inefective.

hus, vaginal progesterone, but not 17 -OHP-C, appears to benefit women with a sonographically measured short cervix. Romero and Stanczyk (2013) provided a review to explain the conlicting evidence and argued that naturally occurring progesterone, which is used in the vaginal preparations, is not the same as synthetic 17-0HP-C. Likewise, Furcron and coworkers (2015) found that 17-0 HP -C did not have local antiinflammatory efects at the maternal-fetal interface or cervix. Further, 17 -OHP-C did not protect against endotoxin-induced preterm birth.

From all these studies, the merican College of Obstetricians and Gynecologists (2016c) concluded that universal cervical length screening in women without a prior preterm birth is not mandatory. However, this screening strategy could be considered in the context of treatment with vaginal progesterone.

The OPPTIMUM Study his study of 1228 high-risk women with singleton pregnancies is the largest to date for vaginal progesterone prophylaxis (N orman, 2016). his randomized trial of vaginal progesterone, 200 mg daily from 22-24 weeks to 34 weeks of gestation, was termed the OPPTIMUM study-dQes Erogesterone Erophyxis Io prevent preterm labor prove High-risk women were defined as those with a prior spontaneous birth :;34 weeks or with a cervical length :;25 mm or a positive FN test result combined with other clinical risk factors for preterm birth.

he primary outcomes of OPPTHvIUM were unique in that both immediate obstetrical and childhood outcomes were examined. These were fetal death or birth <34 weeks; a composite of death, brain injury, or bronchopulmonary dysplasia; and a standardized cognitive score at 2 years of age. Contrary to earlier reports, vaginal progesterone was not associated with a lower risk of preterm birth or composite neonatal adverse outcomes. In children at 2 years of age, vaginal progesterone also had no long-term benefit or harm.

hus, evidence is conflicting as to the eicacy of progestogens across the spectrum of the various specific indications. Some have attempted to resolve these issues through systematic review and metaanalysis (Prior, 2017; Romero, 2016, 2017). s outlined in this entire section, virtually all evidence supporting use of progestogens for a specific indication can be challenged in some way. We agree with the conclusions from the OPPTIMUM trial (Norman, 2016) that the results of recent studies should prompt a major review of progesterone use for preterm birth prophylaxis, a search to identiy specific women who might specifically benefit, and a redoubling of eforts to find alternative strategies to prevent preterm birth in women at risk.

TABLE 42-8. Comparison of 17-0HP-C versus Placebo to Prevent Preterm Birth at

Preterm birth <37 wk:

Cervical length, mm

Preterm birth <34 wk:

Cervical length, mm ap value for Breslow-Day interaction term.

Data are presented as n/N (%).

CI = confidence interval; RR = relative risk; 17-0HP-C = 17-hydroxyprogesterone caproate. Data from Grobman, 201n2.

FIGURE 42-8 Percentage of births before 37 weeks' gestation at Parkland Hospital from 1988 to 2006 compared with that in the United States from 1996 to 2002. Analysis in both cohorts was limited to singleton liveborn infants �500 g who received prenatal care. (Reproduced with permission from with permission from Leveno J, Mcintire DO, Bloom SL, et al: Decreased preterm births in an innercity public hospital, Obstet Gynecol. 2009 Mar;1o13(3):578-584.)

Awell-organized prenatal system lowers the preterm birth rate in high-risk indigent populations (Creasy, 1980). One example is the Parkland Hospital prenatal clinic system (Leveno, 2009). As shown in Figure 42-8, the declining preterm birth rate between 1988 and 2006 coincided with a substantial rise in prenatal care attendance. In the early 1990s, a concerted efort was made to improve access to prenatal care by creating seamless care that began with antenatal enrollment and extended through delivery and the puerperium. Prenatal clinics were placed strategically throughout Dallas County to provide convenient access for our patients. Prenatal protocols are used by nurse practitioners at all clinic sites to guarantee homogeneous care. Women with highrisk pregnancy complications are referred to our hospital-based central clinic system. Here, Maternal-Fetal Medicine clinics operate each weekday and are stafed by residents and midwives and supervised by fellows and faculty.

hus, prenatl care is considered one component of a comprehensive and orchestrated public health-care system that is community-based. We believethat the drop in preterm births experienced at our inner-city hospitl is at least partially attributable to a geographically based public health-care program specifically targeting minority populations ofpregnant women. A similar obstetrical care system for indigent women at the University of Alabama at Birmingham has also produced salutary results (Tita, 2011).

Methods used to diagnose ruptured membranes are detailed in Chapter 22 (p. 435). A history of vaginal leakage of luid, either as a continuous stream or a gush, should prompt a speculum examination to visualize gross vaginal pooling ofamnionic fluid, clear fluid from the cervical canal, or both. Conirmation of PPROM is usually accompanied by sonographic examina tion to assess amnionic fluid volume, to identiY the presenting part, and if not previously determined, to estimate gestational age. Once PPROM is identified, the general scheme shown in

Table 42-9 can guide management.

Cox and associates (1988) describedpregnancy outcomes of298 consecutive womenwho gave birth following spontaneously ruptured membranes between 24 and 34 weeks' gestation at Parkland Hospital. Although this complication was identified in only 1.7 percent of pregnancies, it contributed to 20 percent of all perinatal deaths. By the time they presented, 76 percent of the women were already in labor, and 5 percent were delivered for other complications. Thus, only 19 percent initially were permitted expectant management. Ultimately, deliverywas delayed 48 hours or more ater membrane rupture in only 7 percent of the total study cohort. There was beneit noted from delayed delivery, however, as none of the neonates died in this group. This contrasted with a neonatal death rate of 80 per 1000 in preterm newborns delivered within 48 hours ofmembrane rupture. Nelson and colleagues later (1994) reported similar results.

The time from PPROM to delivery is inversely proportional to the gestational age when rupture occurs (Carroll, 1995). s shown in Figure 42-9, very few days are gained when membranes ruptured during the third trimester compared with midpregnancy.

Most clinicians hospitalize women with ruptured membranes. Concerns regarding the costs oflengthy hospitalizations are usually moot, because most women enter labor within a week or less after membrane rupture. Carlan and coworkers (1993) randomly assigned 67 women with ruptured membranes ro home or hospital management. No benefitswere found for hospitalization, and maternal hospital stays were reduced by 50 percent in those sent home-14 versus 7 days. Importantly, the investigators emphasized that this study was too small to conclude that home management was safe in regard to umbilical cord prolapse.

Before the mid-1970s, labor was usually induced in women with preterm ruptured membranes because of fear of sepsis. Maternal infection risk and fetal prematurity risk vary according to the gestational age at membrane rupture, and management decisions hinge on this balance. With regard ro periviable pregnancy, 110rales (1993b) expectantly managed 94 singleton pregnancies with ruptured membranes before 25 weeks. he average time gained was 11 days. Although 41 percent ofinfants survived to age 1 year, only 2 percent of the original cohort were neurologically normal. Similar results were reported by Farooqi (1998) and Winn (2000) and their colleagues. Management of these early pregnancies is discussed on page 807.

For PPROM in general, two randomized trials in the 1990s compared labor induction with expectant management (Cox, 1995; Mercer, 1993). In both of these studies, the balance of risk and beneit was diicult to ascertain, as neither immediate • •I I . .•.,. . .• I · .......

FIGURE 42-9 Relationship of time between preterm membrane rupture and delivery in 172 singleton pregnancies. (Reproduced with permission from Carroll SG, Blott M, Nicolaides KH: of membranes before 37 weeks' gesPreterm prelabor amniorrhexis: Outcome of live births, Obstet Gynecol 1995 Jul;86(1 ):18-25.) tation without contraindications to

TABLE 42-9. Management of Preterm Premature Rupture of Membranes 34 weeks or more Plan delivery: labor induction unless contraindicated Group B streptococcal

Single corticosteroid course may be considered up to 366/7 weeksb 32 weeks to 33 completed weeks Expectant management

Group B streptococcal prophylaxisa Single corticosteroid coursec Antimicrobials to prolong latency 24 weeks to 31 completed weeks Expectant management

T ocolytics: no consensus Antimicrobials to prolong latency <24 weeks Expectant management or induction of labore

Group B streptococcal prophylaxis is not recommendedf

Single corticosteroid course may be considerede,f f

Tocolytics: no consensuse,n

Antimicrobials: may be considerede,9 aFigure 64-7 (p. 1222) outlines group B streptococcal prophylaxis for preterm gestations.

bMay be considered between 34°17 and 366/7 weeks in those who have not received a previous course of antenatal corticosteroids. (Repeat, or rescue, course of corticosteroids with preterm rupture of membranes is controversial.

dMagnesium sulfate for neuroprotection in accordance with one of the larger studies.

eSee Periviable Neonatal Survival (p. 806) to aid patient counseling and decision making. flntervention not recommended before viability but may be considered as early as 23°(7 weeks of gestation. 9May be considered as early as 20°/7 weeks of gestation.

Data from American College of Obstetricians and Gynecologists 2016a, d, 2017a, e.

delivery nor expectant management were proven to be superior prolonged latency after membrane rupture was not associated for neonatal outcomes. Lieman and associates (2005) found that with a greater incidence of fetal neurological damage. n imporneonatal outcomes did not improve with expectant management tant correlate is that infection-specifically chorioamnionitisbeyond 33 weeks. McElrath and coworkers (2003) found that is recognized as a risk factor for development of neonatal neurological injury (Gaudet, 2001; Wu,r2000).

•Deaths from prematurity complications recently compared planned early 150 birth with expectant management ..Deaths from pulmonary hypoplasia for women with PPROM before 37 weeks' gestation. They evaluated women and 3628 newborns. No �90 • ..0• clinically important diferences in ..,..0. .

D • the incidence of neonatal sepsis

C .•. • between women who immediately ..0. . . • . . • delivered and those managed expec ..,..0. . tantly were identified. Although the .,incidence of chorioamnionitis was ..,:I · : lower, neonates of women random ized to early birth were more likely to be born at an earlier gestational

Gestation at amniorrhexis (weeks) perinatal sequelae. The authors con cluded that in women with rupture continuing the pregnancy, a policy of expectant management with careful monitoring was associated with better outcomes for both the mother and newborn.

he American College of Obstetricians and Gynecologists (2016d) has recognized the controversies of immediate deliv ery compared with expectant management. Clearly, gestational age is an important consideration. At 24°/7 to weeks, expectant management in the absence of nonreassuring fetal status, clinical chorioamnionitis, or placental abruption is rec ommended. At 34°/7 weeks of gestation or greater, delivery is still recommended by the College for all women with ruptured membranes. Our current practices at Parkland Hospital are consistent with these recommendations.

• Considerations with Expectant Management

Several scenarios during expectant management merit consideration. One is performance of digital cervical examination. Alexander and colleagues (2000) analyzed findings in women with PPROM expectantly managed between 24 and 32 weeks' gestation. hey compared those who had one or two digital cervical examinations with women who were not examined. Those who were examined had a rupture-to-delivery interval of 3 days compared with 5 days in those not examined. This diference did not worsen maternal or neonatal outcomes.

Rupture of membranes following second-trimester amniocentesis is uncommon (Chap. 14, p. 293). Compared with women with spontaneous rupture during the second trimester, Borgida and associates (2000) found that pregnancies complicated by PPROM after genetic amniocentesis resulted in signiicantly better perinatal outcomes. The perinatal survival rate was 91 percent. After counseling, afected women are typically managed expectantly as outpatients with serial surveillance of amnionic fluid volume (American College of Obstetricians and Gynecologists, 2016d). In the series cited above, the mean time to documentation of a normal amnionic fluid volume after amniocentesis approximated 2 weeks.

T ocolysis has been used in few studies. In women with ruptured membranes and lack of labor, prophylactic tocolysis does not improve neonatal outcomes but is associated with greater rates of chorioamnionitis (Mackeen, 2014). Similarly, therapeutic tocolysis-for those with ruptured membranes and labor-has also not provided signiicant perinatal beneit (Garite, 1987).

There is uncertainty regarding PPROM in the woman who has undergone cervical cerclage. McElrath and associates (2002) studied 114 women with a cerclage in place who later had ruptured membranes before 34 weeks. They were compared with 288 controls. Pregnancy outcomes were equivalent in both groups. Cerclage retention for more than 24 hours after preterm rupture of membranes may be associated with pregnancy prolongation, however, there is risk of intrauterine infection and its consequences (Giraldo-Isaza, 2011r; Laskin, 2012). As discussed in Chapter 18 (p. 357), such management is controversial.

With PPROM in general, the volume of amnionic luid remaining after rupture appears to have prognostic importance in pregnancies before 26 weeks. Hadi and colleagues (1994) described 178 pregnancies with ruptured membranes between 20 and 25 weeks. Almost 40 percent developed oligohydram nios, defined by the absence of fluid pockets measuring 2 em or more. Virtually all women with oligohydramnios delivered before 25 weeks, whereas 85 percent with adequate amnionic luid volume were delivered in the third trimester. Carroll and coworkers (1995) observed no cases of pulmonary hypoplasia in fetuses born after membrane rupture at 24 weeks or beyond.

This suggests that 23 weeks or less is the threshold for devel opment of lung hypoplasia (Chap. 7, p. 133). Further, when contemplating early expectant management, consideration is also given to oligohydramnios and resultant limb compression deformities (Chap. 11, p. 232).

Other risk factors have also been evaluated. First, in neo nates born to women with active herpetic lesions who were expectantly managed, the infectious morbidity risk appeared to be outweighed by risks associated with preterm delivery (Major, 2003). Second, Lewis and associates (2007) found that expectant management of women with PPROM and nonce phalic presentation was associated with a higher rate of umbili cal cord prolapse, especially before 26 weeks.

As discussed, infection is a major concern with membrane rupture. While some cases remain subclinical, if chorioamnionitis is diagnosed, prompt eforts to efect delivery, preferably vaginally, are initiated. Because maternal leukocytosis alone is not a consistent inding, ever is the ony reliable indicator or the diagnosis of chorioamnionitis. Institutional practices and protocols vary in deining the temperature threshold. T raditionally, a temperature �38°C (100.4°F) accompanying ruptured membranes has implied infection. At Parkland Hospital, we still adhere to this criterion.

In 2015, a workshop sponsored by the NICHD was convened and suggested renaming this condition "intraamnionic infection and inflammation" (Higgins, 2016). The merits and clinical utility of this novel "triple I" terminology have been questioned (Barth, 2016). Nonetheless, the American College of Obstetricians and Gynecologists (20 17b) recently revised both the definitions and temperature thresholds for intraamnionic infection. Using these new deinitions, the diagnosis of suspected intraamniotic infection is made when the maternal temperature is �39.0°C or when the maternal temperature is 38.0 to 38.9°C and one additional clinical risk factor is present. Suggested factors include low parity, multiple digital examinations, use of internal uterine and fetal monitors, meconiumstained amnionic fluid, and the presence of certain genital tract pathogens. Examples are group B streptococcus and sexually transmitted agents. Isolated maternal fever is deined as any maternal temperature between 38.0°C and 38.9°C with no additional risk factors present, and with or without persistent temperature elevation.

With chorioamnionitis, fetal and neonatal morbidity are substantively increased. lexander and colleagues (1998) studied 1367 very-Iow-birthweight neonates delivered at Parkland Hospital. Approximately 7 percent were born to women with overt chorioamnionitis, and their outcomes were compared with similar newborns without clinical infection. Those in the infected group had higher incidences of sepsis, RDS, earlyonset seizures, intraventricular hemorrhage, and periventricular leukomalacia. The investigators concluded that these very-Iowbirthweight newborns were vulnerable to neurological injury attributable to chorioamnionitis. Yoon and colleagues (2000) found that intraamnionic infection in preterm neonates was related to increased rates of cerebral palsy. Petrova and associates (2001) studied more than 11 million singleton live births in the United States from 1995 to 1997. During labor, 1.6 percent of all women had fever, and this was a strong predictor of infection-related death in both term and preterm neonates.

The proposed microbial pathogenesis for spontaneous preterm labor or ruptured membranes has prompted investigators to give various antimicrobials to forestall delivery. Mercer and associates (1995) reviewed 13 randomized trials performed before 35 weeks. heir metaanalysis indicated that only three of 10 outcomes werepossiby beneited: (1) fewer women developed chorioamnionitis, (2) fewer newborns developed sepsis, and (3) pregnancy was more often prolonged 7 days in women given antimicrobials. Rates of neonatal survival, necrotizing enterocolitis, RDS, or intracranial hemorrhage, however, were unafected.

To further address this issue, the MFMU Network designed a trial to study expectant management combined with placebo or with a 7 -day antibiotic regimen. Treatment included intravenous ampicillin plus erythromycin every 6 hours for 48 hours, which was followed by oral amoxicillin plus erythromycin, every 8 hours for 5 days. The women had membrane rupture between 24 and 32 weeks' gestation. Neither tocolytics nor corticosteroids were given. Antimicrobial-treated women had signiicantly fewer newborns with RDS, necrotizing enterocolitis, and composite adverse outcomes (Mercer, 1997). The latency period was also significantly longer. Specifically, 50 percent of women given an antimicrobial regimen remained undelivered after 7 days of treatment compared with only 25 percent of those given placebo. lso, a significantly greater number of treated pregnancies were undelivered at 14 and 21 days. Cervico vaginal group B streptococcal colonization did not alter these results.

Other studies have examined the eicacy of shorter treatment lengths and diferent antimicrobial combinations. hreeday treatments compared with 7 -day regimens using either ampicillin or ampicillin-sulbactam appear equally efective in regard to perinatal outcomes (Lewis, 2003; Segel, 2003). Similarly, erythromycin compared with placebo ofered a range of significant neonatal benefits. The amoxicillin-clavulanate regimen was not recommended, however, because of its association with an increased incidence of neonatal necrotizing enterocolitis (Kenyon, 2004).

Some predicted that prolonged antimicrobial therapy in such pregnancies might have unwanted consequences (Carroll, 1996; Mercer, 1999). Stoll and associates (2002) studied 4337 neonates weighing from 400 to 1500 g and born from 1998 to 2000. Their outcomes were compared with those of 7606 neonates of similar birthweight born from 1991 to 1993 and prior to the practice of antibiotic prophylaxis. The overall rate of early-onset sepsis did not change between these two epochs. But, the rate of group B streptococcal sepsis dropped from 5.9 per 1000 births in the 1991 to 1993 group to 1.7 per 1000 births in the 1998 to 2000 group. Comparing these same epochs, the rate of Escherichia coli sepsis, however, rose from 3.2 to 6.8 per 1000 births. Almost 85 percent of coliform isolates from the more recent cohort were resistant to ampicillin. Neonates with early-onset sepsis were more likely to die, especially if they were infected with coliforms. Long term, Kenyon and coworkers (2008a) found that antimicrobials given for women with PPROM had no efect on the health of children at age 7 years .

• Corticosteroids to Accelerate

The use of antenatal corticosteroids in the setting of PPROM was once considered controversial as the magnitude of the beneits was not as great as when the membranes were intact. A single course of corticosteroids, however, is now recommended for pregnant women with ruptured membranes between 24°/7 and 34°17 weeks' gestation (American College of Obstetricians and Gynecologists, 2017 a). As with periviability (p. 807), a single course of corticosteroids as early as 23°/7 weeks in those who are at risk for preterm delivery within 7 days may be considered (American College of Obstetricians and Gynecologists, 2017e). A similar controversy is found at the other end of the gestational age spectrum, wherein corticosteroid administration in the late-pre term period is also under consideration (p. 823).

Tissue sealants are used for various purposes in medicine, including achieving surgical hemostasis. As discussed in Chap. 18 (p. 351), there are limited reports of sealants in the repair of fetal membranes. Crowley and coworkers (2016) recently reviewed the available evidence and concluded that data are currently insuicient to evaluate sealing procedures for ruptured membranes. At Parkland Hospital, we do not currently use these agents for this indication.

Women with signs and symptoms of preterm labor with intact membranes are managed similarly to those with PPROM. If possible, delivery before 34 weeks' gestation is delayed. Drugs used to abate or suppress preterm uterine contractions are subsequently discussed.

• Amniocentesis to Detect Infection

Several tests have been used to diagnose intraamnionic infection (Andrews, 1995; Romero, 1993; Yoon, 1996). Although such infection can be conirmed with a positive test result, there is little utility for routine amniocentesis (American College of Obstetricians and Gynecologists (2017b).

Because glucocorticosteroids were found to accelerate lung maturation in preterm sheep fetuses, Liggins and Howie (1e972) evaluated them to treat women. Corticosteroid therapy was efective in lowering the incidence of RDS and neonatal initiation of betamethasone. Infants exposed to corticosteroids in these early studies have now been followed to age 31 years with no ill efects detected. In 1995, a National Institutes of ened preterm birth. In a subsequent meeting, another NIH

Conference (2000) concluded that data were insuicient to by hypertension, diabetes, multifetal gestation, fetal-growth restriction, or fetal hydrops. It was concluded, however, that it was reasonable to administer corticosteroids to these women.

A recent metaanalysis by Roberts and associates (20e17) of 30 studies totaling 7774 women and 8158 infants quantiied the beneit of a single course of corticosteroids. Treatment was associated with lower rates of perinatal death, neonatal death, RDS, intraventricular hemorrhage, necrotizing enterocolitis, need for mechanical ventilation, and systemic infection in the first 48 hours of life. No obvious beneits were gained for chronic lung disease, death in childhood, or neurodevelopmental delay in childhood. Therapy was not associated with chorioamnionitis. Parenthetically, corticosteroids given prophylactically to women at risk of preterm birth in low-and middle-income countries actually increase perinatal mortality rates (Althabe, 2015).

A single course of corticosteroids is currently recommended by the American College of Obstetricians and Gynecologists (2017a) for women between 24 and 34 weeks who are at risk for delivery within 7 days. This recommendation for premature twins has been challenged (Viteri, 20e16). Boundaries of gestational age for corticosteroid administration are also now being explored. For pregnancies at 23 weeks and at risk of delivery within 7 days, a single course of corticosteroids may be considered (p. 807). Administration of corticosteroids during the periviable period is linked to a family's decision regarding resuscitation and should be considered in that context (American College of Obstetricians and Gynecologists, 20e1e7e).

Betamethasone and dexamethasone appear to be equivalent for fetal lung maturation (Murphy, 2007). These two drugs are comparable in reducing rates of major neonatal morbidities in preterm newborns (Elimian, 2007). A treatment course may be two 12-mg doses of betamethasone, and each dose is given intramuscularly 24 hours apart. With dexamethasone, 6-mg doses are given intramuscularly every 12 hours for four doses. Because treatment for less than 24 hours may be beneicial and reduce neonatal morbidity and mortality rates, a first dose of antenatal corticosteroids is administered regardless of the ability to complete additional doses before delivery (American College of Obstetricians and Gynecologists, 20e1e7a).

The MFMU Network conducted a randomized trial to assess whether administration of antenatal betamethasone to women who were likely to deliver in the late-pre term period would

Bannerman, 2016). Even though only 60 percent of the study cohort of 283e1 women received both injections, the rate of respiratory complications measured as a composite outcome was lower with corticosteroid use compared with placebo-1 1.6 versus 14.4 percent. Because of these indings, consideration for administration of a single course of betamethasone for women the American College of Obstetricians and Gynecologists (2017a) and the Society for Maternal-Fetal Medicine (2016a).

Adoption of this practice has not been universal. Both shortand long-term neonatal safety are concerns (Crowther, 2016; Kamath-Rayne, 2016). Specifically, in the newborns receiving betamethasone, rates of hypoglycemia were signiicantly greater (Gyami-Bannerman, 20e16) . Neonatal hypoglycemia is particularly worrisome for possible adverse long-term consequences that include developmental delay (Kerstjens, 2012). Another caveat is that the largest efects of betamethasone included a reduction in transient tachypnea of the newborn-a self-limited condition with little clinical signiicance (KamathRayne, 2016). Speciically, the rates of transient tachypnea of the newborn were 6.7 and 9.9 percent in those given betamethasone and placebo, respectively. These rates are three-to fourfold higher than those reported by the Consortium on Safe Labor (20e10), which was a retrospective, observational study that abstracted detailed labor and delivery information from 19 hospitals across the United States on 233,844 deliveries. Because of these issues, we do not provide corticosteroids beyond 34 weeks at Parkland Hospital at this time.

Single versus additional courses of intramuscular corticosteroids for lung maturation has been the topic of two major trials. Although both found repeated courses to be beneicial in reducing neonatal respiratory morbidity rates, the long-term consequences were much diferent. In one randomized study by Crowther and associates (2007), all women at risk for preterm birth were given a primary course of betamethasone. Women were then given serial weekly doses of 11e.4 mg of betamethasone for persistent risk or were given placebo. hese investigators found no adverse efects in the infants followed to age 2 years. Wapner and coworkers (2007) studied infants born to 495 women who were randomly assigned to receive a single corticosteroid course that contained two doses or assigned to repeated courses that were given weekly. A nonsignificant rise in the cerebral palsy rate was identified in infants exposed to repeated courses. The doubled betamethasone dose in this study was worrisome because some experimental evidence supports the view that adverse efects are dose dependent (Bruschettini, 2006). Stiles (2007) summarized these two studies as "early gain, long-term questions." We agree, and at Parkland Hospital, we follow the recommendation by the American College of Obstetricians and Gynecologists (2017a) for singlecourse therapy.

his refers to administration of a second corticosteroid dose when delivery becomes imminent and more than 7 days have elapsed since the initial dose. In one randomized trial, 326 women received placebo or a single 12-mg dose of betamethasone (Peltoniemi, 2007). Paradoxically, the rescue dose of betamethasone increased the risk of RDS. In another randomized study of 437 women with gestations <33 weeks, Garite and associates (2009) reported significantly lower rates of respiratory complications and neonatal composite morbidity with rescue corticosteroids versus placebo. Rates of perinatal mortality and other morbidities, however, did not difer. Last, McEvoy and colleagues (2010) found that treated infants had improved respiratory compliance.

Garite and coworkers (2009) randomly assigned 437 women with singletons or twins <33 weeks' gestation and with intact membranes to one rescue course of either betamethasone or dexamethasone or placebo. These women had all previously completed a single course of corticosteroids before 30 weeks' gestation and at least 14 days before the rescue course. RDS developed in 41 percent of the newborns given rescue corticosteroids compared with 62 percent of those randomized to placebo. Rates of other morbidities attributable to prematurity did not difer. In a metaanalysis, Crowther and colleagues (201e1) concluded that a single course of corticosteroids should be considered in women whose prior course was administered at least 7 days previously and who were <34 weeks' gestation. The American College of Obstetricians and Gynecologists (2017 a) has taken the position that a single rescue course of antenatal corticosteroids be considered in women before 34 weeks whose prior course was administered at least 7 days previously. Efects of rescue therapy beyond 34 weeks are currently unknown. At Parkland Hospital, we currently do not provide additional courses of corticosteroids beyond the initial single-course therapy.

Very-Iow-birthweight neonates whose mothers were treated with magnesium sulfate for preterm labor or preeclampsia were found to have a reduced incidence of cerebral palsy at 3 years (Grether, 2000; Nelson, 1995). Because of this, randomized trials were designed to investigate this hypothesis. In one trial, 1063 women at risk of delivery before 30 weeks were given magnesium sulfate or placebo (Crowther, 2003). Magnesium exposure improved some perinatal outcomes. Namely, rates of both neonatal death and cerebral palsy were lower in the magnesium-treated group-but this study was not suiciently powered. The multicenter French trial reported by Marret and associates (2008) had similar problems.

More convincing evidence for magnesium neuroprotection came from the MFMU Network study-Beneicial Eects of Antenatal Magnesium Suote-BM-Study (Rouse, 2008). This was a placebo-controlled trial in 224e1 women at imminent risk for preterm birth between 24 and 31 weeks. Women randomized to magnesium sulfate were given a 6-g bolus over 20 to 30 minutes followed by a maintenance infusion of 2 g per hour. Magnesium sulfate was actually infusing at the time of delivery in approximately half of the treated women. A 2-year follow-up was available for 96 percent of the children. Results are shown in Table 42-10. his trial can be interpreted diferently depending on statistical methodologies employed. Some interpret these indings to mean that magnesium infusion prevents cerebral palsy regardless of the gestational age at which therapy is given. Those with a difering view conclude that this trial only supports use of magnesium sulfate for prevention of cerebral palsy before 28 weeks.

Subsequent to these studies, Doyle and associates (2009) reviewed five randomized trials to assess neuroprotective efects. A total of 6145 infants were studied, and these reviewers concluded that magnesium exposure compared with no exposure significantly lowered risks for cerebral palsy. Rates of other neonatal morbidity did not difer significantly. It was calculated that treatment given to 63 women would prevent one case of cerebral plsy.

Controversy surrounding magnesium eicacy for neuroprotection prompted a debate at the 20e11 annual meeting of the Society for Maternal-Fetal Medicine. Rouse (2011) spoke for the beneits of magnesium sulfate, whereas Sibai (2011) challenged that the reported benefits were false positive due to random statistical error in the metaanalysis by Doyle (2009). Another peculiarity is the apparent lack of dose-response for eicacy (McPherson, 2014). Because none of the individual studies found a benefit from magnesium sulfate for fetal neuroprotection, the American College of Obstetricians and Gynecologists (20e1e6a) concluded that those electing prophylaxis should develop specific guidelines. To guide such therapy, the American College of Obstetricians and Gynecologists (20e12)

TABLE 42-10. Magnesium Sulfate for the Prevention of Cerebral Palsya

Infants with 2-year follow-up

Moderate or severe cerebral palsy: aSelected results from the Beneficial Efects of Antenatal Magnesium Sulfate (BEAM) Study. bWeeks' gestation at randomization.

CI = confidence index. Data from Rouse, 2008.

issued a Patient Saey Checklist for use of magnesium sulfate for neuroprotection. For those with PPROM, prophylaxis may similarly be considered. At Parkland Hospital, we provide magnesium sulfate for neuroprotection with threatened preterm delivery from 24°/7 to 276/7 weeks.

Results have been disappointing in studies of antimicrobials given to arrest preterm labor. From one Cochrane metaanalysis, antimicrobial prophylaxis given to women with intact membranes did not reduce preterm birth rates or afect other clinically important short-term outcomes (Flenady, 2013). However, rates of short-and longer-term harm were higher for children of mothers exposed to antibiotics. Kenyon (2001) reported the ORACLE Collaborative Group study of 6295 women with spontaneous preterm labor and intact membranes, but without evidence of infection. Women were randomly assigned to receive antimicrobial or placebo therapy. The primary outcomes of neonatal death, chronic lung disease, and major cerebral abnormality were similar in both groups. In a follow-up of the ORACLE II trial, fetal exposure to antimicrobials in this clinical setting was associated with an increased cerebral palsy rate at age 7 years compared with that in children without fetal exposure (Kenyon, 2008b). Importantly, antimicrobial use described here is distinct from that given for group B streptococcal prophylaxis (Chap. 64, p. 1222).

This is one of the most often prescribed interventions during pregnancy, yet one of the least studied. One systematic review concluded that evidence neither supported nor refuted bed rest for prevention of preterm birth (Sosa, 2004). Goulet and coworkers (2001) randomly assigned 250 Canadian women to either home care or hospitalization after treatment of an acute episode of preterm labor and found no beneits. There have, however, been reports of possible harm. Kovacevich and associates (2000) reported that bed rest for 3 days or more increased thromboembolic complications to 16 per 1000 women compared with only 1 per 1000 with normal ambulation. Promislow and colleagues (2004) observed significant bone loss in pregnant women prescribed outpatient bed rest. More recently, Grobman and associates (20e13) noted that women with activity restriction were nearly 2.5 times more likely to have a preterm birth before 34 weeks. his finding, however, may reflect ascertainment bias. hat is, women with restricted activity may have been assigned to bed rest because they were viewed to be at more imminent risk of preterm delivery. McCall and coworkers (2013) summarized the literature on bed rest, and they found insuicient evidence to support its use. The American College of Obstetricians and Gynecologists (20e17 d) suggests that, although frequently prescribed, bed rest is only rarely indicated, and ambulation should be considered in most cases.

Silicone rings, such as the Arabin pessay, are being used to support the cervix in women with a sonographically short cervix. For 385 Spanish women with a cervical length ;25 mm, Goya and associates (2012) provided a silicone pessary or expectant management. Newborns spontaneous delivered before 34 weeks' gestation in 6 percent of women in the pessary group compared with 27 percent in the expectant management group. Another trial randomly assigned almost 100 women with a cervix <25 mm at 20 to 24 weeks to silicone pessaries or expectant management (Hui, 2013). The pessary did not lower the rate of delivery < 34 weeks. Similar indings were reported by Nicolaides and colleagues (2016). he Society for Maternal-Fetal Medicine (2017b) recently recognized the conflicting published reports and lack of an FDA-approved pessary for the indication of preterm birth prevention. They currently recommend pessary prophylaxis only within research protocols.

Some evidence supports the concept that cervical incompetence and preterm labor lie along a spectrum leading to preterm delivery. Consequently, investigators have evaluated cerclage placement after preterm labor begins to manifest clinically. Althuisius and colleagues (2003) randomly assigned 23 women with cervical incompetence before 27 weeks to bed rest, with or without emergency McDonald cerclage. Delivery delay was significantly greater in the cerclage group compared with those assigned to bed rest-54 versus 24 days, respectively. Terkildsen and coworkers (2003) studied 116 women who underwent second-trimester emergency cerclage. Nulliparity, membranes extending beyond the external cervical os, and cerclage before 22 weeks were associated with a signiicantly decreased chance of signiicant pregnancy continuation. For women facing a poor pregnancy prognosis due to cervical dilation at midgestation, it seems reasonable to ofer emergency or rescue cerclage with appropriate counseling. However, it is unclear if such interventions truly confer a beneit or merely increase the risk of membrane rupture and infection (Hawkins, 2017).

• Tocolysis to Treat Preterm Labor

Although several drugs and other interventions have been used to prevent or inhibit preterm labor, none is completely efective. The American College of Obstetricians and Gynecologists (2016b) has concluded that tocolytic agents do not markedly prolong gestation but may delay delivery in some women for up to 48 hours. This may allow transport to an obstetrical center with higher-level neonatal care and permit time for a course of corticosteroid therapy. Although delivery may be delayed to administer corticosteroids, treatment has not improved perinatal outcome rates (Gyetvai, 1999).

Beta-adrenergic agonists, magnesium sulfate, calciumchannel blockers, or indomethacin are the recommended tocolytic agents for this short-term use. The gestational age range for tocolytic use is debatable. But, because corticosteroids are not generally used after 34 weeks, and because the perinatal outcomes in preterm neonates are generally good after this time, most do not recommend use of tocolytics after 33 weeks' gestation (Goldenberg, 2002).

In many women, tocolytics stop contractions temporarily but rarely prevent preterm birth. he College (2016b) notes that maintenance therapy with tocolytics is inefective for preventing preterm birth. Importantly, no trial has ever convincingly shown reductions in rates of any important adverse outcome by a tocolytic drug compared with placebo (Walker, 2016). Maintenance tocolysis after acute therapy is not recommended.

Several compounds react with 3-adrenergic receptors to reduce intracellular ionized calcium levels and prevent activation of myometrial contractile proteins (Chap. 21, p. 406). Of 3-mimetic drugs in the United States, ritodrine and terbutaline have been used in obstetrics, but only ritodrine is approved for preterm labor by the FDA.

Ritodrine was voluntarily withdrawn from the United States market in 2003, but a discussion of ritodrine is included here to present issues with 3-mimetic drug use. In one early trial, neonates whose mothers were treated with ritodrine for threatened preterm labor had lower rates of preterm birth and its complications (NIerkatz, 1980). In a randomized trial at Parkland Hospital, intravenous ritodrine delayed delivery for 24 hours but without other beneits (Leveno, 1986b). Additional studies confirmed a delivery delay up to 48 hours (Canadian Preterm Labor Investigators Group, 1992).

3-Agonist drug infusion has resulted in serious and even fatal maternal side efects. Pulmonary edema is a special concern, and its contribution to morbidity is discussed in Chapter 47 (p. 917). In one early study, tocolysis was the third most common cause of acute respiratory distress and death in pregnant women during a 14-year period in Mississippi (Perry, 1998). The cause of pulmonary edema is multifactorial. isk factors include tocolytic therapy with 3-agonist drugs, multifetal gestation, concurrent corticosteroid therapy, tocolysis for more than 24 hours, and intravenous infusion of large volumes of crystalloid. 3-Agonist agents cause retention of sodium and water, and with time-usually 24 to 48 hours-these can cause volume overload (Hankins, 1988). The drugs have been implicated in increased capillary permeability, cardiac rhythm disturbances, and myocardial ischemia.

Terbutaline is commonly used in the United States to forestall preterm labor. Like ritodrine, it may cause pulmonary edema (Angel, 1988). Low-dose terbutaline can be administered longterm by subcutaneous pump (Lam, 1988; Perry, 1995). But, randomized trials have shown no beneit for terbutaline pump therapy (Guinn, 1998; Wenstrom, 1997). Oral terbutaline given to prevent preterm delivery is also inefective (How, 1995; Parilla, 1993). In one trial, 203 women with arrested preterm labor at 24 to 34 weeks' gestation were randomly assigned to receive 5-mg terbutaline tablets or placebo every 4 hours (Lewis, 1996). Of outcomes, delivery rates at 1 week, median latency duration, mean gestational age at delivery, and incidence of preterm labor relapse were similar in both groups. Because of reports of serious maternal side efects, the FDA (2011) issued a warning regarding the use of terbutaline to treat preterm labor. The American College of Obstetricians and Gynecologists (2016b) recommends only short-term inpatient use of terbutaline as a tocolytic or as acute therapy of uterine tachysystole. Subcutaneous dosages of 0.25 mg are commonly used for the latter indication. T erbutaline, used as a tocolytic prior to external cephalic version, is discussed in Chapter 28 (p. 550).

Ionic magnesium in a suiciently high concentration n alter myometrial contractility. Its role is presumably that of a calcium antagonist, and when given in pharmacological doses, it may inhibit labor. Intravenous magnesium sulfate, given s a 4-g loading dose and followed by a continuous inusion of 2 g/hr, usually arrests labor (Steer, 1977). Like 3-mimetic agents, magnesium treatment can cause pulmonary edema (Samol, 2005). However, this has not been our experience at Parkland Hospitl in the treatment of tens of thousands of preeclamptic women with intravenous magnesium sulfate. Pharmacology and toxicology of magnesium are considered in more detail in Chapter 40 (p. 737).

Only two randomized studies have evaluated tocolysis with magnesium sulfate. Cotton and colleagues (1984) compared magnesium sulfate, ritodrine, and placebo in 54 women with preterm labor. They identified few diferences in outcomes. Cox and coworkers (1990) randomly assigned 156 women to receive magnesium sulfate or infusions of normal saline. Magnesium-treated women and their neonates had identical outcomes compared with those given placebo. Because of these findings, this method of tocolysis was abandoned at Parkland Hospital. Similarly, Crowther and associates (2014) reviewed magnesium sulfate as a tocolytic agent and concluded it was inefective and potentially harmful. Last, the FDA (2013) has warned against prolonged use of magnesium sulfate given to arrest preterm labor because of bone thinning and fractures in fetuses exposed for more than 5 to 7 days. This was attributed to low calcium levels in the fetus.

hese compounds are intimately involved in contractions of normal labor (Chap. 21, p. 416). Antagonists act by inhibiting prostaglandin synthesis or by blocking their action on target organs. A group of enzymes collectively termed prostaglandin synthase is responsible for the conversion of free arachidonic acid to prostaglandins. Several drugs block this system, including acetylsalicylate and indomethacin.

Indomethacin, a nonselective cyclooxygenase inhibitor, was first used as a tocolytic in one study of 50 women (Zuckerman, 1974). Studies that followed reported the eicacy of indomethacin in halting contractions and delaying preterm birth (Muench, 2003; Niebyl, 1980). Morales and coworkers (1989, 1993a), however, compared indomethacin with either ritodrine or magnesium sulfate and found no diference in their eicacy to forestall preterm delivery. Berghella and associates (2006) reviewed four trials of indomethacin given to women with a sonographically determined short cervix and found such therapy to be inefective.

Indomethacin is administered orally or rectally. Most studies have limited indomethacin use to 24 to 48 hours because of concerns for oligohydramnios, which can develop with therapeutic doses. If amnionic luid is monitored, oligohydramnios can be detected early, and it is reversible with drug discontinuation.

In a study of neonates born before 30 weeks, Norton and coworkers (1993) identiied necrotizing enterocolitis in 30 percent of 37 indomethacin-exposed newborns compared with 8 percent of 37 control newborns. Higher incidences of intraventricular hemorrhage and patent ductus arteriosus were also documented in the indomethacin group. Several investigators have challenged the association between indomethacin exposure and necrotizing enterocolitis (Muench, 2001; Parilla, 2000). Similarly, Gardner (1996) and Abbasi (2003) and their colleagues found no link between indomethacin use and intraventricular hemorrhage, patent ductus arteriosus, sepsis, necrotizing enterocolitis, or neonatal death. Two metaanalyses of the efects of antenatal indomethacin on neonatal outcomes had conflicting indings (Amin, 2007; Loe, 2005). Reinebrant and colleagues (2015) in a review of 20 studies reported no clear benefit from cyclooxygenase inhibitors, including indomethacin, compared with placebo or any other tocolytic agent.

These potent smooth-muscle relaxants afect the vasculature, gut, and uterus. In randomized clinical trials, nitroglycerin administered orally, transdermally, or intravenously was ineffective or showed no superiority over other tocolytics. In addition, maternal hypotension was a common side efect (Bisits, 2004; EI-Sayed, 1999; Lees, 1999).

Discussed in Chapter 21 (p. 404), myometrial aCtlVIty is directly related to cytoplasmic free calcium, and reduced calcium concentrations inhibit contractions. Calcium-channel blockers act to inhibit, by various mechanisms, calcium entry through cell membrane channels. Although they were developed to treat hypertension, their ability to arrest pre term labor has been evaluated.

From study results, calcium-channel blockers, especially nifedipine, are safer and more efective tocolytic agents than 3-agonist drugs (King, 2003; Papatsonis, 1997). Lyell and colleagues (2007) randomized 192 women at 24 to 33 weeks' gestation to either magnesium sulfate or nifedipine and found no substantial diferences in eicacy or adverse efects. In another randomized study, 145 women with preterm labor between 24 and 33 weeks received nifedipine or atosiban. Neither proved superior to delay delivery, and neonatal morbidity was equivalent (Salim, 2012).

Flenady and coworkers (20 14b) reviewed 38 trials of calciumchannel blockers (mainly nifedipine) for preterm labor. These investigators suggested that calcium-channel blockers have beneits compared with placebo or no treatment. But, this conclusion stemmed from a trial with unclear risk of selection bias and a three-arm study of 84 women that was not blinded (Ara, 2008; Zhang, 2002). We are currently performing a randomized, double-blind, placebo-controlled trial of nifedipine for acute tocolysis of preterm labor at Parkland Hospital.

Importantly, the combination of nifedipine with magnesium for tocolysis is potentially dangerous. Ben-Ami (1994) and Kurtzman (1993) and their coworkers reported that nifedipine enhances the neuromuscular blocking efects of magnesium, which can interfere with pulmonary and cardiac function. In one small study of 54 women with preterm labor who received either magnesium sulfate plus nifedipine or no tocolytic, neither beneit nor harm was found (How, 2006).

This nonapeptide oxytocin analogue is an oxytocin-receptor antagonist (ORA). Goodwin and colleagues (1995) described its pharmacokinetics in pregnant women. In randomized clinical trials, atosiban failed to improve relevant neonatal outcomes and was linked with signiicant neonatal morbidity (Moutquin, 2000; Romero, 2000). he FDA has denied approval of atosiban because of concerns regarding eicacy and fetal-newborn safety. Further, in 2014, a metaanalysis did not demonstrate superiority of ORAs (largely atosiban) as a tocolytic compared with placebo, 3-mimetic drugs, or calcium-channel blockers in terms of pregnancy prolongation or neonatal outcomes. But, ORAs were associated with fewer maternal adverse efects (Flenady, 20 14a). Recently, van Vliet and coworkers (2016) conducted a randomized trial comparing nifedipine with atosiban in 510 women with threatened preterm birth. Using a composite of adverse perinatal outcomes, no diferences were reported between the two study groups.

Whether preterm labor is induced or spontaneous, abnormalities of fetal heart rate and uterine contractions are sought. We prefer continuous electronic monitoring. Fetal tachycardia, especially with ruptured membranes, is suggestive of sepsis. Some evidence supports that intrapartum acidemia may intensiy some of the neonatal complications usually attributed to preterm delivery. For example, Morgan and associates (2017) found that metabolic acidemia signiicantly raised the risks related to prematurity in neonates delivered prior to 34 weeks' gestation. Low and colleagues (1995) observed that intrapartum acidosis-umbilical artery blood pH <7.0-had an important role in neonatal complications (Chap. 33, p. 621). Group B streptococcal infections are common and dangerous in the preterm neonate, and antimicrobial prophylaxis should be provided (Chap. 64, p. 1222).

In the absence of a relaxed vaginal outlet, an episiotomy for delivery may be necessary once the fetal head reaches the perineum. Perinatal outcome data do not support routine episiotomy or forceps delivery to protect the "fragile" preterm fetal head. Staf proicient in resuscitative techniques commensurate with the gestational age and fully oriented to any speciic problems should be present at delivery. Principles of resuscitation described in Chapter 32 (p. 608) are applicable. The importance of specialized personnel and facilities for preterm newborn care is underscored by the improved survival rates of these neonates when delivered in tertiary-care centers.

• Prevention of Intracranial Hemorrhage

Preterm newborns frequently have intracranial germinal matrix bleeding that can extend to more serious intraventricular hemorrhage (Chap. 34, p. 639). It was hypothesized that cesarean delivery to obviate trauma from labor and vaginal delivery might prevent these complications. his has not been validated by subsequent studies. Malloy (1991) analyzed 1765 newborns with birthweights < 1500 g and found that cesarean delivery did not lower the risk of mortality or intracranial hemorrhage. Anderson and colleagues (1988), however, made an interesting observation regarding the role of cesarean delivery in intracranial hemorrhage prevention. These hemorrhages correlated with exposure to active-phase labor. However, they emphasized that avoidance of active-phase labor is impossible in most preterm births because decisions for delivery route are not required until active labor is irmly established.

Aagaard K, Riehle K, Ma ], et al: A metagenomic approach to characterization of the vaginal microbiome signature in pregnancy. PLoS One (6):e36466, 2012

Abbasi S, Gerdes ]S, Sehdev HM, et al: Neonatal outcomes after exposure to indomethacin in utero: a retrospective case cohort study. Am ] Obstet Gynecol 189:782,n2003

Akgul Y, Word RA, Ensign LM, et al: Hyaluronan in cervical epithelia protects against infection-mediated preterm birth.] Clin Invest 124(12):5481,2014 Alexander ]M, Gilstrap LC, Cox SM, et al: Clinical chorioamnionitis and the prognosis for very low birthweight infants. Obstet Gynecol 25, 1998

Alexander ]M, Mercer BM, Miodovnik M, et al: he impact of digital cervical examination on expectantly managed preterm tuptured membranes. Amn] Obstet Gynecol 183: 1 003, 2000

Alirevic Z, Milan S], Livio S: Caesarean section versus vaginal delivery for preterm birth in singletons. Cochrane Database Syst Rev 9:CD000078, 2013

Althabe F, Belizan ]M, McClure EM, et al: A population-based, multifaceted strategy to implement antenatal corticosteroid treatment versus standard care for the reduction of neonatal mortaliry due to preterm birth in lowincome and middle-income countries: the ACT cluster-randomised trial. Lancet 385(9968):629,n2015

Althuisius SM, Dekker G, Hummel P, et al: Cervical incompetence prevention randomized cerclage trial: emergency cerclage with bed rest versus bed rest alone. Am] Obstet Gynecol 189:907,n2003

Althuisius SM, Dekker GA, Hummel P, et al: Final results of the Cervical Incompetence Prevention Randomized Cerclage Trial (CIPRACT): therapeutic cerclage with bed rest versus bed rest alone. Am ] Obstet Gynecol 185:1106,n2001

American College of Obstetricians and Gynecologists: Magnesium sulfate before anticipated preterm birth for neuroprotection. Patient Safety Checklist No.n7, August 2012

American College of Obstetricians and Gynecologists: Magnesium sulfate use in obstetrics. Committee Opinion No. 652, January 2016a

American College of Obstetricians and Gynecologists: Management of preterm labor. Practice Bulletin No. 171, October 2016b

American College of Obstetricians and Gynecologists: Prediction and prevention of preterm birth. Practice Bulletin No. 130, October 2012, Reairmed 2016c

American College of Obstetricians and Gynecologists: Premature rupture of membranes. Practice Bulletin No. 172, October 2016d

American College of Obstetricians and Gynecologists: Antenatal corticosteroid therapy for fetal maturation. Committee Opinion No. 713, August 2017a

American College of Obstetricians and Gynecologists: Intrapartum management of intraamniotic infection. Committee Opinion No. 712, August 2017b

American College of Obstetricians and Gynecologists: Medically indicated late-preterm and early-term deliveries. Committee Opinion No. 560, April 2013, Reairmed 2017c

American College of Obstetricians and Gynecologists: Physical activity and exercise during pregnancy and the postpartum period. Committee Opinion No. 650, December 2015, Reairmed 2017d

American College of Obstetricians and Gynecologists, Society for MaternalFetal Medicine: Periviable birth. Obstetric Care Consensus No.n6, 2017e Amin SB, Sinkin RA, Glantz C: Metaanalysis of the efect of antenatal indo methacin on neonatal outcomes. Am ] Obstet Gynecol :486, 2007

Ananth CV, Joseph KS, Oyelese Y, et al: Trends in pre term birth and perinatal mortality among singletons: United States, 1989 through 2000. Obstet GynecoIn105:1084,n2005

Ananth CV, Liu S, Joseph KS, et al: A comparison of foetal and infant mortality in the United States and Canada. Intn] Epidemiol 38(2):480, 2009 Anderson GD, Bada HS, Sibai BM, et al: The relationship berween labor and route of delivery in the preterm infant. Am] Obstet Gynecol158: 1382, 1988

Andrews W, Goldenberg L, Hauth ]C, et al: Interconceptional antibiotics to prevent spontaneous preterm birth: a randomized clinical trial. Am ] Obstet Gynecol 194:617, 2006

Andrews W, Hauth ]C, Goldenberg L, et al: Amniotic fluid interleukin-6: correlation with upper genital tract microbial colonization and gestational age in women delivered after spontaneous labor versus indicated delivery. Amn] Obstet Gynecol 173:606, 1995

Andrews WW, Sibai BM, Thon A, et al: Randomized clinical trial of metronidazole plus erythromycin to prevent spontaneous preterm delivery in fetal ibronectin-positive women. Obstet GynecoIn101:847, 2003

Angel ]L, O'Brien F, Knuppel RA, et al: Carbohydrate intolerance in patients receiving oral tocolytics. m ] Obstet Gynecol 159:762, 1988 Annas G]: Extremely preterm birth and parental authority to refuse treatmentthe case of Sidney Miller. N Engl ] Med 35:2118, 2004

Anum A, Springel EH, Shriver MD, et al: Genetic contributions to disparities in preterm birth. Pediatr Res 65(1): 1, 2009

Ara I, Banu H: A prospective randomised trial of nifedipine versus placebo in preterm labour. Bangladesh] Obstet Gynaecol 23(2):61, 2008

Arechavaleta-Velasco F, Mayon-Gonzalezn], Gonzalez-]imenez M, et al: Association of type II apoptosis and 92-kDa type IV collagenase expression in human amniochorion in prematurely ruptured membranes with tumor necrosis factor receptor-1 expression. ] Soc Gynecol Investig 9:60, 2002

Attardi B], Zeleznik A, Simhan H, et al: Comparison of progesterone and glucocorticoid receptor binding and stimulation of gene expression by progesterone, 17 -alpha hydroxyprogesterone caproate, and related progestins. Am] Obstet GynecoIn197(6):599.e1, 200

Aune 0, Schlesinger S, Henriksen T, et al: Physical activity and the risk of preterm birth: a systematic review and meta-analysis of epidemiological studies. B]OG 124(12):1816,n2017 Ball S], Pereira G, Jacoby P, et al: Re-evaluation oflink berween interpregnancy interval and adverse birth outcomes: retrospective cohort study matching rwo intervals per mother. BM] 349:g4333, 2014 Barth H ] r: Lost in translation: the changing language of our specialty. Obstet Gynecol 127(3):423,n2016 Beigi RH, Austin MN, Meyn A, et al: Antimicrobial resistance associated with the treatment of bacterial vaginosis. Am ] Obstet Gynecol 191: 1124, 2004

Ben-Ami M, Giladi Y, Shalev E: The combination of magnesium sulphate and nifedipine: a cause of neuromuscular blockade. B]OG 101n:262, 1994

Berghella V, Odibo AO, Tolosa ]E: Cerclage for prevention of preterm birth in women with a short cervix found on transvaginal ultrasound examination: a randomized trial. Amn] Obstet Gynecol 191:131n1,n2004

Berghella V, Rafael T], Szychowski ]M, et al: Cerclage for short cervix on ultrasonography in women with singleton gestations and previous preterm birth: a meta-analysis. Obstet Gynecol (3):663, 2011

Berghella V, Rust OA, Althuisius SM: Short cervix on ultrasound: does indomethacin prevent preterm birth? m] Obstet Gynecol 195:809,n2006

Bisits A, Madsen G, Knox M, et al: The randomized nitric oxide tocolysis trial (RNOTT) for the treatment of preterm labor. Amn] Obstet Gynecol 191:683,n2004

Bloom SL, Leveno K]: Unproven technologies in maternal-fetal medicine and the high cost of US health care.]AMA 317(10):1025,n2017

Bloom SL, Yost NP, McIntire DD, et al: Recurrence of preterm birth in singleton and rwin pregnancies. Obstet Gynecol 98:379, 2001

Bond OM, Middleton P, Levett , et al: Planned early birth versus expectant management for women with preterm prelabour rupture of membranes prior to 37 weeks' gestation for improving pregnancy outcome. Cochrane Database Syst Rev 3:CD004735, 2017

Borgida AF, Mills A, Feldman DM, et al: Outcome of pregnancies complicated by ruptured membranes after genetic amniocentesis. Am ] Obstet Gynecol 183(4):937,n2000

Bruschettini M, van den Hove DL, Gazzolo D, et al: Lowering the dose of antenatal steroids: the efects of a single course of betamethasone on somatic growth and brain cell proliferation in the rat. Amn] Obstet Gynecol 194:1341,n2006

Buekens P, Alexander S, Boutsen M, et al: Randomised controlled trial of routine cervical examinations in pregnancy. Lancet 344:841, 1994

Buxton IL, Singer CA, Tichenor ]N: Expression of stretch-activated rwo-pore potassium channels in human myometrium in pregnancy and labor. PLoS One 5(8):e12372, 2010

Callaghan M, MacDorman MF, Shapiro-Mendoza CK, et al: Explaining the recent decrease in US infant mortality rate, 2007-2013. Amn] Obstet GynecoIn216(1):73.el,2017

Canadian Preterm Labor Investigators Group: Treatment of preterm labor with the beta-adrenergic agonist ritodrine. N Engl ] Med 327:308, 1992

Cantonwine DE, Zhang Z, Rosenblatt K, et al: Evaluation of proteomic biomarkers associated with circulating micro particles as an efective means to stratiy the risk of spontaneous preterm birth. Am ] Obstet Gynecol 214(5):631.e1,t2016

Careyt]C, Klebanof A: Is a change in the vaginal flora associated with an increased risk of preterm birth? Am ] Obstet Gynecol 192(4): 1341, 2005

Caritis SN, Rouse D], Peaceman M, et al: Prevention of preterm birth in triplets using 17alpha-hydroxyprogesterone caproate. Obstet Gynecol 113:285, 2009

Caritis SN, Sharma S, Venkataramanan R, et al: Pharmacology and placental transport of 17 -hydroxyprogesterone caproate in singleton gestation. Am ] Obstet GynecoIt207(5):398.e1, 2012

Caritis SN, Venkataramanan R, Thon E, et al: Relationship berween 17-alpha hydroxyprogesterone caproate concentration and spontaneous preterm birth. Am] Obstet GynecoI210(2):128.e1, 2014

Carlan S], O'Brien WF, Parsons MT, et al: Preterm premature rupture of membranes: a randomized study of home versus hospital management. Obstet GynecoIt81:61, 1993

Carroll SG, Blott M, Nicolaides KH: Preterm prelabor amniorrhexis: outcome of live births. Obstet Gynecol 86: 18, 1995

Carroll SG, Papaionnou S, Ntumazah IL, et al: Lower genital tract swabs in the prediction of intrauterine infection in preterm prelabour rupture of the membranes. B]OG 103:54, 1996

Casanueva E, Ripoll C, Meza-Camacho C, et al: Possible interplay berween vitamin C deficiency and prolactin in pregnant women with premature rupture of membranes: facts and hypothesis. Med Hypotheses 64:241, 2005

Casey ML, Cox SM, Word A, et al: Cyrokines and infection-induced preterm labour. Reprod Fertil Devel 2:499, 1990

Casey ML, MacDonald PC: Transforming growth factor-beta inhibits progesterone-induced enkephalinase expression in human endometrial stromal cells. ] Clin Endocrinol Metab 81 :4022, 1996

Chat], Bartos A, Egashira M, et al: Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions. ] Clin Invest 123(9):4063, 2013

Chaim W, Mazor M: Intraamniotic infection with fusobacteria. Arch Gynecol Obstet 251:1,t1992

Challis ]R, Sloboda OM, Alfaidy N, et al: Prostaglandins and mechanisms of preterm birth. Reproduction 124: 1, 2002

Chao TT, Bloom SL, Mitchell ]S, et al: he diagnosis and natural history of false preterm labor. Obstet Gynecol 118(6):1301,t2011

Chuang TH, Ulevitch R]: Cloning and characterization of a sub-family of human toll-like receptors: hTLR7, hTLR8, and hTLR9. Eur Cyrokine Nerw 11:372,t2000

Cnattingius S, Villamor E, Johansson S, et al: Maternal obesity and risk of preterm delivery.t]AMA 309(22):2362, 2013

Cohen A W, Copel ]A, Macones GA, et al: Unjustiied increase in cost of care resulting from U.S. Food and Drug Administration approval of Makena (17a-hydroxyprogesterone caproate). Obstet Gynecol 117(6): 1408, 2011

Collaborative Home Uterine Monitoring Study Group: A multicenter randomized controlled trial of home uterine monitoring: active versus sham device. Am] Obstet Gynecol 173: 1170, 1995

Collins ]W ]r, David R], Simon DM, et al: Preterm birth among African American and white women with a lifelong residence in high-income Chicago neighborhoods: an exploratory study. Ethn Dis 17(1): 113, 2007

Conde-Agudelo A, Rosas-Bermudez A, Kafury-Goeta AC: Birth spacing and risk of adverse perinatal outcomes: a meta-analysis. ]MA 295: 1809, 2006 Consortium on Safe Labor: Respiratory morbidity in late preterm births. ]MA 304(4):419,t2010

Cook CM, Ellwood DA: A longitudinal study of the cervix in pregnancy using transvaginal ultrasound. B]OG 103:16, 1996

Copper L, Goldenberg L, Dubard MB, et al: Cervical examination and tocodynamometry at 28 weeks' gestation: prediction of spontaneous preterm birth. Am J Obstet Gynecol 172:666, 1995

Cotton DB, Strassner HT, Hill LM, et al: Comparison berween magnesium sulfate, terbutaline and a placebo for inhibition of preterm labor: a randomized study. ] Reprod Med 29:92, 1984

Cox SM, Leveno K]: Intentional delivery versus expectant management with preterm ruptured membranes at 30-34 weeks' gestation. Obstet Gynecol 86:875, 1995

Cox SM, Sherman ML, Leveno K]: Randomized investigation of magnesium sulfate for prevention of pre term birth. Am] Obstet GynecoIt163:767, 1990 Cox SM, Williams ML, Leveno K]: The natural history of preterm ruptured membranes: what to expect of expectant management. Obstet GynecoI71:558, 1988 Creasy RK, Gummer BA, Liggins GC: System for predicting spontaneous pre term birth. Obstet Gynecol 55(6):692, 1980

Crowley AE, Grivell M, Dodd ]M: Sealing procedures for preterm prelabour rupture of membranes. Cochrane Database Syst Rev 7:CD010218, 2016

Crowther CA, Brownt], �l1cKinlay C], et al: Magnesium sulphate for preventing preterm birth in threatened preterm labour. Cochrane Database Syst Rev 8:CD001060, 2014

Crowther CA, Doyle L W, Haslam RR, et al: Outcomes at 2 years of age after repeat doses of antenatal corticosteroids. N Englt] Med 357: 1179, 2007 Crowther CA, Harding ]E: Antenatal glucocorticoids for late preterm birth.

N Engl] Med 374(14):1376, 2016

Crowther CA, Hiller ]E, Doyle L W, et al: Efect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial. ]AMA 290:2669, 2003

Crowther CA, McKinlay C], Middleton P, et al: Repeat doses of prenatal corticosteroids for women at risk for preterm birth for improving neonatal health outcomes. Cochran Database Syst Rev 6:CD003935, 2011

Culhane ]F, Rauh V, McCollum KF, et al: Exposure to chronic stress and ethnic diferences in rates of bacterial vaginosis among pregnant women. Am ] Obstet 2,t2002

Delnord M, Hindori-Mohangoo AD, Smith LK, et al: Variations in very preterm birth rates in 30 high-income countries: are valid international comparisons possible using routine data. B]OG 124(5):785,t201

Di Mascio D, Magro-Malosso ER, Saccone G, et al: Exercise during pregnancy in normal-weight women and risk of preterm birth: a systematic review and meta-analysis of randomized controlled trials. Am ] Obstet Gynecol 215(5):561,t2016

Dolan SM, Gross S], Merkatz lR, et al: The contribution of birth defects to preterm birth and low birth weight. Obstet Gynecol 110:318, 2007

Donders GG, Van Calsteren K, Bellen G, et al: Predictive value for preterm birth of abnormal vaginal flora, bacterial vaginosis and aerobic vaginitis during the irst trimester of pregnancy. B]OG 116(10): 1315, 2009

Donovan BM, Spracklen CN, Schweizer ML, et al: Intimate partner violence during pregnancy and the risk for adverse infant outcomes: a systematic review and meta-analysis. B]OG 123(8):1289,t2016

Doyle L W, Crowther CA, Middleton S, et al: Magnesium sulfate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev 1:CD004661, 2009

Dutra EH, Behnia F, Boldogh I, et al: Oxidative stress damage-associated molecular signaling pathways diferentiate spontaneous preterm birth and preterm premature rupture of the membranes. Mol Hum Reprod 22(2): 143, 2016

Eichenwald EC, Stark AR: Management and outcomes of very low birth weight. N Engl] Med 358(16):1700, 2008

El-Bastawissi AY, Williams MA, Riley DE, et l: Amniotic fluid interleukin-6 and preterm delivery: a review. Obstet Gynecol 95: 1 056, 2000

Elimian A, Garry D, Figueroa R, et al: Antenatal betamethasone compared with dexamethasone (Betacode Trial): a randomized controlled trial. Obstet Gynecol 110:26, 2007

EI-Sayed Y, Riley ET, Holbrook RH, et al: Randomized comparison of intravenous nitroglycerin and magnesium sulfate for treatment of preterm labor. Obstet GynecoIt93:79, 1999

Esplin MS: The importance of clinical phenotype in understanding and preventing spontaneous preterm birth. Amt] Perinatol 33(3):236, 2016

Esplin MS, Elovitz A, lams ]D, et al: Predictive accuracy of serial transvaginal cervical lengths and quantitative vaginal fetal ibronectin levels for spontaneous preterm birth among nulliparous women.t]AMA 317(10):1047,t2017

Esplin MS, Varner MW: Genetic factors in preterm birth-the future. B]OG 112 (Supplt1):97, 2005

FanarofA, Stoll B], Wright LL, et al: Trends in neonatal morbidity and mortality for very low birthweight infants. Am J Obstet Gynecol 196:e1.147, 2007

Farooqi A, Holmgren PA, Engberg S, et al: Survival and 2-year outcome with expectant management of second trimester rupture of membranes. Obstet Gynecolt92:895, 1998

Ferre C, Callaghan W, Olson C, et al: Efects of maternal age and age-specific preterm birth rates on overall preterm birth rates-United States, 2007 and 2014. MMWR 65(43):1181,2016

Flenady V, Hawley G, Stock OM, et al: Prophylactic antibiotics for inhibiting preterm labour with intact membranes. Cochrane Database Syst Rev 12:CD000246,t2013

Flenady V, Reinebrant HE, Liley HG, et al: Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database Syst Rev 6:CD004452, 2014a

Flenady V, Wojcieszek AM, Papatsonis DN, et al: Calcium channel blockers for inhibiting preterm labour and birth. Cochrane Database Syst Rev 6:CD002255,t2014b

Fonseca EB, Celik E, Para M, et al: Progesterone and the risk of preterm birth among women with a short cervix. N Englt] :462,t2007

Food and Drug Administration: FDA drug safety communication: FDA recommends against prolonged use of magnesium sulfate to stop pre-term labor due to bone changes in exposed babies. May 30, 2013. Available at: http:// ww.fda.gov/drugs/drugsafety/ucm35333.htm. Accessed November 9,t2017

Food and Drug Administration: FDA drug safety communication: new warnings against use of terbutaline to treat preterm labor. February 17, 2011t. Available at: http://ww.fda.gov/drugs/drugsafety/ucm243539.htm. Accessed November 9,t2017

Fortunato SJ, Menon R: IL-1 beta is a better inducer of apoptosis in human fetal membranes than IL-6. Placenta 24:922, 2003

Fortunato SJ, Menon R, Lombardi SJ: MMP/TIMP imbalance in amniotic fluid during PROM: an indirect support for endogenous pathway to membrane rupture. J Perinat Med 27 :362, 1999a

Fortunato SJ, Menon R, Lombardi SJ: Role of tumor necrosis factor-alpha in the premature rupture of membranes and preterm labor pathways. Am J Obstet Gynecol 187: 1159, 2002

Fortunato SJ, Menon R, Lombardi SJ: Stromelysins in placental membranes and amniotic luid with premature rupture of membranes. Obstet Gynecol 94:435, 1999b

Frey HA, Klebanof A: he epidemiology, etiology, and costs of preterm birth. Semin Fetal Neonatal Med 21t(2):68, 2016

Furcron E, Romero R, Plazyo 0, et al: Vaginal progesterone, but not 17a-hydroxyprogesterone caproate, has antiinlammatory efects at the murine maternal-fetal interface. Am J Obstet GynecoIt213(6):846.e1, 2015

Gajer P, Brotman RM, Bai G, et al: Temporal dynamics of the human vaginal microbiota. Sci Transl Med 4(132):132ra52, 2012

Gardner MO, Owen J, Skelly S, et al: Preterm delivery ater indomethacin: a risk factor for neonatal complications? J Reprod Med 41 :903, 1996

Garite TJ, Keegan A, Freeman K, et al: A randomized tril of ritodrine tocolysis versus expectant management in patients with premature rupture of membranes at 25 to 30 weeks of gestation. Am J Obstet Gynecol 157:388, 1987

Garite TJ, Kurtzman J, Maurel K, et al: Impact of a "rescue course" of antenatal corticosteroids: a multicenter randomized placebo-controlled trial. m J Obstet Gynecol 200:248.e.t1, 2009

Gaudet LM, Smith G: Cerebral palsy and chorioamnionitis: the inlammatory cytokine link. Obstet Gynecol Surv 56(7):433, 2001

Gerber S, Vial Y, Hohlfeld P, et al: Detection of Ureaplasma urealyticum in second-trimester amniotic fluid by polymerase chain reaction correlates with subsequent preterm labor and delivery. J Infect Dis 18 :518,t2003

Gibson CS, MacLennan AH, Dekker GA, et al: Genetic polymorphisms and spontaneous preterm birth. Obstet Gynecol 109:384,t2007

Gielchinsky Y, Mankuta 0, Samuelof A, et al: First pregnancy in women over 45 years of age carries increased obstetrical risk [Abstract]. Am J Obstet Gyneco1t187:S87,t2002

Gillespie SL, Christian LM, Alston AD, et al: Childhood stress and birth timing among African American women: cortisol as biological mediator. Psychoneuroendocrinology 84:32, 2017

Giraldo-Isaza A, Berghella V: Cervical cerclage and preterm PROM. Clin Obstet Gynecol 54(2):3t13,t2011

Girsen AI, Mayo JA, Carmichael SL, et al: Women's prep regnancy underweight as a risk factor for preterm birth: a retrospective study. BJOG 123(12):2001,t2016

Goepfert AR, Jefcoat MK, Andrews W, et al: Periodontal disease and upper genital tract inlammation in early spontaneous preterm birth. Obstet Gynecol 104:777,t2004

GoldenbergL: The mnagement of preterm labor. Obstet Gynecolt1 00: 1 020, 2002 Goldenberg L, Culhane JF, lams JD, et al: Preterm birth 1: epidemiology and causes of preterm birth. Lancet 371 :75, 2008

Goldenberg L, Hauth JC, Andrews W: Intrauterine infection and preterm delivery. N Engl J Med 342:1t500,t2000

Goldenberg L, Mwatha A, Read JS, et al: The HPTN 024 Study: the eicacy of antibiotics to prevent chorioamnionitis and preterm birth. Am J Obstet Gynecol 194:650, 2006

Goldstein B, Bradley B, Ressler KJ, et al: Associations between posttraumatic stress disorder, emotion dysregulation, and alcohol dependence symptoms among inner city females. J Clin Psychol 73(3):319, 2017

Gomez R, Romero R, Edwin SS, et al: Pathogenesis of preterm labor and preterm premature rupture of membranes associated with intraamniotic infection. Infect Dis Clin North Am 11: 135, 1997

Gomez R, Romero R, Glasasso M, et al: The value of amniotic luid interleukin-6, white blood cell count, and gram stain in the diagnosis of microbial invasion of the amniotic cavity in patients at term. Am J Reprod Immunol 32:200, 1994

Goncalves LF, Chaiworapongsa T, Romero R: Intrauterine infection and prematurity. Ment Retard Dev Disabil Res Rev 8:3, 2002

Gonzalez JM, Xu H, Ofori E, et al: Toll-like receptors in the uterus, cervix, and placenta: is pregnancy an immunosuppressed state? m J Obstet Gynecol 19 (3):296, 200

Goodwin TM, Millar L, North L, et al: The pharmacokinetics of the oxytocin antagonist atosiban in pregnant women with preterm uterine contractions. Am J Obstet GynecoIt173:913, 1995

Goulet C, Gevry H, Lemay M, et al: A randomized clinical trial of care for women with preterm labour: home management versus hospital management. CMAJ 164:985,2001 Goya M, Pratcorona L, Merced C, et al: Cervical pessary in pregnant women with a short cervix (PECEP): an open-label randomised controlled trial. Lancet 379(9828):1790, 2012

Gravett MG, Adams KM, Sadowsky OW, et al: Immunomodulators plus antibiotics delay preterm delivery after experimental intraamniotic infection in a nonhuman primate model. Am J Obstet GynecoIt197(5):518.e1, 2007

Grether JK, Hoogstrate], Walsh-Greene E, et al: Magnesium sulfate for tocolysis and risk of spastic cerebral palsy in premature children born to women without preeclampsia. Am] Obstet Gynecol 183:717,t2000

Grobman WA, Gilbert SA, lams JD, et al: Activity restriction among women with a short cervix. Obstet GynecoIt121:1181, 2013

Grobman WA, Thon EA, Spong CY, et al: 1 alpha-Hydroxyprogesterone caproate to prevent prematurity in nulliparas with cervical length less than 30 mm. Am] Obstet GynecoIt207(5):390e.1, 2012

Grobman WA, Welshman EE, Calhoun A: Does fetal ibronectin use in the diagnosis of preterm labor afect physician behavior and health care costs? A randomized trial. Amt] Obstet Gyneco1t191t:235, 2004

Guillen U, DeMauro S, Ma L, et al: Survival rates in extremely low birthweight infants depend on the denominator: avoiding potential for bias by speciYing denominators. Am J Obstet Gynecol 205:328.e1, 2011

Guinn DA, Goepfert AR, Owent], et al: Terbutaline pump maintenance therapy for prevention of preterm delivery: a double-blind trial. Am J Obstet Gyneco1t179:874,t1998

Gyamfi-Bannerman C, hon A, Blackwell SC, et al: Antenatal betamethasone for women at risk for late preterm delivery. N Engl J Med 374(14): 1311, 2016 Gyervai K, Hannah ME, Hodnett ED, et al: Tocolytics for preterm labor: a systematic review. Obstet Gynecol 94:869, 1999

Hadi HA, Hodson CA, Strickland 0: Premature rupture of the membranes between 20 and 25 weeks' gestation: role of amniotic fluid volume in perinatal outcome. Am J Obstet Gynecol 1 0:1139, 1994

Hamilton S, Oomomian Y, Stephen G, et al: Macrophages iniltrate the human and rat decidua during term and preterm labor: evidence that decidual inflammation precedes labor. BioI Reprod 86(2):39, 2012

Hampton T: Genetic link found for premature birth risk. JM1A 296: 1713, 2006 Hankins GO, Hauth JC, Cissik JH, et al: Efects of ritodrine hydrochloride on arteriovenous blood gas and shunt in healthy pregnant yellow baboons. Am ] Obstet Gynecol 158:658, 1988

Hassan SS, Romero R, Vidyadhari 0, et al: Vaginal progesterone reduces the rate of preterm birth in women with sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gyneco1t38:18,t2011

Hawkins JS: Lower Genital Tract Procedures. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 2017

Heine P, McGregor JA, Goodwin TM, et al: Serial salivary estriol to detect an increased risk of preterm birth. Obstet Gynecol 96:490, 2000

Heng YJ, Pennell CE, McDonald SW, et al: Maternal whole blood gene expression at 18 and 28 weeks of gestation associated with spontaneous preterm birth in asymptomatic women. PLoS One 11(6):e0155191, 2016

Higgins D, Saade G, Polin A, et al: Evaluation and management of women and newborns with a maternal diagnosis of chorioamnionitis: summary of a workshop. Obstet Gynecol 127(3):426,t2016

Hill WC: US term stillbirth rates and the 39-week rule: a cause for concern?

Am J Obstet GynecoIt216(1):85, 2017

Hillier SL, Martius J, Krohn M, et al: A case-control study of chorioamnionic infection and histologic chorioamnionitis in prematurity. N Engl J Med 319:972, 1988

Hillier SL, Nugent RP, Eschenbach DA, et al: Association between bacterial vaginosis and preterm delivery of a low-birthweight infant. N Engl J Med 333:1737,t1995

Hirota Y, Daikoku T, Tranguch S, et al: Uterine-specific p53 deficiency confers premature uterine senescence and promotes preterm birth in mice. J Clin Invest 120(3):803,t2010

Hitti ], Tarczy-Hornoch P, Murphy J, et al: Amniotic fluid infection, cytokines, and adverse outcome among infants at 34 weeks' gestation or less. Obstet Gynecol 98: 1 080, 200t1

Hobel C, Culhane J: Role of psychosocial and nutritional stress on poor pregnancy outcome. J Nutr 133:1709S, 2003

Hofman MC, Mazzoni SE, Wagner BD, et al: Measures of maternal stress and mood in relation to preterm birth. Obstet Gynecol 127(3):545,t2016

Holmlund U, Cabers G, Dahlfors AR, et al: Expression and regulation of the pattern recognition receptors Toll-like receptor-2 and Toll-like receptor-4 in the human placenta. Immunology 107: 145,t2002

Holt R, Timmons BC, Akgul Y, et 31: he molecular mechanisms of cervic31 ripening difer between term and preterm birth. Endocrinology 152: 1036, 20t1t1 How HY, Hughes SA, Vogel RL, et al: Oral terbutaline in the outpatient management of preterm labor. m J Obstet Gynecol 173: 1518, 1995

How HY, Zafaranchi L, Stella CL, et al: Tocolysis in women with preterm labor between 32°/7 and 34617 weeks of gestation: a randomized controlled pilot study. Am J Obstet Gynecol 194:976, 2006

Hua R, Pease JE, Cheng W, et al: Human labour is associated with decline in myometrial chemokine receptor expression: the tole of prostaglandins, oxytocin, and cytokines. m J Reprod Immunol 69:21, 2013

Hui SY, Chor CM, Lau TK, et al: Cerclage pessary for preventing preterm birth in women with a singleton pregnancy and a short cervix at 20 to 24 weeks: a randomized controlled trial. Am J Perinatol 30:283, 2013 lams JD, Clapp DH, Contox DA, et 31: Does extraamniotic infection cause preterm labor? Gas-liquid chromatography studies of amniotic luid in amnionitis, preterm labor, and normal controls. Obstet Gynecol 70:365, 1987 lams JD, Goldenberg RL, Meis PJ, et al: The length of the cervix and the risk of spontaneous premature delivery. N Engl J Med 334:567, 1996 lams JD, Johnson FF, Parker M: A prospective evaluation of the signs and symptoms of preterm labor. Obstet Gynecol 84:227, 1994 lams JO, Newman RB, Thon EA, et al: Frequency of uterine contractions and the risk of spontaneous preterm birth. N Engl J Med 346:250, 2002 lams JD, Stilson R, Johnson FF, et al: Symptoms that precede preterm labor and preterm premature rupture of the membranes. m J Obstet Gynecol 162:486, 1990

Institute of Medicine: Preterm Birth: Causes, Consequences, and Prevention.

Washington, National Academies Press, 2007

Ishii N, Kono Y, Yonemoto N, et al: Outcomes of infants born at 22 and 23 weeks' gestation. Pediatrics 132(1):62,t2013

Janssens 5, Beyaert R: Role of Toll-like receptors in pathogen recognition. Clin Microbiol Rev 16:637,t2003

Kamath-Rayne BD, Rozance PJ, Goldenberg RL, et al: Antenatal corticosteroids beyond 34 weeks gestation: what do we do now? m J Obstet Gynecol 215(4):423,t2016

Keelan JA, Blumenstein M, Helliwell RJ, et al: Cytokines, prostaglandins and parturition-a review. Placenta 24:533, 2003

Kenyon 5, Boulvain M, Neilson J: Antibiotics for preterm rupture of the membranes: a systematic review. Obstet Gynecolt104:1051, 2004

Kenyon 5, Pike K, Jones DR, et al: Childhood outcomes after prescription of antibiotics to pregnant women with preterm rupture of the membranes: 7-year follow-up of the ORACLE I trial. Lancet 372:1310, 2008a

Kenyon 5, Pike K, Jones DR, et al: Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial. Lancet 372:1319, 200Sb

Kenyon SL, Taylor OJ, Tarnow-Mordi, et al: Broad-spectrum antibiotics for spontaneous preterm labour: the ORACLE II randomized trial. Lancet 35 :989,t2001

Kerstjens J, Bocca-Tjeerres IF, de Winter AF, et al: Neonatal morbidities and developmental delay in moderately preterm-born children. Pediatrics 130(2):e265,t2012

King JF, Flenady V, Papatsonis 0, et al: Calcium channel blockers for inhibiting preterm labour: a systematic review of the evidence and a protocol for administration of nifedipine. Aust N Z J Obstet Gynaecol43: 192,t2003

Korita 0, Sagawa N, Itoh H, et al: Cyclic mechanical stretch augments prostacyclin production in cultured human uterine myometrial cells from pregnant women: possible involvement of up-regulation of prostacyclin synthase expression. J Clin Endocrinol Metab 87:5209, 2002

Kovacevich GJ, Gaich SA, Lavin JP, et al: The prevalence of thromboembolic events among women with extended bed rest prescribed as part of the treatment for premature labor or preterm premature rupture of membranes. m J Obstet Gynecol 182: 1 089, 2000

Kragt H, Keirse MJ: How accurate is a woman's diagnosis of threatened preterm delivery? BJOG 97:3t17, 1990

Kramer MS, Coates AL, Michoud MC, et al: Maternal anthropometry and idiopathic preterm labor. Obstet Gynecol 86:744, 1995

Kurki T, Sivonen A, Renkonen OV, et al: Bacterial vaginosis in early pregnancy and pregnancy outcome. Obstet Gynecol so: 173, 1992

Kurtzman JL, Thorp JM Jr, Spielman FJ, et 31: Do nifedipine and verapanlil potentiate the cardiac toxicity of magnesium sulfate? m J Perinarol 10:450, 1993

Lam F, Gill P, Smith M, et al:

Use of the subcutaneous terbutaline pump for long-term tocolysis. Obstet 2:S10, 1988

Laskin \10, Yinon Y, Whittle WL: Preterm premature rupture of membranes in the presence of cerclage: is the risk for intra-uterine infection and adverse neonatal outcome increased. J Matern Fetal Neonatal Med 25(4):424, 2012

Laughon SK, Albert PS, Leishear K, et al: The NICHD Consecutive Pregnancies Study: recurrent preterm delivery by subtype. Am J Obstet Gynecol 210(2):13l.e1,t2014

Lee SE, Romero R, Jung H: he intensity of the fetal inflammatory response in intraamniotic inflammation with and without microbial invasion of the amniotic cavity. Am J Obstet Gynecol 197(3):294,t2007

Lee SE, Romero R, Park CW: he frequency and signiicance of intraamniotic inflammation in patients with cervical insuiciency. Am J Obstet Gynecol 198(6):633,t2008

Lees CC, Lojacono A, Thompson C, et al: Glyceryl trinitrate and ritodrine in tocolysis: an international multicenter randomized study. Obstet Gynecol 94:403, 1999

Leeson SC, Maresh MJ, Martindale EA, et al: Detection of fetal fibronectin as a predictor of preterm delivery in high risk symptomatic pregnancies. BJOG 103:48,t1996

Leitich H, Bodner-Adler B, Brunbauer M, et al: Bacterial vaginosis as a risk factor for preterm delivery: a meta-an31ysis. m J Obstet Gynecolt1S9:139, 2003a Leitich H, Brunbauer M, Bodner-Adler B, et 31: Antibiotic treatment of bacterial vaginosis in pregnancy: a meta-analysis. m J Obstet GynecoIt18S:752, 2003b Leveno KJ, Cox K, Roark ML: Cervical dilatation and prematurity revisited.

Obstet Gynecol 68(3):434, 1986a

Leveno KJ, Klein VR, Guzick OS, et al: Single-centre randomised trial of ritodrine hydrochloride for preterm labour. Lancet 1:1293, 1986b

Leveno KJ, McIntire DO, Bloom SL, et al: Decreased preterm births in an inner-city public hospital. Obstet Gynecol 113(3):578, 2009

Lewis OF, Adair CD, Robichaux AG, et al: Antibiotic therapy in preterm premature rupture of membranes: are seven days necessary? A preliminary, randomized clinical trial. Am J Obstet Gynecol 188: 1413, 2003

Lewis OF, Robichaux AG, Jaekle RK, et al: Expectant management of preterm premature rupture of membranes and nonvertex presentation: what are the risks? Am J Obstet Gynecol 196:566, 2007

Lewis R, Mercer BM, Salama M, et al: Oral terbutaline after parenteral tocolysis: a randomized, double-blind, placebo-controlled trial. Am J Obstet Gynecol 175:834, 1996

Lieman JM, Brumield CG, Carlo W, et al: Preterm premature rupture of membranes: is there an optimal gestational age for delivery? Obstet Gynecol 105:12,t2005

Liggins Gc, Howie RN: A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 50:515, 1972

Likis FE, Velez Edwards DR, Andrews JC, et al: Progestogens for preterm birth prevention. Obstet Gynecol 120:897,t2012

Lockwood CJ: Stress-associated preterm delivery: the role of corticotropinreleasing hormone. Am J Obstet Gynecol 180:5264, 1999

Lockwood q, Senyei E, Dische MR, et al: Fet31 ibronectin in cervic31 and vaginal secretions as a predictor of preterm delivety. N Engl J Med 325:669, 1991

Loe SM, Sanchez-Ramos L, KaunitzAM: Assessing the neonatal safety of indomethacin tocolysis: a systematic review with meta-analysis. Obstet Gynecol 106: 173, 2005

Low JA, Panagiotopoulos C, Derrick EJ: Newborn complication after intrapartum asphyxia with metabolic acidosis in the preterm fetus. Am J Obstet Gynecol 172:805, 1995

Luke B, Mamelle N, Keith L, et al: The association between occupational factors and preterm birth: a United States nurses study. Am J Obstet Gynecol 173:849, 1995

Lyall F, Lye 5, Teoh T, et al: Expression ofGsalpha, connexin-43, connexin-26, and EP 1, 3, and 4 receptors in myometrium of prelabor singleton versus multiple gestations and the efects of mechanical stretch and steroids on Gsalpha. J Soc Gynecol lnvestig 9:299, 2002

Lyell OJ, Pullen K, Campbell L, et al: Magnesium sulfate compared with nifedipine for acute tocolysis of preterm labor: a randomized controlled trial. Obstet Gynecol 11t08:61,t200

Mackeen AD, Seibel-Seamon J, Muhammad J, et al: Tocolytics for preterm premature rupture of membranes. Cochrane Database Syst Rev 2:CD007062, 2014

Macones GA, Parry 5, Elkousy M, et al: A polymorphism in the promoter region of TNF and bacterial vaginosis: preliminary evidence of geneenvironment interaction in the etiology of spontaneous preterm birth. Am J Obstet Gynecol 190: 1504, 2004

Major CA, Towers CW, Lewis OF, et al: Expectant management of preterm premature rupture of membranes complicated by active recurrent genital herpes. Am J Obstet GynecoIt18S:1551, 2003

Malloy MH, Onstad L, Wright E: The efect of cesarean delivery on birth outcome in very low birth weight infants. Obstet Gynecol 77:498, 1991

Manuck TA, Lai Y, Meis PJ, et al: Progesterone receptor polymorphisms and clinical response to 17 -alpha-hydroxyprogesterone caproate. Am J Obstet GynecoIt205(2):135.e1,t20ltl

Marret S, Marpeau L, Benichou J: Beneit of magnesium sulfate given before very preterm birth to protect infant brain. Pediatrics 121 (1):225, 2008 Martin JA, Hamilton BE, Osterman MJ: Births: inal data for 2015. Natl Vital Stat Rep 66(1):1, 2017

Martin JA, Osterman MJ, Kirmeyer SE, et al: Measuring gestational age in vital statistics data: transitioning to the obstetric estimate. Natl Vital Stat Rep 64(5):1, 2015

Matthews TJ, MacDorman MF, Thoma ME: Infant mortality statistics from the 2013 period linked birth/infant death data set. Natl Vital Stat Rep 64(9):1, 2015

Maymon E, Romero R, Pacora P, et al: Evidence for the participation of interstitial collagenase (matrix metalloproteinase 1) in preterm premature rupture of membranes. Am J Obstet Gynecol 183(4):914,t2000

McCall CA, Grimes DA, Drapkin Lyerly A: "Therapeutic" bed rest in pregnancy unethical and unsupported by data. Obstet GynecoIt12l:1305, 2013

McElrath TF, Allred E, Leviton A: Prolonged latency after pre term premature rupture of membranes: an evaluation of histologic condition and intracranial ultrasonic abnormality in the neonate born at <28 weeks of gestation. Am J Obstet Gynecol 189:794,t2003

McElrath TF, Norwitz ER, Lieberman ES, et al: Perinatal outcome after preterm premature rupture of membranes with in situ cervical cerclage. Am J Obstet GynecoIt187:t1t147, 2002 McEvoy C, Schilling 0, Segel S, et al: Improved respiratory compliance in preterm infants ater a single rescue course of antenatal steroids: a randomized trial. Am J Obstet GynecoI202(6):544.e1, 2010

McGregor JA, Jackson GM, Lachelin Gc, et al: Salivary estriol as risk assessment for preterm labor: a prospective trial. Am J Obstet Gynecol 173: 1337, 1995

McIntire DO, Leveno KJ: Neonatal mortality and morbidity rates in later preterm births compared with births at term. Obstet Gynecol III:35, 2008 McManemy J, Cooke E, Amon E, et al: Recurrence risk for preterm delivery. Am J Obstet GynecoIt196(6):576.e1, 2007

McPherson JA, Rouse OJ, Grobman WA, et al: Association of duration of neuroprotective magnesium sulfate infusion with neonatal and maternal outcomes. Obstet GynecoIt124(4):749, 2014 Meis PJ, Klebanof M, Thom E, et al: Prevention of recurrent preterm delivery by 17alpha-hydroxyprogesterone caproate. N Engl J Med 348:2379, 2003 Meis PJ, Michielutte R, Peters TJ, et al: Factors associated with preterm birth in Cardif, Wales, I. Univariable and multivariable analysis. Am J Obstet Gynecol 173:590, 1995

Menon R: Oxidative stress damage as a detrimental factor in preterm birth pathology. Front Immunol 5:567, 2014a Menon R, Behnia F, Polettini J, et al: Placental membrane aging and HMGB1 signaling associated with human parturition. Aging (Albany ) 8(2):216, 2016 Menon R, Jones J, Gunst PR, et al: Amniotic luid metabolomic analysis in spontaneous preterm birth. Reprod Sci 21(6):791, 2014b Mercer BM: Preterm premature rupture of the membranes. Obstet Gynecol 101:178,t2003 Mercer BM, Arheart L: Antimicrobial therapy in expectant management of preterm premature rupture of the membranes. Lancet 346:1271,t1995 Mercer BM, Carr TL, Beazley DO, et al: Antibiotic use in pregnancy and drugresistant infant sepsis. Am J Obstet GynecoIt181:816, 1999

Mercer BM, Crocker LG, Boe NM, et al: Induction versus expectant management in premature rupture of the membranes with mature amniotic luid at 32 to 36 weeks: a randomized trial. Am J Obstet Gynecol 169:775, 1993 Mercer BM, Miodovnik M, hurnau GR, et al: Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of the membranes. JAMA 278:989, 1997 Merkatz IR, Peter JB, Barden TP: Ritodrine hydrochloride: a betamimetic agent for use in preterm labor, II. Evidence of eicacy. Obstet Gynecol 56:7, 1980 Michalowicz BS, Hodges JS, DiAngelis AJ, et al: Treatment of periodontal disease and the risk of preterm birth. N Engl J Med 355: 1885, 2006 Mogami H, Kishore AH, Shi H, et al: Fetal ibronectin signaling induces matrix metalloproteases and cyclooxygenase-2 (COX-2) in amnion cells and preterm birth in mice. J Bioi Chem 288(3):1953, 2013 Montalbano AP, Hawgood S, Mendelson CR: Mice deficient in surfactant protein A (SP-A) and SP-D or in TLR2 manifest delayed parturition and decreased expression of inlammatory and contractile genes. Endocrinology 154(1):483,t2013 Moralest}, Madhav H: Eicacy and safety of indomethacin compared with magnesium sulfate in the management of preterm labor: a randomized study. Am J Obstet Gynecol 169:9 , 1993a Morales }, Smith SG, Angel JL, et al: Eicacy and safety of indomethacin versus ritodrine in the management of preterm labor: a randomized study. Obstet Gynecol 74:567, 1989

Morales W), Talley T: Premature rupture of membranes at <25 weeks: a management dilemma. Am J Obstet GynecoIt168:503, 1993b Morency AM, Bujold E: he efect of second-trimester antibiotic therapy on the rate of preterm birth. J Obstet Gynaecol Can 29:35, 2007

Morgan JL, Nelson DB, Casey BM, et al: Impact of metabolic acidemia at birth on neonatal outcomes in infants born before 34 weeks' gestation. J Matern Fetal Neonatal Med 30(16):1902, 2017

Moutquin JM, Sherman 0, Cohen H, et al: trolled trial of atosiban and ritodrine in the treatment of preterm labor: a multicenter efectiveness and safety study. Am J Obstet Gynecol 183: 11t91, 2000

Muench MV, Baschat A, Kopelman J, et al: Indomethacin therapy initiated before 24 weeks of gestation for the prevention of preterm birth [Abstract]. Obstet Gynecol 101t:65S, 2003

Muench V, Harman CR, Baschat A, et al: Early fetal exposure to long term indomethacin therapy to prevent preterm delivery: neonatal outcome. Am J Obstet GynecoIt185:S149, 2001

Murphy E: Betamethasone compared with dexamethasone for preterm birth: a call for trials. Obstet Gynecol 110:7,t2007

Nallasamy S, Mahendroo M: Distinct roles of cervical epithelia and stroma in pregnancy and parturition. Semin Reprod Med 35(2):190,t2017

National Institutes of Health: Antenatal corticosteroids revisited: repeat courses. NIH Consens Statement 17(2): 1, 2000

Nelson DB, Hanlon A, Nachamkin I, et al: Early pregnancy changes in bacterial vaginosis-associated bacteria and preterm delivery. Paediatr Perinat Epidemiol 28(2):88, 2014

Nelson DB, McIntire DO, McDonald J, et al: 17-alpha Hydroxyprogesterone caproate did not reduce the rate of recurrent preterm birth in a prospective cohort study. Am J Obstet Gynecol 216(6):600.e1, 201

Nelson KB, Grether JK: Can magnesium sulfate reduce the risk of cerebral palsy in very-Iow-birthweight infants? Pediatrics 95:263, 1995

Nelson LH, Anderson L, O'Shea M, et al: Expectant management of preterm premature rupture of the membranes. Am J Obstet GynecoIt171:350, 1994

Ness RB, Hillier SL, Richter HE: Douching in relation to bacterial vaginosis, lactobacilli, and facultative bacteria in the vagina. Obstet Gynecol 100:765, 2002

Nicholson JM, Kellar LC, Ahmad S, et al: US term stillbirth rates and the 39-week rule: a cause for concern? Am J Obstet GynecoI214(5):621.e1, 2016

Nicolaides KH, Syngelaki A, Poon LC, et al: A randomized trial of a cervical pessary to prevent preterm singleton birth. N Engl J Med 374(11):1044, 2016

Niebyl JR, Blake DA, White RD, et al: he inhibition of premature labor with indomethacin. Am J Obstet Gynecol 136: 1014, 1980

Norman JE, vlarlow N, Messow CM, et al: Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicenter, randomized, double-blind trial. Lancet 387(10033):2106,t2016

Northen AT, Norman GS, Anderson K, et al: Follow-up of children exposed in utero to alpha-hydroxyprogesterone caproate compared with placebo. Obstet Gynecolt110(4):865, 2007

Norton ME, Merrill J, Cooper BA, et al: Neonatal complications after the administration of indomethacin for preterm labor. N Engl J Med 329: 1602, 1993

Nugent RP, Krohn MA, Hillier SL: Reliability of diagnosing bacterial vaginosis by a standardized method of gram stain interpretation. J Clin Microbiol 29:297, 1991

Owen J, Hankins G, lams JD, et al: Multicenter randomized trial of cerclage for preterm birth prevention in high-risk women with shortened mid-trimester cervical length. Am J Obstet GynecoI201(4):375.e1, 2009

Park KH, Chaiworapongsa T, Kim YM, et al: Matrix metalloproteinase 3 in parturition, premature rupture of the membranes, and microbial invasion of the amniotic cavity. J Perinat Med 31: 12, 2003

Papatsonis ON, Van Geijn HP, Ader HJ, et al: Nifedipine and ritodrine in the management of pre term labor: a randomized multicenter trial. Obstet Gynecol 90:230, 1997

Parilla BV, Dooley SL, Minogue JP, et al: he eicacy of oral terbutaline after intravenous tocolysis. Am J Obstet Gynecol 169:965, 1993

Parilla BV, Grobman WA, Holtzman RB, et al: Indomethacin tocolysis and risk of necrotizing enterocolitis. Obstet Gynecol 96: 120, 2000

Peltoniemi OM, Kari A, Tammela 0, et al: Randomized trial of a single repeat dose of prenatal betamethasone treatment in imminent preterm birth. Pediatrics, 119:290,t2007

Perry KG Jr, Martin RW, Blake PG, et al: Maternal mortality associated with adult respiratory distress syndrome. South Med J 91 (5):441, 1998 Perry KG Jr, Morrison JC, Rust OA, et al: Incidence of adverse cardiopulmonary efects with low-dose continuous terbutaline infusion. Am J Obstet GynecoIt173:1273,t1995 Petraglia F, Imperatore A, Challis JR: Neuroendocrine mechanisms in pregnancy and parturition. Endocrine Rev 83,t2010

Petrini ]R, Dias T, McCormick MC, et al: Increased risk of adverse neurological development for late preterm infants.t] Pediatr 154(2):169,2009

Petrova A, Demissie K, hoads GG, et al: Association of maternal fever during labor with neonatal and infant morbidity and mortality. Obstet Gynecol 98:20,t2001

Prior M, Hibberd R, Asemota N, et al: Inadvertent P-hacking among trials and systematic reviews of the efect of progestogens in pregnancy? A systematic review and meta-analysis. B]OG 124(7):1008,t2017

Pritchard ]A, MacDonald PC: Williams Obstetrics, 15th ed. New York, Appleton-Century-Crofts, 1976

PROLONG: Conirmatory Study of 17P Versus Vehicle for the Prevention of Preterm Birth in Women With a Previous Singleton Spontaneous Preterm DelivelY, 2014. Available at: https:llclinicaltrials.gov/ct2/show/ NCT01004029. Accessed November 13,t2017

Promislow]H, Hertz-Picciotto I, Schramm M, et al: Bed rest and other determinants of bone loss during pregnancy. Amt] Obstet Gynecol 191:1077, 2004

Pyeritz E: Ehlers-Danlos syndrome. N Engl] Med 342(10):730,t2000

Racicot K, Cardenas I, Wiinsche V, et al: Viral infection of the pregnant cervix predisposes to ascending bacterial infection.t] ImmunoIt191(2):934, 2013 Racicot K, Mor G: Risks associated with viral infections during pregnancy.

] Clin Invest 127(5):1591,t2017

Raju TN, Higgins RD, Stark AR, et al: Optimizing care and outcome for latepreterm (near-term) infants: a summaY of the workshop sponsored by the National Institute of Child Health and Human Development. Pediatrics 118:1207,t2006

Raju TN, Mercer BM, Burchield D], et al: Periviable birth: executive summary of a joint workshop by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Academy of Pediatrics, and American College of Obstetricians and Gynecologists. Obstet GynecoIt123(5):1083, 2014

Reddy UM, Ko CW, Raju TN, et al: Delivery indications at late-preterm gestations and infant mortality rates in the United States. Pediatrics 124(1):234, 2009

Reddy UM, Zhangt], Sun L, et al: Neonatal mortality by attempted route of delivery in early preterm birth. Am] Obstet Gynecol 207: 117.e 1, 2012

Reinebrant HE, Pileggi-Castro C, Romero CL, et al: Cyclo-oxygenase (COX) inhibitors for treating preterm labour. Cochrane Database Syst Rev 6:CD00t1992,t20t15

Roberts D, Brown], Medley N, et al: Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 3:CD004454, 2017

Romero R, Chaiworapongsa T, Espinoza J, et al: Fetal plasma MMP-9 concentrations are elevated in preterm premature rupture of the membranes. Am ] Obstet GynecoIt187:1125, 2002

Romero R, Conde-Agudelo A, Da Fonseca E, et al: Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data. Am ] Obstet Gynecol November 16, 2017 [Epub ahead of print]

Romero R, Mirandat], Chaiworapongsa T, et al: Prevalence and clinical signiicance of sterile intra-amniotic inlammation in patients with preterm labor and intact membranes. Am] Reprod Immunol 72(5):458, 2014

Romero R, Nicolaides KH, Conde-Agudelo A, et al: Vaginal progesterone decreases preterm birth S34weeks of gestation in women with a singleton pregnancy and a short cervix: an updated meta-analysis including data from the OPPTIMUM study. Ultrasound Obstet GynecoIt48(3):308, 2016

Romero R, Nores ], Mazor M, et al: Microbial invasion of the amniotic cavity during term labor. Prevalence and clinical signiicance. ] Reprod Med 38:543, 1993

Romero R, Sibai BM, Sanchez-Ramos L, et al: An oxytocin receptor antagonist (atosiban) in the treatment of preterm labor: a randomized, doubleblind, placebo-controlled trial with tocolytic rescue. Am ] Obstet Gynecol 182: 1173, 2000

Romero R, StanczykFZ: Progesterone is not the same as 17t-hydroxyprogesterone caproate: implications for obstetrical practice. Am ] Obstet Gynecol 208(6):421,t2013

Rouse D]: Magnesium sulfate for fetal neuroprotection. Amt] Obstet Gynecol 205(4):296,t2011

Rouse D], Caritis SN, Peaceman AM, et al: A trial of 1 alpha-hydroxyprogesterone caproate to prevent prematutity in twins. N Engl ] Med 357:454, 2007

Rouse D], Hirtz DG, Thom E, et al: A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl ] Med 359:895, 2008

Ruiz RJ, Fullerton], Dudley D]: he interrelationship of maternal suess, endocrine factors and inlammation on gestational length. Obstet Gynecol Surv 58:415, 2003

Rust OA, Atlas RO, Reedt], et al: Revisiting the short cervix detected by transvaginal ultrasound in the second trimester: why cerclage therapy may not help. Amt] Obstet Gynecol 185:1098,t2001

Rysavy A, Li L, Bell EF: Between-hospital variation in treatment and outcomes in extremely preterm infants. N Engl] Med 372(19):1801, 2015

Salim R, Garmi G, Zohar N, et al: Nifedipine compared with atosiban for treating preterm labor: a randomized controlled trial. Obstet Gynecol 120(6):1323,t2012

Samol ]M, Lambers DS: Magnesium sulfate rocolysis and pulmonary edema: the drug or the vehicle? Am ] Obstet Gynecol 192: 1430, 2005

Sanz M, Kornman K, Working group 3 of the joint EFP/AAP workshop: Periodontitis and adverse pregnancy outcomes: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. ] Periodontol 84(4 Suppl):S164, 2013

Segel SY, Miles M, Clothier B, et al: Duration of antibiotic therapy after preterm premature rupture of fetal membranes. Am] Obstet Gynecol 189:799, 2003

Serenius F, Kallen K, Blennow M, et al: Neurodevelopmental outcome in extremely preterm infants at 2.5 years after active perinatal care in Sweden. ]AMA 309(17):1810,t2013

Sharma S, Ou ], Strom S, et al: Identiication of enzymes involved in the metabolism of 17alpha-hydroxyprogesterone caproate: an efective agent for prevention of preterm birth. Drug Metab Dispos 36(9): 1896, 2008

Shaw ]G, Asch SM, Katon ]G, et al: Post-traumatic stress disorder and antepartum complications: a novel risk factor for gestational diabetes and preeclampsia. Paediatr Perinat Epidemiolt31(3):185, 2017

Shynlova 0, Nedd-Roderique T, Li Y, et al: Iniltration of myeloid cells into decidua is a critical early event in the labour cascade and post-partum uterine remodeling.] Cell Mol Med 17(2):311, 2013a

Shynlova 0, Nedd-Roderique T, Li Y, et al: Myometrial immune cells contribute to term parturition, preterm labour and post-partum involution in mice. ] Cell Mol Med 17(1):90, 2013b

Sibai BM: Magnesium sulfate for neuroprotection in patients at risk for early preterm delivery: not yet. Am] Obstet Gynecol 205(4):296, 2011

Smith SB, Ravel ]: The vaginal microbiota, host defence and reproductive physiology.] PhysioI595(2):451, 2017

Society for Maternal-Fetal Medicine: Implementation of the use of antenatal corticosteroids in the late preterm birth period in women at risk for preterm delivery. Amt] Obstet GynecoIt215(2):B13, 2016a

Society for Maternal-Fetal Medicine: The choice of progestogen for the prevention of preterm birth in women with singleton pregnancy and prior preterm birth. Am J Obstet Gynecol 216(3):B11, 2017a

Society for Maternal-Fetal Medicine: The role of cervical pessary placement to prevent preterm birth in clinical practice. Am] Obstet GynecoI216(3):B8, 2017b

Society for Maternal-Fetal Medicine, McIntosh ], Feltovich H, et al: he role of routine cervical length screening in selected high-and low-risk women for preterm birth prevention. Am] Obstet GynecoI215(3):B2, 2016b

Sooranna SR, Lee Y, Kim LU, et al: Mechanical stretch activates type 2 cyclooxygenase via activator protein-1 transcription factor in human myometrial cells. Mol Hum Reprod 10:109,t2004

Sosa C, Althabe F, Belizan ], et al: Bed rest in singleton pregnancies for preventing preterm birth. Cochrane Database Syst Rev 1 :CD003581, 2004 Spong CY: Deining "term" pregnancy. Recommendations from the Deining "Term" Pregnancy Workgroup.]AMA 309(23):2445,t2013 Spong CY: Improving birth outcomes key to improving global health. ]AMA 316(4):395,t2016 Spong CY, Mercer BM, D'alton M,et al: Timing of indicated late-preterm and early-term birth. Obstet Gyneco1t118(2 Pt 1):323, 2011

Steer CM, Petrie RH: A comparison of magnesium sulfate and alcohol for the prevention of premature labor. Amt] Obstet Gynecol 129: 1, 7 Steer P: The epidemiology of preterm labour. B]OG 112(1): 1,t2005

Stiles AD: Prenatal corticosteroids-early gain, long-term questions. N Englt] Med 357:1248,t2007

Stoll B], Hansen NI, Bell EF, et al: Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 126:443, 2010

Stoll B], Hansen N, Fanarof AA, et al: Changes in pathogens causing earlyonset sepsis in very-low-birth-weight infants. N Engl ] Med 347:240, 2002

Stout M], Zhou Y, Wylie M, et al: Early pregnancy vaginal microbiome trends and preterm birth. Am] Obstet GynecoI217(3):356.e1, 2017

Tattershell M, Cordeaux Y, Charnock-Jones DS, et al: Expression of gastrinreleasing peptide is increased by prolonged stretch of human myometrium, and antagonists of its receptor inhibit contractility. ] Physiol 590(Pt 9): 2018,t2012

Terkildsen MF, Parilla BV, Kumar P, et al: Factors associated with success of emergent second-trimester cerclage. Obstet Gynecol 101 :565, 2003

Timmons Be, Reese ], Socrate S, et al: Prostaglandins are essential for cervical ripening in LPS-mediated preterm birth but not term or antiprogestindriven preterm ripening. Endocrinology 155(1):287, 2014

Tita A, Owen], Cliver S, et al: Decreasing temporal trends in adjusted preterm birth among women receiving prenatal care at a university-based health system. Am] Obstet GynecoI204:S183, 2011

Tita AT, Cliver SP, Goepfert AR, et al: Clinical trial of interconceptional antibiotics to prevent preterm birth: subgroup analyses and possible adverse antibiotic-microbial interaction. Amt] Obstet Gynecol 196:367, 2007

Tita AT, Landon MB, Spong CY, et al: Timing of elective repeat cesarean delivery at term and neonatal outcomes. N Engl] Med 360(2): 111, 2009

To MS, Alirevic Z, Heath Ve, et al: Cervical cerclage for prevention of preterm delivery in women with short cervix: randomized controlled trial. Lancet 363(9424):] 849, 2004

Tomashek M, Shapiro-Mendoza CK, DavidofM], et al: Diferences in mortality between late-preterm and term singleton infants in the United States, 1995-2002. ] Pediatr 151 :450, 2007

Urquhart e, Currell R, Harlow F, et al: Home uterine monitoring for detecting preterm labour. Cochrane Database Syst Rev 2:CD006172, 2017 Ustiin C, Kocak I, Baris S, et al: Subclinical chorioamnionitis as an etiologic factor in preterm deliveries. Int] Obstet Gynecol 72: 109, 2001 van Vliet EO, Nijman T A, Schuit E, et al: Nifedipine versus atosiban for threatened preterm birth (APOSTEL III): a multicentre, randomised controlled trial. Lancet 38 (10033):2117,t2016

Varner MW, Esplin MS: Genetic factors in preterm birth-the future. B]OG 112(Suppltl):28,t2005

Velez DR, Fortunato S, horsen P, et al: Spontaneous preterm birth in Mrican Americans is associated with infection and inflammatory response gene variants. Am] Obstet GynecoI200(2):209.el, 2009 Velez DR, Fortunato S], Williams SM, et al: Interleukin-6 (IL-6) and receptor (IL6-R) gene haplotypes associate with amniotic luid protein concentrations in preterm birth. Hum Mol Genet 17: 1619, 2008 Venkatesh KK, iley L, Castro VM, et al: Association of antenatal depression symptoms and antidepressant treatmet with preterm birth. Obstet Gynecol 127(5):926,t2016 Vergnes ]N, Sixou M: Preterm low birthweight and maternal periodontal status: a meta-analysis. Am] Obstet Gynecol 196: 135.e 1, 2007 Viteri OA, Blackwell SC, Chauhan SP, et al: Antenatal corticosteroids for the prevention of respiratory distress syndrome in premature twins. Obstet Gynecol 128(3):583,t2016 Vornhagen ], Adams Waldorf M, Rajagopal L: Perinatal group B streptococcal infections: virulence factors, immunity, and prevention strategies. Trends Microbiol 25(11):919, 2017 Wadhwa PD, Culhane ]F, Rauh V, et al: Stress and preterm birth: neuroendocrine, immune/inlammatory, and vascular mechanisms. Matern Child Health] 5:119, 2001 Walker KF, Thornton ]G: Tocolysis and preterm labour. Lancet 387(10033): 2068,t2016 Wang H, Parry S, Macones G, et al: A functional SNP in the promoter of the SERPINH1 gene increases risk of preterm premature rupture of membranes in Mrican Americans. PNAS 103: 13463, 2006 Wapner R], Sorokin Y, Mele L, et al: Long-term outcomes after repeat doses of antenatal corticosteroids. N Englt] Med 357: 1190, 2007

Ward K: Genetic factors in common obstetric disorders. Clin Obstet Gynecol 51t:74,t2008

Warren ]E, Silver i, Daltont], et al: Collagen 1A1 and transforming growth factor-3 polymorph isms in women with cervical insuiciency. Obstet Gynecol 110:619, 2007

Warren B, Goland RS, Wardlaw SL, et al: Elevated maternal plasma corticotropin releasing hormone levels in twin gestation. ] Perinat Med 18:39, 1990

Watts DH, Krohn A, Hillier SL, et al: he association of occult amniotic luid infection with gestational age and neonatal outcome among women in preterm labor. Obstet Gynecol 9:35t1,t1992

Weiss ]L, Malone FD, Vidaver ], et al: hreatened abortion: a risk factor for poor pregnancy outcome, a population-based screening study. Am ] Obstet Gynecol 190:745,t2004

Wenstrom K, Weiner CP, Merrill D, et al: A placebo controlled randomized trial of the terbutaline pump for prevention of preterm delivery. Amt] PerinatoIt14:87, 1997

Werner EF, Han CS, Savitz DA, et al: Health outcomes for vaginal compared with cesarean delivery of appropriately grown preterm neonates. Obstet Gynecol 121:1195,t2013

White BA, Creedon D], Nelson E, et al: The vaginal microbiome in health and disease. Trends Endocrinol Metab 22(10):389, 2011

Winn HN, Chen M, Amon E, et al: Neonatal pulmonary hypoplasia and perinatal mortality in patients with mid-trimester rupture of amniotic membranes-a critical analysis. Am ] Obstet Gynecol 182:1638, 2000

Wolfe CD, Patel SP, Linton EA, et al: Plasma corticotrophin-releasing factor (CRF) in abnormal pregnancy. B]OG 95:1003, 1988

Wu W, Colfordt]M ]r: Chorioamnionitis as a risk factor for cerebral palsy: a meta-analysis. ]AMA 284 (11): 1417, 2000

Yoon BH, Romero R, Park]S, et al: Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years. Am ] Obstet Gynecol 182:675,t2000

Yoon BH, Romero R, Park ]S, et al: Microbial invasion of the amniotic cavity with Ureaplasma urealyticum is associated with robust host response in fetal, amniotic, and maternal compartments. Am ] Obstet Gynecol 179: 1254, 1998

Yoon BH, Yang SH, ]un ]K, et al: Maternal blood C-reactive protein, white blood cell count, and temperature in preterm labor: a comparison with amniotic luid white blood cell count. Obstet GynecoIt87:23t1, 1996

Young A, Thomson A], Ledingham M, et al: Immunolocalization of proinlammatory cytokines in myometrium, cervix, and fetal membranes during human parturition at term. BioI Reprod 66:445, 2002

Young D: Clinical trials and tribulations: 170HPC and preventing recurrent preterm birth. Am] Obstet GynecoI216(6):543, 2017

Younge N, Goldstein RF, Bann CM, et al: Survival and neurodevelopmental outcomes among periviable infants. N Engl ] Med 376(7):617, 2017 Zhang X, Liu M: Clinical observations on the prevention and treatment of premature labor with nifedipine. [Chinese] Hua i Yi Ke Da Xue Xue Bao 33(2):288, 2002

Zuckerman H, Reiss U, Rubinstein I:

Inhibition of human premature labor by indomethacin. Obstet , 1974 t must be admitted that the duration ofpregnancy not infrequenty exceeds 280 days rom the last menstrual period and that when it lasts much longer large children are developed which are frequenty delivered ony after great dficuly. Thus, whenever the menstrual history of the patient indicates that she has passed much beyond the tenth and is approaching the eleventh lunar month, we should consider the pro priey of the induction of labour, provided that examination shows the child is larger than usual.

-J. Whitridge Williams (1903) he above passage from Williams shows that pregnancies exceeding the expected normal length were problematic more than 100 years ago. These postterm pregnancies remain so today.

The adjectives postterm, prolonged, postdates, and postmature are often loosely used interchangeably to describe pregnancies that have exceeded a duration considered to be the upper limit of normal. We eschew use of the term postdates because the real issue in many postterm pregnancies is "post-what dates?" Post mature is reserved for the relatively uncommon speciic clinical fetal syndrome in which the newborn has recognizable features indicating a pathologically prolonged pregnancy. herefore, postterm or prolonged pregnancy is our preferred expression for an extended pregnancy.

The international definition of prolonged pregnancy, endorsed by the American College of Obstetricians and Gynecologists (2016b,d) is one that exceeds 42°/7 weeks, namely, 294 days or more from the first day of the last menstrual period. Importantly, this is 42 "completed weeks," as pregnancies between 41 weeks 1 day and 41 weeks 6 days, although in the 42nd week, do not complete 42 weeks until the seventh day has elapsed. The method that we use widely in this book is to divide the 42nd week into 7 days, that is, 42°/7 through 426' weeks.

The current deinition of postterm pregnancy assumes that the last menses was followed by ovulation 2 weeks later. hat said, some pregnancies may not actually be postterm. Instead, the because of faulty menstrual date recall or delayed ovulation. Thus, the two categories of pregnancies that reach 42 completed weeks are those truly 40 weeks past conception and those of less-advanced gestation but with inaccurately estimated gestational age. Even with exactly recalled menstrual dates, there still is imprecision, and the American College of Obstetricians and Gynecologists (2016d, 20 17b) considers first-trimester sonography to be the most accurate method to establish or confirm gestational age. Several clinical studies support this practice (Bennett, 2004; Blondel, 2002; Joseph, 2007).

Of the 3.93 million neonates born in the United States during 2015, 0.4 percent were delivered at 42 weeks or later (11artin, 2017). In the past, the proportion was much higher. This trend suggests earlier intervention, however, the added accuracy from earlier sonographic dating ofgestational age is another factor.

To identiy potential predisposing factors for postterm pregnancy, Olesen and associates (2006) analyzed various characteristics in the Danish Birth Cohort. Only prepregnancy body mass index (BMI) :25 and nulliparity were signiicantly associated with prolonged pregnancy. Mission (2015) and Arrowsmith (2011) and their coworkers also reported similar associations. In nulliparas, those whose cervical length at midpregnancy is longer, that is, in the third or fourth quartile, are twice as likely to deliver after 42 weeks (van der Ven, 2016).

The tendency for some mothers to have repeated postterm births suggests that some prolonged pregnancies are biologically determined. Oberg and colleagues (2013) reported that when mother and daughter had a prolonged pregnancy, the risk for the daughter to have a subsequent postterm pregnancy was signiicantly increased. Laursen and associates (2004) found that maternal, but not paternal, genes inluenced prolonged pregnancy. As discussed in Chapter 5 (p. 105), rare fetal-placental factors that predispose to postterm pregnancy include anencephaly, adrenal hypoplasia, and X-linked placental sulfatase deiciency (Ayyavoo, 2014; MacDonald, 1965).

Rates of stillbirth, neonatal death, and infant morbidity all rise after the expected due date has passed. This is best seen when perinatal mortality rates are analyzed from times before widespread intervention for postterm pregnancies. In two large Swedish studies shown in Figure 43-1, after reaching a nadir at � 7.2 4.0 c 2.32.4 ing to gestational age of all births in Sweden during 1943-1952 compared with those during 1977-1o978. The partially compressed scale is used for convenience in depiction. (Adapted from

Bakketeig, 1991; Lindell, 1956.)

TABLE 43-1 . Adverse Maternal and Perinatal Outcomes Associated with Postterm Pregnancy

NICU = neonatal intensive care unit.

39 to 40 weeks, the perinatal mortality rate rose as pregnancy duration exceeded 41 weeks. his trend is also reported for the United States (Cheng, 2008; MacDorman, 2009). As shown in

Table 43-1, the major cause of death in these studies includes gestational hypertension, prolonged labor with cephalopelvic disproportion, birth injuries, and hypoxic-ischemic encephalopathy. Similar outcomes were reported by Olesen and colleagues (2003) in 78,022 women with postterm pregnancies delivered before routine labor induction was adopted in Denmark. Moster and associates (2010) found higher rates of cerebral palsy in postterm births, and Yang and coworkers (2010) reported lower intelligence quotient (IQ) scores at age 6.5 years in children born :42 weeks' gestation. Conversely, autism was not associated with postterm birth (Gardener, 2011).

Alexander and colleagues (2000a) reviewed 56,317 consecutive singleton pregnancies delivered at :40 weeks between 1988 and 1998 at Parkland Hospital. Labor was induced in 35 percent of pregnancies completing 42 weeks. he rate of cesarean delivery for dystocia and fetal distress was signiicantly greater at 42 weeks compared with earlier deliveries. More newborns of postterm pregnancies were admitted to intensive care units. Importantly, the incidence of neonatal seizures and deaths was doubled at 42 weeks. Smith (2001) has challenged analyses such as these because the population at risk for perinatal mortality in a given week consists ofall ongoing pregnancies rather than just the births in a givenweek. He calculated perinatal mortality rates calculated using only births in a given week of gestation from 37 to 43 completedweeks comparedwith the cumulative probabilitythe perinatal index-of death when all ongoing pregnancies are included in the denominator. Using this computation, delivery at 38 weeks had the lowest risk index for perinatal death.

The postmature newborn is unique, and features include wrinkled, patchy, peeling skin; a long, thin body suggesting wasting; and advanced maturity in that the infant is open-eyed, unusually alert, and appears old and worried 43-2). Skin wrinkling can be particularly prominent on the palms and soles. The nails are typically long. Most postmature neonates are not technically

FIGURE 43-2 Postmaturity syndrome. Neonate delivered at 43 weeks' gestation with thick, viscous meconium coating the desquamating skin. Note the long, thin appearance and wrinkling of the hands.

growth restricted because their birthweight seldom falls below the 10th percentile for gestational age (Chap. 44, p. 847). On the other hand, severe growth restriction-which logically must have preceded completion of 42 weeks-may be present.

he incidence of postmaturity syndrome in newborns at 41, 42, or 43 weeks, respectively, has not been conclusively determined. From data, the syndrome complicates 10 to 20 percent of pregnancies at 42 completed weeks (American College of Obstetricians and Gynecologists, 2016d). Associated oligohydramnios substantially raises the likelihood of postmaturity. Trimmer and associates (1990) reported that 88 percent of fetuses were postmature if there was oligohydramnios deined by a sonographic maximal vertical amnionic fluid pocket that measuredr; 1 cm at 42 weeks.

Many believe that postterm pregnancy is an abnormal state. Redman and Staf (2015) posit that limited placental capacity, which is characterized by dysfunctional syncytiotrophoblast, explains the greater risks of the postmaturity syndrome.

Cliford (1954) proposed that the associated skin changes were due to loss of the protective efects of vernix caseosa. He also attributed the postmaturity syndrome to placental senescence, although he did not ind placental degeneration histologically. Still, the concept that postmaturity stems from placental insuiciency has persisted despite an absence of morphological or signiicant quantitative findings (Larsen, 1995; Redman, 2015; Rushton, 1991). here are indings that the

FIGURE 43-3 Mean daily fetal growth during previous week of gestation. (Redrawn from Hendricks CH: Patterns of fetal and placental growth: the second half of pregnancy. Obstet Gynecol 24:357, 1964.) rate of placental apoptosis-programmed cell death-is significantly greater at 41 to 42 completed weeks compared with that at 36 to 39 weeks (Smith, 1999). Several proapoptotic genes such as kisspeptin are upregulated in postterm placental explants compared with the same genes in term placental explants (Torricelli, 2012). The clinical significance of such apoptosis is currently unclear.

Jazayeri and coworkers (1998) investigated cord blood erythropoietin levels in 124 appropriately grown newborns delivered from 37 to 43 weeks. he only known stimulator of erythropoietin is decreased partial oxygen pressure. Thus, they sought to assess whether fetal oxygenation was compromised due to placental aging in postterm pregnancies. All women had an uncomplicated labor and delivery. These investigators found that cord blood erythropoietin levels were significantly higher in pregnancies reaching 41 weeks or more. Although Apgar scores and acid-base studies were normal, these researchers concluded that fetal oxygenation was decreased in some postterm gestations.

Another scenario is that the postterm fetus may continue to gain weight and thus be unusually large at birth. This at least suggests that placental function is not severely compromised. Indeed, continued fetal growth is the norm-albeit at a slower rate beginning at 37 completed weeks (Fig. 43-3). Nahum and colleagues (1995) conirmed that fetal growth continues until at least 42 weeks. However, Link and associates (2007) showed that umbilical blood low did not increase concomitantly.

The principal reasons for increased risks to postterm fetuses were described by Leveno and associates (1984). Both antepartum fetal jeopardy and intrapartum fetal distress were found to be the consequence of cord compression associated with oligohydramnios. In their analysis of 727 postterm pregnancies, intrapartum fetal distress detected with electronic monitoring was not associated with late decelerations characteristic of uteroplacental insuiciency. Instead, one or more prolonged 1008060 -.0 100f80 -0

FIGURE 43-4 A. Prolonged fetal heart rate deceleration before emergency cesarean delivery in a postterm pregnancy with oligohydramnios. B. Severe-less than 70 bpm for 60 seconds or longer-variable decelerations in a postterm pregnancy with oligohydramnios. C. Saltatory baseline fetal heart rate showing oscillations exceeding 20 bpm and associated with oligohydramnios in a postterm pregnancy. (Reproduced with permission from Leveno J, Quirk JG, Cunningham FG, et al: Prolonged pregnancy, I. Observations concerning the causes of fetal distress, Am J Obstet Gynecol. 1984 Nov 1 ;1o50(5 Pt 1 ):465-473.) decelerations such as shown in of emergency cesarean deliveries for nonreassuring fetal heart rate tracings. In all but two cases, there were also variable decelerations. Another common fetal heart rate pattern, although not ominous by itself, was the saltatory baseline. As described in Chapter 24 (p. 468), these indings are consistent with cord occlusion as the proximate cause of the nonreassuring tracings. Other correlates included oligohydramnios and viscous meconium. Schafer and colleagues (2005) implicated a nuchal cord in abnormal intrapartum fetal heart rate patterns, meconium, and compromised newborn condition in prolonged pregnancies.

he volume of amnionic luid normally continues to decline ater 38 weeks and may become problematic. Moreover, meconium release into an already reduced amnionic luid volume results in thick, viscous meconium that may cause meconium aspiration syndrome (Chap. 33, p. 620).

Trimmer and coworkers (1990) sonographically measured hourly fetal urine production using sequential bladder volume measurements in 38 postterm pregnancies. Diminished urine production was found to be associated with oligohydramnios. They hypothesized that decreased fetal urine flow was likely the result of preexisting oligohydramnios that limited fetal swallowing. Oz and associates (2002), using Doppler waveforms, concluded that fetal renal blood low is reduced in those postterm pregnancies complicated by oligohydramnios. s a possible cause, again, the study by Link and associates (2007) showed that umbilical blood flow did not increase past term.

In the late 19905, the clinical significance of fetal-growth restriction in the otherwise uncomplicated pregnancy became more fully appreciated. Divon (1998) and Clausson (1999) and their coworkers analyzed births between 1991 and 1995 in the National Swedish Medical Birth Registry. Stillbirths were more common among growth-restricted newborns who were delivered after 42 weeks. Indeed, a third of postterm stillborn neonates were growth restricted. During this time in Sweden, labor induction and antenatal fetal testing usually commenced at 42 weeks. In a study from Parkland Hospital, Alexander and colleagues (2000d) analyzed outcomes for 355 neonates from pregnancies ::42 weeks and whose birthweights were <3rd percentile. hey compared these with outcomes of 14,520 similarly aged newborns above the 3rd percentile and found that morbidity and mortality rates were significantly increased in the growth-restricted neonates. Notably, a fourth of all stillbirths associated with prolonged pregnancy were in this comparatively small number of growth-restricted fetuses.

In the event of a medical or other obstetrical complication, it is generally not recommended that a pregnancy be allowed to continue past 42 weeks. Indeed, in many such instances, earlier delivery is indicated. Common examples include gestational hypertensive disorders, prior cesarean delivery, and diabetes. Other clinically important factors include amnionic luid volume and potential fetal macrosomia.

Most clinical studies support theview that diminished amnionic fluid determined by various sonographic methods identifies a postterm fetus with increased risks. Indeed, decreased amnionic luid in any pregnancy signiies increased fetal risk (Chap. 11r, p. 231). Unfortunately, lack of an exact method to define "decreased amnionic luid" has limited investigators, and many diferent criteria for sonographic diagnosis have been proposed. Fischer and colleagues (1993) attempted to determine which criteria were most predictive of normal versus abnormal outcomes in postterm pregnancies. As shown in Figure 43-5, the smaller the amnionic luid pocket, the greater the likelihood that there was clinically signiicant oligohydramnios. Importantly, normal amnionic luid volume did not preclude abnormal outcomes. lfirevic and coworkers (1997) randomly assigned 500 women with postterm pregnancies to assessment using either the amnionic luid index (AFI) or the deepest vertical pocket described in Chapter 11 (p. 226). They concluded that the AFI overestimated the number of abnormal outcomes in postterm pregnancies.

Regardless of the criteria used to diagnose oligohydramnios in postterm pregnancies, most investigators have found a higher incidence of some measure of "fetal distress" during labor. Thus, oligohydramnios by most definitions is a clinically meaningful finding. Conversely, reassurance of continued fetal well-being in the presence of "normal" amnionic luid volume is tenuous. This may be related to how quickly pathological oligohydramnios develops. Although such cases are unusual, Clement and coworkers (1987) described six postterm pregnancies in which amnionic luid volume diminished abruptly over 24 hours, and in one of these, the fetus died.

: 80 00 20 : 6.7em< 5em< 2em< 1 em

FIGURE 43-5 Comparison of the prognostic value of various pregnancies. Abnormal outcomes include cesarean or operative vaginal delivery for fetal jeopardy, 5-minute Apgar score �6, umbili cal arterial blood pH <7.1, or admission to the neonatal intensive care unit. (Redrawn from Fischer RL, McDonnell M, Bianculli KW, et al: Amniotic fluid volume estimation in the postdate pregnancy: a comparison oftechniques. Obstet Gynecol 81 :698, 1993.) he velocity of fetal weight gain peaks at approximately 37 weeks (see Fig. 43-3). Although growth velocity slows at that time, most fetuses continue to gain weight. For example, the percentage of fetuses born in 2009 whose birthweight exceeded 4000 g was 8.2 percent at 37 to 41 weeks and increased to 11.0 percent at 42 weeks or more (Martin, 2011). According to Duryea and associates (2014), the 95th percentile at 42 weeks is 4475 g. Even so, in some studies, brachial plexus injurywas not related to postterm gestation (Walsh, 2011). Intuitively, it seems that both maternal and fetal morbidity associated with macrosomia would be mitigated with timely induction to preempt urther growth. This, however, does not appear to be the case. The American College ofObstetricians and Gynecologists (2016c) has concluded that current evidence does not support such a practice in women at term with suspected fetal macrosomia. Moreover, the College concluded that in the absence of diabetes, vaginal delivery is not contraindicated for women with an estimated fetal weight up to 5000 g (Chap. 27, p. 520). Obvious problems with all such recommendations are substantive variations in fetal weight estimation.

Although some intervention is indicated for prolonged pregnancies, the method and timing of this are not unanimous. he decision focuses on whether labor induction is warranted or if expectant management with fetal surveillance is best. In a survey done more than 10 years ago, Cleary-Goldman and associates (2006) reported that 73 percent of members of the American College ofObstetricians and Gynecologists routinely induced women at 41 weeks. Most of the remainder performed twice weekly fetal testing until 42 weeks.

Although all obstetricians know what an "unfavorable cervix" is, the term unfortunately defies precise objective deinition. Thus, investigators have used difering criteria for studies of prolonged pregnancies. Harris and coworkers (1983) defin�d an unfavorable cervix by a Bishop score <7 and reported thiS m 92 percent of women at 42 weeks (Chap. 26, p. 505). Hannah and colleagues (1992) found that 40 percent of 3407 women with a 41-week pregnancy had an "undilated cervix." In a study of 800 women undergoing induction for postterm pregnancy at Parkland Hospital, Alexander and associates (2000b) reported that women in whom there was no cervical dilation had a twofold higher cesarean delivery rate fore" dystocia. " Yang and coworkers (2004) found that cervical length 53 em measured with transvaginal sonography was predictive of successful induction. In a similar study, Vankayalapati and associates (2008) found that cervical length 525 mm was predictive of spontaneous labor or successful induction.

Several investigators have evaluated prostaglandin E2 (PGE2) and E1 (PGE1) for induction in women with an unfavorable cervix and prolonged pregnancies. A study by the MaternalFetal Medicine Units Network (1994) found that PGE2 gel was not more efective than placebo. Alexander and associates (2000c) treated 393 women with a postterm pregnancy with PGE2, regardless of cervical "favorability," and reported that almost half of the 84 women with cervical dilatation of 2 to 4 em entered labor with PGE2 use alone. In another study, mifepristone was reported to increase uterine activity without uterotonic agents in women beyond 41 weeks (Fasset, 2008). Prostaglandins and other agents used for cervical ripening are discussed in Chapter 26 (p. 506).

Sweeping or stripping of the membranes to induce labor and thereby prevent postterm pregnancy was studied in 15 randomized trials during the 1990s. Boulvain and coworkers (2005) performed a metaanalysis of these and found that membrane stripping at 38 to 40 weeks lowered the frequency of postterm pregnancy. Although maternal and neonatal infection rates were not increased, this practice did not modiy the cesarean delivery rate. Since then, randomized trials by Wong (2002), Kashanian (2006), Hill (2008), and their coworkers found that sweeping membranes did notereduce the need to induce labor.

Drawbacks of membrane stripping included pain, vaginal bleeding, and irregular contractions without labor.

The station of the fetal head within the pelvis is another predictor of successful postterm pregnancy induction. Shin and colleagues (2004) studied 484 nulliparas who underwent induction after 41 weeks. The cesarean delivery rate was directly related to station. The rate was 6 percent if the vertex before induction was at -1 station; 20 percent at -2 station; 43 percent at -3 station; and 77 percent at -4 station.

Because of the marginal benefits from induction with an unfavorable cervix, as just discussed, some clinicians prefer instead to implement a strategy of fetal testing beginning at 41 completed weeks. For example, in a Canadian study, 3407 women were randomly assigned at 41 or more weeks to induction or to fetal testing (Hannah, 1992). In the surveillance group, evaluation included: (1) counting fetal movements during a 2-hour period each day, (2) nons tress testing three times weekly, and (3) amnionic fluid volume assessment two to three times weekly, with pockets <3 em considered abnormal. Labor induction resulted in a small but signiicant reduction in the cesarean delivery rate compared with fetal testing-2e1 versus 24 percent, respectively. This diference was due to fewer procedures for fetal distress. here were only two stillbirths in the fetal testing group.

The !v1aternal-Fetal Medicine Network performed a randomized trial of induction versus fetal testing beginning at 41 weeks (Gardner, 1996). Fetal surveillance included nonstress testing and sonographic estimation of amnionic fluid volume performed twice weekly in 175 women. Perinatal outcomes were compared with those of 265 women also at 41 weeks randomly assigned to induction with or without cervical ripening. There were no perinatal deaths, and the cesarean delivery rate was not diferent between management groups. he results of this study could be used to support the validity of either management scheme.

In an analysis of 22 trials, Gulmezoglu and colleagues (2012) found that induction after 41 weeks rather than surveillance was associated with significantly fewer perinatal deaths and meconium aspiration syndrome cases and a lower cesarean delivery rate. In a review of two metaanalyses and a randomized study, similar conclusions were reached (Mozurkewich, 2009).

In most studies, labor induction at 42°/7 weeks has a higher cesarean delivery rate compared with spontaneous labor. From Parkland Hospital, Alexander and coworkers (2001) evaluated pregnancy outcomes in 638 such women in whom labor was induced and compared them with outcomes of 687 women with postterm pregnancies who had spontaneous labor. Cesarean delivery rates were signiicantly increased-19 versus 14 percent-in the induced group because of failure to progress. When these investigators corrected for risk factors, however, they concluded that intrinsic maternal factors, rather than the induction itself, led to the higher rate. These factors included nulliparity, an unfavorable cervix, and epidural analgesia.

A large study from Denmark by Zizzo and associates (20e17) is also instructive. In 2011e, the Danish national guidelines were changed from labor induction at 42°/7 weeks with no fetal sur veillance to labor induction at 41e/7 to 416/7 weeks with fetal surveillance beginning at 41°/7 weeks. They compared two 3-year epochs-one before and one ater 20 II-and the results are shown in Table 43-2. The rate of pregnancies that progressed past 42°/7 weeks decreased from 2.85 to 0.62 percent. Concu�rently, as expected, the induction rate rose signiicantly, and thiS was accompanied by a drop in the perinatal mortality rate-22 to 13 per 1000 births. The cesarean delivery rate was not changed. A similar before-and-ater observational study reported that induction at ::42 weeks was associated with a signiicantly lower cesarean delivery rate-15 versus 19.4 percent (Bleicher, 2017).

From the foregoing, evidence to substantiate interventionwhether induction or fetal testing-commencing at 41 versus 42 weeks is limited. Most evidence used to justiy intervention

TABLE 43-2. National Death Cohort Study of 102,1e67 Pregnancies that Reached 41e°/7 Weeks' Gestation

EGA >42°/7 2.85% 0.62%

Stillbirths 9/1000 5/1000 0.018

Neonatal deaths 13/1000 811000 .033

Vacuum delivery 11.3% 10.2% <0.001

Induction 28% 43% <0.001 aNational guidelines changed between epochs as described in text.

NS = not significant.

Data from Zizzo, 201n7.

at 41 weeks is from the randomized Canadian and American investigations cited earlier. No randomized studies have specifically assessed intervention at 41 weeks versus an identical intervention used at 42 weeks. A large Swedish multicenter randomized trial of more than 10,000 women at 41°1 weeks has been designed to address the question (Elden, 2016).

he American College of Obstetricians and Gynecologists (2016a) deines postterm pregnancies as having completed 42 weeks, namely, beyond 42°/7 weeks. There is insuicient evidence to mandate a management strategy between 40 and 42 completed weeks. hus, although not considered mandatory, initiation of fetal surveillance at 41 weeks is a reasonable option. After completing 42 weeks, recommendations are for labor induction as summarized in Figure 43-6.

When gestational age is uncertain, the American College of Obstetricians and Gynecologists (2017b) recommends delivery at 41 weeks' gestation using the best clinical estimate of gestational age. he College also recommends against amniocentesis for fetal lung maturity.

At Parkland Hospital, based on results from the trials just discussed, we consider 41-week pregnancies without other

FIGURE 43-6 Algorithm for management of postterm pregnancy. (Summarized from American College of Obstetricians and Gynecologists,o201o6d.) complications to be normal. hus, no interventions are practiced solely based on fetal age until 42 completed weeks. With complications such as hypertension, decreased fetal movement, or oligohydramnios, labor induction is carried out. It is our view that large, randomized trials should be performed before otherwise uncomplicated 41-week gestations are routinely considered pathologically prolonged. In women in whom a certain gestational age is known, labor is induced at the completion of 42 weeks. Almost 90 percent of such women are induced successfully or enter labor within 2 days of induction. For those who do not deliver with the first induction, a second induction is performed within 3 days. lmost all women are delivered using this management plan, but in the unusual few who are not delivered, management decisions involve a third-or even more-induction versus cesarean delivery. Women classiied as having uncertain postterm pregnancies are managed with weekly nonstress fetal testing and assessment ofamnionic luid volume. Women with an AFI ;5 cm or with reports ofdiminished fetal movement undergo labor induction.

Labor is a particularly dangerous time for the postterm fetus.

Therefore, women whose pregnancies are known or suspected to be postterm ideally come to the hospital as soon as they suspect labor. While being evaluated for active labor, we monitored electronically for variations consistent with fetal compromise.

During labor, the decision to perform amniotomy is problematic. Further reduction in luid volume following amniotomy can enhance the possibility of cord compression. Conversely, after membrane rupture, a scalp electrode and an intrauterine pressure catheter can be placed. These usually provide more precise data concerning fetal heart rate and uterine contractions. Amniotomy also aids identification of thick meconium.

Thick meconium in the amnionic luid is particularly worrisome. The viscosity probably signiies the lack of liquid and thus oligohydramnios. Aspiration of thick meconium may cause severe pulmonary dysfunction and neonatal death (Chap. 33, p. 620). Because of this, amnioinfusion during labor has been proposed as a way of diluting meconium to lower the incidence of aspiration s) ndrome (Wenstrom, 1989). As discussed in Chapter 24 (p. 475), the benefits of amnioinfusion remain controversial. In a large randomized trial by Fraser and colleagues (2005), amnioinfusion did not reduce the risk of meconium aspiration syndrome or perinatal death. According to the American College of Obstetricians and Gynecologists (2016a), amnioinfusion does not prevent meconium aspiration, however, it remains a reasonable treatment approach for repetitive variable decelerations.

he likelihood of a successful vaginal delivery is reduced appreciably for the nullipara who is in early labor with thick, meconium-stained amnionic fluid. Therefore, if the woman is remote from delivery, strong consideration should be given to prompt cesarean delivery, especially when cephalopelvic disproportion is suspected or either hypotonic or hypertonic dysfunctional labor is evident. Some practitioners choose to avoid oxytocin use in these cases.

Until recently, it was taught-including at Parkland Hospital -that aspiration of meconium could be minimized but not eliminated by suctioning the pharynx as soon as the head was delivered. According to the American Heart Association guidelines, this in no longer recommended (Wyckof, 2015). The merican College of Obstetricians and Gynecologists (2017a) does not recommend routine intrapartum suctioning. Alternatively, if the depressed newborn has meconium-stained fluid, then intubation is carried out.

Alexander JM, McIntire DO, Leveno KJ: Forty weeks and beyond: pregnancy outcomes by week of gestation. Obstet Gynecol 96:291, 2000a lexander JM, McIntire DO, Leveno KJ: Postterm pregnancy: does induction increase cesarean rates? J Soc Gynecol Invest 7:79A, 2000b lexander JM, McIntire DO, Leveno KJ: Postterm pregnancy: is cervical "ripening" being used in the right patients? J Soc Gynecol Invest 7:247 A, 2000c Alexander JM, McIntire DO, Leveno KJ: Prolonged pregnancy: induction of labor and cesarean births. Obstet Gynecol 97:9t11t, 2001

Alexander JM, McIntire DO, Leveno KJ: he efect of fetal growth restriction on neonatal outcome in postterm pregnancy. Abstract No. 463. Am J Obstet Gynecol 182:S148, 2000d

Alfirevic Z, Luckas M, Walkinshaw SA, et al: A randomized comparison between amniotic fluid index and maximum pool depth in the monitoring of postterm pregnancy. Br J Obstet Gynaecol 104:207, 1997

American College of Obstetricians and Gynecologists: Amnioinfusion does not prevent meconium aspiration syndrome. Committee Opinion No. 346, October 2006, Reairmed 2016a

American College of Obstetricians and Gynecologists Qoint with the Society for Maternal-Fetal Medicine): Deinition of term pregnancy. Committee Opinion No. 579, November 20t13, Reairmed 20t16b

American College of Obstetricians and Gynecologists: Fetal macrosomia. Practice Bulletin No. 173, November 20t16c

American College of Obstetricians and Gynecologists: Management of lateterm and postterm pregnancies. Practice Bulletin No. 146, August 20t14, Reairmed 2016d

American College of Obstetrics and Gynecologists: Management of delivery of a newborn with meconium-stained amniotic fluid. Committee Opinion No. 689, March 20t17a

American College of Obstetricians and Gynecologists: Management of suboptimally dated pregnancies. Committee Opinion No. 688, March 2017b

Arrowsmith S, Wray S, Quenby S: Maternal obesity and labour complications following induction of labour in prolonged pregnancy. BJOG 118(5):578, 2011

Ayyavoo A, Derraik JG, Hofman PL, et al: Postterm births: are prolonged pregnancies roo long? J Pediatr 164(3):647,t2014

Bakketeig LS, Bergsj0 P: Post-term pregnancy: magnitude of the problem.

In Chalmers I, Enkin M, Keirse M (eds): Efective Care in Pregnancy and Childbirth. Oxford, Oxford University Press, 1991, p 765

Bennett A, Crane JM, O'Shea P, et al: First trimester ultrasound screening is efective in reducing postterm labor induction rates: a randomized controlled trial. Am J Obstet Gynecol 190: 107 , 2004

Bleicher I, Vinter 0, Iofe A, et al: When should pregnancies that extended beyond term be induced? J Matern Fetal Neonatal Med 30(2):219,t2017

Blondel B, Morin I, Platt RW, et al: Algorithms for combining menstrual and ultrasound estimates of gestational age: consequences for rates of preterm and postterm birth. Br J Obstet Gynaecol 109: 18, 2002

Boulvain M, Stan CM, Irion 0: Membrane sweeping for induction of labour.

Cochrane Database Syst Rev 1 :CD00045t1, 2005

Cheng W, Nicholson JM, Nakagawa S, et al: Perinatal outcomes in low-risk term pregnancies: do they difer by week of gestation? Am J Obstet Gynecol 0.e1,t2008

Clausson B, Cnattingus S, Axelsson 0: Outcomes of postterm births: the role of fetal growth restriction and malformations. Obstet Gynecol 94:758, 1999

Cleary-Goldman J, Bettes B, Robinon IN, et al: Postterm pregnancy: practice patterns of contemporary obstetricians and gynecologists. Am J Perinatol 23:15,t2006

Clement 0, Schifrin BS, Kates RB: Acute oligohydramnios in postdate pregnancy. Am J Obstet Gynecol 157:884, 1987

Cliford SH: Postmaturity with placental dysfunction. Clinical syndromes and pathologic indings. J Pediatr 44: 1, 1954

Divon MY, Haglund B, Nisell H, et al: Fetal and neonatal mortality in the postterm pregnancy: the impact of gestational age and fetal growth restriction. Am J Obstet Gynecol 178:726, 1998

Duryea EL, Hawkins JS, McIntire DO, et al: A revised birth weight reference for the United States. Obstet GynecoIt124:16, 2014

Elden H, Hagberg H, Wessberg A, et al: Study protocol of SWEPIS a Swedish multicentre register based randomised controlled trial to compare induction of labour at 41 completed gestational weeks versus expectant management and induction at 42 completed gestational weeks. BMC Pregnancy Childbirth 16:49,t2016

Fasset MJ, Wing DA: Uterine activity after oral mifepristone administration in human pregnancies beyond 41 weeks' gestation. Gynecol Obstet Invest 65(2): ll2, 2008

Fischer RL, McDonnell M, Bianculli W, et al: Amniotic luid volume estimation in the postdate pregnancy: a comparison of techniques. Obstet Gynecol 81t:698, 1993

Fraser WD, Hofmeyr J, Lede R, et al: Amnioinfusion for the prevention of the meconium aspiration syndrome. New Engl J Med 353:909, 2005 Gardener H, Spiegelman D, Buka SL: Perinatal and neonatal risk factors for autism: a comprehensive meta-analysis. Pediatrics 128:344,t2011

Gardner M, Rouse 0, Goldenberg R, et al: Cost comparison of induction of labor at 41 weeks versus expectant management in the postterm pregnancy. Am J Obstet 4:351, 1996

Gulmezoglu M, Crowther CA, Middleton P, et l: Induction of labour for improving birth outcomes for women at or beyond term. Cochrane Database Syst Rev 6:CD004945, 2012

Hannah ME, Hannah J, Hellman J, et al: Induction of labor as compared with serial antenatal monitoring in post-term pregnancy. N Engl J vIed 326:1587, 1992

Harris BA Jr, Huddleston JF, Sutlif G, et al: he unfavorable cervix in prolonged pregnancy. Obstet Gynecol 62: 1, 1983

Hendricks CH: Patterns of fetal and placental growth: the second half of pregnancy. Obstet Gynecol 24:357, 1964

Hill MJ, McWilliams GC, Garcia-Sur, et al: he efect of membrane sweeping on prelabor rupture of membranes: a randomized controlled trial. Obstet Gynecoltll1(6):1313,t2008

Jazayeri A, Tsibris JC, Spellacy N: Elevated umbilical cord plasma erythropoietin levels in prolonged pregnancies. Obstet Gynecol 92:6t1, 1998 Joseph KS, Huang L, Liu S, et l: Reconciling the high rates of preterm and postterm birth in the United States. Obstet Gynecol 109(4):798,t200

Kashanian M, Aktarian A, Baradaron H, et al: Efect of membrane sweeping at term pregnancy on duration of pregnancy and labor induction: a randomized trial. Gynecol Obstet Invest 62:41,t2006

Larsen LG, Clausen HV, Andersen B, et al: A stereologic study of postmature placentas fixed by dual perfusion. Am J Obstet Gynecol 2:500, 1995

Laursen M, Bille C, Olesen A W, et al: Genetic inluence on prolonged gestation: a population-based Danish twin study. Am J Obstet Gynecol 190:489, 2004

Leveno KJ, Quirk JG, Cunningham FG, et al: Prolonged pregnancy, 1.

Observations concerning the causes of fetal distress. Am J Obstet Gynecol 150:465, 1984

Lindell A: Prolonged pregnancy. Acta Obstet Gynecol Scand 35: 136, 1956

Link G, Clark KE, Lang U: Umbilical blood low during pregnancy: evidence for decreasing placental perfusion. Am J Obstet Gynecol 196(5)489.e1, 2007

MacDonald PC, Siiteri PK: Origin of estrogen in women pregnant with an anencephalic fetus. J Clin Invest 44:465, 1965

MacDorman MF, Kirmeyer S: Fetal and perinatal mortality, United States, 2005. Natl Vital Stat Rep 57(8):1, 2009

Martin JA, Hamilton BE, Osterman MJK, et al: Births: inal data for 2013.

Natl Vital Stat Rep 64:t1,t2015

Martin JA, Hamilton BE, Sutton PO, et al: Births: inal data for 2015. Natl Vital Stat Rep 66(1):1,t2017

Maternal-Fetal Medicine Units Network: A clinical trial of induction of labor versus expectant management in postterm pregnancy. Am J Obstet Gynecol 170:716,t1994

Mission JF, Marshall NE, Caughey AB: Pregnancy risks associated with obesity. Obstet Gynecol Clin North Am 42:335,t2015

Moster 0, Wilcox AJ, Vollset SE, et al: Cerebral palsy among term and postterm births. JAMA 304(9):976,t2010

Mozurkewich E, Chilimigras J, Koepke E, et al: Indications for induction of labour: a best-evidence review. BJOG 116(5):626, 2009

Nahum GG, Stanislaw H, Hufaker B]: Fetal weight gain at term: linear with minimal dependence on maternal obesity. Amt] Obstet Gynecol 172: 1387, 1995

Oberg AS, Frisell T, Svensson AC, et al: Matenal and fetal genetic contributions to postterm birth: familial clustering in a population-based sample of 475,429 Swedish births. Amt] Epidemiol 177(6):531,t2013

Olesen A W, Westergaard ]G, Olsen ]: Perinatal and maternal complications related to postterm delivery: a national register-based study, 1978-1993. Amt] Obstet Gynecol 189:227,t2003

Olesen AW, Westergaard ]G, Olsent]: Prenatal risk indicators of a prolonged pregnancy. The Danish Birth Cohort 1998-2001. Acta Obstet Gynecol Scand 85: 1338, 2006

Oz AU, Holub B, Mendilcioglu 1, et aI: Renal artery Doppler investigation of the etiology of oligohydramnios in postterm pregnancy. Obstet Gynecol 100:715,t2002

Redman CW, Staf AC: Preeclamptic biomarkers, syncytiotrophoblast stress, and placental capacity. Amt] Obstet Gynecol 213 (4 Suppl):S9.e 1, 2015 Rushton DI: Pathology of placenta. In Wigglesworth ]5, Singer DB (eds):

Textbook of Fetal and Perinatal Pathology. Boston, Blackwell, 1991, P 171 Schafer L, Burkhardt T, Zimmerman R, et al: Nuchal cords in term and postterm deliveries-do we need to know? Obstet Gynecol 106:23,t2005

Shin KS, Brubaker L, Ackerson LM: Risk of cesarean delivery in nulliparous women at greater than 41 weeks' gestational age with an unengaged vertex. Am] Obstet Gynecol 190:129,t2004

Smith GC: Life-table analysis of the risk of perinatal death at term and post term in singleton pregnancies. Amt] Obstet Gynecol 184:489,t2001

Smith Sc, Baker PN: Placental apoptosis is increased in postterm pregnancies. B]OG 106:861, 1999

Torricelli M, Novembri R, Conti N, et al: Correlation with kisspeptin in postterm pregnancy and apoptosis. Reprod Sci 19(10): 1133, 2012

Trimmer K], Leveno K], Peters MT, et al: Observation on the cause of oligohydramnios in prolonged pregnancy. Am] Obstet Gynecol 163: 1900, 1990

Van del' Ven Aj, van Os MA, Kleinrouweler CE, et al: Midpregnancy cervical length in nulliparous women and its association with postterm delivery and intrapartum cesarean delivery. Am ] Perinatol 33 (1) :40, 2016

Vankayalapati P, Sethna F, Roberts N, et al: Ultrasound assessment of cervical length in prolonged pregnancy: prediction of spontaneous onset of labor and successful vaginal delivery. Ultrasound Obstet Gynecol 31 (3):328, 2008

Walsh ]M, Kandamany N, Shuibhne NN, et al: Neonatal brachial plexus injury: comparison of incidence and antecedents between 2 decades. Amt] Obstet Gynecol 204:324, 201t1.

Wenstrom KD, Parsons MT: The prevention of meconium aspiration in labor using amnioinfusion. Obstet Gynecol 73:647, 1989

Wong SF, Hui SK, Choi H, et al: Does sweeping of membranes beyond 40 weeks reduce the need for formal induction of labour? Br] Obstet Gynaecol 109:632, 2002 Wyckof MH, Aziz K, Escobedo MB, et al: Part 13: neonatal resuscitation. 2015 American Heart Association guidelines for cardiopulmonaty resuscitation and emergency cardiovascular care. Circulation 132:5543, 20t15

Yang 5, Platt RW, Kramer MS: Variation in child cognitive ability by week of gestation among healthy term births. Am] Epidemiol 171 :399, 2010

Yang SH, Roh CR, Kim ]H: Transvaginal ultrasonography for cervical assessment before induction of labor. Obstet Gynecol Surv 59:577, 2004

Zizzo AR, Kirkegaard I, Pin borg A, et al: Decline in stillbirths and perinatal mortality after implementation of a more aggressive induction policy in post-date pregnancies: a nationwide register study. Acta Obstet Gynecol Scand 96(7):862, 2017

FETAL GROWTH. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 844

FETAL-GROWTH RESTRICTION.................... 847

RISK FACTORS AND ETIOLOGIES.................. 849

FETAL-GROWTH RESTRICTION RECOGNITION....... 852

MANAGEMENT................................. 854

FETAL OVERGROWTH......................... 856

RISK FACTORS ................................. 857

MANAGEMENT. ............................... 858

When inants are of large size and abundant, they may mechanicaly throw out of function so great a portion of the placenta as seriousy to inteere with the nutrition of the oetus, and sometimes cause its death. Excessive development of the oetus can usualy be traced to prolongation of pregnancy, large size of one or both parents, advancing age, or multipariy of the mother.

-J. Whitridge Williams (1903) he concept of excessive or impaired fetal growth was not considered in detail by Williams in his irst edition. Abnormally diminished fetal growth was attributed to placental lesions and fetal infections. Conversely, a large fetus was of obvious concern because of associated dystocia. Currently, fetal-growth disorders at both ends of the spectrum are major problems in obstetrics.

Nearly 20 percent of the almost 4 million neonates born in the United States are at the low and high extremes of fetal growth.

In 2015, 8.1 percent of newborns weighed <2500 g at birth, whereas 8.0 percent weighed >4000 g. And, although almost 70 percent of low-birthweight neonates are born preterm, the balance of low-birthweight newborns accounted for approximately 3 percent of term births in 2015 (Martin, 2017). Between 1990 and 2006, the proportion of newborns with birthweights <2500 g grew by more than 20 percent when the rate peaked at 8.3 percent (Martin, 2012). his trend toward smaller babies has slowed since the mid-to late-2000s and might partly be explained by the concurrent movement toward fewer deliveries prior to 39 weeks' gestation (Richards, 2016). In contrast, between 1990 and 2006, the incidence of birth weights >4000 g declined approximately 30 percent to a nadir of 7.6 percent in 2010 (Martin, 2012). This trend away from the upper extreme is diicult to explain because it coincides with the epidemic prevalence of obesity, a known cause of macrosomia (Morisaki, 2013).

Human fetal growth is characterized by sequential patterns of tissue and organ growth, diferentiation, and maturation. However, the "obstetrical dilemma" postulates a conlict between the need to walk upright-requiring a narrow pelvis-and the need to think-requiring a large brain, and thus a large head. Some speculate that evolutionary pressures restrict growth late in pregnancy (Mitteroecker, 2016). Thus, the ability to growth restrict may be adaptive rather than pathological.

Fetal growth has been divided into three phases. The initial phase of hyperplasia occurs in the irst 16 weeks and is characterized by a rapid increase in cell number. The second phase, which extends up to 32 weeks' gestation, includes both cellular hyperplasia and hypertrophy. After 32 weeks, fetal mass accrues by cellular hypertrophy, and it is during this phase that most fetal fat and glycogen are accumulated. The corresponding c 5..,

FIGURE 44-1 Increments in fetal weight gain in grams per day from 24 to 42 weeks' gestation. The black line represents the mean and the outer blue lines depict ±2 standard deviations. (Data from pregnancies managed at Parkland Hospital.) levels below the threshold for diabetes. Overgrowth does occur in the fetuses of euglycemic women. Its etiology is thus likely more complicated than merely dysregulated glucose metabolism (Catalano, 2011). Genetic factors, including genomic imprinting and epigenetic modifications via gene methylation, are also important and emphasize the potential role of inheritance (Begemann, 2015; Nawathe, 2016).

Excessive transfer of lipids may also lead to fetal overgrowth (Higa, 2013). Free or nonesteriied fatty acids in maternal plasma may be transferred to the fetus via facilitated diusion or ater liberation of fatty acids from triglycerides by trophoblastic lipases (Gil-SGnchez, 2012). Generally speaking, lipolytic activity is augmented in pregnancy, and fatty acid levels are increased in nonobese women during the third trimester (Diderholm, 2005).

fetal-growth rates during these three phases are 5 g/d at 15 weeks' gestation, 15 to 20 g/d at 24 weeks', and 30 to 35 g/d at 34 weeks' (Williams, 1982). As shown in Figre 44-1, the velocity of fetal growth varies considerably.

Fetal development is determined by maternal provision of substrate and placental transfer of these, whereas fetal growth potentil is governed by the genome. The precise cellular and molecular mechanisms by which normal fetal growth ensues are incompletely understood. That said, considerable evidence support an important role for insulin and insulin-like growth factors (IGFs) in regulation offetal growth and weight gain (Luo, 2012). hese growth factors are produced by virtually all fetal organs and are potent stimulators of cell division and diferentiation.

Other hormones implicated in fetal growth have been identified, particularly hormones derived from adipose tissue. These hormones are known broadly as adipokines and include leptin, the protein product of the obesiy gene. Fetal leptin concentrations rise during gestation, and they correlate both with birthweight and with neonatal fat mass (Brifa, 2015; Logan, 2017; Simpson, 2017). Other adipokines possibly involved include adiponectin, ghrelin, follistatin, resistin, visfatin, vaspin, omentin-I, apelin, and chemerin.

Fetal growth is also dependent on an adequate supply of nutrients. As discussed in Chapter 7 (p. 138), both excessive and diminished maternal glucose availability afect fetal growth. Reduced maternal glucose levels may result in a lower birthweight. Still, growth-restricted neonates do not typically show pathologically low glucose concentrations in cord blood (Pardi, 2006). Fetal-growth restriction in response to glucose deprivation generally results only after long-term severe maternal caloric deprivation (Lechtig, 1975).

Conversely, excessive glycemia produces macrosomia. Varying levels of glucose afect fetal growth via insulin and its associated IGFs. he Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study Cooperative Research Group (2008) found that elevated cord C-peptide levels, which relect fetal hyperinsulinemia, are associated with greater birthweight. his relationship was noted even in women with maternal glucose

Independent of prepregnancy body mass index (BMI), higher free fatty acid levels during the latter half of pregnancy correlate with birthweight (Crume, 2015). Other studies have correlated mater nal triglyceride levels with birthweight (Di Cianni, 2005; Vrijkotte, 2011). Greater intake of certain fatty acids, particularly omega-3, is also associated with greater birthweight (Calabuig-Navarro, 2016).

Placental fatty acid metabolism and transfer may be dysregulated in fetal-growth restriction and in maternal conditions associated with fetal overgrowth. For example, levels of endothelial lipase are reduced with deicient fetal growth, and this enzyme is overexpressed in placentas of women with diabetes (Gauster, 2007, 2011). Others have reported that diabetes and obesity are associated with altered placental lipid-transport gene expression (Radaelli, 2009). Obesity is also linked with greater expression of fatty acid binding/transport proteins within the trophoblast (Myatt, 2016; Scifres, 2011). he end result of these alterations is an abnormal accumulation of lipids that can result in pathological placental inlammation and dysfunction (Calabuig-Navarro, 2016; Myatt, 2016; Yang, 2016).

mino acids undergo active transport, which explains the normally higher fetal concentrations compared with maternal levels. In growth restriction, this pattern is reversed. One possible mechanism is altered transport of these amino acids. Remember, amino acids that reach the fetus must first cross the microvillus membrane at the maternal interface. Amino acids then traverse the trophoblastic cell, and inally cross the basal membrane into fetal blood (Chap. 5, p. 90). In human placentas, fetal growth correlates with peroxisome proliferator activator receptor gamma (PPAR-,) activity, which governs placental regulation of L-type amino acid (A T) receptors 1 and 2 (Chen, 2015b). Additional modulation is from rap amycin complex (mTORC) 1 and 2 receptors (Rosario, 2013). Placental mTORC activity is reduced in fetal-growth restriction. Others have shown that increasing birthweight and maternal BMI are linked to expression and activity of particular aminoacid transporters at the microvillus membrane (Jansson, 2013).

Normative data for fetal growth based on birthweight vary with ethnicity and geographic region. Accordingly, researchers have developed fetal-growth curves using various populations and geographic locations throughout the United States (Brenner, 1976; Ott, 1993; Overpeck, 1999; Williams, 1975). Because

TABLE 4-1. 2011 Gestational Age Birthweight (g) Percentiles for 3,252,01e1 Singleton Live Births in the United States (Duryea, 2014). hese current curves plot birthweight against a gestational age based on n obsteical estimate, formed in part by sonography. hese curves are thought to be more accurate and reflect more precise pregnancy dating. Older curves used gestational age derived rom a last menstrual period. Comparing birthweights rom 1991 to data from 2011, the more recent growth curves indicate that the earlier assessments overestimated birthweihts in the ase of preterm birth. In particular, the 50th percentile for fetal growth that previ ously corresponded to 31 to 32 weeks' gestation now corresponds to 33 to 34 weeks' when improved obstetrical dating is used.

The curves by Alexander (1996) and Duryea (2014) and their associates are most accurately termed a population rerence, rather than a standard. A population reference incorporates pregnancies of varying risks, along with the resulting outcomes, both normal and abnormal. In contrast, a stanard incorporates normal 1414 1573 2053 2579 2861 pregnancies with normal outcomes. Because population refer 34 1632 1793 2296 2846 3093 ences include preterm births, which are more likely to be growth 1871 2030 2549 3119 3345 restricted, it has been argued that the associated birthweight data 36 2117 2270 2797 3380 3594 overestimate deficient fetal growth (Mayer, 2013; Zhang, 2010).

37 2353 2500 3025 361n2 381n8 One recent project sought to define regional standards in health and socioeconomic conditions. Growth trajectories from the International Fetal and Newborn Growth Consortium for these curves are based on speciic ethnic or regional groups, they do not represent the entire population.

To address this, birthweights such as those shown in Table 4-1 are derived nationwide in the United States. Shown in Figure 4-2 are growth curves rom more thn 3.2 million mothers with singleton livebon neonates in the United States during 1991 and 2011 5,000 -By last menstrual period 4,000 impaired growth. hus, they cannot be used to identiy the fetus that fails to achieve an expected size but whose birthweight is above the 21st Century-INTERGROWTH 21 were similar in these eight: China, India, Kenya, Brazil, Oman, Italy, the United Kingdom, and the United States (Villar, 2014). However, an international standard based on the healthiest women is of questionable value (Hanson, 2015).

Most of what is known regarding normal and abnormal human fetal growth is actually based on birthweights that are assembled as references for fetal growth at particular gestational ages.

his is problematic, however, because birth weight does not deine the rate of fetal growth.

Indeed, such birthweight curves reveal com- the of � the 10th percentile. For example, a fetus with 3,000 ) a birthweight in the 40th percentile may not have achieved its genomic growth potential for a birthweight in the 80th percentile.

: 2,000 m The rate or velociy of fetal growth can be estimated by serial sonographic anthropometry. For example, Milovanovic (2012) 1,000 demonstrated that the growth rate of intrin borns (those below the 10th percentile) 22 24 26 28 30 32 34 36 38 40 42 44 approximates that of appropriate-for-gestaGestational age (weeks) tional-age neonates. However, diminished growth velocity may be linked to perinatal

FIGURE 44-2 Fetal-growth curves for births in the United States in 2011. Curves vary depending on whether gestational age was calculated from the last menstrual changes that are independent of birthweight.

period or from an improved obstetrical estimate, derived in part using sonography. (Modified with permission from Duryea EL, Hawkins JS, Mcintire DO, et al: A revised Recently, Sovio and colleageus (2015) demonbirth weight reference for the United States. Obstet Gynecol. 2014 Jul;124(1 ):16-22.) strated that growth velocity of the abdominal circumference in the lowest decile distinguishes SGA newborns who sufer increased morbidity. Conversely, an excessive fetalgrowth velocity, particularly ofthe abdominal circumferencewhich may be correlated with increased hepatic blood low-is associated with an overgrown neonate (American College of Obstetricians and Gynecologists, 2016a).

Several conditions or disorders can adversely afect the normal growth of a fetus. It is important clinically to distinguish between fetal-growth restriction and constitutional low birth weight. u

Fetal-Growth Disorders 100 -Morbidity 175 90 -Mortality) 150U) 80D �S s· C 70 > 0 100g0 60 30 0-E �� 75 50 -30 � u 0S 20 0E 259J) 10 >1010987654321<1 Birthweightpercentile FIGURE 44-3 Relationship between birthweight percentile and perinatal mortality and morbidity rates in 1560 small-for-gestationalage fetuses. A progressive increase in both mortality and morbidity rates is observed as birthweight percentile decreases.. (Data from Manning, 1995.) • Symmetrical versus Asymmetrical Growth Restriction Campbell and Thoms (1977) described the use of the sonographically determined head-to-abdomen circumerence ratio (HCIA) to diferentiate growth-restricted fetuses. Those who were symmetrical were proportionately small, and those who were asymmetrical had disproportionately lagging abdominal growth compared with head growth. The onset or etiology of a particular fetal insult is hypothetically linked to either type of growth restriction. In the instance ofsymmetricalgrowth restriction, an early insult could result in a relative decrease in cell number and size. For example, early global insults such as those from chemical exposure, viral infection, or cellular maldevelopment with aneuploidy may cause a proportionate reduction of both head and body size. Asymmetricalgrowth restriction might follow a later pregnancy insult such as placental insuiciency from hypertension. In this variation, resultant diminished glucose transfer and hepatic storage would primarily afect cell size and not number. Thereby, fetal abdominal circumferencewhich relects liver size-would be reduced. Brain Sparing Such somatic growth restriction is proposed to result from preferential shunting of oxygen and nutrients to the brain. This allows normal brain and head growth, that is-brain sparing. Accordingly, the ratio of brain weight to liver weight during the last 12 weeks-usually about 3 to I-may be increased to 5 to 1 or more in severely growth-restricted infants. Because of brainsparing efects, asymmetrical fetuses were thought to be preferentially protected from the full efects ofgrowth restriction. Considerable evidence has since accrued that fetal growth patterns are much more complex. For example, fetuses with 847 .�..,40

Lubchenco and coworkers (1963) published detailed comparisons of gestational ages with birthweights to derive norms for expected fetal size at a given gestational week. Battaglia and Lubchenco (1967) then classiied smalor-gestational-age neonates as those whose weights were below the 10th percentile for their gestational age. Low-birthweight newborns who are small for gestational age are often designated as having etalgrowth restriction. Such infants were shown to be at increased risk for neonatal death. For example, the mortality rate of SGA neonates born at 38 weeks was 1 percent compared with 0.2 percent in those with appropriate birthweights.

Importantly, manyneonates with birthweights < 10th percentile are not pathologically growth restricted, but instead are small simply because of normal biological factors. s many as 70 percent ofsuch SGA infants have normal outcomes and are thought to be appropriately grown when maternal ethnic group, parity, weight, and height are considered (Unterscheider, 2015). These small but normal infants also do not show evidence ofthe postnatal metabolic derangements commonly associated with deficient fetal growth. Moreover, intrinsically SGA newborns remain significantly smaller during surveillance to 2 years compared with appropriate-for-gestational age neonates, but they do not show diferences in measures ofmetabolic risk (Milovanovic, 2012).

Because of these disparities, other classifications have been developed. Usher and McLean (1969) suggested that fetal growth standards should be based on mean weights-for-age, with normal limits deined by ±2 standard deviations. This definition would limit SGA infants to 3 percent of births instead of 10 percent. In a population-based analysis of 122,754 births at Parkland Hospital, McIntire and colleagues (1999) showed this definition to be clinically meaningful. Also, as shown in

Figure 44-3, most adverse outcomes are in newborns smaller than the 3rd percentile. The importance ofthis cut-ofhas been independently confirmed in a prospective study by Unterscheider and colleagues (2013a).

More recently, individual or customized fetal-growth potential is proposed to replace a population-based threshold. In this model, a fetus that deviates from its individual optimal size at a given gestational age is considered either overgrown or growth restricted (Chiossi, 2017). Such optimal projections are based on maternal race or ethnicity. But, the superiority of customized growth curves has not been established (Chiossi, 2017; Costantine, 2013; Grobman, 2013; Zhang, 2011).

aneuploidy typically have disproportionately large head sizes and thus are asymmetricaLy growth restricted, which is contrary to contemporaneous thinking (Nicolaides, 1991). Moreover, most preterm neonates with growth restriction due to preeclampsia and associated utero placental insuiciency are found to have more symmetrical growth impairment-again, a departure from accepted principles (Salaia, 1995).

More evidence of the complexity of growth patterns was presented by Dashe and associates (2000). These investigators analyzed 8722 consecutive liveborn singletons who had undergone sonographic examination within 4 weeks of delivery. Although only 20 percent of growth-restricted fetuses demonstrated sonographic head-to-abdomen asymmetry, these fetuses were at greater risk for intrapartum and neonatal complications. Symmetrically growth-restricted fetuses were not at increased risk for adverse outcomes compared with those appropriately grown. These investigators concluded that asymmetrical fetalgrowth restriction represented signiicantly disordered growth, whereas symmetrical growth restriction more likely represented normal, genetically determined small stature.

Other data further challenge the concept of brain sparing.

Roza and associates (2008) found that fetuses with circulatory redistribution-brain sparing-had a higher incidence of later behavioral problems. In another study, evidence of brain sparing was found in half of 62 growth-restricted fetuses with birthweights < 10th percentile and who showed abnormal middle cerebral artery Doppler low studies (Figueras, 2011). Compared with controls, these neonates had significantly lower neurobehavioral scores in multiple areas, suggesting profound brain injury. Zhu and coworkers (2016) prospectively compared late-onset growth restriction in 14 fetuses with that in 26 non-growth-restricted fetuses using magnetic resonance imaging to analyze hemodynamic flow. Despite the concept of brain sparing, growth-restricted infants had significantly smaller brains than controls. he complex efects of such insults-with respect to timing and severity-on brain structure, connectivity, and neurobehavioral outcomes have been recently reviewed by Miller and colleagues (2016).

Fetal-growth restriction is one of the "major obstetrical syndromes" associated with defects in early placentation (Brosens, 2015). Rogers and coworkers (1999) concluded that implantation-site disorders may be both a cause and consequence of hypoperfusion at the placental site. This comports with the association of certain placental angiogenic factors with pregnancy hypertensive disorders (Chap. 40, p. 716). Thus, it may be that placentas from pregnancies complicated by hypertension elaborate these angiogenic factors in response to placental-site hypoperfusion, whereas pregnancies complicated by fetal-growth restriction without hypertension do not Qeyabalan, 2008).

Mechanisms leading to abnormal trophoblastic invasion are likely multifactorial, and both vascular and immunological etiologies have been proposed. For example, atriaL natriuretic peptide converting enzyme, also known as corin, plays a critical role in trophoblastic invasion and remodeling of the uterine spiral arteries (Cui, 2012). hese processes are impaired in corin-deficient mice, which also develop evidence of preeclampsia. Moreover, mutations in the gene for corin have been reported in women with preeclampsia (Chen, 2015a).

Several immunological abnormalities are associated with fetalgrowth restriction. This raises the prospect of maternal rejection of ther" paternal semiallograft." Rudzinski and colleagues (2013) studied C4d, a component of complement that is associated with humoral rejection of transplanted tissues. They found this to be highly associated with chronic villitis-88 percent of cases versus only 5 percent of controls-and with reduced placental weight. In a study of 10,204 placentas, chronic villitis was associated with placental hypoperfusion, fetal acidemia, and fetal-growth restriction and its sequelae (Greer, 2012). im and coworkers (2015) extensively reviewed chronic inflammatory placental lesions and their association with fetal-growth restriction, preeclampsia, and preterm birth.

Several short-term and long-term adverse sequelae are linked with fetal-growth restriction. First, perinatal morbidity and mortality rates are substantive (see Fig. 44-3). Rates of stillbirth and adverse neonatal outcomes that include birth asphyxia, meconium aspiration, hypoglycemia, and hypothermia are all increased, as is the prevalence of abnormal neurological development. This is true for both term and preterm growth-restricted newborns. In one analysis of nearly 3000 newborns born before 27 weeks' gestation, those weighing < 10th percentile had a nearly fourfold higher risk of neonatal death or neurodevelopmental impairment and a 2.6-fold increased risk of cerebral palsy compared with non-SGA neonates (De Jesus, 2013). In another analysis of more than 91,000 uncomplicated pregnancies, newborns with weights < 5th percentile had a higher risk of low 5-minute Apgar score, respiratory distress, necrotizing enterocolitis, and neonatal sepsis than appropriate-weight neonates. The risks of stillbirth and neonatal death were sixfold and fourfold higher, respectively .\1endez-Figueroa, 2016).

The most severely growth-impaired newborns also have the worst outcomes. In one study of more that 44,561 neonates, only 14 percent of those weighing < 1st percentile at birth survived to discharge (Griin, 2015). For those infants who survive, the risks of adverse neurodevelopmental outcomes are substantial, especially for growth-impaired fetuses with either brain sparing or a major birth defect (Meher, 2015; Nelson, 2015b). Poor motor, cognitive, language and attention, and behavioral outcomes in growth-restricted newborns unfortunately persist into early childhood and adolescence (Baschat, 2014; Levine, 2015; Rogne, 2015).

Barker (1992) hypothesized that aduLt mortality and morbidity are related to fetal and infant health. This includes both under-and overgrowth. In the context of fetal-growth restriction, numerous reports describe a relationship between suboptimal fetal nutrition and an increased risk of subsequent adult hypertension, atherosclerosis, type 2 diabetes, and metabolic derangement (Burton, 2016; J ornayvaz, 2016). he degree to which low birthweight mediates adult disease is controversial, as weight gain in early life also appears important (Breij, 2014;

Kerhof, 2012; McCloskey, 2016).

Mounting evidence suggests that fetal-growth restriction may afect organ development, particularly that of the heart. Individuals with low birthweight demonstrate cardiac structural changes and dysfunction persisting through childhood, adolescence, and adulthood. In one study, 80 infants who were born SGA before 34 weeks' gestation were compared at 6 months with 80 normally grown children (Cruz-Lemini, 2016). The heart in the SGA children had a more globular ventricle that resulted in systolic and diastolic dysfunction. In another study, echocardiography in 418 adolescents showed that low birthweight was associated with a thicker let ventricular posterior wall (Hietalampi, 2012). In their review, Cohen and colleagues (2016) concluded, however, that these findings have unclear long-term signiicance.

Deficient fetal growth is also associated with postnatal structural and functional renal changes. In a review by Luyckx and Brenner (2015), birthweight abnormalities were evaluated for linkage with disordered nephrogenesis, renal dysfunction, chronic kidney disease, and hypertension. Both low and high birthweight, as well as maternal obesity and gestational diabetes, afect in-utero development of the kidney and its health into adulthood. However, other variables that include childhood nutrition, acute kidney injury, excessive childhood weight gain, and obesity also worsen long-term renal function.

Particularly in women with diabetes and elevated cord blood levels of IGF-1, fetal overgrowth is associated with greater neonatal fat mass and morphological heart changes. Pedersen (1954) irst proposed that hyperglycemia leads to fetal hyperinsulinemia and fetal overgrowth. This has been extended to organ dysmorphia, for example, increased interventricular septal thickness in neonates of mothers with gestational diabetes (nan, 2011; Garcia-Flores, 2011). he cardiopulmonary vasculature is also adversely afected by diabetes in pregnancy. In 3277 cases of persistent pulmonary hypertension of the newborn (PPHN), maternal obesity, diabetes, and both deficient and excessive fetal growth were independent risk factors (Steurer, 2017). Longterm consequences of fetal overgrowth from obesity and diabetes are discussed in Chapters 48 (p. 941) and 57 (p. 1097).

Numerous reports have described accelerated fetal pulmonary maturation in complicated pregnancies associated with growth restriction (Perelman, 1985). One possible explanation is that the fetus responds to a stressed environment by augmenting adrenal glucocorticoid secretion, which leads to accelerated fetal lung maturation (Laatikainen, 1988). Although this concept pervades modern perinatal thining, evidence to support it is negligible.

To examine this hypothesis, Owen and associates (1990) analyzed perinatal outcomes in 178 women delivered because of hypertension. hey compared these with outcomes in newborns of 159 women delivered because of spontaneous preterm labor or ruptured membranes. They concluded that a "stressed" pregnancy did not confer an appreciable survival advantage. Similar findings were described by Friedman and colleagues (1995) in women with severe preeclampsia. Two studies from Parkland Hospital also substantiate that the preterm infant accrues no apparent advantages from fetal-growth restriction (McIntire, 1999; Tyson, 1995).

Risk factors for impaired fetal growth include potential abnormalities in the mother, fetus, and placenta. hese three "compartments" are depicted in Figure 44-4. Some of these factors are known causes of fetal-growth restriction and may afect more than one compartment. For instance, cytomegalovirus infections can afect the fetus directly. In contrast, bacterial infections such as tuberculosis may have signiicant maternal efects that lead to poor fetal growth. Similarly, malaria, a protozoal infection, is a recognized cause of fetal-growth restriction (Briand, 2016). Importantly, many causes of diminished fetal growth are prospectively considered risk factors, because impaired fetal growth is not consistent in all afected women.

It is axiomatic that small women typically have smaller newborns. As discussed subsequently, both prepregnancy weight and gestational weight gain modulate this risk. Durie and colleagues (2011) showed that the risk of delivering an SGA neonate was highest among underweight women who gained less weight than recommended by the Institute of Medicine (Chap. 9, p. 166). Also, both maternal and paternal size inluences birthweight. In a Swedish study of 137,538 term births, it was estimated that the maternal and paternal birthweights explained 6 and 3 percent of variance in birthweight, respectively (Mattsson, 2013).

In the study by Durie (2011) cited above, gestational weight gain during the second and third trimesters that was less than

FIGURE 44-4 Risk factors and causes of impaired fetal growth centering on the mother, her fetus, and the placenta.

that recommended by the Institute of Medicine was associated with SGA neonates in women of all weight categories except class II or III obesity. Conversely, excessive gestational weight gain was associated with an overgrown newborn in all weight categories (Blackwell, 2016).

As perhaps expected, eating disorders are linked with significantly higher risks for low birthweight and preterm birth (Micali, 2016). Marked weight gain restriction ater midpregnancy should not be encouraged even in obese women (Chap. 48, p. 941). Even so, it appears that food restriction to < 1500 kcal/d adversely afects fetal growth minimally (Lechtig, 1975). The best documented efect of famine on fetal growth was in the Hunger Winter of 1944 in Holland. For 6 months, the German occupation army restricted dietary intake to 500 kcal/ d for civilians, including pregnant women. This resulted in an average birthweight decline of only 250 g (Stein, 1975).

It is unclear whether undernourished women may beneit from micronutrient supplementation. In one study, almost 32,000 Indonesian women were randomly assigned to receive micronutrient supplementation or only iron and folate tablets (Prado, 2012). Ofspring of those receiving the supplement had lower risks of early infant mortality and low birthweight and had improved childhood motor and cognitive abilities. Conversely, Liu and coworkers (2013) randomly assigned 18,775 nulliparas to folic acid alone; folic acid and iron; or folic acid, iron, and 13 other micronutrients. Folic acid and iron, with or without the additional micro nutrients, resulted in a 30-percent reduction in risk of third-trimester anemia. But, supplementation did not afect other maternal or neonatal outcomes. A Cochrane database review of 19 trials involving 138,538 women concluded that supplementation of iron and folic acid improved birth outcomes, including lower risks of low birthweight and SGA (Haider, 2017). he importance of antenatal vitamins and trace metals is further discussed in Chapter 9 (p. 168).

Exercise in pregnancy may be beneficial for optimal fetal growth. One metaanalysis of28 studies involving 5322 women concluded that exercise reduces the risk of fetal overgrowth without raising the risk of poor growth (Wiebe, 2015). Another metaanalysis concluded that aerobic exercise did not result in low-birthweight neonates (Di Mascio, 2016).

The efect of social deprivation on birthweight is interconnected with lifestyle factors such as smoking, alcohol or other substance abuse, and poor nutrition. With appropriate modiying interventions, women with psychosocial factors were signiicantly less likely to deliver a low-birthweight infant and also had fewer preterm births and other pregnancy complications (Coker, 2012).

Women who are immigrants may be at particular risk for poor fetal growth. In one study of 56,443 singleton pregnancies in Rotterdam, social deprivation was associated with adverse perinatal outcomes that included SGA newborns (Poeran, 2013). That said, a similar linkage was not found in socially deprived women of non-Western origin. The efect of immigration, however, is complex and dependent on the population studied (Howell, 2017; Sanchez-Vaznaugh, 2016).

Especially when complicated by superimposed preeclampsia, chronic vascular disease commonly causes growth restriction (Chap. 50, p. 980). In a study of more than 2000 women, vascular disease as evidenced by abnormal uterine artery Doppler velocimetry early in pregnancy was associated with higher rates of preeclampsia, SGA neonates, and delivery before 34 weeks (Groom, 2009). Using Washington state birth certiicate data, Leary and colleagues (2012) found that maternal ischemic heart disease was linked to SGA infants in 25 percent of 186 births. Roos-Hesselink and coworkers (2013) described similar pregnancy outcomes in 25 women with ischemic heart disease.

Chronic renal insuiciency is frequently associated with underlying hypertension and vascular disease. Nephropathies are commonly accompanied by restricted fetal growth (Cunningham, 1990; Feng, 2015; Saliem, 2016). hese relationships are considered further in Chapter 53 (p. 1034).

Fetal-growth restriction in the newborns of women with diabetes may be related to congenital malformations or may follow substrate deprivation from advanced maternal vascular disease (Chap. 57, p. 1100). Also, the likelihood of restricted growth increases with worsening White classification, particularly nephropathy (Klemetti, 2016). hat said, the prevalence of serious vascular disease associated with diabetes in pregnancy is low, and the primary efect of overt diabetes, especially type 1, is fetal overrowth. For example, in a prospective study of 682 consecutive pregnancies complicated by diabetes, women with type 1 diabetes were significantly more likely than women with type 2 diabetes to have a neonate weighing above the 90th and 97.7th percentiles (Murphy, 2011). Additionally, women with type 1 diabetes were significantly less likely to deliver an SGA newborn. In a recent study of 375 term singleton pregnancies complicated by type 1 diabetes, the risk of fetal overgrowth correlated with rising third-trimester glycemic values (C yganek, 2017) . Nearly a fourth of neonates were macrosomic. And, third-trimester hemoglobin Al c and fasting glucose values were independent predictors for the risk of macrosomia.

Conditions associated with chronic uteroplacental hypoxia include preeclampsia, chronic hypertension, asthma, maternal cyanotic heart disease, smoking, and high altitude. When exposed to a chronically hypoxic environment, some fetuses have signiicantly reduced birthweight. In more than 1.8 million births in Austria, the birthweight declined 150 g for each 1000meter rise in altitude (Waldhoer, 2015). In 63,620 Peruvian live births, the mean birthweight was significantly decreased at higher compared with lower altitudes-3065 g ± 475 g versus 3280 g ± 525 g (Gonzales, 2009). In this study, the rate of birth weights <2500 g was 6.2 percent at low altitudes, and it was 9.2 percent at high altitudes. In contrast, the rate of birthweights >4000 g was 6.3 percent at low altitudes and 1.6 percent at high altitudes.

In most cases, maternal anemia does not restrict fetal growth. Exceptions include sickle-cell disease and some other inherited anemias (Desai, 2017; Thame, 2016). Importantly, curtailed maternal blood-volume expansion is linked to fetal-growth restriction (de Haas, 2017; Stott, 2017). This is further discussed in Chapter 40 (p. 718).

Adverse obstetrical outcomes including fetal-growth restriction have been associated with three species of antiphospholipid antibodies: anticardiolipin antibodies, lupus anticoagulant, and anti-32 gycoprotein-I antibodies. Mechanistically, a "wohit" hypothesis suggests that initial endothelial damage is then followed by intervillous placental thrombosis. More specifically, oxidative damage to certain membrane proteins such as 32 glycoprotein-I is followed by antiphospholipid antibody binding, which leads to immune complex formation and ultimately to thrombosis (Giannakopoulos, 2013). his syndrome is considered in detail in Chapters 52 (p. 1008) and 59 (p. 1143). Pregnancy outcomes in women with these antibodies may be poor and include fetal-growth restriction and fetal demise (Cervera, 2015). he primary autoantibody that predicts obstetrical antiphospholipid syndrome appears to be lupus anticoagulant (Yelnik,r2016).

It is controversial whether pregnancies in women with prior infertility with or without treatment have an increased risk of SGA newborns (Zhu, 2007). Dickey and colleagues (2016) compared birthweight curves for singletons conceived by in vitro fertilization to the birthweight curves of Duryea (2014), described on page 846. hey found no reduction in fetal growth. Kondapalli and Perales-Puchalt (2013) reviewed possible links between low birthweight and infertility with its various interventions and concluded that any association remains unexplained for singletons.

Placental, Cord, and Uterine Abnormalities

Several placental abnormalities may cause poor fetal growth. These are discussed further throughout Chapter 6 and include chronic placental abruption, extensive chorioangioma, velamentous cord insertion, placenta previa, and umbilical artery thrombosis. Growth failure in these cases is presumed secondary to uteroplacental insuiciency. Abnormal placental implantation leading to endothelial dysfunction may also limit fetal growth (Brosens, 2015). This pathology is implicated in pregnancies complicated by preeclampsia (Chap. 40, p. 714). If the placenta is implanted outside the uterus, the fetus is usually growth restricted (Chap. 19, p. 383). Finally, some uterine malformations have been linked to impaired fetal growth (Chap. 3, p. 44).

Pregnancy with two or more fetuses is more likely to be complicated by diminished growth of one or more fetuses compared with that ofnormal singletons. This is illustrated in Figure 44-5 and discussed in Chapter 45 (p. 872).

Drugs with Teratogenic and Fetal Effects

Several drugs and chemicals are capable oflimiting fetal growth. Some are teratogenic and afect the fetus before organogenesis is ::,1500

FIGURE 44-5 Birthweight and gestational age relationships in multifetal gestations without malformations delivered at Parkland Hospital.

complete. Some exert-or continue to exert-fetal efects after embryogenesis ends at 8 weeks. Many ofthese are considered in detail in Chapter 12, and examples include anticonvulsants and antineoplastic agents. Cigarette smoking, opiates and related drugs, alcohol, and cocaine may also cause growth restriction, either primarily or by decreasing maternal food intake. he link with cafeine use and fetal-growth restriction remains speculative (American College of Obstetricians and Gynecologists, 2016b). In contrast, Cyganek and colleagues (2014) studied growth restriction in pregnancies complicated by renal and liver transplants and concluded that common immunosuppressive drugs-prednisone, azathioprine, cyclosporine A, and tacrolimus-did not significantly afect fetal-growth rates.

Viral, bacterial, protozoan, and spirochetal infections have been implicated in up to 5 percent of fetal-growth restriction cases and are discussed throughout Chapters 64 and 65. The best known of these are rubela and cytomegalovirus inection. Both promote calcifications in the fetus that are associated with cell death, and infection earlier in pregnancy correlates with worse outcomes. Toda and colleagues (2015) described a Vietnamese epidemic in which 39 percent of 292 term newborns with congenital rubella syndrome were low birthweight. In one study of 238 primary cytomegalovirus infections, no severe cases were observed when infection occurred after 14 weeks' gestation (Picone, 2013). hese investigators later identified sonographic findings in 30 of 69 cases of congenital infection, and growth restriction was noted in 30 percent of these 30 cases (Picone, 2014).

Tuberculosis and syphilis have also both been associated with poor fetal growth. Both extrapulmonary and pulmonary tuberculosis are linked with low birthweight (Chap. 51, p. 995). Sobhy (2017) analyzed 13 studies that included a total of3384 women with active tuberculosis. The odds ratio was 1.7 for low birthweight. The etiology is uncertain, however, the adverse efects on maternal health, compounded by efects of poor nutrition and poverty, are important Gana, 2012). Congenital syphilis is more common, and paradoxically, the placenta is almost always larger and heavier due to edema and perivascular inflammation (Chap. 65, p. 1237). Congenital syphilis is strongly linked with preterm birth and thus low-birthweight newborns (Sheield, 2002).

Toxoplasma gondii can also cause congenital infection, and Paquet and Yudin (2013) describe its classic association with fetal-growth restriction. Capobiango (2014) described 31 Brazilian pregnancies complicated by congenital toxoplasmosis. Only 13 percent were treated antepartum for toxoplasmosis, and low birthweight complicated nearly 40 percent of all the pregnancies. Congenital maaria also causes low birthweight and poor fetal growth. Briand and colleagues (2016) emphasize the importance of prophylaxis early in pregnancy for women at risk.

In a study of more than 13,000 fetuses with major structural anomalies, 22 percent had accompanying growth restriction (Khoury, 1988). In one study of 111 pregnancies complicated by fetal gastroschisis, a third had birthweights < 10th percentile (Nelson, 20 15a). As a general rule, the more severe the malformation, the more likely it is that the fetus will be SGA. This is especially evident in fetuses with chromosomal abnormalities or those with serious cardiovascular malformations.

Depending on which chromosome is redundant, fetuses with autosomal trisomies may display poor fetal growth. For example, in trisomy 21, fetal-growth restriction is generally mild. By contrast, fetal growth in trisomy 18 is virtually always significantly limited. he crown-rump length in fetuses with trisomy 18 and 13, unlike that with trisomy 21, is typically shorter than expected (Bahado-Singh, 1997; Schemmer, 1997). By the second trimester, long-bone measurements usually are below the 3rd percentile. In one group of 174 children with trisomy 13, the mean birthweight with trisomy 13 was 2500 g, and in 254 children with trisomy 18, it was 1800 g (Nelson, 2016).

Poor fetal growth also complicates Turner syndrome, and the severity correlates with increasing haploinsuiciency of the short arm of the X chromosome (Fiot, 2016). In contrast, poor growth is not characteristic of an increased number of X chromosomes (Ottesen, 2010; Wigby, 2016). As discussed in Chapter 13 (p. 263), aneuploidic patches in the placentaconined placental mosaicism (CPM)-is a recognized cause of fetal-growth restriction. Evidence suggests that aneuploidy afecting both the cytotrophoblast and mesenchymal core of the placenta, which is type 3 CPM, is associated with fetalgrowth restriction (Toutain, 2010).

First-trimester prenatal programs that screen for fetal aneuploidy'may incidentally identiy pregnancies at risk for fetalgrowth restriction unrelated to karyotype. In their analysis of 8012 women, the risk for growth restriction was higher in eukaryotic fetuses with extremely low free 3-human chorionic gonadotropin (3-hCG) and pregnancy-associated plasma protein-A (PAPP-A) levels (Krantz, 2004). From her review, Dugof (2010) concluded that a low PAPP-A level is strongly associated with poor fetal growth, but studies of free 3-hCG are conflicting.

Second-trimester analytes, including elevated alpha-fetoprotein and inhibin A levels and low unconjugated serum estriol concentrations, are significantly associated with birthweight below the 5th percentile. An even greater risk of poor growth is linked with certain combinations of these analytes. Still, these markers are poor screening tools for complications such as fetalgrowth restriction due to low sensitivity and positive-predictive values (Dugof, 2010). Nuchal translucency is also not predictive of fetal-growth restriction. he role of all these markers in aneuploidy screening is discussed in Chapter 14 (p. 281).

Identification of the inappropriately growing fetus remains a challenge. Eary establishment of gestational age, ascertainment of maternal weight gain, and careful measurement of uterine fundal growth throughout pregnancy will identiy many cases of abnormal fetal growth in low-risk women. Risk factors, including aprior growth-restricted etus, raise the recurrence risk to nearly 20 percent (American College of Obstetricians and Gynecologists, 2015). In women with risk factors, serial sonographic evaluation is considered. Although examination frequency varies depending on indications, an initial early dating examination followed by an examination at 32 to 34 weeks, or when otherwise clinically indicated, will identiy many growthrestricted fetuses. Even so, deinitive diagnosis frequently cannot be made until delivery.

According to one systematic review, insuicient evidence supports the utility of fundal height measurement to detect fetalgrowth restriction (Robert Peter, 2015). Nonetheless, carefully performed serial fundal height measurements are recommended as a simple, safe, inexpensive, and reasonably accurate screening method to detect growth-restricted fetuses. As a screening tool, its principal drawback is imprecision. Haragan and coworkers (2015) reported sensitivities of 71 and 43 percent for detecting excessive or deficient fetal growth. Specificities were 85 and 66 percent, respectively.

he method used by most for fundal height measurement is described in Chapter 9 (p. 164). Between 18 and 30 weeks' gestation, the uterine fundal height in centimeters coincides within 2 weeks of gestational age. Thus, if the measurement is more than 2 to 3 cm from the expected height, inappropriate fetal growth is suspected and sonography is considered.

One supporting point for routine sonographic evaluation of all pregnancies is the opportunity to diagnose growth restriction. Typically, such routine screening incorporates an early initial sonographic examination-usually at 16 to 20 weeks' gestation. Increasingly, a first-trimester examination is added to establish gestational age and identiy anomalies. Some then recommend repeat sonographic evaluation at 32 to 34 weeks to evaluate fetal growth.

First-trimester sonography has limited accuracy to predict SGA newborns. For example, Croverro and associates (2017) reported detection rates of 35 and 42 percent with false-positive rates of 5 and 10 percent, respectively. From nearly 9000 screened pregnancies, Tuuli and colleagues (2011) concluded

FIGURE 44-6 Correlation of sonographic fetal weight estimation using abdominal circumference (A C) and actual birthweight. (Data from pregnancies managed at Parkland Hospital.) that second-trimester sonography is superior to first-trimester scans for predicting SGA neonates. At Parkland Hospital, we provide midpregnancy sonographic screening examination of all pregnancies. Additional sonographic evaluations of fetal growth are performed as clinically indicated.

With sonography, the most common method for identiying poor fetal growth is estimation of weight using multiple fetal biometrical measurements. Combining head, abdomen, and femur dimensions provides optimum accuracy, whereas little incremental improvement is gained by adding other biometrical measurements (Platz, 2008). Of the dimensions, femur length measurement is technically the easiest and the most reproducible. Biparietal diameter and head circumference measurements are dependent on the plane of section and may also be afected by deformative pressures on the skull. Last, abdominal circumference measurements are more variable. However, these are most frequently abnormal with fetal-growth restriction because soft tissue predominates in this dimension (Fig. 44-6). Shown in Figure 44-7 is an example of a severely growth-restricted newborn.

Some studies have reported a significant predictive value for small abdominal circumference with respect to lagging fetal growth. One study screened nearly 4000 pregnancies using either clinically indicated or universal sonography in the third trimester (Sovio, 2015) . Universal sonography raised the rate of detection of SGA from 20 percent to 57 percent. Importantly, however, the neonatal morbidity rate was increased only if the abdominal circumference growth velocity was in the lowest decile.

Sonographic estimates of fetal weight and actual weight may be discordant by 20 percent or more, leading to both false-positive and false-negative indings. Dashe and associates (2000) studied 8400 live births at Parkland Hospital in which fetal sonographic evaluation had been performed within 4 weeks of delivery. They reported that 30 percent of growth-restricted fetuses were not detected. In a study of 2586 women with low-risk pregnancies randomly assigned to sonography at 32 or 36 weeks' gestation, sensitivity to identiy grow restriction was improved at the later gestational age (Roma, 2015). Still, nearly 40 percent of cases of growth restriction deined as birthweight <3rd percentile were missed. A Cochrane database analysis of 13 trials with 34,980 women concluded that routine late pregnancy ultrasound for a low-risk or an unselected population is not associated with maternal or fetal benefit (Bricker, 2015).

FIGURE 44-7 A 36-week newborn with severe fetal-growth restriction. (Used with permission from Dr. Roxane Holt.)

An association between pathological fetal-growth restriction and oligohydramnios has long been recognized. Petrozella and associates (201r1) reported that decreased amnionic fluid volume between 24 and 34 weeks' gestation was signiicantly associated with malformations. In the absence of malformations, a birthweight < 3rd percentile was seen in 37 percent of pregnancies with oligohydramnios, in 21 percent with borderline amnionic fluid volume, but in only 4 percent with normal volumes. Also, from a recent metaanalysis of 15 studies involving more than 35,000 pregnancies, high-risk pregnancies with oligohydramnios were more likely to be complicated by low birthweight compared with low-risk pregnancies with oligohydramnios (Rabie, 2017). Hypoxia and diminished renal blood low are proposed explanations for oligohydramnios.

With this technique, early changes in placenta-based growth restriction are detected in peripheral vessels such as the umbilical and middle cerebral arteries. Late changes are characterized by reversal of umbilical artery flow and by abnormal flow in the ductus venosus and fetal aortic and pulmonary outlow tracts.

Of these, abnormal umbilical artery Doppler velocimetry indings-characterized by absent or reversed end-diastolic low-are uniquely linked with fetal-growth restriction (Chap. 10, p. 213). hese abnormalities highlight early versus severe growth restriction and represent the transition from fetal adaptation to failure. Thus, persistently absent or reversed end-diastolic flow, such as that shown in Figure 44-8, has long been correlated with hypoxia, acidosis, and fetal death. In one prospective sonographic examination of 1116 fetuses with estimated fetal weights < 10th percentile, only 1.3 percent of fetuses with normal umbilical artery Doppler studies had adverse outcomes compared with 11.5 percent of those with Doppler abnormalities (O'Dwyer, 2014). Unterscheider and associates (2013a) reported that abnormal umbilical artery Doppler velocimetry combined with an estimated fetal weight <3rd percentile is most strongly associated with poor obstetrical outcome.

FIGURE 44-8 Doppler velocity waveforms. A. Normal waveform with normal SID ratio. B. Increased impedance to flow with abnormally elevated SID ratio. C. Absent end-diastolic flow. D. Reversed end-diastolic flow.

Because of these findings, umbilical artery Doppler velocimetry is considered standard in the evaluation and management of the growth-restricted fetus. he American College of Obstetricians and Gynecologists (2015) has concluded that umbilical-artery Doppler velocimetry improves clinical outcomes. It is recommended in the management of fetal-growth restriction as an adjunct to standard surveillance techniques such as nonstress testing and biophysical proile.

Other Doppler assessments are still investigational. Interrogation of the ductus venosus was evaluated in a series of 604 fetuses <33 weeks' gestation who had an abdominal circumference <5th percentile (Baschat, 2007). Ductus venosus Doppler parameters were the primary cardiovascular factor in predicting neonatal outcome. These late changes are felt to relect myocardial deterioration and acidemia, which are major contributors to adverse perinatal and neurological outcome. In another study of 46 growth-restricted fetuses, Doppler flow abnormalities of the aortic valve isthmus preceded those in the ductus venosus by 1 week (Figueras, 2009). In their evaluation of several fetal vessels, Turan and associates (2008) described the seq uence of changes characteristic of mild placental dysfunction, progressive placental dysfunction, and severe, early-onset placental dysfunction. However, Unterscheider and colleagues (2013b) questioned whether a predictable progression of Doppler indices actually exists in fetal-growth restriction.

Fetal-growth restriction prevention ideally begins before conception. Maternal medical conditions, medications, and nutrition are optimized, and smoking cessation is critical. Other risk factors are tailored to the maternal condition, such as antimalarial prophylaxis for women living in endemic areas and correction of nutritional deficiencies. Of note, treatment of mild-to-moderate hypertension does not reduce the incidence of growth-restricted newborns (Chap. 50, p. 981).

Accurate dating is essential during early pregnancy. Serial sonographic evaluations are typically used, but the best interval between assessments has not been clearly established. Given that a prior SGA newborn is associated with other adverse outcomes in a subsequent pregnancy, particularly stillbirth and preterm birth, surveillance during a subsequent pregnancy may be beneicial (Mendez-Figueroa, 2016; Spong, 2012). he American College of Obstetricians and Gynecologists (2015) notes that if growth is normal during a pregnancy following a prior pregnancy complicated by fetal-growth restriction, then Doppler velocimetry and fetal surveillance are not indicated. A recent metaanalysis of 45 trials involving 20,909 women reported that low-dose aspirin initiated prior to 16 weeks' gestation was associated with a significantly lower risk of fetal-growth restriction (Roberge, 2017). Moreover, they described a dose-response efect. he American College of Obstetricians and Gynecologists (2015) has not endorsed prophylaxis with low-dose aspirin for women with a prior growth-restricted fetus.

If fetal-growth restriction is suspected, then eforts are made to conirm the diagnosis, assess fetal condition, and search for possible causes. Early-onset growth restriction is especially problematic. In pregnancies in which fetal anomalies are suspected, patient counseling and prenatal diagnostic testing are indicated (American College of Obstetricians and Gynecologists, 2015).

Ifnoindications for immediate delivery, Ifnoindications for immediate delivery: begin antepartum fetal surveillance: -Antepartum fetal surveillance-BPP, NST, etc. -Regular fetal testing -Umbilical artery Doppler velocimetry weekly -Weekly umbilical artery Doppler velocimetry -Amnionic fluid evaluation weekly -Weekly evaluation of amnionic fluid surveillance until delivery 38 weeks, then deliver delivery 34 weeks, then begin

FIGURE 44-9 Algorithm for management of fetal-growth restriction at Parkland Hospital. BPP = biophysical profile; NST = nonstress test.

One management algorithm is shown in Figure 44-9. In pregnancies with suspected fetal-growth restriction, antepartum fetal surveillance includes periodic Doppler velocimetry of the umbilical arteries in addition to more frequent fetal testing. At Parkland Hospital, for women whose fetus measures ;3rd percentile and has reached a viable age, we encourage hospitalization on our High-Risk Pregnancy Unit. Daily fetal heart rate tracings, weekly Doppler velocimetry, and sonographic assessment of fetal growth every 3 to 4 weeks are initiated. Other modalities of Doppler velocimetry, such as middle cerebral arteries or ductus venosus assessment, are considered experimental. he American College of Obstetricians and Gynecologists (2015) recommends that antenatal corticosteroids for pulmonary maturation be given to pregnancies complicated by fetal-growth restriction and at risk for birth before 34 weeks' gestation.

he timing of delivery is crucial, and the risks of fetal death versus the hazards of preterm birth must be considered. Several multicenter studies address these problems, but unfortunately, none have elucidated the optimal timing of delivery. For the preterm fetus, the only randomized trial of delivery timing is the Growth Restriction Intervention Trial (GRIT) (hornton, 2004). This trial involved 548 women between 24 and 36 weeks' gestation with clinical uncertainty regarding delivery timing. Women were randomly assigned to immediate delivery or to delayed delivery until the situation worsened. he primary outcome was perinatal death or disability after reaching age 2 years. Mortality rates did not difer through 2 years of age. Moreover, children aged 6 to 13 years did not show clinically signiicant diferences between the two groups (Walker, 2011).

In the Trial of Randomized Umbilical and Fetal Flow in Europe (TRUFFLE), ductus venosus Doppler evaluation was compared with fetal heart rate monitoring. There were 310 pregnancies between 26 and 32 weeks' gestation with fetuses displaying an abdominal circumference < 10th percentile and an umbilical artery pulsatility index >95th percentile (Lees, 2015). Delivery timing was determined by the results of three difering antenatal fetal assessment arms that were: short-term fetal heart rate variability, early ductus venosus Doppler velocimetry changes, or late ductus changes. he proportion of children with neuroimpairment at 2 years of age was not diferent among the groups. Of note, only 32 percent of the newborns overall were delivered according to this randomization. Safety net criteria and other maternal/fetal indications prompted these protocol deviations (Visser, 2016). In a post-hoc analysis, these authors concluded that before 32 weeks, delaying delivery until ductus venosus Doppler or fetal heat rate abnormalities occur is likely safe and possibly beneits long-term outcome (Ganzevoort, 2017).

he Disproportionate Intrauterine Growth Intervention Trial at Term (DIGITAT) study examined the delivery timing of growth-restricted fetuses who were 36 weeks' gestation or older. In these 321 women who were randomized to induction or to expectant management, composite neonatal morbidity did not difer, except that neonatal admissions were lower after 38 weeks in a secondary analysis (Boers, 2010, 2012). Another secondary analysis of DIGITAT did not identiy a clear subgroup that beneited from labor induction (T ajik, 2014). Other secondary analyses included assessment of neurodevelopmental and behavioral outcomes at age 2, and these also were similar between the randomized groups (Van Wyk, 2012).

Management of the Near-Term Fetus

As shown in Figure 44-9, delivery of a suspected growthrestricted fetus with normal umbilical artery Doppler velocimetry, normal amnionic luid volume, and reassuring fetal heart rate testing can likely be deferred until 38 weeks' gestation. Said another way, uncertainty regarding the diagnosis should preclude intervention until fetal lung maturity is assured. Expectant management can be guided using antepartum fetal surveillance techniques described in Chapter 17. Most clinicians, however, recommend delivery at 34 weeks or beyond if there is clinically signiicant oligohydramnios. Consensus statements by the Society for Maternal-Fetal Medicine (Spong, 2011) and the American College of Obstetricians and Gynecologists (2017a) are similar. These recommend delivery between 34 and 37 weeks when there are comorbid conditions such as oligohydramnios. With a reassuring fetal heart rate pattern, vaginal delivery is planned. Notably, some of these fetuses do not tolerate labor.

Management of the Fetus Remote from Term

If growth restriction is identiied in an anatomically normal fetus before 34 weeks, and amnionic luid volume and fetal surveillance indings are normal, observation is recommended. Screening for toxoplasmosis, cytomegalovirus infection, rubella, herpes, and other infections is recommended by some. However, we and others have not found this to be productive (Yamamoto, 2013).

As long as interval fetal growth and fetal surveillance test results are normal, pregnancy is allowed to continue until fetal lung maturity is reached (see Fig. 44-9). Reassessment of fetal growth is typically made no sooner than 3 to 4 weeks. Weekly assessment of umbilical artery Doppler velocimetry and amnionic fluid volume is combined with periodic nons tress testing, although the optimal frequency has not been determined. As mentioned, we hospitalize these women in our High-Risk Pregnancy Unit and monitor their fetuses daily. If interval growth, amnionic luid volume, and umbilical artery Doppler velocimetry are normal, then the mother is discharged home and seen intermittently for outpatient surveillance.

With growth restriction remote from term, no speciic treatment ameliorates the condition. For example, evidence does not support diminished activity or bed rest to accelerate growth or improve outcomes. Despite this, many clinicians intuitively advise a program of modiied rest. Nutrient supplementation, attempts at plasma volume expansion, oxygen therapy, antihypertensive drugs, heparin, and aspirin are all inefective (American College of Obstetricians and Gynecologists, 2015).

In most cases diagnosed before term, neither a precise etiology nor a specific therapy is apparent. Management decisions hinge on assessment of the relative risks of fetal death during expectant management versus the risks from preterm delivery. lthough reassuring fetal testing may allow observation with continued maturation, long-term neurological outcome is a concern (Baschat, 2014; Lees, 2015; Thornton, 2004). Baschat and associates (2009) showed that neurodevelopmental outcome at 2 years in growth-restricted fetuses was best predicted by birthweight and gestational age. Doppler abnormalities are generally not associated with poor childhood cognitive developmental scores among low-birthweight fetuses delivered in the third trimester (Llurba, 20l3). hese indings emphasize that adverse neurodevelopmental outcomes cannot always be predicted.

Fetal-growth restriction is commonly the result of placental insuiciency due to faulty maternal perfusion, reduction of functional placenta, or both. If present, these conditions are likely aggravated by labor. Equally important, diminished amnionic luid volume raises the likelihood of cord compression during labor. For these and other reasons, the frequency of cesarean delivery is increased. Accordingly, a woman with a suspected growth-restricted fetus should undergo "high-risk" intrapartum monitoring (Chap. 24, p. 478).

The risk of neonatal hypoxia or meconium aspiration is also greater. hus, care for the newborn should be provided immediately by an attendant who can skillfully clear the airway and ventilate a neonate as needed (Chap. 32, p. 608). he severely growth-restricted newborn is particularly susceptible to hypothermia and may also develop other metabolic derangements such as hypoglycemia, polycythemia, and hyperviscosity. In addition, low-birthweight newborns are at higher risk for motor and other neurological disabilities. Risk is greatest at the lowest extremes of birth weight (Baschat, 2009, 2014; Llurba, 2013).

The term macrosomia is used rather imprecisely to describe a very large fetus or newborn. Although there is general agreement among obstetricians that neonates weighing < 4000 g are not excessively large, a similar consensus has not been reached for the definition of macrosomia. Newborn weight rarely exceeds 11 pounds (5000 g), and excessively large infants are a curiosity. The largest newborn cited in the Guinness Book of World Records was a 23-lb 12-oz (10,800 g) infant boy born in 1879 to a Canadian woman (Barnes, 1957).

In the United States in 2015, of more than 4 million births, 6.9 percent weighed 4000 to 4499 g; 1 percent weighed 4500 to 4999 g; and 0.1 percent were born weighing 5000 g or more 4500-4649 3221 (Martin, 2017) . To be sure, the incidence of excessively large 4750-4999 1146 0.3 134 12 infants grew during the 20th century. According to Williams 5000-5249 385 0.1 57 15 (1903), at the beginning of the 20th century, the incidence 5250-5499 127 0.04 31

TABLE 44-2. Birthweight Distribution of 354,509 Liveborn Infants at Parkland Hospital between 1988 and 2012 (g) No. % No. /0 500-3999 322,074 90.9 13,365 4 4000-4249 19,106 5.4 1043 5 4250-4499 8391 2.4 573 7 of birthweight > 5000 g was 1 to 2 per 10,000 births. his 5500 or more 0.02 14 24 compares with 16 per 10,000 births at Parland Hospital from 1988 through 2008 and with 11 per 10,000 in the United States in 2010. he influence of increasing maternal obesity rates is overwhelming, and its association with diabetes is well known. Of Parkland mothers with newborns weighing > 5000 g, more than 15 percent were diabetic.

Several terms currently describe pathological fetal overgrowth. he most common ofthese-macrosomia-is defined by birthweights that exceed certain percentiles for a given population. Another commonly used scheme is to deine macrosomia by an empirical birthweight threshold.

Macrosomia is frequently deined based on mathematical distributions of birthweight. Those newborns exceeding the 90th percentile for a given gestational week are usually used as the threshold for macrosomia or large-for-gestational age (LGA) birthweight. For example, the 90th percentile at 39 weeks is 4000 g. If, however, birthweights that are 2 standard deviations above the mean are used, then thresholds lie at the 97th percentile. Thus, substantially larger newborns are considered macrosomic compared with those at the 90th percentile. Specifically, the birthweight threshold at 39 weeks to be macrosomic would be approximately 4500 g for the 97th percentile rather than 4000 g for the 90th percentile.

Newborn weight exceeding 4000 g (8 lb 13 oz) is also a frequently used threshold to deine macrosomia. Others use 4250 g or even 4500 g (10 lb). As shown in Table 44-2, birthweights ::4500 g are uncommon. During a 30-year period at Parkland Hospital, during which there were more than 350,000 singleton births, only 1.4 percent of newborns weighed 4500 g or more. We are of the view that the upper limit of fetal growth, above which growth can be deemed abnormal, is likely two standard deviations above the mean, representing perhaps 3 percent of births. At 40 weeks, such a threshold would correspond to approximately 4500 g. The American College of Obstetricians and Gynecologists (2016a) concludes that the term macrosomia was an appropriate appellation for newborns who weigh 4500 g or more at birth.

Total 354,509 15,501

Some factors associated with fetal overgrowth are listed in

Table 44-3. Many are interrelated and thus likely are additive.

For example, advancing age is usually related to multiparity and diabetes, and obesity is related to diabetes. In one study, the incidence of macrosomia exceeded 24 percent in China among obese women, and macrosomia rates were also signiicantly higher (approximately 2.5-fold) for prolonged pregnancy and gestational diabetes (Wang, 2017). Of these, maternal diabetes is an important risk factor for fetal overgrowth (Chap. 57, p. 1100). s shown in Table 44-2, the incidence of maternal diabetes grows s birthweights >4000 g rise. It should be emphasized, however, that maternal diabetes is associated with only a small percentage of the total number of such large newborns.

The adverse consequences of excessive fetal growth are considerable. Neonates with a birthweight of at least 4000 g have cesarean delivery rates > 50 percent. This is particularly true with maternal obesity or diabetes or with birthweights >5000 g (Cordero, 2015; Crosby, 2017; Gaudet, 2014; Hehir, 2015). One study found a higher risk for traumatic neonatal morbidity in LGA neonates compared with normal-weight ones (Chauhan, 2017). Rates of shoulder dystocia vary greatly and can reach nearly 30 percent for macrosomic neonates when maternal diabetes is comorbid (Cordero, 2015). In general obstetrical populations that include diabetic mothers, dystocia rates are at least 5 percent for neonates with birthweights ::5000 g (Crosby,

TABLE 44-3. Risk Factors for Fetal Overgrowth

Large size of parents Advancing maternal age Previous macrosomic infant Racial and ethnic factors

TABLE 4-4. Maternal and Fetal Outcomes for 208,090 Pregnancies Delivered at Parkland Hospital from 1998 through 201e2 <4000 9 4000-4499 9 4500-4999 9 �5000 9 Outcomea n = 187,1 19 n = 17,750 n = 2849 n = 372 P value

Cesa rea n totaI 46,577 (25) 5,362 (30) 1204 (42) 224 (60) <0.001 Scheduled 12,564 (7) 1,481 (8) 316 (11) 65 (17) <0.001

Dystocia 7589 (4) 1388 (8) 337 (1n2) 46 (1n2) <0.001

Shou Ider dystocia 437 (0) 366 (2) 192 (7) 56 (15) <0.001 3rd-or 4th-degree laceration 7296 (4) 932 (5) 190 (7) 37 (1n0) <0.001

Labor induction 26,118 (13) 2499 (14) 420 (15) 39 (10) 0.141 Prolonged second stage 6905 (4) 899 (5) 147 (5) 14 (4) <0.001 Chorioamnionitis 13,448 (7) 1778 (1n0) 295 (1n0) 35 (9) <0.001 pH <7.0 925 (0.5) 96 (0.6) 20 (0.7) 4 (1.1) 0.039

Apgar <7 @ 5 minutes 1898 (1n.0) 80 (0.5) 22 (0.8) 10 (2.7) <0.001

ICN admission 4266 (2.2) 123 (0.7) 36 (1n.3) 9 (2.4) <0.00'1

Fractured clavicle 1880 (1.0) 616 (3.5) 125 (4.4) 16 (4.3) <0.001

Mechanical ventilation 2305 (1n.2) 54 (0.3) 11 (0.4) 9 (2.4) <0.001

Hypoglycemia 480 (0.2) 89 (0.5) 31 (1.1) 12 (3.2) <0.001

Hyperbilirubinemia 5829 (3.0) 305 (1.7) 60 (2.1) 12 (3.2) <0.001

Erb palsy 470 (0.2) 224 (1n.3) 74 (2.6) 22 (5.9) <0.001

Neonatal death 402 (0.2) 3 (0) 2 (0.1) 1 (0.3) <0.001 aOutcome data presented as n (%).

ICN = intensive care nursery.

2017; Hehir, 2015). Rates of postpartum hemorrhage, perineal laceration, and maternal infection, which are related complications, are also higher in mothers delivering overgrown newborns. Maternal and neonatal outcomes by birthweight for large babies >4000 g delivered at Parkland Hospital are shown in Table 44-4.

Because current methods fail to accurately estimate excessive fetal size, macrosomia cannot be deinitively diagnosed until delivery. Inaccuracy in clinical estimates of fetal weight by physical examination is often attributable, at least in part, to maternal obesity. Numerous attempts have been made to improve the accuracy of sonographic fetal-weight estimation. Several formulas have been proposed to calculate fetal weight using measurements of the head, femur, and abdomen. Estimates provided by these computations are reasonably accurate for predicting the weight of small, preterm fetuses but are less valid in predicting the weight of large fetuses. In one study of 248 LGA and 655 non-LGA newborns from pregnancies complicated by diabetes, only 23 percent of women diagnosed with an LGA fetus before delivery actually delivered an LGA infant (Scifres, 2015). his resulted in a more than threefold rise in the cesarean delivery rate for suspected LGA birthweights.

From the foregoing, it is apparent that sonographic estimation of fetal weight is unreliable, and its routine use to identiy macrosomia is not recommended. Indeed, the American College of Obstetricians and Gynecologists (2016a) concludes that clinical fetal weight estimates are just as accurate as sonographic ones.

Several interventions have been proposed to interdict fetal overgrowth. Some include prophylactic labor induction for poorly deined indications such as "impending macrosomia," or elective cesarean delivery to avoid diicult delivery and shoulder dystocia. For women with diabetes in pregnancy, insulin therapy and close attention to good glycemic control reduces birthweight. However, this has not consistently translated into reduced cesarean delivery rates. Furthermore, as noted above, erroneous diagnosis of fetal overgrowth among women with diabetes raises cesarean delivery rates (Scifres, 2015). Also previously mentioned, fetal overgrowth irrespective of the diagnosis of diabetes mellitus is strongly associated with maternal obesity and excessive gestational weight gain (Durie, 2011; Durst, 2016; Harper, 2015). Dietary intervention to limit fetal overgrowth by curbing gestational weight gain, for example, is an active area of research. Currently recommended weight gains for pregnancy according to maternal BMI are described in Chapter 9 (p. 165).

Some clinicians induce labor when fetal macrosomia is suspected in nondiabetic women. his approach is suggested to obviate further fetal growth and thereby reduce potential delivery complications. Such prophylactic induction should theoretically reduce the risk of shoulder dystocia and cesarean delivery. In one systematic review of 11 studies of expectant management versus labor induction for suspected macrosomia, labor induction increased cesarean delivery rates without improving perinatal outcomes (Sanchez-Ramos, 2002). In contrast, Magro-Malosso and colleagues (2017) performed a metaanalysis of four randomized trials involving 1r190 women and concluded that labor induction at 38 or more weeks for suspected macrosomia significantly reduces the frequency of fetal overgrowth and fractures. In one of these studies, 822 women with suspected LGA fetuses were randomly assigned either to early term delivery (37°/7 to weeks) or to expectant management (Boulvain, 2015). here was a higher rate of vaginal delivery that was marginally significant and a lower composite measure of morbidity. These authors cautioned that any beneits should be balanced with the risks of earlyterm labor induction and delivery. Namely, a review of earlyterm births indicates that elective delivery before 39 weeks' gestation does not improve maternal outcomes and is associated with worse neonatal outcomes (Tita, 2016). We agree with the American College of Obstetricians and Gynecologists (2016a, 2017a,b) that current evidence does not support a policy for early labor induction or delivery before 39 weeks' gestation. It remains unclear whether delivery or induction for suspected macrosomia at term is better than expectan t management.

With the delivery of macrosomic infants, shoulder dystocia and its attendant risks described in Chapter 27 (p. 520) are major concerns. That said, the American College of Obstetricians and Gynecologists (20 17b) concluded that fewer than 10 percent of all shoulder dystocia cases result in a persistent brachial plexus injury, and 4 percent of these injuries still follow cesarean delivery.

For prevention, planned cesarean delivery on the basis of suspected macrosomia to prevent brachial plexopathy is an unreasonable strategy in the general population (Chauhan, 2005). Ecker and coworkers (1997) analyzed 80 cases of brachial plexus injury in 77,616 consecutive infants born at Brigham and Women's Hospital. They concluded that an excessive number of otherwise unnecessary cesarean deliveries would be needed to prevent a single brachial plexus injury in neonates born to women without diabetes. Rouse and colleagues (1996) echoed these sentiments in their analysis of nondiabetic mothers.

Conversely, planned cesarean delivery may be a reasonable strategy for diabetic women with an estimated fetal weight >4250 or >4500 g. Conway and Langer (1998) described a protocol of routine cesarean delivery for sonographic estimates of �4250 g in diabetic women. This management significantly lowered the shoulder dystocia rate from 2.4 to 1.1 percent.

In summaly, we agree with the College that elective delivery for the fetus that is suspected to be overgrown is inadvisable, particularly before 39 weeks' gestation. Finally, we also conclude that elective cesarean delivery is not indicated when estimated fetal weight is <5000 g among women without diabetes and < 4500 g among women with diabetes (American College of Obstetricians and Gynecologists, 2016a, 2017b).

Alexander GR, Himes ]H, Kaufman RB, et al: A United States national refer ence for fetal growth. Obstet Gynecol 87: 163, 1996 Aman ], Hansson U, Osrlund I, et al: Increased fat mass and cardiac septal hypertrophy in newborn infants of mothers with well-controlled diabetes during pregnancy. Neonatology 100(2): 14 ,201t1

American College of Obstetricians and Gynecologists: Fetal growth restriction.

Practice Bulletin No. 134, May 2013, Reairmed 2015

American College of Obstetricians and Gynecologists: Fetal macrosomia. Practice Bulletin No. 173, November 2016a

American College of Obstetricians and Gynecologists: Moderate cafeine consumption during pregnancy. Committee Opinion No. 462, August 2010, Reairmed 2016b

American College of Obstetricians and Gynecologists: Nonmedically indicated earlyterm deliveries. Committee Opinion No. 561, AprU 2013, Reairmed 2017a American College of Obstetricians and Gynecologists: Shoulder dystocia. Prac tice Bulletin No. 178, May 2017b

Bahado-Singh RO, Lynch L, Deren 0, et al: First-trimester growth restriction and fetal aneuploidy: the efect of type of aneuploidy and gestational age. Amt] Obstet GynecoIt176(5):976, 1997

Barker 0] (ed): Fetal and Infant Origins of Adult Disease. London, BM] Publishing, 1992

Barnes AC: An obstetric record from the medical record. Obstet Gynecol 9(2):237, 1957

Baschat A: Neurodevelopment after fetal growth restriction. Fetal Diagn her 36:136,t2014

Baschat A, Cosmi E, Bilardo CM, et al: Predictors of neonatal outcome in early-onset placental dysfunction. Obstet Gynecol 109(2, pt 1):253, 2007

Baschat A, Viscardi RM, Hussey-Gardner B, et al: Infant neurodevelopment following fetal growth restriction: relationship with antepartum surveillance parameters. Ultrasound Obstet Gynecol 33(1):44, 2009

Battaglia FC, Lubchenco LO: A practical classiication of newborn infants by weight and gestational age.t] Pediatr 71(2):159, 1967

Begemann M, Zirn B, Santen G, et al: Paternally inherited IGF2 mutation and growth restriction. N Engl] Med 373:349, 2015

Blackwell SC, Landon MB, Mele L, et al: Relationship between excessive gestational weight gain and neonatal adiposity in women with mild gestational diabetes mellitus. Obstet GynecoIt128:1325, 2016

Boers KE, van Wyk L, van der Post ]A, et al: Neonatal morbidity after induction vs expectant monitoring in intrauterine growth restriction at term: a subanalysis of the DIGITAT RCT. Am] Obstet GynecoIt206:344.e1, 2012

Boers E, Vijgen SM, Bijlenga 0, et al: Induction versus expectant monitoring for intrauterine growth restriction at term: randomised equivalence trial (DIGITAT). BM] 341:c7087, 2010

Boulvain M, Senat MY, Perrotin F, et al: Induction oflabour versus expectant management for large-for-date fetuses: a randomised controlled trial. Lancet 385:2600,t2015

Breij LM, Kerkhof GF, Hokken-Koelega AC: Accelerated infant weight gain and risk for nonalcoholic fatty liver disease in early adulthood.t] Clin Endocrinol Metab 99:1t189, 2014

Brenner WE, Edelman DA, Hendricks CH: A standard of fetal growth for the United States of America. Am] Obstet Gynecol 126:555, 1976

Briand Y, Saal ], Ghafari C, et al: Fetal growth restriction is associated with malaria in pregnancy: a prospective longitudinal study in Benin. ] Infect Dis 214:417, 2016

Bricker L, Medley N, Pratt]]: Routine ultrasound in late pregnancy (after 24 weeks' gestation). Cochrane Database Syst Rev 6:CDOO 1451, 2015

Brifa ]F, McAinch A], Romano T, et al: Leptin in pregnancy and development: a contributor to adulthood disease? Am ] Physiol Endocrinol Metab 308:E335,t20t15

Brosens I, Benagiano G, Brosenst]J: The potential perinatal origin of placentation disorders in the young primigravida. Amt] Obstet Gynecol 212:580, 2015

Burton G], Fowden AL, Thornburg KL: Placen tal origins of chronic disease.

Physiol Rev 96:t1t509, 2016

Calabuig-Navarro Y, Puchowicz M, Glazebrook P, et al: Efect of w-3 supplementation on placental lipid metabolism in overweight and obese women. Am] Clin Nutr 103:1064,t2016

Campbell S, Thoms A: Ultrasound measurement of the fetal head to abdomen circumference ratio in the assessment of growth retardation. B]OG 84(3):165, 1977

Capobiango ]0, Bregan6 M, Navarro IT, et al: Congenital toxoplasmosis in a reference center of Parana, Southern Brazil. Braz] Infect Dis 18:364, 2014 Catalano PM, Hauguel-De Mouzon S. Is it time to revisit the Pedersen hypothesis in the face of the obesity epidemic? Am] Obstet GynecoIt204(6):479, 2011

Cervera R, Serrano R, Pons-Estel G], et al: Morbidity and mortality in the anti phospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis 74:1011, 2015

Chauhan SP, Grobman WA, Gherman A, et al: Suspicion and treatment of the macrosomic fetus: a review. Am] Obstet Gynecol 193(2):332, 2005

Chauhan SP, Rice MM, Grobman WA, et al: Neonatal morbidity of small-and large-for-gestational-age neonates born at term in uncomplicated pregnancies. Obstet Gynecol 130(3):511, 2017

Chen S, Cao P, Dong N, et al: PCSK6-mediated corin activation is essential for normal blood pressure. Nat Med 21:1048, 2015a

Chen Z, He P, Ding X, et al: PPAR, stimulates expression of I-type amino acid and taurine transporters in human placentas: the evidence of PPAR, regulating fetal growth. Sci Rep 5:12650, 2015b

Chiossi G, Pedroza C, Costantine MM, et al: Customized versus populationbased growth charts to identiy neonates at risk of adverse outcomes: a systematic review and Bayesian meta-analysis of observational studies. Ultrasound Obstet Gynecol 50(2): 156, 2017

Cohen E, Wong FY, Horne RS, Yiallourou SR: Intrauterine growth restriction: impact on cardiovascular development and function throughout infancy. Pediatr Res 79:821, 2016

Coker L, Garcia LS, Williams CM, et al: Universal psychosocial screening and adverse pregnancy outcomes in an academic obstetric clinic. Obstet GynecoIt119(6):1180,t2012

Conway DL, Langer 0: Elective delivety of infants with macrosomia in diabetic women: reduced shoulder dystocia versus increased cesarean deliveries. Am J Obstet Gynecol 178(5):922, 1998

Cordero L, Paetow P, Landon MB, et al: Neonatal outcomes of macrosomic infants of diabetic and non-diabetic mothers. J Neonatal Perinatal Med 8:lO5, 2015 Costantine MM, Mele L, Landon MB, et al: Customized versus population approach for evaluation of fetal overgrowth. m J Perinatol 30:565, 2013

Crosby DA, Ahmed S, Razley A, et al: Obstetric and neonatal characteristics of pregnancy and delivery for infant birthweight �5.0 kg. J Matern Fetal Neonatal Med 30(24):2961, 201 Crovetto F, T riunfo S, Crispi F, et al: Diferential performance of first trimester screening in predicting small for gestational age neonates or fetal growth restriction. Ultrasound Obstet GynecoIt49(3):349, 2017

Crume TL, Shapiro AL, Brinton JT, et al: Maternal fuels and metabolic measures during pregnancy and neonatal body composition: the healthy start study. J Clin Endocrinol Metab 100:1672,t2015

Cruz-Lemini M, Crispi F, Valenzuela-Alcaraz B, et al: Fetal cardiovascular remodeling persists at 6 months in infants with intrauterine growth restriction. Ultrasound Obstet GynecoIt48:349, 2016

Cui Y, Wang W, Dong N, et al: Role of corin in trophoblast invasion and uterine spiral artery remodelling in pregnancy. Nature 484(7393):246,t2012 Cunningham FG, Cox SM, Harstad W, et al: Chronic renal disease and pregnancy outcome. Am J Obstet Gynecol 163(2):453, 1990

Cyganek A, Pietrzak B, Kociszewska-Najman B, et al: Intrauterine growth restriction in pregnant renal and liver transplant recipients: risk factors assessment. Transplant Proc 46:2794,t20t14

Cyganek K, Skupien J, Katra B, et al: Risk of macrosomia remains glucosedependent in a cohort of women with pregestational type 1 diabetes and good glycemic control. Endocrine 55(2):447, 2017 Dashe JS, McIntire DO, Lucas MJ, et al: Efects of symmetric and asymmetric fetal growth on pregnancy outcomes. Obstet Gynecol 96(3):321, 2000 de Haas S, Ghossein-Doha C, van Kuijk SM, et al: Physiologic adaptation of maternal plasma volume during pregnancy: a systematic review and metaanalysis. Ultrasound Obstet Gynecol 49(2): 7, 201 De Jesus Le, Pappas A, Shankaran S, et al: Outcomes of small for gestational age infants born at <27 weeks' gestation. J Pediatr 163:55.e1, 2013 Desai G, Anand A, Shah P, et al: Sickle cell disease and pregnancy outcomes: a study of the community-based hospital in a tribal block of Gujarat, India. J Health Popul Nutr 36:3,t2017 Dickey RP, Xiong X, Pridjian G, et al: Singleton birthweight by gestational age following in vitro fertilization in the United States. m J Obstet Gynecol 214:101.e1,t2016 Diderholm B, Stridsberg M, Ewald U, et al: Increased lipolysis in non-obese pregnant women studied in the third trimester. BJOG 112(6):713,t2005 Di Mascio 0, Magro-Malosso R, Saccone G, et al: Exercise during pregnancy in normal-weight women and risk of preterm birth: a systematic review and metaanalysis of randomized controlled trials. m J Obstet Gynecol 215(5):561, 2016 Dugof L, Society for Maternal-Fetal Medicine: First-and second-trimester maternal serum markers for aneuploidy and adverse obstetric outcomes. Obstet GynecoIt1l5(5):1052, 2010 Durie DE, Thornburg LL, Glantz JC: Efect of second-trimester and thirdtrimester rate of gestational weight gain on maternal and neonatal outcomes. Obstet Gynecol 118(3):569,2011 Durst JK, Sutton L, Cliver SP, et al: Impact of gestational weight gain on perinatal outcomes in obese women. m J PerinatoIt33:849, 2016 Duryea EL, Hawkins JS, Mclntire DO, et al: A revised birth weight reference for the United States. Obstet GynecoIt124:t16, 2014 Ecker JL, Greenberg JA, Norwitz ER, et al: Birthweight as a predictor of brachial plexus injury. Obstet Gynecol 89(5 pt 1):643, 1997 Feng Z, Minard C, Raghavan R: Pregnancy outcomes in advanced kidney disease. Clin Nephrol 83:272; 2015

Figueras F, Benavides A, Del Rio M, et al: Monitoring of fetuses with intrauterine growth restriction: longitudinal changes in ductus venosus and aortic isthmus flow. Ultrasound Obstet Gynecol 33(1):39, 2009

Figueras F, Cruz-Martinez R, Sanz-Cortes M, et al: Neurobehavioral outcomes in preterm, growth-restricted infants with and without prenatal advanced signs of brain-sparing. Ultrasound Obstet Gynecol 38(3):288, 2011

Fiot E, Zenaty 0, Boizeau P, et al: X-chromosome gene dosage as a determinant of impaired pre and postnatal growth and adult height in Turner syndrome. Eur J Endocrinol 174:281, 2016

Friedman SA, Schif E, Kao L, et al: Neonatal outcome after preterm delivery for preeclampsia. Am J Obstet Gynecol 1 2(6):1785,t1995

Ganzevoort W, Mensing Van Charante N, et al: How to monitor pregnancies complicated by fetal growth restriction and delivery before 32 weeks: posthoc analysis of TRUFFLE study. Ultrasound Obstet Gynecol 49(6):769, 2017

Garcia-Flores J, Janez M, Gonzalez Me, et al: Fetal myocardial morphological and functional changes associated with well-controlled gestational diabetes. Eur J Obstet Gynecol Reprod Bioi 154(1):24, 2011

Gaudet L, Wen SW, Walker M. he combined efect of maternal obesity and fetal macrosomia on pregnancy outcomes. J Obstet Gynaecol Can 36:776, 2014

Gauster M, Hiden U, Blaschitz A, et al: Dysregulation of placental endothelial lipase and lipoprotein lipase in intrauterine growth-restricted pregnancies. J Clin Endocrinol Metab 92(6):2256, 200~

Gauster M, Hiden U, van Poppel M, et al: Dysregulation of placental endothelial lipase in obese women with gestational diabetes mellitus. Diabetes 60(10):2457,t2011

Giannakopoulos B, Krilis SA: he pathogenesis of the anti phospholipid syndrome. N Engl J Med 368(11):1033,t2013

Gil-Sanchez A, Koletzko B, Larque E: Current understanding of placental fatty acid transport. Curr Opin Clin Nutr Metab Care 15(3):265,t2012

Gonzales GF, Tapia \ : Birth weight charts for gestational age in 63,620 healthy infants born in Peruvian public hospitals at low and at high altitude. Acta Paediatr 98(3):454, 2009

Greer LG, Ziadie MS, Casey BM, et al: An immunologic basis for placental insuiciency in fetal growth restriction. Am J Perinatol 29(7):533,t2012

Griin IJ, Lee HC, Profit J, et al: The smallest of the small: short-term outcomes of profoundly growth restricted and profoundly low birth weight preterm infants. J PerinatoIt35:503, 2015

Grobman WA, Lai Y, Rouse OJ, et al: The association of cerebral palsy and death with small-for-gestational-age birthweight in preterm neonates by individualized and population-based percentiles. Am J Obstet Gynecol 209(4):340.e1,t2013

Groom KM, North A, Stone PR, et al: Patterns of change in uterine artery Doppler studies berween 20 and 24 weeks of gestation and pregnancy outcomes. Obstet Gynecol 113(2 pt 1):332, 2009

HAPO Study Cooperative Research Group: Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 358(19):1991, 2008 Haider BA, Bhutta ZA: Multiple-micronutrient supplementation for women during pregnancy. Cochrane Database Syst Rev 4:CD004905, 2017 Hanson M, Kiserud T, Visser GH, et al: Optimal fetal growth: a misconception? Am J Obstet GynecoIt213:332.e1, 2015

Haragan AF, Hulsey TC, Hawk AF, et al: Diagnostic accuracy of fundal height and handheld ultrasound-measured abdominal circumference to screen for fetal growth abnormalities. Am J Obstet GynecoIt212:820.e1, 2015 Harper LM, Tita A, Biggio JR: he Institute of Medicine guidelines for gestational weight gain after a diagnosis of gestational diabetes and pregnancy outcomes. Am J PerinatoIt32:239, 2015 Hehir MP, Mchugh AF, Maguire PJ, et al: Extreme macrosomia-obstetric outcomes and complications in birthweights > 5000 g. Aust N Z J Obstet Gynaecol 55:42, 2015 Hietalampi H, Pahkala K, Jokinen E, et al: Left ventricular mass and geometry in adolescence: early childhood determinants. Hypertension 60(5): 1266, 2012 Higa R, Jawerbaum A: Intrauterine efects of impaired lipid homeostasis in pregnancy diseases. Curr Med Chen 20(1t8):2338, 2013 Howell A, Egorova NN, Janevic T, et al: Severe maternal morbidity among Hispanic women in New York City: investigation of health disparities. Obstet Gynecol 129(2):285,t201

Jana N, Barik S, Arora N, et al: Tuberculosis in pregnancy: the challenges for South Asian countries. J Obstet Gynaecol Res 38(9):1125, 2012

Jansson N, Rosario FJ, Gaccioli F, et al: Activation of placental mTOR signaling and amino acid transporters in obese women giving birth to large babies. J Clin Endocrinol Metab 98(1):105, 2013

Jeyabalan A, McGonigal S, Gilmour C, et al: Circulating and placental endoglin concentrations in pregnancies complicated by intrauterine growth restriction and preeclampsia. Placenta 29(6):555, 2008 ]ornayvaz FR, Vollenweider P, Bochud M, et al: Low birth weight leads to obesity, diabetes and increased leptin levels in adults: the CoLaus study. Cardiovasc Diabetol 2016;15:73

Kerkhof GF, Willemsen RH, Leunissen RW, et al: Health profile of young adults born preterm: negative efects of rapid weight gain in early life. ] Clin Endocrinol Metab 97(12):4498, 2012

Khoury M], Erickson ]0, Cordero ]F, et al: Congenital malformations and intrauterine growth retardation: a population study. Pediatrics 82(1):83, 1988

Kim CJ, Romero R, Chaemsaithong P, et aI: Chronic inlammation of the placenta: deinition, classification, pathogenesis, and clinical significance. Am ] Obstet Gynecol 2213:S53, 2015

Klemetti MM, Laivuori H, Tikkanen M, et al: White's classification and pregnancy outcome in women with type 1 diabetes: a population-based cohort study. Diabetologia 59(1):92, 2016

Kondapalli A, Perales-Puchalt A: Low birth weight: is it related to assisted reproductive technology or underlying infertility? Fertil SteriI99(2):303, 2013

Krantz 0, Goetzl L, Simpson ], et al: Association of extreme first-trimester free human chorionic gonadotropin-3, pregnancy-associated plasma protein A, and nuchal translucency with intrauterine growth restriction and other adverse pregnancy outcomes. Am] Obstet Gynecol 191 (4): 1452, 2004

Laatikainen T], Raisanen I], Salminen KR: Corticotrophin-releasing hormone in amnionic fluid during gestation and labor and in relation to fetal lung maturation. Am] Obstet GynecoIt159(4):891, 1988

Leary P], Leary SE, Stout KK, et al: Maternal, perinatal, and post neonatal outcomes in women with chronic heart disease in Washington State. Obstet GynecoIt120:1283,t2012

Lechtig A, Delgado H, Lasky E, et al: Maternal nutrition and fetal growth in developing societies. Am] Dis Child 129(5):434, 1975

Lees CC, Marlow N, van Wassenaer-Leemhuis A, et al: 2 year neurodevelopmental and intermediate perinatal outcomes in infants with very preterm fetal growth restriction (TRUFFLE): a randomised trial. Lancet 385:2162, 2015

Levine TA, Grunau E, McAulife FM, et I. Early childhood neurodevelopment after intrauterine growth restriction: a systematic review. Pediatrics 135:126,t2015

Liu ]M, Mei Z, Ye R, et I: Micronutrient supplementation and pregnancy outcomes: double-blind randomized controlled trial in China. ]AMA Intern Med 173(4):276,t2013

L1urba E, Baschat A, Turan OM, et al: Childhood cognitive development ater fetal growth restriction. Ultrasound Obstet GynecoIt41(4):383, 2013

Logan CA, Bornemann R, Koenig W, et I: Gestational weight gain and fetalmaternal adiponectin, leptin, and CRP: results of two birth cohorts studies. Sci Rep 7:41847, 2017

Lubchenco LO, Hansman C, Dressler M, et al: Intrauterine growth as estimated from liveborn birth-weight data at 24 to 42 weeks of gestation. Pediatrics 32:793, 1963

Luo Zc, NuyttAM, Delvin E, et al: Maternal and fetal IGF-I and IGF-II levels, fetal growth, and gestational diabetes. ] Clin Endocrinol Metab 97(5): 1720, 2012

Luyckx VA, Brenner BM: Birth weight, malnutrition and kidney-associated outcomes-a global concern. Nat Rev Nephrol 11:135,t2015

Magro-Malosso ER, Saccone G, Chen M, et aI: Induction of labour for suspected macrosomia at term in non-diabetic women: a systematic review and meta-analysis of randomized controlled trials. B]OG 124:414,t2017

Manning FA (ed): Intrauterine growth retardation. In Fetal Medicine Principles and Practice. Norwalk, Appleton & Lange, 1995

Martin ]A, Hamilton BE, Osterman M], et aI: Births: final data for 2015. Nat!

Vital Stat Rep 66(1):1, 2017

Martin ]A, Hamilton BE, Venture S], et al: Births: inal data for 2010. Nat!

Vital Stat Rep 61(1):1, 2012

Mattsson K, Rylander L: Inluence of maternal and paternal birthweight on ofspring birthweight-a population-based intergenerationl study. Paediatr Perinat EpidemioIt27(2):138, 2013

Mayer C, Joseph KS: Fetal growth: a review of terms, concepts and issues relevant to obstetrics. Ultrasound Obstet Gynecol 41 (2): 136, 2013

McCloskey K, Burgner 0, Carlin ]B, et I: Infant adiposity at birth and early postnatal weight gain predict increased aortic intima-media thickness at 6 weeks of age: a population-derived cohort study. Clin Sci 130:443, 2016

McIntire DO, Bloom SL, Casey BM, et aI: Birthweight in relation to morbidity and mortality among newborn infants. N Englt] Med 340(16):1234, 1999

Meher S, Hernandez-Andrade E, Basheer SN, et I: Impact of cerebral redistribution on neurodevelopmentl outcome in small-for-gestational-age or growth-restricted babies: a systematic review. Ultrasound Obstet Gynecol 46:398, 2015

Mendez-Figueroa H, Truong T, Pedroza C, et aI: Small-for-gestationl-age infants among uncomplicated pregnancies at term: a secondary analysis of 9 Maternal-Fetal Medicine Units Network studies. Amt] Obstet Gynecol 215:628.el, 2016

Micali N, Stemann Larsen P, Strandberg-Larsen K, et aI: Size at birth and preterm birth in women with lifetime eating disorders: a prospective population-based study. B]OG 123:1301,t2016

Miller SL, Huppi PS, Mallard C: he consequences of fetal growth restriction on brain structure and neurodevelopmental outcome.t] Physiol 594:807, 2016 Milovanovic I, Njuieyon F, Deghmoun S, et aI: Innate small babies are meta bolically healthy children.t] Clin Endocrinol Metab 97(12):4407, 2012 Mitteroecker P, Huttegger SM, Fischer B, et al: Clif-edge model of obstetric selection in humans. Proc Nat! Acad Sci USA 113:14680,2016

Morisaki N, Esplin MS, Varner MW, et aI: Declines in birth weight and fetal growth independent of gestational length. Obstet Gynecol 121 0):51, 2013

Murphy HR, Steel SA, Roland ]M, et al: East Anglia Study Group for Improving Pregnancy Outcomes in Women with Diabetes (EASIPOD). Obstetric and perinatal outcomes in pregnancies complicated by Type 1 and Type 2 diabetes: inluences of glycaemic contro!tobesity and social disadvantage.

Diabet Med 28(9):1060,t2011

Myatt L, Maloyan A: Obesity and placental function. Semin Reprod Med 34:42,t2016

Nawathe AR, Christian M, Kim SH, et al: Insulin-like growth factor axis in pregnancies afected by fetal growth disorders. Clin Epigenetics 8: 11, 2016

Nelson DB, Martin R, Twickler OM, et aI: Sonographic detection and clinical importance of growth restriction in pregnancies with gastroschisis. ] Ultrasound Med 34:2217, 2015a

Nelson KB, Blair E: Prenatal factors in singletons with cerebral palsy born at or near term. N Engl] Med 373:946, 2015b

Nelson E, Rosella LC, Mahant S, et I: Survival and surgical interventions for children with trisomy 13 and 18.t]AMA 316:420,2016

Nicolaides H, Snijders RJ, Noble P: Cordocentesis in the study of growth-retarded fetuses. In Divon Y (ed): Abnormal Fetal Growth. New York, Elsevier, 1991

O'Dwyer V, Burke G, Unterscheider ], et al: Defining the residual risk of adverse perinatal outcome in growth-restricted fetuses with normal umbilical artery blood low. m] Obstet Gynecol 211 :420.el, 2014

Ott W: Intrauterine growth retardation and pre term delivery. Am ] Obstet GynecoIt168:710, 1993

OttesenAM, Aksglaede L, Garn I, et al: Increased number of sex chromosomes afects height in a nonlinear fashion: a study of 305 patients with sex chromosome aneuploidy. Am] Med Genet A 152A:1206, 2010

Overpeck MD, Hediger ML, Zhang ], et I: Birthweight for gestational age of Mexican American infants born in the United States. Obstet Gynecol 93:943, 1999

Owen ], Baker SL, Hauth ]C: Is indicated or spontaneous preterm delivery more advantageous for the fetus? Am] Obstet Gynecol 163(3):868, 1990 Paquet C, Yudin MH: Toxoplasmosis in pregnancy: prevention, screening, and treatment.t] Obstet Gynaecol Can 35(1):78, 2013

Pardi G, Cetin I: Human fetal growth and organ development: 50 years of discoveries. Amt] Obstet GynecoIt194(4):1008, 2006 Pedersen ]: Weight and length at birth of infants of diabetic mothers. Acta Endocrinol (Copenh) 16:330, 1954

Perelman RH, Farrell PM, Engle M], et I: Development aspects oflung lipids.

Annu Rev PhysioIt47:803, 1985

Petrozella LN, Dashe ]S, McIntire DO, et al: Clinical signiicance of borderline amniotic luid index and oligohydramnios in preterm pregnancy. Obstet Gynecol 117(2 Pt 1):338,t2011

Picone 0, Teissier N, Cordier AG, et I: Detailed in utero ultrasound description of 30 cases of congenital cytomegalovirus infection. Prenat Diagn 34:518,t2014

Picone 0, Vauloup-Fellous C, Cordier AG, et aI: A series of 238 cytomegalovirus primary infections during pregnancy: description and outcome. Prenat Diagn 2:1, 2013

Poeran ], Maas AF, Birnie E, et I: Social deprivation and adverse perinatal outcomes among Western and non-Western pregnant women in a Dutch urban population. Soc Sci Med 83:42, 2013

Rabie N, Magann E, Steelman S, et I: Oligohydramnios in complicated and uncomplicated pregnancies: a systematic review and meta-analysis. Ultrasound Obstet GynecoIt49(4):442, 2017

Radaelli T, Lepercq ], Varastehpour A, et al: Diferential regulation of genes for fetoplacental lipid pathways in pregnancy with gestational and type 1 diabetes mellitus. Am] Obstet Gynecol 201 :209.e 1, 2009

Richards ]L, Kramer MS, Deb-Rinker P, et I: Temporal trends in late preterm and early term birth rates in 6 high income countries in North merican and Europe and association with clinician-initiated obstetric interventions. ]MA 316:410,t2016

Roberge S, Nicolaides K, Demers S, et aI: The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis. Amt] Obstet GynecoIt216(2):1t10, 2017

Robert Peter J, Ho J], Valliapan J, et al: Symphysial fundal height (SFH) measurement in pregnancy for detecting abnormal fetal growth. Cochrane Database Syst Rev 8:CD008136, 2015

Rogers BB, Bloom SL, Leveno KJ: Atherosis revisited: current concepts on the pathophysiology of implantation site disorders. Obstet Gynecol Surv 54(3):189, 1999

Rogne T, Engstf0m A,Jacobsen GW, et al: Fetal growth, cognitive function, and brain volumes in childhood and adolescence. Obstet GynecoIt125:673, 2015

Roma E, Arnau A, Berdala R, et al: Ultrasound screening for fetal growth restriction at 36 vs 32 weeks' gestation: a randomized trial (ROUTE). Ultrasound Obstet Gynecol 46:39t1, 2015

Roos-Hesselink JW, Ruys TP, Stein JI, et al: Outcome of pregnancy in patients with structural or ischaemic heart disease: results of a registry of the European Society of Cardiology. Eur Heart J 34(9):657, 2013

Rosario FJ, Kanai Y, Powell TL, et al: Mammalian target of rapamycin signaling modulates amino acid uptake by regulating transporter cell surface abundance in primary human trophoblast cells. J Physiol 591 :609, 2013

Rouse DJ, Owen J, Goldenberg RL, et al: he efectiveness and costs of elective cesarean delivery for fetal macrosomia diagnosed by ultrasound. JAMA 276(2):1480, 1996

Roza SJ, Steegers A, Verburg BO, et al: What is spared by fetal brain-sparing? Fetal circulatory redistribution and behavioral problems in the general population. Am J Epidemiol 168(10):1145,t2008

Rudzinski E, Gilroy M, Newbill C, et al: Positive C4d immunostaining of placental villous syncytiotrophoblasts supports host-versus-graft rejection in villi tis of unknown etiology. Pediatr Dev Pathol 16(1):7,t2013

Salafia CM, Minior VK, Pezzullo JC, et al: Intrauterine growth restriction in infants of less than 32 weeks' gestation: associated placental pathologic features. AmJ Obstet GynecoIt173(4):1049, 1995

Saliem S, Patenaude V, Abenhaim HA: Pregnancy outcomes among renal transplant recipients and patients with end-stage renal disease on dialysis. J Perinat Med 44:321,t2016

Sanchez-Ramos L, Bernstein S, Kaunitz AM: Expectant management versus labor induction for suspected fetal macrosomia: a systematic review. Obstet Gynecol 100(5 pt 1):997, 2002

Sanchez-Vaznaugh EV, Braveman PA, Egerter S, et al: Latina birth outcomes in California: not so paradoxical. Matern Child Health J 20:1849, 2016 Schemmer G, Wapner RJ, Johnson A, et al: First-trimester growth patterns of aneuploid fetuses. Prenat Diagn 17(2):155,t1997

Scifres CM, Chen B, Nelson DM, et al: Fatty acid binding protein 4 regulates intracellular lipid accumulation in human trophoblasts. J Clin Endocrinol Metab 96:E1083, 2011

Scifres CM, Feghali M, Dumont T, et al: Large for gestational age ultrasound diagnosis and risk for cesarean delivery in women with gestational diabetes mellitus. Obstet Gynecol 126:978, 2015

Sheield JS, Sanchez PJ, Morris G, et al: Congenital syphilis after maternal treatment for syphilis during pregnancy. Am J Obstet Gynecol 186(3):569, 2002

Simpson J, Smith AD, Fraser A, et al: Programming of adiposity in childhood and adolescence: associations with birth weight and cord blood adipokines. J Clin Endocrinol Metab 102(2) :499, 2017

Sobhy S, Babiker Z, Zamora J, et al: Maternal and perinatal mortality and morbidity associated with tuberculosis during pregnancy and the postpartum period: a systematic review and meta-analysis. BJOG 124(5):727,2017

Sovio U, White IR, Dacey A, et al: Screening for fetal growth restriction with universal third trimester ultrasonography in nulliparous women in the Pregnancy Outcome Prediction (POP) study: a prospective cohort study. Lancet 386:2089,t2015

Spong CY: Add stillbirth to the list of outcomes to worry about in a pregnant woman with a history of preterm birth or fetal growth restriction. Obstet Gynecol 119(3):495,t2012

Spong CY, Mercer BM, D'Alton M, et al: Timing of indicated late-preterm and early-term birth. Obstet Gynecol 118(2 Pt 1):323, 2011

Stein Z, Susser M, Saenger G, et al: Famine and Human Development: The Dutch Hunger Winter of 1944-1945. New York, Oxford University Press, 1975

Stott D, IP, Paraschiv D, et al: Longitudinal maternal haemodynamics in fetal growth restriction in pregnancies at high risk for placental insuiciency. Ultrasound Obstet GynecoIt49(6):761, 2017

Tajik P, van Wyk L, Boers E, et al: Which intrauterine growth restricted fetuses at term benefit from early labour induction? A secondary analysis of the DIGITAT randomised trial. Eur J Obstet Gynecol Reprod Bioi 172:20, 2014 hame MM, Singh-Minott I, Osmond C, et al: Pregnancy in sickle cell-haemoglobin C (SC) disease. A retrospective study of birth size and maternal weight gain. Eur J Obstet Gynecol Reprod Bioi 203:16, 2016

Thornton JG, Hornbuckle J, Vail A, et al: Infant well-being at 2 years of age in the Growth Restriction Intervention Trial (GIT): multicenter randomized controlled trial. Lancet 364(9433):513, 2004

Tita AT: What we have learned about scheduling elective repeat cesarean delivery at term. Semin Perinarol ,t2016

Toda K, Reef S, Tsuruoka M, et al: Congenital rubella syndrome (CRS) in Vietnam 2011-2012-CRS epidemic after rubella epidemic in 2010-201 I. Vaccine 33:3673, 2015

Toutain J, Labeau-Gaiizere C, Barnetche T, et al: Conined placental mosaicism and pregnancy outcome: a distinction needs to be made between types 2 and 3. Prenat Diagn 30:1155, 2010

Turan OM, Turan S, Gungor S, et al: Progression of Doppler abnormalities in intrauterine growth restriction. Ultrasound Obstet Gynecol 32(2): 160,t2008

Tuuli MG, Cahill A, Stamilio D, et al: Comparative eiciency of measures of early fetal growth restriction for predicting adverse perinatal outcomes. Obstet GynecoIt117(6):1331, 2011

Tyson JE, Kennedy K, Broyles S, et al: he small for gestational age infant: accelerated or delayed pulmonary maturation? Increased or decreased survival? Pediatrics 95(4):534, 1995 Unterscheider J, Daly S, Geary MP, et al: Optimizing the deinition of intrauterine growth restriction: the multicenter prospective PORTO study. Am J Obstet GynecoIt208(4):290.e1, 2013a

Unterscheider J, Daly S, Geary MP, et al: Predictable progressive Doppler deterioration in IUGR: does it really exist? Am J Obstet Gynecol 209:539. e1, 2013b

Unterscheider J, O'Donoghue K, Malone FD: Guidelines of fetal growth restriction: a comparison of recent national publications. Am J Perinatol 32:307,t2015 Usher R, McLean F: Intrauterine growth of live-born Caucasian infants at sea level: standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks' gestation. J Pediatr 4( 6) :90 1, 1969 van Wyk L, Boers E, van der Post JA, et al: Efects on (neuro)developmental and behavioral outcome at 2 years of age of induced labor compared with expectant management in intrauterine growth-restricted infants: long-term outcomes of the DIGITAT trial. Am J Obstet GynecoIt206(5):406.e1, 2012

Villar J, Papageorghiou AT, Pang R, et al: The likeness of fetal growth and newborn size across non-isolated populations in the INTERGROWTH-21st Project: the Fetal Growth Longitudinal Study and Newborn Cross-Sectional Study. Lancet Diabetes Endocrinol 2: 781, 2014

Visser GH, Bilardo CM, Derks JB, et al: he TRUFFLE study; fetal monitoring indications for delivery in 310 IUGR infants with 2 year's outcome delivered before 32 weeks of gestation. Ultrasound Obstet Gynecol November 11t, 2016 [Epub ahead of print]

Waldhoer T, K1ebermass-Schrehof K: he impact of altitude on birth weight depends on further mother-and infant-related factors: a population-based study in an altitude range up to 1600 m in Austria between 1984 and 2013. J Perinatol 35:689, 2015

Walker DM, Marlow N, Upstone L, et al: he Growth Restriction Intervention Trial: long-term outcomes in a randomized trial of timing of delivery in fetal growth restriction. Am J Obstet Gynecol 204(1):34.e1, 2011

Wang D, Hong Y, Zhu L, et al: Risk factors and outcomes of macrosomia in China: a multicentric survey based on birth data. J Matern Fetal Neonatal Med 30:623,t2017

Wiebe HW, Boule NG, Chari R, et al: he efect of supervised prenatal exercise on fetal growth: a meta-analysis. Obstet Gynecol 125: 1185, 2015

Wigby K, D'Epagnier C, Howell S, et al: Expanding the phenotype of Triple X syndrome: a comparison of prenatal versus postnatal diagnosis. Am J Med Genet A 170:2870, 2016

Williams JW: Williams Obstetrics, New York, D. Appleton and Co., 1903

Williams RL: Intrauterine growth curves. Intra-and international comparisons with diferent ethnic groups in California. Prev Med 4: 163, 1975

Williams RL, Creasy RK, Cunningham GC, et al: Fetal growth and perinatal viability in California. Obstet Gynecol 59:624, 1982

Yamamoto R, Ishii K, Shimada M, et al: Signiicance of maternal screening for toxoplasmosis, rubella, cytomegalovirus and herpes simplex virus infection in cases offetal growth restriction. J Obstet Gynaecol Res 39(3):653, 2013

Yang X, Li M, Haghiac M, Catalano PM, et al: Causal relationship between obesity-related traits and TLR4-driven responses at the maternal-fetal interface. Oiabetologia 59:2459, 2016

Yelnik CM, Laskin CA, Porter TF, et al: Lupus anticoagulant is the main predictor of adverse pregnancy outcomes in aPL-positive patients: validation of PROMISSE study results. Lupus Sci Med 3:e000131, 2016

Zhang J, Merialdi M, Platt LO, et al: Deining normal and abnormal fetal growth: promises and challenges. Am J Obstet Gynecol 202(6):522, 2010 Zhang J, Mikolajczyk R, Grewal J, et al: Prenatal application of the individual ized fetal growth reference. Am J Epidemiol 173(5):539,t2011

Zhu JL, Obel C, Hammer Bech B, et al: Infertility, infertility treatment, and fetal growth restriction. Obstet Gynecol 110(6):1326,200

Zhu MY, Milligan N, Keating S, et al: The hemodynamics of late-onset intrauterine growth restriction by MRI. Am J Obstet Gynecol 214:367.e1, 2016

MECHANISMS OF MULTIFETAL GESTATIONS ......... 864

DIAGNOSIS OF MULTIFETAL GESTATION ........... 869 MATERNAL PHYSIOLOGICAL ADAPTATIONS ........ 870

PREGNANCY COMPLICATIONS ....................i. 871

UNIQUE FETAL COMPLICATIONS ................... 873 DISCORDANT GROWTH OF TWIN FETUSES .......... 881

FETAL DEMISE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 882 PRENATAL CARE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 884 PRETERM BIRTH ................................ 885

LABOR AND DELIVERY ......................... 887

SELECTIVE REDUCTION OR TERMINATION .......... 891

In single-ovum twins, there is always a certain area of the placenta in which there is anastomosis between vascular systems which is never present in the fused placenta of doubleovum twins. Thus, if at an eary period the heart of one embryo is consideraby stronger than that of the other, a gradualy increasing area of the communicating portion of the placenta is monopolized by the ormer, so that its heart increases rapidy in size, whilst that of the latter receives less blood and eventualy atrophies.

-J. Whitridge Williams (1903)

In Williams' time, a great deal concerning the embryological and morphological development of multifetal pregnancies was unknown. These pregnancies may result from two or more fer tilization events, from a single fertilization followed by a split ting of the zygote, or from a combination of both. Multifetal today for both the mother and her fetuses. For example, in this country, approximately a fourth of very-low-birthweight gestations (Martin, 2017).

Fueled largely by infertility therapy, both the rate and the number of twins and higher-order multi fetal births grew dramatically during the 1980s and 1990s in the United States. National data from Martin and coworkers (2017) presented here is informative. he twinning rate rose 76 percent from 18.9 per 1000 live births in 1980 to 33.2 in 2009. During the same time, the number of higher-order multifetal births peaked in 1998 at a rate of 1.9 per 1000 total births. Since then, however, evolving infertility management has lowered rates of higher-order multifetal births-especially among nonHispanic white women. For example, the rate of triplets or more declined by more than 50 percent from 1998 to 2015 in this demographic group. And, in 2015, the overall m ultifetal birth rate was 34.5 per 1000, with twins representing nearly 97 percent of these births.

These rates of multi fetal pregnancies have a direct efect on the rates of preterm birth and its comorbidities. In addition, the risks for congenital malformation and its consequences are greater with multifetal gestations. Importantly, this increased risk applies to each fetus and is not simply the result of more fetuses. In sum, in 2013 in the United States, multifetal births accounted for 3 percent of all live births but for 15 percent of all infant deaths. Moreover, the risk of infant death rose proportionally with the number of fetuses in the pregnancy (Matthews, 2015). Speciically, the infant mortality rate for twins was more than four times the rate for single births. In the same year, the infant mortality rate for triplets was nearly 12 times the rate for singletons, and for quadruplets, it was a staggering 26 times that

TABLE 45-1. Selected Outcomes in Singleton and Twin

Outcome Singletons (No.) Twins (No.)

Pregnancies 202,306 241n2

Birthsa 202,306 4824

Stillbirths 1 011 (5.0) 114 (23.6)

Neonatal deaths 590 (2.9) 92 (1n9.5)

Perinatal deaths 1601 (7.9) 206 (42.7)

Very low birthweight 1927 (9.6) 507 (1n07.6) aBirth data are represented as number (per 1000). bDenominator for neonatal deaths and very low birthweight is liveborn infants. Data from Dr. Don Mcintire.

for singletons! From Parkland Hospital, a comparison of singleton and twin outcomes is shown in Table

These risks are magnified further with higher-order births.

he mother may also experience higher obstetrical morbidity and mortality rates. hese rates lso rise with the number of fetuses (Mhyre, 2012; Young, 2012). In one study of more than 44,000 multifetal pregnancies, the risks for preeclampsia, postpartum hemorrhage, and maternal death were twofold higher than these rates in singleton gestations (Walker, 2004). The risk for peripartum hysterectomy is also greater. Francois and associates (2005) reported this to be threefold for twins and 24-fold for triplets or quadruplets. Last, compared with women with a singleton pregnancy, these mothers are at increased risk for depression as well as parental divorce (Choi, 2009; Jenna, 2011).

Twin fetuses usually result from fertilization of two separate ova, which yields dizygotic orratenal twins. Less often, twins arise from a single fertilized ovum that then divides to create monozygotic or identical twins. Either or both processes may be involved in the formation of higher numbers. Quadruplets, for example, may arise from as few as one to as many as four ova. These traditional models of twinning discussed in the next sections have been taught for more than 50 years and remain the widely accepted theory. More recently, Herranz (2015) ofered a provocative alternative hypothesis, which posits that monozygotic twinning occurs with splitting at the postzygotic twocell stage. Notably, data are not robust in support of either the traditional or the newly proposed model (Denker, 2015).

Dizygotic twins are not in a strict sense true twins because they result from the maturation and fertilization of two ova during a single ovulatory cycle. Moreover, from a genetic perspective, dizygotic twins are like any other pair of siblings.

On the other hand, monozygotic or identical twins, although they have virtually the same genetic heritage, are usually not identical. Namely, the division of one fertilized zygote into two does not necessarily result in equal sharing of protoplasmic material. Monozygotic twins may actually be discordant for genetic mutations because of a postzygotic mutation, or may have the same genetic disease but with marked variability in expression. In female fetuses, skewed lyonization can produce diferential expression of X-linked traits or diseases. Further, the process of monozygotic twinning is in a sense a teratogenic event, and monozygotic twins have a higher incidence of often discordant malformations (Glinianaia, 2008). For example, in one study of 926 monozygotic twins, the prevalence of congenital heart defects was 12-fold greater than the general population rate, but 68 percent of afected infants had a normal sibling (Pettit, 20l3). From any of these mechanisms, dizygotic twins of the same sex may appear more nearly identical at birth than monozygotic twins.

• Genesis of Monozygotic Twins

The developmental mechanisms underlying monozygotic twinning are poorly understood. The incidence of monozygotic twins is increased two-to fivefold in pregnancies conceived using assisted reproductive technology (ART). he predisposition to splitting may stem from specimen handling, growth media, or sperm DNA microinjection or may arise from intrinsic abnormalities associated with infertility (McNamara, 2016).

The outcome of the monozygotic twinning process depends on when division oCCuts. If zygotes divide within the irst 72 hours after fertilization, two embryos, two amnions, and two chorions develop, and a diamnionic, dichorionic twin pregnancy evolves (Fig. 45-1). Two distinct placentas or a single, fused placenta may develop. If division occurs between the fourth and eighth day, a diamnionic, monochorionic twin pregnancy results. By approximately 8 days after fertilization, the chorion and the amnion have already diferentiated, and division results in two embryos within a common amnionic sac, that is, a monoamnionic, monochorionic twin pregnancy. Conjoined twins result if twinning is initiated later.

It has long been accepted that monochorionicity incontrovertibly indicated monozygosity. Rarely, however, monochorionic twins may in fact be dizygotic (Hackmon, 2009). Mechanisms for this are speculative, but in one review of 14 cases, nearly all had been conceived after ART procedures (Ekelund, 2008) . McNamara and colleagues (2016) ofer an excellent review of the mechanisms and evidence for both typical and atypical twinning.

In supeetation, an interval as long as or longer than a menstrual cycle intervenes between fertilizations. Superfetation requires ovulation and fertilization during the course of an established pregnancy, which is theoretically possible until the uterine cavity is obliterated by fusion of the decidua capsularis to the decidua parietalis. Although known to occur in mares, superfetation is not known to occur spontaneously in humans. Lantieri and associates (2010) reported a case ater ovarian hyperstimulation and intrauterine insemination in the presence of an undiagnosed tubal pregnancy. Most authorities believe that alleged cases of human superfetation result from markedly

FIGURE 45-1 Mechanism of monozygotic twinning. Black boxing and blue arrows in columns A, B, and C indicates timing of division.

A. At 0 to 4 days postfertilization, an early conceptus may divide into two. Division at this early stage creates two chorions and two amnions (dichorionic, diamnionic). Placentas may be separate or fused. B. Division between 4 to 8 days leads to formation of a blastocyst with two separate embryoblasts (inner cell masses). Each embryoblast will form its own amnion within a shared chorion (monochorionic, diamnionic). C. Between 8 and 12 days, the amnion and amnionic cavity form above the germinal disc. Embryonic division leads to two embryos with a shared amnion and shared chorion (monochorionic, monoamnionic). D. Difering theories explain conjoined twin development. One describes an incomplete splitting of one embryo into two. The other describes fusion of a portion of one embryo from a monozygotic pair onto the other.

unequal growth and development of twin fetuses with the same setting of paternity lawsuits (Girela, 1997). Given that superfegestational age. cundation may also occur with ART, women should be advised

Supeecundation refers to fertilization of two ova within the to consider avoiding intercourse after embryo transfer (McNasame menstrual cycle but not at the same coitus, nor necesmara, 2016; Peigne, 201r1). sarily by sperm from the same male. An instance of superfecundation or heteropaternity, documented by Harris (1982), is demonstrated in Figure 45-2. he mother was delivered of • Factors Afecting Twinning a black neonate whose blood type was A and a white neonate Dizygotic twinning is much more common than monozygotic whose blood type was O. The blood type of the mother and her splitting of a single oocyte, and its incidence is influenced by husband was O. More recent cases have been reported in the race, heredity, maternal age, parity, and, especially, fertility )c::0)�000 5.)�:

FIGURE 45-2 An example ofdizygotic twin boys as the consequence of superfecundation.

treatment. By contrast, the frequency of monozygotic twin births is relatively constant worldwide-approximately 1 set per 250 births, and this incidence is generally independent of demographic factors. One exception is that rates of zygotic splitting are increased following ART (Aston, 2008).

Among diferent races and ethnic groups, the frequency of multifetal births varies significantly. In one analysis of more than 8 million births in the United States between 2004 and 2008, the rate oftwinning was 3.5 percent in black women and 3 percent in whites (Abel, 2012). Hispanic, Asian, and Native merican women had comparatively lowerrates than white women. In one rural community in Nigeria, twinning occurred once in every 20 births (nox, 1960)! hese marked diferences in twinning frequency may be the consequence ofracial variations in levels of follicle-stimulating hormone-FSH (Nylander, 1973).

Maternal age is another important risk factor for multifetal pregnancies (Fig. 45-3). Dizygotic twinning frequency rises almost fourfold between the ages of 15 and 37 years (Painter, 2010). As such, there is a paradox of declining fertility but increasing twinning rates with advancing maternal age (Beemsterboer, 2006). Another explanation for the dramatic rise in twinning with advancing maternal age may be a higher use of ART in older women (Ananth, 2012). Paternal age has also been linked to twinning frequency, but its efect is felt to be small (Abel, 2012). Although twin pregnancy is associated with greater risks for most adverse perinatal outcomes, McLennan and associates (2017) did not find advanced maternal age to be an additional risk factor for fetal and infant death. From this population-based study of the United States, they concluded that women in their 30s may be counseled that their age is not a major additional risk factor for adverse obstetric outcomes in the setting oftwin pregnancy.

Increasing pariy independently raises the incidence of twinning in all populations studied. During a 30-year period, Antsaklis and coworkers (2013) noted a progressively increasing positive correlation between multiparity and twinning. However, they

FIGURE 45-3 Multifetal birth rates in the United States according to maternal age and race, 2015. (Data from Martin, 201o7.) cautioned that greater use ofRT may be partially contributory. In a two-year study from Nigeria, where such technology is not commonly available, Olusanya (2012) calculated the efects of multiparity compared with primiparity. They found an eightfold rise in multifetal gestation rates when parity was ;4, and a 20-fold rise when parity was :5.

As a determinant of twinning, the family history ofthe mother supersedes that of the father. One study of 4000 genealogical records showed that women who themselves were a dizygotic twin gave birth to twins at a rate of 1 set per 58 births (White, 1964). Women who were not a twin, but whose husbands were a dizygotic twin, gave birth to twins at a rate of 1 set per 116 pregnancies. Painter and associates (2010) performed genomewide linkage analyses on more than 500 families of mothers of dizygotic twins and identified four potential linkage peaks. he highest peak was on the long arm ofchromosome 6, and other suggestive peaks were on chromosomes 7, 9, and 16. That said, the contribution of these variants to the overall incidence of twinning is likely small (Hoekstra, 2008).

In animals, the litter size number grows in proportion to nutritional suiciency. Evidence from various sources indicates that this occurs in humans as well. Nylander (1971) showed an increasing gradient in the twinning rate related to greater nutritional status as relected by maternal size. Taller, heavier women had a twinning rate 25 to 30 percent greater than short, nutritionally deprived women. Likewise, Reddy and associates (2005) found an association of maternal weight and dizygotic twinning in the

United States, in the absence of fertility drugs. Indeed, the influ ence of maternal weight s a factor for twinning will continue to rise in importance s the percentage of obese women in the United

States continues to grow.

Evidence acquired during and after World War II suggested that twinning correlated more with nutrition than with body size. Widespread undernourishment in Europe during those years was associated with a marked fall in the dizygotic twinning rate (Bulmer, 1959). Several investigators have reported a greater prevalence of twinning among women who have taken supplementary folic acid (Ericson, 2001; Haggarty, 2006). Conversely, in a systematic review, Muggli and Halliday (2007) were unable to demonstrate a significant association. Analysis of twinning rate in Texas after folic acid fortiication of cerealgrain products also failed to demonstrate an independent increase in twinning rates (Waller, 2003).

he common factor linking race, age, weight, and fertility to multifetal gestation may be FSH levels (Benirschke, 1973). This theory is supported by the fact that greater fecundity and a higher rate of dizygotic twinning have been reported in women who conceive within 1 month after stopping oral contraceptives, but not during subsequent months (Rothman, 1977). This may be due to the sudden release of pituitary gonadotropin in amounts greater than usual during the irst spontaneous cycle after stopping hormonal contraception. Indeed, the paradox of declining fertility but increasing twinning with advancing maternal age can be explained by an exaggerated pituitary release of FSH in response to decreased negative feedback from impending ovarian failure (Beemsterboer, 2006).

Ovulation induction with FSH plus human chorionic gonadotropin (hCG) or clomiphene citrate remarkably enhances the likelihood of multiple concurrent ovulations. In their review of this practice, McClamrock and coworkers (2012) reported rates of twins and higher-order multifetal pregnancies as high as 28.6 percent and 9.3 percent, respectively. Rates this high remain a major concern. Two ongoing multicenter trialsAssessment of Multiple Gestations from Ovarian Stimulation (AMIGOS) and Pregnancy in Polycystic Ovary Syndrome II (PPCOSII)-are designed to provide guidance on achieving maximum pregnancy rates while minimizing multifetal gestation rates (Diamond, 2015; Legro, 2014).

In general with in vitro fertilization (IVF), the greater the number of embryos that are transferred, the greater the risk of twins and other multifetal gestations. In 2014, ART contributed to 1.6 percent of all newborns in the United States and to 18.3 percent of all neonates in multifetal gestations (Sunderam, 2017). The American Society for Reproductive Medicine (2017) recently revised their age-related guidelines regarding the number of cleavage-stage embryos or blastocysts to transfer during IVF. This efort aims to reduce the incidence of higher-order multifetal pregnancies. Based on these new recommendations, women younger than 35 years are encouraged to receive a single-embryo transfer, regardless of embryo stage.

hese practices have efectively lowered multifetal rates, and the rate of triplet or higher-order multifetal pregnancy has declined every year since 2009 (Kulkarni, 2013; Martin, 2017).

In humans, as the number of fetuses per pregnancy rises, the percentage of male conceptuses declines. Strandskov and coworkers (1946) found the percentage of males in 31 million singleton births in the United States was 51.6 percent. For twins, it was 50.9 percent; for triplets, 49.5 percent; and for quadruplets, 46.5 percent. Swedish birth data spanning 135 years reveals the number of males per 100 female newborns was 106 among singletons, 103 among twins, and 99 among triplets (Fellman, 2010). Females predominate even more in twins from late twinning events. For example, 68 percent of thoracopagus conjoined twins are female (Mutchinick, 2011). Two explanations have been ofered. First, beginning in utero and extending throughout the life cycle, mortality rates are lower in females. Second, female zygotes have a greater tendency to divide.

Twins of opposite sex are almost always dizygotic. In rare instances, due to somatic mutations or chromosome aberrations, the karyotype or phenotype of a monozygotic twin gestation can be diferent (Turpin, 1961). Most reported cases describe postzygotic loss of the Y chromosome in one 46,XY twin resulting in a phenotypically female twin with Turner syndrome (45,X). Zech and coworkers (2008) found a rare case of a 47,Y zygote that underwent postzygotic loss of the X chromosome in some cells and loss of the Y chromosome in other cells. The phenotype of the resultant twins was one male and one female. Karyotype analyses revealed both to be 46,XXJ46,XY genetic mosaics.

he risk for twin-speciic complications varies in relation to both zygosity and chorionicity-the number of chorions. Shown in Table 45-2, the latter is the more important determinant. Speciically, perinatal mortality and neurological injury rates are greater in monochorionic diamnionic twins compared with dichorionic diamnionic pairs (Hack, 2008; Lee, 2008). In one retrospective analysis of more than 2000 twins, the risk of fetal demise in one or both monochorionic twin(s) was twice that in dichorionic multifetal gestations (McPherson, 2012). Moreover, the prospective risk of antepartum stillbirth is higher for monochorionic than for dichorionic twins at all preterm gestational ages. he highest risk is before 28 weeks' gestation (Glinianaia, 2011). In contrast, chorionicity diferences do not signiicantly afect maternal outcomes (Carter, 2015).

This has become an integral tool to assist in multifetal pregnancy management. Indeed, the diagnosis and evaluation of a multifetal gestation is now considered a recognized indication for irst-trimester sonography (Reddy, 2014). In addition, the North American Fetal Therapy Network (NAFTNet)-a

TABLE 45-2. Overview of the Incidence of Twin Pregnancy Zygosity and Corresponding Twin-Specific Complications

Rates of Twin-Specific Complications in Percent consortium of 30 medical institutions in the United States and Canada-have provided recommendations for determination of chorionicity using sonography (Emery, 2015).

Sonographic features used to evaluate chorionicity vary according to gestational age. Accuracy is greatest in the irst trimester and diminishes as gestational age advances. Namely, chorionicity can be determined sonographically with 98-percent accuracy in the irst trimester but may be incorrect in up to 10 percent of second-trimester examinations (Emery, 2015; Lee, 2006). Moreover, for sonographic evaluations between 15 and 20 weeks' gestation, the odds of chorionicity misclassiication rise by approximately 10 percent for each week of advancing gestational age in pregnancies compared with those completed before 14 weeks (Blumenfeld, 2014). Overall, chorionicity can be correctly determined with sonography before 24 weeks in approximately 95 percent of cases (Lee, 2006).

Early in the first trimester, the number of chorions equates to the number of gestational sacs. A thick band of chorion separating two gestational sacs signals a dichorionic pregnancy, whereas monochorionic twins have a single gestational sac. If the gestation is monochorionic diamnionic, it may be diicult to visualize the thin intervening amnion before 8 weeks' gestation (Emery, 2015). If the intervening membrane is diicult to visualize, the number of yolk sacs usualy correlates with the number of amnions. However, the number of yolk sacs as a predictor of amnionicity may not always be accurate (Shen, 2006). Although uncommonly seen early, cord entanglement identifies a monoamnionic gestation. When chorionicity is uncertain, additional later sonographic examinations are performed.

Ater 10 to 14 weeks' gestation, sonographic assessment of chorionicity may be determined using four features. These are the number of placental masses, thickness of the membrane dividing the sacs, presence of an intervening membrane, and fetal gender (Emery, 2015). First, two separate placentas suggest dichorionicity. The converse is not necessarily true, such as cases with a single fused placental mass. Second, identiication of a thick dividing membrane-generally �2 mm-supports a presumed diagnosis of dichorionicity. In a dichorionic pregnancy, this visualized membrane is composed of a total of four layers-two amnion and two chorion. Also, the twin peak sign-also called lambda or delta sign-is seen by examining the point of origin of the dividing membrane on the placental surface. he peak appears as a triangular projection of placental tissue extending a short distance between the layers of the dividing membrane (Fig. 45-4).

FIGURE 45-4 A. Sonographic image of the "twin-peak" sign, also termed the "lambda sign," in a 24-week gestation. At the top of this sonogram, tissue from the anterior placenta is seen extending downward between the amnion layers. This sign confirms dichorionic twinning. B. The "tWin-peak" sign is seen at the bottom of this schematic diagram. The triangular portion of placenta insinuates between the amniochorion layers.

FIGURE 45-5 A. Sonographic image of the '" sign in a monochorionic diamnionic gestation at 30 weeks. B. Schematic diagram of the '" sign. Twins are separated only by a membrane created by the juxtaposed amnion of each twin. A '" is formed at the point at which amnions meet the placenta.

In contrast, monochorionic pregnancies have a dividing membrane that is so thin (generally <2 mm) that it may not be seen until the second trimester. The relationship between the membranes and placenta without apparent extension of placenta between the dividing membranes is called the T sign (Fig. 45-5). Evaluation of the dividing membrane can establish chorionicity in more than 99 percent of pregnancies in the first trimester (Miller, 2012). Lack of a dividing membrane signals a monochorionic monoamnionic gestation.

Last, twins with difering gender indicates a dichorionic (and dizygotic) gestation (Emery, 2015). A rare exception to this scenario would be a heterokaryotypic monochorionic gestation, described earlier (p. 867). If both twins are the same gender, additional measures are necessary.

A carefully performed visual examination of the placenta and membranes ater delivery serves to establish zygosity and chorionicity promptly in approximately two thirds of cases. The following systematic examination is recommended. As the irst neonate is delivered, one damp is placed on a portion of its

FIGURE 45-6 Dichorionic diamnionic twin placenta. The membrane partition that separated twin fetuses is elevated and consists of chorion (c) between two amnions (0).

cord. Cord blood is generally not collected until after deliv ery of the other twin. As the second neonate is delivered, two damps are placed on that cord, and so on as necessary. lter natively, in higher-order deliveries, color-tagged damps can be simpler. Until the delivery of the last fetus, each cord segment must remain damped to prevent fetal hypovolemia and anemia caused by blood leaving the placenta via anastomoses and then through an undamped cord. At this time, evidence is insuicient in multifetal gestations (American College of Obstetricians and

Gynecologists, 2017a). At Parkland Hospital, we currently do not perform delayed cord damping in these pregnancies.

The placenta is carefully delivered to preserve the attachment of the amnion and chorion. With one common amnionic sac or with juxtaposed amnions not separated by chorion, the fetuses are monozygotic (see Fig. 45-1). If adjacent amnions are separated by chorion, the fetuses could be either dizygotic or monozygotic, but dizygosity is more common (Fig. 45-6). If the neonates are of the same sex, blood typing of cord blood samples may be helpful. Diferent blood types conirm dizygosity, although demonstrating the same blood type in each fetus does not conirm monozygosity. For deinitive diagnosis, more complicated techniques such as DNA ingerprinting can be used. However, these tests are generally not performed at birth unless medical indications dictate a need.

During physical examination, accurate fundal height measurement, described in Chapter 9 (p. 164), is essential. With multifetal pregnancies, uterine size is typically larger during the second trimester than expected for a singleton. Rouse and associates (1993) reported fundal heights in 336 well-dated twin pregnancies. Between 20 and 30 weeks' gestation, fundal heights averaged approximately 5 cm greater than expected for singletons of the same fetal age.

FIGURE 45-7 Sonograms of first-trimester twins. A. Dichorionic diamnionic twin pregnancy at 6 weeks' gestation. Note the thick dividing chorion (yellow arrow). One of the yolk sacs is indicated (blue arrow). B. Monochorionic diamnionic twin pregnancy at 8 weeks' gestation. Note the thin amnion encircling each embryo, resulting in a thin dividing membrane (blue arrow).

Diagnosing twins by palpation of fetal parts before the third trimester is diicult. Even late in pregnancy, this may be challenging, especially if one twin overlies the other, if the woman is obese, or if there is hydramnios. Palpating two fetal heads, often in diferent uterine quadrants, strongly supports a twin diagnosis. Late in the first trimester, two fetal heartbeats may be diferentiated with Doppler ultrasonic equipment if their rates are clearly distinct from each other and from that of the mother.

Overall, however, using clinical criteria alone to diagnose multifetal gestations is unreliable. For example, in the Routine Antenatal Diagnostic Imaging with Ultrasound (RADIUS) trial, for 37 percent of women who did not have a screening ultrasound examination, their twin pregnancies were not diagnosed until 26 weeks' gestation. And, in 13 percent of unscanned women, their multifetal gestations were only diagnosed during their admission for delivery (American College of Obstetricians and Gynecologists, 2016; LeFevre, 1993).

Sonographic examination should detect practically all sets of twins. And, given the increased frequency of sonographic examinations during the first trimester, early detection of a twin pregnancy is common. Sonography can also be used to determine fetal number, estimated gestational age, chorionicity, and amnionicity. With careful examination, separate gestational sacs, if present, can be identiied early in twin pregnancy (Fig. 45-7). Subsequently, each fetal head should be seen in two perpendicular planes so as not to mistake a cross section of the fetal trunk for a second fetal head. Ideally, two fetal heads or two abdomens should be seen in the same image plane to avoid scanning the same fetus twice and interpreting it as twins.

Higher-order multifetal gestations are more challenging to evaluate. Even in the irst trimester, it can be diicult to identiY the actual number of fetuses and their position. This determination is especially important if pregnancy reduction or selective termination is considered (p. 891).

Abdominal radiography can be used if fetal number in a higherorder multifetal gestation is uncertain. However, radiographs generally have limited utility and may lead to an incorrect diagnosis if fetuses move during the exposure or if exposure time is inadequate. Additionally, fetal skeletons before 18 weeks' gestation are insuiciently radiopaque and may be poorly seen.

Although not typically used to diagnose multifetal pregnancy, magnetic resonance (MR) imaging may help delineate complications in monochorionic twins (Hu, 2006). In one review of 17 complicated twin gestations evaluated by both sonographic and MR imaging, the latter provided a more detailed assessment of twin pathology (Bekiesinska-Figatowska, 2013). This was particularly helpful in cases of conjoined twins.

No biochemical test reliably identifies multifetal gestations.

Serum and urine levels of 3-hCG and maternal serum levels of alpha-fetoprotein (MSAFP) are generally higher with twins compared with those in singletons. However, levels may vary considerably and overlap with those of singletons.

he various physiological burdens of pregnancy and the likelihood of serious maternal complications are typically greater with multifetal gestations than with a singleton pregnancy. his is considered, especially when counseling a woman whose health is compromised and in whom a multifetal gestation is recognized early. Similar consideration is given to the woman who is not pregnant but is considering infertility treatment.

Beginning in the first trimester, and temporarily associated with higher serum 3-hCG levels, women with a multifetal gestation oten have nausea and vomiting in excess of that with a singleton pregnancy. In women carrying more than one fetus, blood volume expansion is greater and averages 50 to 60 percent compared with 40 to 50 percent in those with a singleton (Pritchard, 1965). This augmented hypervolemia teleologically ofsets blood loss with vaginal delivery of twins, which is twice that with a single fetus. Although red cell mass also accrues, it does so proportionately less in twin pregnancies. Combined with greater iron and folate requirements, this predisposes to anemia.

Women carrying twins also have a typical pattern of arte rial blood pressure change. MacDonald-Wallis and coworkers (2012) analyzed serial blood pressures in more than 13,000 singleton and twin pregnancies. As early as 8 weeks' gestation, the diastolic blood pressure in women with twins was lower than that with singleton pregnancies but generally rose by a greater degree at term. An earlier study demonstrated that this rise was at least 15 mm Hg in 95 percent of women with twins compared with only 54 percent of women with a singleton (Campbell, 1986).

Hypervolemia along with decreased vascular resistance has an impressive efect on cardiac function. In one study of 119 women with a twin pregnancy, cardiac output rose another 20 percent above that in women with a singleton pregnancy (Kametas, 2003). Similarly, Kuleva and coworkers (201l) using serial echocardiography found a greater increase in cardiac output in 20 women with uncomplicated twin pregnancies. Both studies found the augmented cardiac output was predominantly due to greater stroke volume rather than higher heart rate. Vascular resistance was signiicantly lower in twin gestations throughout pregnancy compared with singleton ones. In a study of 30 uncomplicated twin pregnancies, this same group of investigators using echocardiography later identified progressive diastolic dysfunction from the irst to third trimester. The dysfunction subsequently normalized after delivery (Ghi, 2015).

Uterine growth in a multifetal gestation is substantively greater than in a singleton pregnancy. The uterus and its nonfetal contents may achieve a volume of 10 L or more and weigh in excess of 20 pounds. Especially with monozygotic twins, excessive amounts of amnionic luid may rapidly accumulate. In these circumstances, maternal abdominal viscera and lungs can be appreciably compressed and displaced by the expanding uterus. As a result, the size and weight of the large uterus may preclude more than a sedentary existence for these women.

Ifhydramnios develops, maternal renal function can become seriously impaired, most likely as the consequence of obstructive uropathy (Quigley, 1977). With severe hydramnios, therapeutic amniocentesis may provide relief for the mother, may improve obstructive uropathy, and possibly may lower the preterm delivery risk that follows preterm labor or prematurely ruptured membranes. Unfortunately, hydramnios is often characterized by acute onset remote from term and by rapid reaccumulation despite amniocentesis.

Miscarriage is more likely with multifetal gestation. In one 16-year study, the spontaneous abortion rate per live birth in singleton pregnancies was 0.9 percent compared with 7.3 percent in multifetal ones (Joo, 2012). Also, twins achieved through ART are at greater risk for abortion compared with those conceived spontaneously (Szymusik, 2012).

In some cases, one fetus may be spontaneously lost rather than the entire gestation. As a result, the incidence of twins in the irst trimester is much greater than the incidence of twins at birth. It has been estimated that 1 in 80 births are multifetal, whereas 1 in 8 pregnancies begin multifetal but are spontane ously reduced (Corsello, 2010). Sonography studies in the first trimester have shown that one twin is spontaneously reduced or "vanishes" before the second trimester in up to 10 to 40 percent of all twin pregnancies (Brady, 20l3). The incidence is higher following ART conception. Also, monochorionic twins have a significantly greater risk of spontaneous reduction than dicho rionic twins (Sperling, 2006). Undoubtedly, some threatened abortions are the result of death and resorption of one embryo from an unrecognized twin gestation.

tion in 709 multifetal pregnancies. Before 12 weeks, one or more embryos died in 36 percent of twin pregnancies, in 53 percent of triplet pregnancies, and in 65 percent of quadru plet pregnancies. Interestingly, ultimate pregnancy duration and birthweight were inversely related to the initial gestational sac number regardless of the final number of fetuses at deliv ery. This efect was most pronounced in twins who started as quadruplets. Chasen and coworkers (2006) reported that spon taneous reduction of an IVF twin pregnancy to a singleton pregnancy was associated with perinatal outcomes intermediate did not undergo spontaneous reduction. Evidence for adverse immediate and long-term efects of twin spontaneous reduction on the remaining pregnancy is conflicting (MeN amara, 2016).

Notably, spontaneous reduction of a twin gestation may afect prenatal screening results. In one study of ART-conceived gestations, Gjerris and colleagues (2009) compared 56 twin pregnancies with a single early demise and 897 singleton gestations. They found no diferences in irst-trimester serum marker concentrations as long as the embryonic loss was identiied before 9 weeks' gestation. If diagnosed ater 9 weeks, the serum markers were higher and less precise in gestations with an early demise of one twin than in the singleton gestations. With a vanishing twin, first-trimester maternal serum levels of the pregnancy associated plasma protein-A (PAPP-A) can be elevated. Second-trimester MSAFP and dimeric inhibin A levels can also be higher (Huang, 2015). his phenomenon may also afect noninvasive prenatal testing using cell-free DNA (cDNA). In one report, this efect was thought to be responsible for 15 percent of the false-positive results from quantitative counting methods (Futch, 20l3). The recent development of single nucleotide polymorphism technology for cDNA testing appears to hold promise in better identiYing these cases (Curnow, 2015). Regardless, the diagnosis of a spontaneously reduced abortus is ideally excluded to help avoid confusion with results from aneuploidy and neural-tube defect screening.

As noted earlier, the incidence of congenital malformations is appreciably higher in multifetal gestations compared with that in singleton pregnancies. In one survey-based study, the congenital malformation rate was 406 per 10,000 twins compared with 238 per 10,000 singletons (Glinianaia, 2008). The malformation rate in monochorionic twins was almost twice that of dichorionic twin gestations. This increase has been attributed to the higher incidence of structural defects in monozygotic twins. Indeed, one large population-based study between 1998 and 2010 found that twins had a 73-percent greater risk of congenital heart disease than singletons. The risk was substantially higher among monochorionic twins (Best, 2015). But, from a 30-year European registry of multifetal births, structural anomaly rates rose steadily from 2.16 percent in 1987 to 3.26 percent in 2007 (Boyle, 2013). Yet, during this time, the proportion of dizygotic twins grew by 30 percent, whereas the proportion of monozygotic twins remained stable. his higher risk of congenital malformations in dizygotic twins over time correlated with increased availability of AR. An increase in rates of birth defects related to ART has been reported repeatedly (Boulet, 2016; Talauliker, 2012).

Multifetal gestations are more likely to be low birthweight than singleton pregnancies due to restricted fetal growth and preterm delivery. From 1988 to 2012 at Parkland Hospital, data were collected from 357,205 singleton neonates without malformations and from 3714 normal twins who were both liveborn. Birthweights in twins closely paralleled those of singletons until 28 to 30 weeks' gestation. Thereafter, twin birthweights progressively lagged (Fig. 45-8). Beginning at 35 to 36 weeks' gestation, twin birthweights clearly diverge from those of singletons.

In general, the degree of growth restriction increases with fetal number. The caveat is that this assessment is based on growth curves established for singletons. Several authorities argue that fetal growth in twins is diferent from that of singleton pregnancies. And thus, abnormal growth should be diagnosed only when fetal size is less than expected for multietal gestation. Accordingly, twin and triplet growth curves have been developed (Kim, 2010; Odibo, 2013; Vora, 2006). At Parkland, we use the standards of birthweight in twin gestations stratified by placental chorionicity for identification of suspected fetal-growth restriction (Ananth, 1998).

FIGURE 45-8 Birthweight percentiles (25th to 75th) for 357,205 singleton neonates compared with the 50th birthweight percentile for 3714 twins, Parkland Hospital 1988-2012. Infants with major

FIGURE 45-9 Marked growth discordance in monochorionic twins. (Used with permission from Dr. Laura Greer.) he degree of growth restriction in monozygotic twins is likely to be greater than that in dizygotic pairs (Fig. 45-9). With monochorionic embryos, allocation of blastomeres may not be equal, vascular anastomoses within the placenta may cause unequal distribution of nutrients and oxygen, and discordant structural anomalies resulting from the twinning event itself may afect growth. For example, the quintuplets shown in Figure 45-10 represent three dizygotic and two monozygotic fetuses. When delivered at 31 weeks, the three neonates from separate ova weighed 1420, 1530, and 1440 g, whereas the two derived from the same ovum weighed 990 and 860 g.

In the third trimester, the larger fetal mass leads to accelerated placental maturation and relative placental insuiciency. In dizygotic pregnancies, marked size discordancy usually results from unequal placentation, with one placental site receiving more perfusion than the other. Size diferences may also reflect diferent genetic fetal-growth potentials. Discordancy can also result from fetal malformations, genetic syndromes, infection, or umbilical cord abnormalities such as velamentous insertion ' marginal insertion, or vasa previa (Chap. 44, p. 849).

Pregnancy-related hypertensive disorders are more likely to develop with multifetal gestations. The exact incidence attributable to twin pregnancy is diicult to determine because these gestations are more likely to deliver preterm and before preeclampsia usually develops. Also, women with twin pregnancies are often older and multiparous, qualities associated with lower rates of preeclampsia (Francisco, 2017). The incidence of pregnancy-related hypertension in women with twins is 20 percent at Parkland Hospital. In their analysis of 513 twin malformations, pregnancies complicated by stillbirth, and twin gestations with >25 percent discordance were also excluded. (Data from Dr. Don Mcintire.) pregnancies, Fox and coworkers (2014) identified 15 percent of parturients with preeclampsia. Another study compared 257 women with twins and gestational diabetes against 277 nondiabetic women carrying twins. hese researchers found a twofold greater risk of preeclampsia in women diagnosed with gestational diabetes (Gonzalez, 2012). Conversely, no specific zygosity confers a greater rate of hypertensive disorder in twin pregnancies (Lucovnik, 2016). Finally, from the National Center for Health Statistics, Luke and associates (2008) analyzed 316,696 twin, 12,193 triplet, and 778 quadruplet pregnancies. hese investigators noted that the risk for pregnancy-associated hypertension was significantly increased for triplets and quadruplets (11 and 12 percent, respectively) compared with that for twins (8 percent).

FIGURE 45-10 Davis quintuplets at 3 weeks following delivery. The first, second, and fourth newborns from the left each arose from separate ova, whereas the third and fifth neonates are from the same ovum.

hese data suggest that fetal number and placental mass are involved in preeclampsia pathogenesis. Women with twin pregnancies have levels of antiangiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) that are twice that of singletons. Levels are seemingly related to greater placental mass rather than primary placental pathology (Bdolah, 2008; Maynard, 2008). Rana and coworkers (2012) measured antiangiogenic sFlt-1 and proangiogenic placental growth factor (PIGF) in 79 women with twins referred for evaluation of preeclampsia. In the 58 women identiied with either gestational hypertension or preeclampsia, there was an incremental rise in sFlt-1 concentrations, decline in PIGF levels, and increase in sFlt-lIPIGF ratios compared with normotensive twin pregnancies. With multifetal gestation, hypertension not only develops more often but also tends to develop earlier and be more severe. In the analysis of angiogenic factors mentioned above, more than half of afected women presented before 34 weeks, and their sFlt-lIPIGF ratio rise was more striking (Rana, 2012). This relationship is discussed in Chapter 40 (p. 716).

The duration of gestation shortens with accruing fetal number. More than five of every 10 twins and nine of 10 triplets born in the United States in 2015 were delivered preterm (Martin, 2017). Prematurity is sixfold and tenfold greater in twins and triplets, respectively (Giufre, 2012). One review showed that approximately 60 percent of preterm births in twins are indicated, about a third result from spontaneous labor, and 10 percent follow prematurely ruptured membranes (Chauhan, 2010). In another analysis of almost 300,000 live births, the proportion of preterm birth associated with premature membrane rupture rose with gestational plurality from 13 percent with singletons to 20 percent with triplets or more (Pakrashi, 2013).

Although the causes of preterm delivery in twins and singletons may be diferent, neonatal outcome is generally the same at similar gestational ages (Kilpatrick, 1996; Ray, 2009; Salem, 2017). However, outcomes for pre term twins who are markedly discordant may not be comparable with those for singletons because whatever caused the discordance may have long-lasting efects (Yinon, 2005) .

Historically, twins have been considered cognitively delayed compared with singletons (Record, 1970; Ronalds, 2005). However, in cohort studies evaluating normal-birthweight term newborns, cognitive outcomes between twins and singletons are similar (Lorenz, 2012). Christensen and associates (2006) found similar national standardized test scores in the ninth grade in 341r1 twins and 7796 singletons born between 1986 and 1988.

In contrast, among normal-birthweight neonates, the cerebral palsy risk is higher among twins and higher-order multiples. For example, the cerebral palsy rate has been reported to be 2.3 per 1000 in singletons, 12.6 per 1000 in twins, and 44.8 per 1000 in triplets (Giufre, 2012). Greater risks of fetalgrowth restriction, congenital anomalies, twin-twin transfusion syndrome, and fetal demise of a cotwin are suggested contributors to these diferences (Lorenz, 2012).

Several unique complications arise in multifetal pregnancies. These are described in twins but can be found in higher-order multifetal gestations. Most fetal complications due to the twinning process itself are seen with monozygotic twins. heir pathogenesis is best understood after reviewing the possibilities shown in Figure 45-1.

Only about 1 percent of all monozygotic twin gestations will share an amnionic sac, and approximately 1 in 20 monochorionic twin gestations are monoamnionic (Hall, 2003; Lewi, 2013). Diamnionic twins can become monoamnionic if the dividing membrane spontaneous or iatrogenically ruptures. Their morbidity and mortality rates then mirror those of monoamnionic twins.

Historical mortali ty rates in monoamnionic twins were reported to be as high as 70 percent. Contemporary outcomes are improved, yet the demise rate after viability remains elevated (Post, 2015). Of those fetuses alive before 16 weeks' gestation, less than half survive until the neonatal period. Fetal abnormalities and spontaneous miscarriage contribute to most losses (Prefumo, 2015). After 20 weeks, the perinatal mortality rate for monoamnionic twin pregnancies approximates 15 percent (Shub, 2015). A high fetal death rate is attributable to preterm birth, congenital anomalies, twin-twin transfusion syndrome, or cord entanglement.

Congenital anomaly rates in monoamnionic twins reach 18 to 28 percent (Post, 2015). Since concordance of anomalies is found in only approximately one quarter of cases, the finding of normal anatomy in one twin does not negate the need for a thorough evaluation in the second. Also, because of the higher risk of cardiac anomalies, fetal echo cardiography is indicated in these pregnancies. Of note, monoamnionic twins are by definition monozygotic and thus presumed to be genetically identical. Consequently, either both or none of the fetuses have chromosomal abnormalities except in rare cases of discordance (Zwijnenburg, 2010). Indeed, the risk for Down syndrome in each fetus of the monozygotic pair is similar to or lower than the risk in maternal age-matched singletons (Sparks, 2016). he standard methods for Down syndrome screening in these pregnancies can be applied (Chap. 14, p. 281).

The rate of twin-twin transfusion syndrome in monoamnionic twins is lower than the rate reported in monochorionic diamnionic pregnancies. This may be due to the near universal presence in monoamnionic twins of arterioarterial anastomoses, which are presumed to be protective (Hack, 2009b; Post, 2015). Nonetheless, twin-twin transfusion syndrome surveillance is recommended and described on page 879.

Umbilical cords frequently entangle (Fig.

lorbid cord entanglement appears to occur early, and monoamnionic pregnancies that have successfully reached 30 to 32 weeks' gestation are at reduced risk. In one Dutch series, the incidence of intrauterine demise dropped from 15 percent after 20 weeks to 4 percent at gestational ages >32 weeks (Hack, 2009a). Although color-low Doppler sonography is used to diagnose entanglement (Fig. 45-12), factors that lead to pathological umbilical vessel constnctton are unknown. A consequence is that fetal death from cord entanglement is unpredictable. Unfortunately, monitoring for this is relatively inefective. In one study, after analysis of more than 10,000 hours of fetal tracing from 17 sets of monoamnionic twins, Quinn and colleagues (2011) concluded that monitoring was physically

FIGURE 45-1 1 Monozygotic twins in a single amnionic sac. The smaller fetus apparently died first, and the second subsequently succumbed when umbilical cords entwined.

FIGURE 45-12 Monochorionic monoamnionic cord entanglement.

A. Despite marked knotting of the cords, vigorous twins were delivered by cesarean. B. Preoperative sonogram of this pregnancy shows entwined cords. C. This finding is accentuated with application of color Doppler. (Used with permission from Dr. Julie Lo.)

FIGURE 45-13 Possible outcomes of monozygotic twinning. The asymmetrical category contains twinning types in which one twin complement is substantially smaller and incompletely formed.

possible in only 50 percent of cases. An abnormal fetal heart rate tracing prompted delivery in only six cases.

One proposed management scheme is based on a study by Heyborne and coworkers (2005), who reported no stillbirths in 43 twin pregnancies of women admitted at 26 to 27 weeks' gestation for daily fetal surveillance. However, in 44 women managed as outpatients and admitted only for obstetrical indications, there were 13 stillbirths. Because of this report, women with monoamnionic twins are recommended to undergo 1 hour of daily fetal heart rate monitoring, either as an outpatient or inpatient, beginning at 26 to 28 weeks' gestation. With initial testing, a course of betamethasone is given to promote pulmonary maturation (Chap. 42, p. 823). If fetal testing remains reassuring and no other intervening indications arise, cesarean delivery is performed at 32 to 34 weeks. A second course of betamethasone can be given before this (American College of Obstetricians and Gynecologists, 2016). his management scheme is used at Parkland Hospital and resulted in the successful 34-week delivery of the twins depicted in Figure 45-12.

Of monoamnionic twins just described, one interesting subset derives from embryonic splitting on postfertilization day 9. These "mirror image twins" are genetically identical but have mirror image features such as handedness and hair whorls (Post, 2015).

More seriously, several aberrations in monozygotic twinning result in a spectrum of fetal malformations. hese are traditionally ascribed to incomplete splitting of an embryo into two separate twins. However, it is possible that they may result from early secondary fusion of two separate embryos. These separated embryos are either symmetrical or asymmetrical, and the spectrum of anomalies is shown in Figure 45-13.

In the United States, united or conjoined twins have been referred to as Siamese twins-after Chang and Eng Bunker of Siam (Thailand), who were displayed worldwide by P. T. Barnum. Joining of the twins may begin at either pole and produce characteristic forms depending on which body parts are joined or shared (Fig. 45-14). Of these, thoracopagus is the most common (Mutchinick, 2011). he frequency of conjoined twins is not well established. In Singapore, Tan and coworkers (1971) identified seven cases of conjoined twins among more than 400,000 deliveries-an incidence of 1 in 60,000.

Conjoined twins can frequently be identiied using sonography at midpregnancy (McHugh, 2006). his provides an opportunity for parents to decide whether to continue the pregnancy. As shown in Figure 45-15, identification of cases during the first trimester is also possible. During sonographic interrogation, fetal poles are closely associated and do not change relative position from one another. A targeted examination, including a careful evaluation of the organs involved, is necessary before counseling can be provided. As shown in Figure 45-16, MR imaging is a valuable adjunct to clariY shared organs. Compared with sonography, MR imaging can provide superior views, especially in later pregnancy when amnionic luid is diminished and fetal crowding is greater (Hibbeln, 2012).

Surgical separation of an almost completely joined twin pair may be successful if essential organs are not shared (O'Brien, 2015; Tannuri, 20l3). Conjoined twins may have discordant structural anomalies that further complicate decisions about whether to continue the pregnancy. Consultation with a pediatric surgeon often assists parental decision making. A recent

FIGURE 45-14 Types of conjoined twins. (Modified with permission from Spencer R: Theoretical and analytical embryology of conjoined . Parapagus Parapagus twins: part I: embryogenesis, (lin Anat. 2000;13(1 ):36-53.) series in Seminars in Pediatric Surgey with a preface by Spitz (2015) provide an excellent reference regarding postnatal management.

Viable conjoined twins should be delivered by cesarean. For the purpose of pregnancy termination, however, vaginal delivery is possible because the union is most often pliable (Fig. 45-17). Still, dystocia is common, and if the fetuses are mature, vaginal delivery may be traumatic to the uterus or cervix.

his is a grossly defective fetus or merely fetal parts, attached externally to a relatively normal twin. A parasitic twin usually consists of externally attached supernumerary limbs, often with some viscera. Classically, however, a functional heart or brain is absent. Attachment mirrors those sites described earlier for conjoined twins (see Fig. 45-14). Parasites are believed to result from demise of the defective twin. Its surviving tissue attaches to and receives vascularity from the normal cotwin (Spencer, 2001). In one large epidemiological study, parasitic twins accounted for 4 percent of all conjoined twins and occurred more frequently in male fetuses (Mutchinick, 2011).

FIGURE 45-15 Sonogram of a conjoined twin pregnancy at 13 weeks' gestation. These thoracoomphalopagus twins have two heads but a shared chest and abdomen.

Early in development, one embryo may be enfolded within its twin. Normal development of this rare parasitic twin usually arrests in the first trimester. As a result, norml spatial arrangement of and presence of many organs is lost. Classically, vertebral or xial bones are found in the fetiform mass, whereas a heart and brain are absent. hese masses are believed to represent a monozygotic, monochorionic diamnionic twin gestation and are typically supported by large parasitic vessels to the host (McNamara, 2016; Spencer, 2000). Malignant degeneration is rare (Kaufman, 2007).

All monochorionic placentas likely share some anastomotic connections. And, with rare exceptions, anastomoses between

FIGURE 45-16 Magnetic resonance imaging of conjoined twins. This T2-weighted HASTE sagittal image demonstrates fusion from the level of the xiphoid process to just below the level of the umbilicus, that is, omphalopagus twins. Below the fused liver (L)/ there is a midline cystic mass (arrow) within the tissue connecting the twins. An omphalomesenteric cyst was favored given the location within the shared tissue. (Used with permission from

Dr. April Bailey.)

FIGURE 45-17 Conjoined twins aborted at 17 weeks' gestation. (Used with permission from Dr. Jonathan Willms.) twins are unique to monochorionic twin placentas. However, the number, size, and direction of these seemingly haphazard connections vary markedly (Fig. 45-18). In one analysis of more than 200 monochorionic placentas, the median number of anastomoses was 8, with an interquartile range of 4 to 14 (Zhao, 2013).

Artery-to-artery anastomoses are most frequent and are identiied on the chorionic surface of the placenta in up to 75 percent of monochorionic twin placentas. Vein-to-vein and artery-to-vein communications are each found in approximately half. One vessel may have several connections, sometimes to both arteries and veins. In contrast to these supericial vascular connections on the surface of the chorion, deep arteryto-vein communications can extend through the capillary bed of a given villus (Fig. 45-19). hese deep arteriovenous anastomoses create a common villous compartment or "third circulation" that has been identiied in approximately half of monochorionic twin placentas.

FIGURE 45-19 Anastomoses between twins may be artery-tovein (AV), artery-to-artery (AA), or vein-to-vein (W). Schematic representation of an AV anastomosis in twin-twin transfusion syndrome that forms a "common villous district" or "third circulation" deep within the villous tissue. Blood from a donor twin may be transferred to a recipient twin through this shared circulation. This transfer leads to a growth-restricted discordant donor twin with markedly reduced amnionic fluid, causing it to be "stuck."

Whether these anastomoses are dangerous to either twin depends on the degree to which they are hemodynamically balanced. In those with signiicant pressure or low gradients, a shunt will develop between fetuses. his chronic fetofetal transfusion may result in several clinical syndromes that include

FIGURE 45-18 Shared placenta from pregnancy complicated by twin-twin transfusion syndrome. The following color code was applied for injection. Left twin: yellow = artery, blue = vein; right twin: red = artery, green = vein. A. Part of the arterial network of the right twin is filled with yellow dye, due to the presence of a small artery-to-artery anastomosis (arrow). B. Close-up of the lower portion of the placenta displays the yellow dye-filled anastomosis. (Reproduced with permission from De Paepe ME, DeKoninck P, Friedman RM: Vascular distribution patterns inmonochorionic twin placentas, Placenta. 2005 Jul;26(6):471-475.)

FIGURE 45-20 These serial sonograms depict an interventricular hemorrhage with parenchymal extension and eventual porencephaly that developed following cotwin demise in a monochorionic pregnancy. From left to right, these images were obtained 1 week,o5 weeks, and 8 weeks following demise of the cotwin.

twin-twin transfusion syndrome (TTTS), twin anemia poycythemia sequence (TAPS), and acardiac twinning.

In this syndrome, blood is transfused from a donor twin to its recipient sibling such that the donor may eventually become anemic and its growth may be restricted. In contrast, the recipient becomes polycythemic and may develop circulatory overload manifest as hydrops. Classically, the donor twin is pale, and its recipient sibling is plethoric. Similarly, one portion of the placenta often appears pale compared with the remainder. The recipient neonate may also have circulatory overload from heart failure and severe hypervolemia and hyperviscosity. Occlusive thrombosis is another concern. Finally, polycythemia in the recipient twin may lead to severe hyperbilirubinemia and kernicterus (Chap. 33, p. 626). he prevalence of TTTS approximates 1 to 3 cases per 10,000 births (Society for Maternal-Fetal Medicine, 2013).

Chronic TTTS results from unidirectional low through deep arteriovenous anastomoses. Deoxygenated blood from a donor placental artery is pumped into a cotyledon shared by the recipient (see Fig. 45-19). Once oxygen exchange is completed in the chorionic villus, the oxygenated blood leaves the cotyledon via a placental vein of the recipient twin. Unless compensatedtypically through superficial arterioarterial anastomoses-this unidirectional low leads to an imbalance in blood volumes (Lewi, 2013). Clinically important TTTS frequently is chronic and results from significant vascular volume diferences between the twins. Even so, the pathogenesis is more complex than a net transfer of red blood cells from one twin to another. Indeed, in most monochorionic twin pregnancies with the syndrome, hemoglobin concentrations between the donor and recipient twin do not difer (Lewi, 2013).

TTTS typically presents in midpregnancy when the donor fetus becomes oliguric from decreased renal perfusion (Society for Maternal-Fetal Medicine, 2013). This fetus develops oligohydramnios, and the recipient fetus develops severe hydramnios, presumably due to increased urine production. Virtual absence of amnionic fluid in the donor sac prevents fetal motion, giving rise to the descriptive term stuck twin or poyhydramnios-oligohydramnios syndrome-'poy-oli. " This amnionic fluid imbalance is associated with growth restriction, contractures, and pulmonary hypoplasia in the donor twin, and premature rupture of the membranes and heart failure in the recipient.

Fetal Brain Damage. Cerebral palsy, microcephaly, porencephaly, and multicystic encephalomalacia are serious complications associated with placental vascular anastomoses in multifetal gestation. he exact pathogenesis of neurological damage is not fully understood but is likely caused by ischemic necrosis leading to cavitary brain lesions (Fig. 45-20). In the donor twin, ischemia results from hypotension, anemia, or both. In the recipient, ischemia develops from blood pressure instability and episodes of profound hypotension (Lopriore, 2011). Cerebral lesions may also be due to postnatal injury associated with preterm delivery (Chap. 34, p. 639). In one review of315 liveborn fetuses from pregnancies with TTTS, cerebral abnormalities were found in 8 percent (Quarello, 2007).

If one twin of an afected pregnancy dies, cerebrl pathology in the survivor probably results from acute hypotension. A less likely cause is emboli of thromboplastic material originating from the dead fetus. Fusi and coworkers (1990, 1991) observed that with the death of one twin, acute twin-twin anastomotic transusion from the high-pressure vessels of the living twin to the lowresistance vessels of the dead twin leads rapidly to hypovolemia and ischemic antenatal brain damage in the survivor. In one review of 343 twin pregnancies complicated by single fetal demise, the risk of neurodevelopmental morbidity in monochorionic twins was 26 percent compared with 2 percent in dichorionic twins (Hillman, 2011). This morbidity was related to the gestational age at the death of the cotwin. If the death occurred between 28 and 33 weeks' gestation, monochorionic twins had an almost eightfold risk of neurodevelopmental morbidity compared with dichorionic twins of the same gestational age. With fetal death ater 34 weeks, the likelihood dramaticlly decreased-odds ratio 1.48.

he acuity of hypotension following the death of one twin with TTTS makes successful intervention for the survivor nearly impossible. Even with delivery immediately ater a cotwin demise is recognized, the hypotension that occurs at the moment of death has likely already caused irreversible brain damage (Langer, 1997; Wada, 1998). s such, immediate delivery is not considered beneficial in the absence of another indication.

Diagnosis. he criteria used to diagnose and classiy varying severities of TTTS have dramatically changed. Previously, weight discordancy and hemoglobin diferences in monochorionic twins were calculated. However, in many cases, these are late findings. According to the Society for Maternal-Fetal Medicine (2013), TTTS is diagnosed based on two so nographic criteria. First, a monochorionic diamnionic pregnancy is identified. Second, hydramnios defined by a largest vertical pocket > 8 em in one sac and oligohydramnios defined by a largest vertical pocket <2 em in the other twin is found. Only 15 percent of pregnancies complicated by lesser degrees of luid imbalance progress to TTTS (Huber, 2006). Although growth discordance or growth restriction may be found with TTTS, these per se are not considered diagnostic criteria.

Organizations that include the American College of Obstetricians and Gynecologists (2016), Society for Maternal-Fetal Medicine (2013), and North American Fetal herapy Network (Emery, 2015) recommend sonography surveillance of pregnancies at risk for TTTS. To aid earlier identification of amnionic luid abnormalities and other complications of monochorionic twins, these examinations begin at approximately 16 weeks' gestation, and subsequent studies are considered every 2 weeks. Once identiied, TTTS is typically classiied by the Quintero (1999) staging system (Fig. 45-21):

Stage I-discordant amnionic fluid volumes as described in the earlier paragraph, but urine is still visible sonographically within the bladder of the donor twin

Stage II-criteria of stage I, but urine is not visible within the donor bladder

Stage III-criteria of stage II and abnormal Doppler studies of the umbilical artery, ductus venosus, or umbilical vein

Stage V-demise of either fetus.

In addition to these criteria, evidence suggests that cardiac function of the recipient twin correlates with fetal outcome (Crombleholme, 2007). Although fetal echocardiographic indings are not part of the Quintero staging system, many centers routinely perform fetal echocardiography for TTTS. heoretically, earlier diagnosis of cardiomyopathy in the recipient twin may identiy pregnancies that would beneit from early intervention. One system for evaluating cardiac function-the myocardial peormance index (MPI) or Tei index-is a Doppler index of ventricular function calculated for each ventricle (Michelfelder, 2007). lthough scoring systems that include assessment of cardiac function have been developed, their usefulness to predict outcomes remains controversial (Society for Maternal-Fetal Medicine, 2013).

Management and Prognosis. he prognosis for mulrifetal gestations complicated by TTTS is related to Quintero stage and gestational age at presentation. More than three fourths of stage I cases have been reported to remain stable or regress without intervention. Conversely, outcomes in those identiied at stage III or higher are much worse, and the perinatal loss rate is 70 to 100 percent without intervention (Society for Maternal-Fetal Medicine, 2013). At Parkland Hospital, among expectantly managed pregnancies with TTTS, most had early disease at diagnosis, and 50 percent of stage I cases progressed (Duryea, 2016).

Several therapies are available for TTTS and include amnioreduction, laser ablation of vascular placental anastomoses, selective feticide, and septosromy. Described further in Chapter 11 (p. 230), amnioreduction describes needle drainage of excess amnionic fluid. Septostomy is intentionally creating a hole in the dividing amnionic membrane but has largely been abandoned as treatment (Society for Maternal-Fetal Medicine, 2013). Comparative data from randomized trials for some of these other techniques are discussed below.

The Eurofetus trial included 142 women with severe TTTS diagnosed before 26 weeks. Participants were randomly assigned to laser ablation of vascular anastomoses or to serial amnioreduction (Senat, 2004). A higher survival rate to age 6 months for at least one twin was found in pregnancies undergoing laser ablation-76 versus 51 percent, respectively. Moreover, analyses of randomized studies confirm better neonatal outcomes with laser therapy compared with selective amnioreduction (Roberts, 2008; Rossi, 2008, 2009). In contrast, Crombleholme and associates (2007), in a randomized trial of 42 women, found equivalent rates of 30-day survival of one or both twins treated with either amnioreduction or selective fetoscopic laser ablation-75 versus 65 percent, respectively. Furthermore, evaluation of twins from the Eurofetus trial through 6 years of age did not demonstrate an additional survival benefit beyond 6 months or improved neurological outcomes in those treated with laser (Salomon, 2010). At this time, laser ablation of anastomoses is preferred for severe TTTS (stages II-IV). Optimal therapy for stage I disease is controversial.

FIGURE 45-21 A. Sonogram of stage I ms at 19 weeks' gestation. Oligohydramnios in the donor twin sac causes the membrane to essentially wrap around the "stuck twin" and suspend it from the anterior uterine wall. B. In this same pregnancy, hydramnios is seen in the recipient twin sac. The measured pocket exceeds 10 cm. C. Stage II ms in a donor twin at 17 weeks' gestation. Color Doppler highlights the arteries that outline the fetal bladder, which contains no urine.

After laser therapy, close ongoing surveillance is necessary.

Robyr and colleagues (2006) reported that a fourth of 101 pregnancies treated with laser required additional invasive therapy because of either recurrent TTTS, or middle cerebral artery (MCA) Doppler evidence of anemia or polycythemia. Recently, in a comparison of selective laser ablation of individual anastomoses versus ablation of the entire surface of the chorionic plate along the vascular equator, Baschat and coworkers (2013) found that equatorial photocoagulation reduced the likelihood of recurrence.

Selective fetal reduction has generally been considered if severe amnionic luid and growth disturbances develop before 20 weeks. In such cases, both fetuses typically will die without intervention. Any substance injected into one twin may afect the other twin because of shared circulations. hus, for the fetus chosen for reduction, feticidal techniques include methods that occlude the umbilical vein or umbilical cord of using radiofrequency ablation, fetoscopic ligation, or coagulation with laser, monopolar, or bipolar energy (Challis, 1999; Chang, 2009; Parra-Cordero, 2016). Even after these procedures, however, the risks to the remaining fetus are still appreciable (Rossi, 2009). This topic is further discussed on page 891.

This form of chronic fetofetal transfusion, referred to as TAPS, is characterized by significant hemoglobin diferences between donor and recipient twins. However, TAPS lacks the discrepancies in amnionic luid volumes typical of TTTS (Slaghekke, 2010). It is diagnosed ante natally by M CA peak systolic velocity (PSV) > 1.5 multiples of the median (MoM) in the donor and < 1.0 MoM in the recipient twin (Society for MaternalFetal Medicine, 2013). The spontaneous form of TAPS reportedly complicates 3 to 5 percent of monochorionic pregnancies, and it occurs in up to 13 percent of pregnancies after laser photocoagulation of the placenta. Spontaneous TAPS usually occurs after 26 weeks' gestation, and iatrogenic TAPS develops within 5 weeks of a procedure (Lewi, 2013). Although a staging system has been proposed by Slaghekke and colleagues (2010), further studies are necessary to better elucidate the natural history of TAPS and its management. In brief, evidence of fetal compromise or greater diferences in MCA PSV between twins raise the stage.

lso known as an acardiac twin, this is a rare but serious complication of monochorionic multifetal gestation. n estimated incidence is 1 case in 35,000 births. In the classic twin reversedarterial-perfusion (TRAP) sequence, there is a normally formed donor twin that shows features of heart failure and a recipient twin that lacks a heart (acardius) and other structures. In one theory, the TRAP sequence is caused by a large artery-to-artery placental shunt, often also accompanied by a vein-to-vein shunt

FIGURE 45-22 Twin reversed-arterial-perfusion sequence. In the TRAP sequence, there is usually a normally formed donor twin that has features of heart failure, and a recipient twin that lacks a heart. It has been hypothesized that the TRAP sequence is caused by a large artery-to-artery placental shunt, often also accompanied by a vein-to-vein shunt. Within the single, shared placenta, perfusion pressure of the donor twin overpowers that in the recipient twin, who thus receives reverse blood flow from its twin sibling. The "used" arterial blood that reaches the recipient twin preferentially goes to its iliac vessels and thus perfuses only the lower body. This disrupts growth and development of the upper body.

(Fig. 45-22). Within the single, shared placenta, arterial perfusion pressure of the donor twin exceeds that in the recipient twin, who thus receives reverse blood low containing deoxygenated arterial blood from its cotwin (Lewi, 2013). his "used" arterial blood reaches the recipient twin through its umbilical arteries and preferentially goes to its iliac vessels. Thus, only the lower body is perfused, and therefore disrupted growth and development of the upper body results. In these cases, failed head growth is called acardius acephalus; a partially developed head with identifiable limbs is called acardius myelacephalus; and failure of any recognizable structure to form is acardius amorphous, which is shown in Figure 45-23 (Faye-Petersen, 2006). Because of this vascular connection, the normal donor twin must not only support its own circulation but also pump blood through the underdeveloped acardiac recipient. This may lead to cardiomegaly and high-output heart failure in the normal twin (Fox, 2007).

In the past, the mortality rate among the pump twins exceeded 50 percent. This stemmed largely from complications of prematurity or from a prolonged high-output state leading to cardiac failure (Dashe, 2001). Risk appears to be directly related to size of the acardiac twin. One sonographic method to estimate acardiac twin size uses the volume of an ellipse: length X width X height x \/6. When the acardiac twin volume is < 50 percent of that of the pump twin, expectant management may be reasonable given the inherent risks of fetal intervention (Chap. 15, p. 326)(Jelin, 2010). When the volume of the

FIGURE 45-23 Photograph of an acardiac twin weighing 475 grams. The underdeveloped head is indicated by the black arrow, and its details are shown in the inset. A yellow clamp is seen on its umbilical cord. Its viable donor cotwin was delivered vaginally at 36 weeks and weighed 2325 grams. (Used with permission from Dr. Michael D. Hnat.) acardiac twin is large, however, treatment has generally been ofered. Radiofrequencyrablation (RFA) is the preferred modality of therapy, and contemporary reports now suggest improved perinatal outcomes. he North American Fetal Therapy Network reviewed their experiences with 98 cases from 1998 to 2008 in which RF A of the umbilical cord was performed (Lee, 2013). Median gestational age at delivery was 37 weeks, and 80 percent of neonates survived (Lee, 20l3). he average gestational age at the time of the RF A was 20 weeks, and the estimated acardius-to-pump twin volume on average was 90 percent. Major complications were prematurely ruptured membranes and preterm birth.

Interestingly, TRAP sequences can also occur within monoamnionic pregnancies. he perinatal outcomes of such pregnancies appear to be worse than that of monochorionic diamnionic cases. Sugibayashi and associates (2016) in a review of 40 cases recently reported that pump twin survival following RF A was 88 percent in monochorionic diamnionic pregnancies but only 67 percent in monoamnionic pregnancies.

• Hydatidiform Mole with Coexisting Normal Fetus his unique gestation contains one normal fetus, and its cotwin is a complete molar pregnancy. Reported prevalence rates range from 1 in 22,000 to 1 in 100,000 pregnancies (Dolapcioglu, 2009). It must be diferentiated from a partial molar pregnancy, in which an anomalous singleton fetususually triploid-is accompanied by molar tissue (Fig. 20-4, p. 391). At times, a twin pregnancy may occur with a normal twin in one sac and a partial mole in the other sac (McN amara, 2016).

Diagnosis is usually made in the first half of pregnancy.

Sonographically, a normal-appearing twin is accompanied by its cotwin, which is a large placenta containing multiple small anechoic cysts (Fig. 20-4, p. 391). Often, these pregnancies are terminated, but pregnancy continuation is increasingly adopted. First, the pregnancy prognosis is not as poor as previously thought, and live birth rates range between 20 and 40 percent (Dolapcioglu, 2009; McNamara, 2016). Second, the risk of persistent trophoblastic disease is similar whether the pregnancy is terminated or not (Massardier, 2009; Sebire, 2002). That said, given the limited number of cases, robust data for irm recommendations are lacking. Importantly, complications of expectant management include vaginal bleeding, hyperemesis gravidarum, thyrotoxicosis, and early-onset preeclampsia (McNamara, 2016). Many of these complications result in preterm birth with its attendant adverse perinatal sequelae as well as perinatal loss. Logically, close surveillance is needed for those continuing the pregnancy.

Fetal size inequality develops in approximately 15 percent of twin gestations and may relect pathological growth restriction in one fetus (Lewi, 2013; Miller, 2012). Generally, as the weight diference within a twin pair rises, the perinatal mortality rate increases proportionately. If it develops, restricted growth of one twin fetus, often termed selective etal-growth restriction, usually develops late in the second and early third trimester. Earlier discordancy indicates higher risk for fetal demise in the smaller twin. Speciically, when discordant growth is identified before 20 weeks, fetal death occurs in approximately 20 percent of the growth-restricted fetuses (Lewi, 2013).

he cause of birthweight inequality in twin fetuses is often unclear, but the etiology in monochorionic twins likely difers from that in dichorionic twins. Because the single placenta is not always equally shared in monochorionic twins, these twins have greater rates of discordant growth outside of TTTS than dichorionic twins. Discordancy in monochorionic twins is usually attributed to placental vascular anastomoses that cause hemodynamic imbalance between the twins. Reduced pressure and perfusion of the donor twin can cause diminished placental and fetal growth. Even so, unequal placental sharing is probably the most important determinant of discordant growth in monochorionic twins (Lewi, 2013). Occasionally, monochorionic twins are discordant in size because they are discordant for structural anomalies.

Discordancy in dichorionic twins may result from various factors. Dizygotic fetuses may have diferent genetic growth potential, especially if they are of opposite genders. Second, because the placentas are separate and require more implantation space, one placenta might have a suboptimal implantation site. Bagchi and associates (2006) observed that the incidence of severe discordancy is twice as great in triplets as it is in twins. This finding lends credence to the view that in utero crowding is a factor in multifetal growth restriction. Placental pathology may playra role as well. In one study of 668 twin placentas, a strong relationship between histological placental abnormalities and birthweight discordancy was observed in dichorionic, but not monochorionic, twin pregnancies (Kent, 2012).

Size discordancy between twins can be determined sonographically. hat said, diferences in crown-rump length are not reliable predictors for birthweight discordance (Miller, 2012). hus, most begin surveillance for discordancy ater the first trimester. One common method uses sonographic fetal biometry to compute an estimated weight for each twin (Chap. 10, p. 184). The weight of the smaller twin is then compared with that of the larger twin. hus, percent discordancy is calculated as the weight of the larger twin minus the weight of the smaller twin, then divided by the weight of the larger twin. Alternatively, given that abdominal circumference (AC) relects fetal nutrition, some use the sonographic AC value of each twin.

With these methods, some diagnose selective fetal-growth restriction if the AC measurements difer more than 20 mm or if the estimated fetal weight diference is 20 percent or more. That said, several diferent weight disparities between twins have been used to deine discordancy. Accumulated data suggest that weight discordancy greater than 25 to 30 percent most accurately predicts an adverse perinatal outcome. At Parkland, Hollier and coworkers (1999) retrospectively evaluated 1370 delivered twin pairs and stratiied twin weight discordancy in 5-percent increments within a range of 15 to 40 percent. They found that the incidence of respiratory distress syndrome, intraventricular hemorrhage, seizures, periventricular leukomalacia, sepsis, and necrotizing enterocolitis rose directly with the degree of weight discordancy. Rates of these conditions grew substantially if discordancy exceeded 25 percent. The relative risk of fetal death increased significantly to 5.6 if discordancy was more than 30 percent and rose to 18.9 if it was greater than 40 percent.

Sonographic monitoring of twin growth has become a mainstay in management. Monochorionic twins are generally monitored more frequently. his is because their risk of death is higher-3.6 percent versus 1.1 percent-and the risk of neurological damage in the surviving twin is substantial compared with those risks in dichorionic twins (Hillman, 2011; Lee, 2008). Thorson and colleagues (2011) retrospectively analyzed 108 monochorionic twin pregnancies and found that a sonographic evaluation interval > 2 weeks was associated with a higher Quintero stage at the time of TTTS diagnosis. hese indings have led some to recommend serial sonographic examination every 2 weeks in monochorionic twins (Simpson, 2013; Society for MaternalFetal Medicine, 2013). However, there have been no randomized trials of the optimal frequency of sonographic surveillance in monochorionic twin pregnancies. At Parkland Hospital, monochorionic twins undergo sonographic evaluation to assess interval growth every 4 weeks. In addition, a specific ultrasound examination to search for TTTS is completed at each intervening 2-week mark between these sonograms.

For dichorionic pregnancies, a recent report suggests that sonographic evaluation every 2 weeks would identiY more abnormalities prompting delivery (Corcoran, 2015). It has yet to be determined if this practice would improve perinatal outcomes. At our institution, dichorionic twins are sonographically evaluated every 6 weeks.

Depending on the degree of discordancy and the gestational age, fetal surveillance may be indicated, especially if one or both fetuses exhibit restricted growth. Nonstress testing, biophysical profile, and umbilical artery Doppler assessment have all been recommended in the management of twins. However, none has been assessed in appropriately sized prospective trials (Miller, 2012).

If discordancy is identiied in a monochorionic twin pregnancy, umbilical artery Doppler studies in the smaller fetus may help guide management (Gratac6s, 2007). Namely, investigators have correlated umbilical artery Doppler results with placental indings and with the degree of selective fetal-growth restriction to predict fetal outcome (Gratac6s, 2012). hese correlations have yielded categories of selective fetal-growth restriction. Type I is characterized by positive end-diastolic low, a smaller degree of weight discordance, and a relatively benign clinical course. Type II displays persistently absent end-diastolic flow in the smaller twin and carries a high risk of deterioration and demise. Type III is intermittently absent or reversed end-diastolic flow. Because of large artery-to-artery anastomoses associated with the placentas in this category, type III is associated with a lower risk of deterioration than type II. In all evaluated cases, unequally shared placenta was noted to some degree.

With uncomplicated dichorionic multifetal gestations, use of antepartum surveillance has not improved perinatal outcomes. In sum, the American College of Obstetricians and Gynecologists (2016) recommends that antepartum testing be performed in multi fe tal gestations for indications similar to those for singleton fetuses (Chap. 17, p. 331).

At Parkland, all women with twin discordancy :25 percent undergo daily monitoring as an inpatient. Data are limited to establish the optimal timing of delivery of twins for size discordancy alone. For those at advanced gestational ages, delivery can be pursued.

• Death of One Fetus

At any time during multifetal pregnancy, one or more fetuses may die, either simultaneously or sequentially. Causes and incidence of fetal death are related to zygosity, chorionicity, and growth concordance.

In some pregnancies, one fetus dies remote from term, but pregnancy continues with one or more live fetuses. When this occurs early in pregnancy, it may manifest as a vanishing twin, discussed on page 871. In a slightly more advanced pressed against the fetal membranes. Anatomical parts can be identified as marked. Demise of this twin had been noted during sonographic examination performed at 17 weeks' gestation. Its viable cotwin delivered at 40 weeks. (Used with permission from

Dr. Michael V. Zaretsky.) gestation, fetal death may go undetected until delivery. In this case, delivery ofa normal newborn is followed by expulsion of a dead fetus that is barely identiiable. It may be compressed appreciably-'tus compressus, or it may be lattened remarkably through desiccation-'tuspapyraceus (Fig. 45-24).

As shown in Figure 45-25, the risk ofstillbirth is related to gestational age in all twins but is much higher for monochorionic twin pregnancies before 32 weeks' gestation. In a review of 9822 twin pregnancies, Morikawa and associates (2012) reported that 2.5 percent of monochorionic diamnionic twins �o 0: .� 15 ..0

FIGURE 45-25 Prospective risk of stillbirth among women who reached a given gestational week (per 1000 women). (Reproduced with permission from Morikawa M, Yamada 1, Yamada T, et al: Prospective risk of stillbirth: monochorionic diamniotic twins vs dichorionic twins, J Perinat Med. 2012 Jan 10;40(3):245-249.) greater than 22 weeks had a death of one or both twins. This compared with 1.2 percent of dichorionic twins. In this same review, women with monochorionic diamnionic twins who lost one twin were 16 times more likely to experience death of the cotwin than women with dichorionic twins who lost one twin.

Other investigations have found similar trends (Danon, 2013;

Hillman, 2011; Mahony, 2011).

Other factors that afect the prognosis for the surviving twin include gestational age at the time of the demise and duration between the demise and delivery of the surviving twin. With a vanishing twin, the risk of death after the irst trimester is not increased for the survivor. However, when a fetus dies in the second trimester or later, the efect ofgestational age at the time ofdeath and the mortality risk to the cotwin are less clear. In an analysis by Hillman and colleagues (2011), cotwin demise rates were unafected regardless of whether the irst death occurred at 13 to 27 weeks' gestation or at 28 to 34 weeks. In cases with the death ofone twin after the irst trimester, however, the odds of spontaneous and iatrogenic preterm delivery of the remain ing living twin were increased (Hillman, 2011). Preterm birth gestation. Ifthe fetus died after 34 weeks, preterm delivery rates were similar.

The neurological prognosis for a surviving cotwin depends almost exclusively on chorionicity. In their comprehensive review, Ong and coworkers (2006) found an 18-percent rate of neurological abnormality in twins with monochorionic placentation compared with only 1 percent in those with dichorionic placentation. In another review, in twin pregnancies complicated by a single fetal demise before 34 weeks, a ivefold higher risk ofneurodevelopmental morbidity was identiied in monochorionic twins compared with dichorionic twins. If the one fetus died after 34 weeks, the likelihood ofneurological deicits was essentially the same between monochorionic and dichorionic twin pregnancies (Hillman, 201r1).

Later in gestation, the death ofone ofmultiple fetuses could theoretically trigger coagulation defects in the mother. Only a few cases of maternal coagulopathy after a single fetal death in a twin pregnancy have been reported. This is probably because the surviving twin is usually delivered within a few weeks ofthe demise (Eddib, 2006). That said, we have observed transient, spontaneously corrected consumptive coagulopathy in multifetal gestations in which one fetus died and was retained in utero along with its surviving twin. he plasma ibrinogen concentration initially decreased but then increased spontaneously, and the level of serum ibrinogen-ibrin degradation products increased initially but then returned to normal levels. At delivery, the portions of the placenta that supplied the living fetus appeared normal. In contrast, the part that had once provided for the dead fetus was the site of massive ibrin deposition.

Decisions should be based on gestational age, the cause of death, and the risk to the surviving fetus. First-trimester losses require no additional surveillance for this speciic indication. If the loss occurs after the irst trimester, the risk ofdeath or damage to the survivor is largely limited to monochorionic twin gestations. Morbidity in the monochorionic twin survivor is almost always due to vascular anastomoses, which often cause the demise of one twin followed by sudden hypotension in the other (p. 878). For this reason, if one fetus of a monochorionic twin gestation dies ater the first trimester but before viability, pregnancy termination can be considered (Blickstein, 2013). Occasionally, death of one but not all fetuses results from a maternal complication such as diabetic ketoacidosis or severe preeclampsia with abruption. Pregnancy management is based on the diagnosis and the status of both the mother and surviving fetus. If the death of one dichorionic twin is due to a discordant congenital anomaly in the irst trimester, it should not afect the surviving twin.

Single fetal death during the late second and early third trimesters presents the greatest risk to the surviving twin. Although the risks of subsequent death or neurological damage to the survivor are comparatively higher for monochorionic twins at this gestational age, the risk of preterm birth is equally increased in mono-and dichorionic twins (Ong, 2006). Delivery generally occurs within 3 weeks of diagnosis of fetal demise, thus antenatal corticosteroids for survivor lung maturity should be considered (Blickstein, 2013). Regardless, unless the intrauterine environment is hostile, the goal is to prolong the preterm pregnancy.

Timing of elective delivery after conservative management of a late second-or early third-trimester single fetal death is debatable. Dichorionic twins can probably be safely delivered at term. Monochorionic twin gestations are more diicult to manage and are often delivered between 34 and 37 weeks' gestation (Blickstein, 2013). In cases of single fetal death at term, especially when the etiology is unclear, most opt for delivery instead of expectant management. The American College of Obstetricians and Gynecologists (2016) also endorse an individualized approach to such cases.

• Impending Death of One Fetus

During antepartum surveillance tests of well-being, abnormal results in one twin, but not the other, pose a particular dilemma. Delivery may be the best option for the compromised fetus yet may result in death from immaturity of the cotwin. If fetal lung maturity is conirmed, salvage of both the healthy fetus and its jeopardized sibling is possible. Unfortunately, ideal management if twins are immature is problematic but should be based on the chances of intact survival for both fetuses. Often the compromised fetus is severely growth restricted or anomalous. Thus, performing amniocentesis for fetal chromosomal analysis in women of advanced maternal age carrying twin pregnancies is advantageous, even for those who would continue their pregnancies regardless of the diagnosis. Chromosomal abnormality identification in one fetus allows rational decisions regarding interventions.

With prenatal management of multifetal pregnancy, primary goals aim to prevent or interdict complications as they develop. A major imperative is to prevent preterm delivery of markedly immature neonates. At Parkland Hospital, women with multifetal gestations are seen every 2 weeks beginning at 22 weeks' gestation. A digital cervical examination is performed at each visit to screen for cervical shortening or dilation. Identification of other unique complications discussed earlier may also lead to interventions including admission or early delivery.

long with more frequent prenatal VISItS, the maternal diet should provide additional requirements for calories, protein, minerals, vitamins, and essential fatty acids. he Institute of Medicine (2009) recommends a 37-to 54-lb weight gain for women with twins and a normal BMI. In their review, Goodnight and Newman (2009) endorse supplementation of micronutrients such as calcium, magnesium, zinc, and vitamins C, D, and E. his is based on upper intake levels from the Food and Nutrition Board of the Institute of Medicine. he daily recommended augmented caloric intake for women with twins is 40 to 45 kcal/kg/d. Diets contain 20 percent protein, 40 percent carbohydrate, and 40 percent fat divided into three meals and three snacks daily.

As noted earlier (p. 882), serial sonographic examinations are usually performed throughout the third trimester to search for abnormal fetal growth and assess amnionic fluid volume. Associated oligohydramnios may indicate utero placental pathology and should prompt further evaluation of fetal well-being. That said, quantiYing amnionic luid volume in multifetal gestation is sometimes diicult. Some measure the deepest vertical pocket in each sac or assess the luid subjectively. Magann and coworkers (2000) compared subjective assessment and several objective methods of assessing amnionic fluid volume in 23 sets of twins. They found all methods to be equally poor in predicting abnormal volumes in diamnionic wins. At Parkland Hospital, the single deepest vertical pocket is measured in each sac. A measurement < 2 em is considered oligohydramnios, and a measurement > 8 cm is considered hydramnios (Duryea, 2017; Hernandez, 2012).

Of surveillance methods, the nons tress test or biophysical profile is often selected for twin or higher-order multifetal gestations. Because of the complex complications associated with these gestations and the potential technical diiculties in differentiating fetuses during antepartum testing, the usefulness of these methods appears limited. According to DeVoe (2008), the few exclusive studies of nonstress testing in twins suggest that the method performs the same as in singleton pregnancies.

Elliott and Finberg (1995) used the biophysical profile as the primary method for monitoring higher-order multifetal gestations. They reported that four of 24 monitored pregnancies had a poor outcome despite reassuring biophysical proile scores. Although biophysical testing is commonly performed in multifetal gestations, there are insuicient data to determine its eicacy (DeVoe, 2008).

Similar indings have been reported with the addition of umbilical artery Doppler velocimetry in twins with concordant growth. For example, when umbilical artery Doppler velocime try was added to management compared with fetal testing based on fetal-growth parameters alone in the absence of growth dis cordance, perinatal outcomes were not improved (Giles, 2003).

Likewise, Hack and associates (2008) investigated the utility mortality rates using pulsatility indices of the umbilical artery.

tons, and data suggest that testing in multifetal gestations per forms no better. In cases of abnormal testing in one twin and normal results in another, iatrogenic preterm delivery remains a major concern. Options are similar to those described in the management of impending fetal death (p. 884).

Preterm labor is common in multifetal pregnancies and may complicate up to 50 percent of twin, 75 percent of triplet, and 90 percent of quadruplet pregnancies (Elliott, 2007). Similar to singleton preterm labor, intraamnionic infection is docu mented in approximately one third of twin pregnancy cases (Oh,r2017).

In twins, the proportion of preterm births varies widely from 40 to 70 percent (Giufre, 2012). For example, black women have disparately higher risks for preterm delivery (Grant, 2017).

• Prediction of Preterm Birth

A major goal of multi fetal prenatal care is accurate prediction of women likely to experience preterm delivery. Within the past decade, cervical length has been shown to be a potent predictor of preterm labor and delivery. To and associates (2006) so no graphically measured cervical length in 1163 twin pregnancies at 22 to 24 weeks' gestation. Rates of preterm delivery before 32 weeks were 66 percent in those with cervical lengths of 10 mm; 24 percent for lengths of 20 mm; and only 1 percent for 40 mm. In one review, Conde-Agudelo and coworkers (2010) concluded that a cervical length <20 mm was most accurate for predicting birth before 34 weeks, with a speciicity of 97 percent and positive likelihood ratio of 9.0. Kindinger and colleagues (2016) noted that prediction depended on both cervical length and gestational age at ascertainment. One study compared serial cervical length measurements with a single midgestation measurement. hese authors found that multiple assessments were more accurate to determine the risk of pre term twin birth in asymptomatic women (Melamed, 2016a). In another study, a change in cervical length :0.2 cm identified pregnancies at risk for delivery before 35 weeks (Moroz, 2017). Interestingly, a closed internal os by digital examination was found to be as predictive of postponed delivery as was the combination of a normal sonographically measured cervical length and negative fetal fibronectin test result (McMahon, 2002). Unfortunately, cervical length assessment in twin pregnancies has not been associated with improved outcomes (Gordon, 2016).

• Prevention of Preterm Birth

Several schemes have been evaluated to prevent preterm labor and delivery. In recent years, some have been shown to decrease the risk of pre term delivery, but only in subgroups of singleton pregnancies. In general, most have been disappointingly ineffective for both singleton and multifetal pregnancies (American College of Obstetricians and Gynecologists, 2016).

The bulk of evidence suggests that routine hospitalization does not prolong multifetal pregnancy. In one metaanaly sis, the practice did not reduce the risk of preterm birth or perinatal mortality (Crowther, 2010). At Parkland Hospital, elective hospitalization was compared with outpatient manage ment, and no advantages were found (Andrews, 1991). Impor tantly, however, almost half of women managed as outpatients required admission for specific indications such as hypertension or threatened preterm delivery.

Limited physical activity, early work leave, more frequent health-care visits and sonographic examinations, and structured advocated to reduce pre term birth rates in women with mul tiple fetuses. However, little evidence suggests that these mea sures substantially change outcome.

his has not been studied extensively in multifetl pregnancies. In one review of prophylactic oral beta-mimetic therapy that included 374 twin pregnancies, treatment did not reduce the rate of twins delivering before 37 or before 34 weeks' gestation (Ymasmit, 2015). In light of the Food and Drug Administration warning against the use of oral terbutaline because of maternal side efects, the prophylactic use of beta-mimetic drugs in multifetal gestations seems unwarranted.

lthough somewhat efective in reducing recurrent preterm birth in women with a singleton pregnancy, weekly injections of 17 alpha-hydroxyprogesterone caproate (17 -OHP-C) are not efective for multifetal gestations (Caritis, 2009; Rouse, 2007). hese results were corroborated in a randomized trial of 240 twin pregnancies (Combs, 2011). Moreover, women carrying twins and having a cervical length <36 mm (25th percentile) did not beneit despite their greater risk for preterm birth (Durnwald, 2010). Senat and colleagues (2013) assigned 165 asymptomatic women with twins and a cervical length <25 mm to 17-0HP-C and also found no reduction in delivery rate before 37 weeks. Last, in an evaluation of plasma drug concentrations, higher concentrations of 17 -OHP-C were associated with earlier gestational age at delivery (Caritis, 2012). he authors concluded that 17-0HP-C may adversely lower the gestational age at delivery in women with twin gestations. In sum, administration of intramuscular 17 -OHP-C to women with twin pregnancies, even to those with a shortened cervix, does not lower the preterm birth risk.

Micronized progesterone administered vaginally to women with twins to prevent preterm birth has provided conlicting results.

Cetingoz and coworkers (2011) gave 100 mg of micronized progesterone intravaginally daily from 24 to 34 weeks' gestation. his practice reduced rates of delivery before 37 weeks from 79 to 51 percent in 67 women with twins. In contrast, several studies have failed to demonstrate any preterm birth rate reduction in women receiving various formulations of vaginal progesterone. In the Prevention of Preterm Delivery in Twin Gestations (PREDICT) trial, 677 women with twins were randomly assigned to receive prophylactic, 200-mg progesterone pessaries or placebo pessaries (Rode, 2011). Progesterone failed to reduce delivery rates before 34 weeks. In a subgroup analysis that included only women with a short cervix or a history of prior preterm birth, also no benefit was found (Klein, 2011). Norman and colleagues (2009) also noted no lower rates of delivery before 34 weeks with progesterone gel treatment.

Romero and colleagues (2017) performed a metaanalysis of individual patient data for 303 women with twin gestation and a short cervix randomized to receive either vaginal progesterone or no treatment. They reported a significantly reduced risk of preterm birth before 30 weeks' gestation and improved composite perinatal outcomes in the treated women. Currently at Parkland Hospital, management of women with multifetal gestations does not typically include progestetone in any formulation.

The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) is currently enrolling patients into a randomized, placebo-controlled trial to further evaluate the use of micronized vaginal progesterone or the Arabin pessary, describe subsequently (PROSPECT, 2015). The primary outcome is delivery prior to 35 weeks or fetal loss.

Prophylactic cerclage does not improve perinatal outcome in women with multifetal pregnancies. Studies have included women who were not specially selected but also those who were selected because of a shortened cervix that was identified sonographically (Houlihan, 2016; Newman, 2002; Rebarber, 2005). Indeed, in the latter group, cerclage may actually worsen outcomes (Berghella, 2005; Roman, 2013).

Rescue cerclage in women with a second-trimester twin gestation and a dilated cervix may be beneficial. Roman and coworkers (2016) reported a retrospective cohort study in which women undergoing rescue cerclage had significantly better neonatal outcomes than those without cerclage.

A vaginal pessary that encircles and theoretically compresses the cervix, alters the inclination of the cervical canal, and relieves direct pressure on the internal cervical os has been proposed as an alternative to cerclage. One of the most popular is the silicone Arabin pessary. In a study of its use in women with a short cervix between 18 and 22 weeks' gestation, a subgroup analysis of 23 women with twins showed a signiicant reduction in the delivery rate before 32 weeks compared with the rate in 23 control pregnancies (Arabin, 2003). In another randomized trial, women treated with a cervical pessary had signiicantly fewer births before 34 weeks (Goya, 2016).

Other studies have been less favorable. In the randomized Pessaries in Multiple Pregnancy as a Prevention of Preterm Birth (ProTWIN) trial, 813 un selected women with twins received either the Arabin pessary between 12 and 20 weeks or no treatment (Liem, 2013). The pessary failed to reduce preterm birth overall but did decrease delivery rates before 32 weeks-29 versus 14 percent-in a subset of women with a cervical length <38 mm. Similar results were reported from a randomized multicenter trial with a total of 11r80 twin pregnancies (Nicolaides, 2016). A smaller randomized study using a Bioteque cup pessay showed no diference in outcomes (Berghella, 2017). At this time, pessary use is not recommended by the merican College of Obstetricians and Gynecologists (2016). As noted above, results from the ongoing PROSPECT trial are anticipated to provide more data.

• Treatment of Preterm Labor

Although many advocate their use, therapy with tocolytic agents to forestall preterm labor in multifetal pregnancy does not result in measurably improved neonatal outcomes (Chauhan, 2010; Gyetvai, 1999). Another caveat is that tocolytic therapy in women with a multifetal pregnancy entails higher risks than in singleton pregnancy. This stems in part from augmented pregnancy-induced hypervolemia, which raises cardiac demands and increases the susceptibility to iatrogenic pulmonary edema (Chap. 47, p. 917). Gabriel and colleagues (1994) compared outcomes of 26 twin and six triplet pregnancies with those of 51 singletons-all treated with a beta-mimetic drug for preterm labor. Women with a multifetal gestation had significantly more cardiovascular complications-43 versus 4 percent-including three gravidas with pulmonary edema. In a retrospective analysis, Derbent and coworkers (2011) evaluated nifedipine tocolysis in 58 singleton and 32 twin pregnancies. hese authors reported higher incidences of side efects such as maternal tachycardia in women with twins-19 versus 9 percent.

Administration of corticosteroids to stimulate fetal lung maturation has not been well studied in multifetal gestation. However, these drugs logically should be as beneicial for multiples as they are for singletons (Roberts, 2006). In a large retrospective study evaluating betamethasone therapy eicacy in preterm twin versus preterm singleton pregnancies, no diferences in neonatal morbidity between the two groups were identiied (Melamed, 2016b). Gyamfi and associates (2010) evaluated betamethasone concentrations in women receiving weekly antenatal corticosteroids and found no diferences in levels between twins and singletons. Conversely, another study found lower cord/maternal ratios of dexamethasone in twin versus singleton pregnancies (Kim, 2017). hese treatments are discussed in Chapter 42 (p. 823). At this time, guidelines for the use of these agents do not difer from those for singleton gestations (American College of Obstetricians and Gynecologists, 2016).

The frequency of preterm premature rupture of membranes (PPROM) rises with increasing plurality. In a populationbased study of more than 290,000 live births, the proportion of preterm birth complicated by premature rupture was 13.2 percent in singletons (Pakrashi, 2013). This rate compared with rates of 17, 20, 20, and 100 percent in twins, triplets, quadruplets, and even higher-order multiples, respectively. Multifetal gestations with PPROM are managed expectantly similar to singleton pregnancies (Chap. 42, p. 820). Ehsanipoor and colleagues (2012) compared outcomes of 41 twin and 82 singleton pregnancies, both with ruptuted membranes between 24 and 32 weeks. They found the median number of days to subsequent delivery was overall shorter for twins-3.6 days compared with 6.2 days for singletons. This latency diference was significant in pregnancies after 30 weeks-l.7 days and 6.9 days. Importantly, latency beyond 7 days approximated 40 percent in both groups.

• Delayed Delivery of Second Twin

Infrequently, after preterm birth of the presenting fetus, it may be advantageous for undelivered fetus(es) to remain in utero. Trivedi and Gillett (1998) reviewed 45 case reports of asynchronous birth in multifetal gestations. Although reported outcomes may relect bias, pregnancies with a surviving retained twin or triplet continued for an average of 49 days. No advantage was gained by management with tocolytics, prophylactic antimicrobials, or cerclage. In their 10-year experience, Roman and associates (2010) reported a median latency of 16 days in 13 twin and ive triplet pregnancies with delivery of the irst fetus between 20 and 25 weeks' gestation. Survival of the irstborn neonate was 16 percent. Although 54 percent of the retained fetuses survived, only 37 percent of survivors did so without major morbidity. Livingston and coworkers (2004) described 14 pregnancies in which an active attempt was made to delay delivery of 19 fetuses after delivery of the irst neonate. Only one fetus survived without major sequelae, and one mother developed sepsis syndrome with shock. Arabin and van Eyck (2009) reported better outcomes in a few of the 93 twin and 34 triplet pregnancies that qualiied for delayed delivery in their center during a 17 -year period.

If asynchronous birth is attempted, there must be careful evaluation for infection, abruption, and congenital anomalies. The mother must be thoroughly counseled, particularly regarding the potential for serious, life-threatening infection. The range of gestational age in which the beneits outweigh the risks for delayed delivery is likely narrow. Avoidance of delivery from 23 to 26 weeks would seem most beneficial. In our experience, good candidates for delayed delivery are rare.

A litany of complications may be encountered during labor and delivery of multiple fetuses. In addition to preterm birth, rates of uterine contractile dysfunction, abnormal fetal presentation, umbilical cord prolapse, placenta previa, placental abruption, emergent operative delivery, and postpartum hemorrhage from uterine atony are higher. All of these must be anticipated, and thus certain precautions and special arrangements are prudent. These should include the following.

1.

An appropriately trained obstetrical attendant should remain with the mother throughout labor. Continuous electronic monitoring is preferable. If membranes are ruptured and the cervix dilated, the presenting fetus is monitored internally.

2.

An intravenous infusion system capable of delivering fluid rapidly is established. In the absence of hemorrhage, lactated Ringer or an aqueous dextrose solution is infused at a rate of 60 to 125 mLlhr.

3.

Blood for transfusion is readily available if needed.

4.

n obstetrician skilled in intrauterine identification of fetal parts and in intrauterine manipulation of a fetus should be present.

5.

A sonography machine is readily available to evaluate the presentation and position of the fetuses during labor and to image the remaining fetus(es) after delivery of the irst.

6.

An anesthesia team is immediately available in the event that emergent cesarean delivery is necessary or that intrauterine manipulation is required for vaginal delivery.

7.

For each fetus, at least one attendant who is skilled in resuscitation and care of newborns and who has been appropriately informed of the case should be immediately available.

8.

he delivery area should provide adequate space for the nursing, obstetrical, anesthesia, and pediatric team members to work efectively. Equipment must be on site to provide emergent anesthesia, operative intervention, and maternal and neonatal resuscitation.

• Timing of Delivery

Several factors afect this timing and include gestational age, fetal growth, lung maturity, and presence of maternal complications. As measured by determination of the lecithin-sphingomyelin ratio, pulmonary maturation is usually synchronous in twins (Leveno, 1984). Moreover, although this ratio usually does not exceed 2.0 until 36 weeks in singleton pregnancies, it oten exceeds this value by approximately 32 weeks in multifetal pregnancies. Similar increased values of surfactant have been noted in twins after 31 weeks' gestation (McElrath, 2000). In a comparison of respiratory morbidity in 100 twins and 241 singleton newborns delivered by cesarean before labor, Ghi and associates (2013) found less neonatal respiratory morbidity in twins, especially those delivered <37 weeks' gestation. In some cases, however, pulmonary function may be markedly diferent, and the smallest, most stressed twin fetus is typically more mature.

At the other end of the spectrum, Bennett and Dunn (1969) suggested that a twin pregnancy of 40 weeks or more should be considered postterm. Twin stillborn neonates delivered at 40 weeks or beyond commonly had features similar to those of postmature singletons (Chap. 43, p. 836). From an analysis of almost 300,000 twin births, at and beyond 39 weeks, the risk of subsequent stillbirth was greater than the risk of neonatal mortality (Kahn, 2003).

From their guidelines, the American College of Obstetricians and Gynecologists (2016) recommends delivery at 38 weeks for uncomplicated dichorionic twin pregnancies. Women with uncomplicated monochorionic diamnionic twin pregnancies can undergo delivery between 34 and weeks. And, for women with monoamnionic twin pregnancies, delivery is recommended at 32 to 34 weeks. At Parkland Hospital, we generally follow these recommendations but do not routinely deliver monochorionic diamnionic twin pregnancies before 37 weeks unless another obstetrical indication develops.

• Evaluation of Fetal Presentation

In addition to the standard preparations for the conduct oflabor and delivery discussed in Chapter 22, there are special considerations for women with a multifetal pregnancy. First, the positions and presentations of fetuses are best confirmed sonographically. Although any possible combination of positions may be encountered, those most common at admission for delivery are cephalic-cephalic, cephalic-breech, and cephalic-transverse. At Parkland Hospital between 2008 and 2013, 71 percent of twin pregnancies had a cephalic presentation of the irst fetus at the time of admission to labor and delivery. Importantly, with perhaps the exception of cephalic-cephalic presentations, these are all unstable before and during labor and delivery. Accordingly, compound, face, brow, and footling breech presentations are relatively common, and even more so if fetuses are small, amnionic luid is excessive, or maternal parity is high. Cord prolapse is also frequent in these circumstances.

After this initial evaluation, if active labor is conirmed, then a decision is made to attempt vaginal delivery or to proceed with cesarean delivery. The latter is usually chosen because of fetal presentations. In general, cephalic presentation of the irst fetus in a laboring woman with twins may be considered for vaginal delivery (American College of Obstetricians and Gynecologists, 2016). The proportion of women undergoing an attempted vaginal delivery varies greatly depending on the skills of the delivering physician (de Castro, 2016; Easter, 2017; Schmitz, 2017). Still, the cesarean delivery rate is high. For example, of the 547 women with the irst twin presenting cephalic who were admitted to Parkland Hospital during 5 years, only 32 percent were delivered spontaneously. And, the overall cesarean delivery rate in twin pregnancies during those years was 77 percent. Notably, 5 percent of cesareans performed were for emergent delivery of the second twin following vaginal delivery of the first twin. The desire to avoid this obstetrical dilemma has contributed to the rising cesarean delivery rate in twin pregnancies across the United States (Antsalis, 2013).

After a comparison of 891 twins with more than 100,000 singleton pregnancies included in the Consortium of Safe Labor, Leftwich and colleagues (2013) concluded that active labor progressed more slowly in both nulliparas and multiparas with twins. Provided women with twins meet all criteria for oxytocin administration, it may be used as described in Chapter 26 (p. 509). Wolfe and associates (2013) evaluated the success of labor induction and concluded that oxytocin alone or in combination with cervical ripening can safely be used in twin gestations. Taylor and coworkers (2012) reported similar results. Conversely, Razavi and colleagues (2017) found that maternal morbidity was increased with labor induction. In an analysis of twin births in the United States, induction rates of twin pregnancies have decreased from a maximum of 13.8 percent in 1999 to 9.9 percent in 2008 (Lee, 2011). Generally, at Parkland Hospital we do not induce or augment labor in women with a multifetal gestation. In suitable candidates with a strong desire for vaginal birth, amniotomy induction has been one option.

During labor and delivery of multiple fetuses, decisions regarding analgesia and anesthesia may be complicated by problems imposed by preterm labor, preeclampsia, desultory labor, need for intrauterine manipulation, and postpartum uterine atony and hemorrhage.

Labor epidural analgesia is ideal because it provides excellent pain relief and can be rapidly extended cephalad if internal podalic version or cesarean delivery is required. If general anesthesia becomes necessary for intrauterine manipulation, uterine relxation can be accomplished rapidly with one of the halogenated inhalation agents discussed in Chapter 25 (p. 499). Some clinicians use intravenous or sublingual nitroglycerin or intravenous terbutaline to achieve uterine relaxation yet avoid the risks associated with general anesthetics. hese agents are usually best administered by the anesthesia team.

Regardless of fetal presentation during labor, obstetricians must be ready to deal with any change of fetal position during delivery. This is especially true following delivery of the first twin. Importantly, related to delivery method, second twins at term have worse composite neonatal outcomes compared with outcomes of their cotwin regardless of delivery method (Muleba, 2005; Smith, 2007; Thorngren-Jerneck, 2001).

If the first twin presents cephalic, delivery can usually be accomplished spontaneously or with forceps. According to D'Alton (2010), there is general consensus that a trial oflabor is reasonable in women with cephalic-cephalic twins. From their review, Hogle and associates (2003) found that planned cesarean delivery does not improve neonatal outcome when both twins are cephalic. The randomized trial by Barrett and coworkers (2013) airms this conclusion.

The optimal delivery route for cephalic-noncephalic twin pairs remains controversial. Patient selection is crucial, and options include cesarean delivery of both twins, or less commonly, vaginal delivery with intrapartum external cephalic version of the second twin. Longer intertwin delivery time has been shown in some studies to be associated with poorer second twin outcome (Edris, 2006; Stein, 2008). Thus, breech extraction may be preferable to version. Least desirable, vaginal delivery of the first but cesarean delivery of the second twin may be required due to intrapartum complications such as umbilical cord prolapse, placental abruption, contracting cervix, or fetal distress.

·Most but not all studies report the worst composite fetal out comes for this scenario (Alexander, 2008; Rossi, 2011; Wen, 2004).

Several reports attest to the safety of vaginal delivery of second noncephalic twins whose birthweight is > 1500g. A French multicenter study of 5915 twin pregnancies illustrates this (Schmitz, 2017). Of these, 25 percent had a planned cesarean delivery. The other 75 percent with a first twin cephalic and gestational age > 32 weeks had a planned trial of vaginal delivery, which was successful in 80 percent. Interestingly, perinatal mortality and morbidity rates were significantly higher in the planned cesarean delivery group delivered <37 weeks-5.2 versus 3.0 percent, respectively. Fox and colleagues (2014) reported outcomes in 287 diamnionic twin pregnancies, of which 130 underwent a planned vaginal delivery. Only 15 percent of the planned vaginal delivery group underwent a cesarean delivery. Perinatal outcomes were similar in both groups. hese two studies included only those fetuses with estimated weightsr> 1500 g. Notably, comparable or even better fetal outcomes with vaginal delivery have been reported with neonates weighing < 1500 g compared with those weighing > 1500 g (Caukwell, 2002; Davidson, 1992).

Other investigators advocate cesarean delivery for both members of a cephalic-noncephalic twin pair (Armson, 2006; Hofmann, 2012). Yang and coworkers (2005a,b) studied 15,185 cephalicnoncephalic twin pairs. he risks of asphyxia-related neonatal deaths and morbidity were higher in the group in which both twins were delivered vaginally compared with the group in which both twins underwent cesarean delivery.

To add insight into the clinical complexities just discussed, a randomized trial was designed by the Twin Birth Study Collaborative Group from Canada. he study results described by Barrett and associates (2013) included 2804 women carrying a presumed diamnionic twin pregnancy with the irst fetus presenting cephalic. Women were randomly assigned between 32 and 38 weeks' gestation to planned cesarean or vaginal delivery. The time from randomization to delivery-12.4 versus 13.3 days, the mean gestational age at delivery-36.7 versus 36.8 weeks, and use of regional analgesia-92 versus 87 percent, were similar in both groups. Salient maternal and perinatal outcomes are shown in Table 45-3. No significant diferences in outcomes were noted between the two groups of women. Although risks to mother or fetuses with planned vaginal delivery in these circumstances were not increased, Greene (2013) posited that this trial would have only modest efects on the cesarean delivery rate of women with twins.

Breech Presentation of First Twin

Problems with the first twin presenting as a breech are similar to those encountered with a singleton breech fetus. hus, major diiculties may develop in the following settings. First, the fetus may be large, and the aftercoming head is larger than the birth canal. Second, the fetal body can be small, and delivery of the extremities and trunk through an inadequately efaced and dilated cervix causes the relatively larger head to become trapped above the cervix. his is more likely when there is significant disproportion between the head and body. Examples are preterm or growth-restricted fetuses or those with

Serious morbidity 1.3% 1.3% Possible 0.5% 0.4%

Intubation 1.0% 0.6% alncludes coma; stupor; hyperalert, drowsy or lethargic; or ::2 seizu res.

Data from Barrett, 20ln3.

macrocephaly from hydrocephaly. Last, umbilical cord prolapse is an ever-present risk.

If these problems are anticipated or identiied, cesarean delivery is often preferred with a viable-sized fetus. But even without these problems, many obstetricians perform cesarean delivery if the irst twin presents as breech. This is despite data that support the safety of vaginal delivery. Specifically, Blickstein and associates (2000) reported experiences from 13 European centers with 613 twin pairs and the first twin presenting breech. Vaginal delivery was attempted in 373 of these cases and was successful in 64 percent. Cesarean delivery of the second twin was done in 2.4 percent. here was no diference in the rate of 5-minute Apgar scores <7 or of mortality in breech-presenting first twins who weighed at least 1500 g. Details of techniques for delivery of a breech presentation are described in Chapter 28 (p. 544).

Twin fetuses may become locked together during delivery if the irst presents breech and the second cephalic. As the breech of the irst twin descends through the birth canal, the chin locks between the neck and chin of the second cephalic-presenting cotwin. This phenomenon is rare, and Cohen and coworkers (1965) described it only once in 817 twin gestations. Cesarean delivery should be considered when the potential for locking is identiied.

• Vaginal Delivery of the Second Twin

Following delivery of the first twin, the presenting part of the second twin, its size, and its relationship to the birth canal should be quickly and careully ascertained by combined abdominal, vaginal, and at times, intrauterine examination. Sonography is a valuable aid. If the fetal head or the breech is fixed in the birth canal, moderate undal pressure is applied and membranes are ruptured. Immediately aterward, digital examination of the cervix is repeated to exclude cord prolapse. Labor is allowed to resume. If contractions do not begin within approximately 10 minutes, dilute oxytocin may be used to stimulate contractions.

In the past, the safest interval between delivery of the irst and second twins was frequently cited as <30 minutes. Rayburn and colleagues (1984) and others have shown that if continuous fetal monitoring is used, a good outcome is usually achieved even if this interval is longer. A direct correlation between worsening umbilical cord blood gas values and increasing time between delivery of irst and second twins has been shown (Leung, 2002; Stein, 2008). From review of 239 twin gestations, Gourheux and associates (2007) determined that mean umbilical arterial pH was signiicantly lower after the delivery interval exceeded 15 minutes. In a study of more than 175,000 twin pairs, Cheng and colleagues (2017) reached similar conclusions for maternal and perinatal morbidity.

If the occiput or breech presents immediately over the pelvic inlet, but is not ixed in the birth canal, the presenting part can often be guided into the pelvis by one hand in the vagina, while a second hand on the uterine fundus exerts moderate pressure caudally. A presenting shoulder may be gently converted into a cephalic presentation. Alternatively, with abdominal manipulation, an assistant can guide the presenting part into the pelvis. Sonography can aid guidance and allow heart rate monitoring. Intrapartum external version of a noncephalic second twin has also been described.

If the occiput or breech is not over the pelvic inlet and cannot be so positioned by gentle pressure or if appreciable uterine bleeding develops, delivery of the second twin can be problematic. To obtain a favorable outcome, an obstetrician skilled in intrauterine fetal manipulation and anesthesia personnel skilled in providing anesthesia to efectively relax the uterus for vaginal delivery of a noncephalic second twin are essential (American College of Obstetricians and Gynecologists, 2016). To take maximum advantage of the dilated cervix before the uterus contracts and the cervix retracts, delay should be avoided. Prompt cesarean delivery of the second fetus is preferred if no one present is skilled in the performance of internal podalic version or if anesthesia that will provide efective uterine relaxation is not immediately available.

With internal podalic version, a fetus is turned to a breech presentation using the hand placed into the uterus (Fig. 45-26). he obstetrician grasps the fetal feet to then efect delivery by breech extraction (Chap. 28, p. 548). As mentioned earlier, Fox and associates (2010) described a strict protocol for management of the delivery of the second twin, which included internal podalic version. hey reported that none of the 110 women who delivered the irst twin vaginally underwent a cesarean delivery for the second twin. Chauhan and coworkers (1r995) compared outcomes of 23 second twins delivered by internal podalic version and breech extraction with those of 21 who underwent external cephalic version. Breech extraction was considered superior to external version because less fetal distress developed. Additional information and illustrations of this procedure are found in Cunningham and Gilstrap 5 Operative Obstetrics, 3rd edition (Yeomans, 2017).

FIGURE 45-26 Internal podalic version. Upward pressure on the head by an abdominal hand is applied as downward traction is exerted on the feet.

Any attempt to deliver twins vaginally in a woman who has previously undergone one or more cesarean deliveries should be carefully considered. Some studies support the safety of attempting a vaginal birth after cesarean delivery (VBAC) for selected women with twins (Cahill, 2005; Ford, 2006; Varner, 2005). According to the American College of Obstetricians and Gynecologists (2017 c), no evidence currently suggests an increased risk of uterine rupture, and women with twins and one previous cesarean delivery with a low transverse incision may be considered candidates for trial of labor. At Parkland Hospital, we recommend repeat cesarean delivery.

Several unusual intraoperative problems can arise during cesarean delivery of twins or higher-order multiples. Supine hypotension is common, and thus gravidas are positioned in a left lateral tilt to delect uterine weight of the aorta (Chap. 4, p. 63). A low transverse hysterotomy is preferable if the incision can be made large enough to allow atraumatic delivery of both fetuses. Piper forceps can be used if the second twin is presenting breech (Fig. 28-11, p. 547). In some cases, a vertical hysterotomy beginning as low as possible in the lower uterine segment may be advantageous. For example, if a fetus is transverse with its back down and the arms are inadvertently delivered irst, it is much easier and safer to extend a vertical uterine incision upward than to extend a transverse incision laterally or to make a "T" incision vertically.

Fetal heart rate monitoring during labor with triplet pregnancies is challenging. A scalp electrode can be attached to the presenting fetus, but it is diicult to ensure that the other two fetuses are each being monitored separately. With vaginal deliv ery, the first neonate is usually born with little or no manipula tion. Subsequent fetuses, however, are delivered according to the presenting part. his often requires complicated obstetri cal maneuvers such as total breech extraction with or without internal podalic version or even cesarean delivery. Associated with malposition of fetuses is an increased incidence of cord prolapse. Moreover, reduced placental perfusion and hemor rhage from separating placentas are more likely during delivery.

For all these reasons, many clinicians believe that preg cesarean delivery (American College of Obstetricians and

Gynecologists, 2016). Vaginal delivery is reserved for those cir cumstances in which survival is not expected because fetuses are delivery hazardous to the mother. Others believe that vaginal delivery is safe under certain circumstances. Grobman and asso delivery completion rates of 88 and 84 percent, respectively, in women carrying triplets who underwent a trial of labor. Neo natal outcomes did not difer from those of a matched group of triplet pregnancies undergoing elective cesarean delivery. Con versely, in one review of more than 7000 triplet pregnancies, vaginal delivery was associated with a higher perinatal mortality rate (Vintzeleos, 2005). Lappen and coworkers (2016) reported similar results from the database of the Consortium on Safe

Labor. They recommended prelabor cesarean delivery for trip lets. Importantly, the overall cesarean delivery rate among trip lets was 95 percent.

In some cases of higher-order multi fetal gestation, reduction of the fetal number to two or three improves survival of the remaining fetuses. Selective reduction implies early pregnancy intervention, whereas selective termination is performed later. he procedure should be performed by an operator skilled and experienced in sonographically guided procedures.

Reduction of a selected fetus or fetuses in a multichorionic multifetal gestation may be chosen as a therapeutic intervention to enhance survival of the remaining fetuses (American College of Obstetricians and Gynecologists, 20 17b). One metaanalysis of nonrandomized prospective studies indicates that pregnancy reduction to twins compared with expectant management is associated with lower rates of maternal complications, preterm birth, and neonatal death (Dodd, 2004, 2012).

Pregnancy reduction can be performed transcervically, transvaginally, or transabdominally, but the transabdominal route is usually easiest. Transabdominal fetal reductions are typically performed between 10 and 13 weeks' gestation. This gestational age is chosen because most spontaneous abortions have already occurred, the remaining fetuses are large enough to be evaluated sonographically, the amount of devitalized fetal tissue remaining after the procedure is small, and the risk of aborting the entire pregnancy as a result of the procedure is low. The smallest fetuses and any anomalous fetuses are cho sen for reduction. Potassium chloride is then injected under sonographic guidance into the heart or thorax of each selected fetus. Care is used to avoid entry or traverse the sacs of fetuses selected for retention.

pregnancies from 1995 to 1998. he pregnancy loss rate var ied from a low of 4.5 percent for triplets that were reduced to twins. The loss rate rose with each addition to the starting num ber of fetuses and peaked at 15 percent for six or more fetuses.

Operator skill and experience are believed responsible for the low and declining rates of pregnancy loss.

With the identification of multiple fetuses discordant for struc tural or genetic abnormalities, three options are available: abor tion of all fetuses, selective termination of the abnormal fetus, or pregnancy continuation. Because anomalies are typically not discovered until the second trimester, selective termination is greater risk. This procedure is therefore usually not performed unless the anomaly is severe but not lethal. In some cases, ter mination is considered because the abnormal fetus may jeopar dize the normal one.

Prerequisites to selective termination include a precise diagnosis for the anomalous fetus and absolute certainty of fetal location. Unless a special procedure such as umbilical cord interruption is used, selective termination should be performed only in multichorionic multifetal gestations to avoid damaging the surviving fetuses (Lewi, 2006). Roman and coworkers (2010) compared 40 cases of bipolar umbilical cord coagulation with 20 cases of radiofrequency ablation for treatment of complicated monochorionic multifetal gestations at midpregnancy. hey found similar survival rates of 87 and 88 percent, and a median gestational age > 36 weeks at delivery in both. Prefumo and colleagues (2013) reported their preliminary experience with microwave ablation of the umbilical cord for selective termination in two monochorionic twin pregnancies. One pregnancy aborted within 7 days, and the other resulted in a term singleton delivered at 39 weeks' gestation.

Evans and coworkers (1999) have provided the most comprehensive results to date on second-trimester selective termination for fetal abnormalities. A total of 402 cases were analyzed from eight centers worldwide. Included were 345 twin, 39 triplet, and 18 quadruplet pregnancies. Selective termination using potassium chloride resulted in delivery of a viable neonate or neonates in more than 90 percent of cases, with a mean age of 35.7 weeks at delivery. The entire pregnancy was lost in 7 percent of pregnancies reduced to singletons and in 13 percent of those reduced to twins. The gestational age at the time of the procedure did not appear to afect the pregnancy loss rate.

Before selective termination or reduction, a discussion should include the morbidity and mortality rates expected if the pregnancy is continued; the morbidity and mortality rates expected with surviving twins or triplets; and the risks of the procedure itself (American College of Obstetricians and Gynecologists, 2017b). Speciic risks of selective termination or reduction are: abortion of the remaining fetuses; (2) abortion or retention of the wrong fetus(es); (3) damage without death to a fetus; preterm labor; (5) discordant or growth-restricted fetuses; and (6) maternal complications. he last includes potential infection, hemorrhage, or disseminated intravascular coagulopathy because of retained products of conception. The final decision to continue the pregnancy without intervention, to terminate the entire pregnancy, or to elect selective termination is solely the patient' s (Chervenak, 2013).

Abel EL, Kruger ML: Maternal and paternal age and twinning in the United States, 2004-2008. J Perinat Med 40:237,t2012

Alexander JM, Leveno KJ, Rouse 0, et al: Cesarean delivery for the second twin. Obstet Gynecol 112(4):748, 2008

Alran S, Sibony 0, Luton 0, et al: Maternal and neonatal outcome of 93 consecutive triplet pregnancies with 71 % vaginal delivery. Acta Obstet Gynecol Scand 83:554, 2004

American College of Obstetricians and Gynecologists: Multifetal gestations: twin, triplets, and higher-order multifetal pregnancies. Practice Bulletin No. 169, October 2016, Reairmed 2016

American College of Obstetricians and Gynecologists: Delayed umbilical cord clamping after birth. Committee Opinion No. 684, January 2017a American College of Obstetricians and Gynecologists: Multifetal pregnancy reduction. Committee Opinion No. 719, September 2017b

American College of Obstetricians and Gynecologists: Vaginal birth after previous cesarean delivery. Practice Bulletin No. 115, August 2010, Reairmed 2017c

American Sociery for Reproductive Medicine, Sociery for Assisted Reproductive Technology: Guidance on the limits to the number of embryos to transfer: a committee opinion. Fertil Sterilt107(4):901, 2017

Ananth CV, Chauhan SP: Epidemiology of twinning in developed countries.

Semin Perinatol 36: 156, 2012

Ananth CV, Vintzileos M, Shen-Schwarz S, et al: Standards of birth weight in twin gestations stratiied by placental chorionicity. Obstet Gynecol 91(6):917,t1998

Andrews W, Leveno KJ, Sherman ML, et al: Elective hospitalization in the management of twin pregnancies. Obstet Gynecol 77:826, 1991

Antsaklis A, Fotodotis M, Sindos M, et al: Trends in twin pregnancies and mode of delivery during the last 30 years: inconsistency between guidelines and clinical practice. J Perinat Med 41(4):355,t2013

Arabin B, Halbesma JR, York F, et al: Is treatment with vaginal pessaries an option in patients with a sonographically detected short cervix? J Perinat Med 31:122,t2003

Arabin B, van Eyck J: Delayed-interval delivery in twin and triplet pregnancies: 17 years of experience in 1 perinatal center. Am J Obstet Gynecol 200(2): 154.e1, 2009

Armson BA, O'Connell C, Persad V, et al: Determinants of perinatal mortality and serious neonatal morbidity in the second win. Obstet Gynecol 108(3 Pt 1):556, 2006

Aston K, Peterson C, Carrell 0: Monozygotic twinning associated with assisted reproductive technologies: a review. Reproduction 136(4):377, 2008 Bagchi 5, Salihu HM: Birth weight discordance in multiple gestations: occurrence and outcomes. J Obstet GynaecoIt26(4):291, 2006

Barrett JFR, Hannah ME, Hutton EK, et al: A randomized trial of planned cesarean or vaginal delivery for twin pregnancy. N Engl J Med 369: 1295, 2013

Baschat A, Barber J, Pedersen N, et al: Outcome after fetoscopic selective laser ablation of placental anastomoses vs equatorial laser dichorionization for the treatment of twin-to-twin transfusion syndrome. Am J Obstet Gynecol 209:1.e1,t2013

Bdolah Y, Lam C, Rajakumar A, et al: Twin pregnancy and the risk of preeclampsia: bigger placenta or relative ischemia? Am J Obstet Gynecol 198:438.e1,t2008

Beemsterboer SN, Homburg R, Gorter NA, et al: The paradox of declining fertility but increasing twinning rates with advancing maternal age. Hum Reprod 21:1531, 2006

Bekiesinska-Figatowska M, Herman-Sucharska I, Romaniuk-Doroszewska A, et al: Diagnostic problems in case of twin pregnancies: US vs MRI study. J Perinat Med 41 (5):535,t2013

Benirschke K, Kim CK: Multiple pregnancy. N Engl J Med 288:1276, 1973 Bennett 0, Dunn LC: Genetical and embryological comparisons of semilethal t-alleles from wild mouse populations. Genetics 61 :411, 1969

Berghella V, Dugof L, Ludmir J: Prevention of preterm birth with pessary in twins (PoPPT): a randomized controlled trial. Ultrasound Obstet Gynecol 49(5):567,t2017

Berghella V, Odibo AO, To MS, et al: Cerclage for short cervix on ultrasonography: meta-analysis of trials using individual patient-level data. Obstet Gynecol 106(1):181,t2005

Best E, Rankin J: Increased risk of congenital heart disease in twins in the North of England between 1998 and 2010. Heart 101(22):1807,t2015 Blickstein I, Goldman RD, Kupferminc M: Delivery of breech first twins: a multicenter retrospective study. Obstet Gynecol 95:37, 2000

Blickstein I, Perlman 5: Single fetal death in twin gestations. J Perinat Med 41:65,t2013

Blumenfeld j, Momirova V, Rouse OJ, et al: Accuracy of sonographic chorionicity in twin gestations. J Ultrasound Med 33(12):2187,2014

Boulet SL, Kirby RS, Reefhuis J, et al: Assisted reproductive technology and birth defects among liveborn infants in Florida, Massachusetts, and Michigan, 2000-2010. JAMA Pediatr 170(6):e154934, 2016

Boyle B, McConkey R, Game E, et al: Trends in the prevalence, risk and pregnancy outcome of multiple births with congenital anomaly: a registry-based study in 14 European countries 1984-2007. BJOG 120:707,t2013

Brady PC, Correia KF, Missmer SA, et al: Early 3-human chorionic gonadotropin trends in vanishing twin pregnancies. Fertil Steril 100(1): 116,t2013 Bulmer MG: The efect of parental age, parity, and duration of marriage on the twinning rate. Hum Genet 23:454, 1959

Cahill A, Stamilio OM, Pare E, et al: Vaginal birth after cesarean (VBAC) attempt in twin pregnancies: is it safe? Am J Obstet Gynecol 193: 1050, 2005

Campbell OM: Maternal adaptation in twin pregnancy. Semin Perinatol 10:14, 1986

Caritis SN, Rouse OJ, Peaceman M, et al: Prevention of preterm birth in triplets using 17alpha-hydroxyprogesterone caproate: a randomized controlled trial. Obstet Gynecol 113(2 Pt 1):285, 2009

Caritis SN, Simhan H, Zhao Y, et al: Relationship between 17-hydroxyprogestrone caproate concentrations and gestational age at delivery in twin gestation. Am J Obstet Gynecol 207:396.e1, 2012

Carter EB, Bishop KC, Goetzinger KR, et al: The impact of chorionicity on maternal pregnancy outcomes. Am J Obstet Gynecol 213(3):390.e1, 2015

Caukwell 5, Murphy OJ: The efect of mode of delivery and gestational age on neonatal outcome of the non-cephalic-presenting second twin. Am J Obstet Gynecol 187:t1t356,t2002

Cetingoz E, Cam C, Sakalh M, et al: Progesterone efects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial. Arch Gynecol Obstet 283:423, 2011

Challis 0, Gratacos E, Deprest JA: Cord occlusion techniques for selective termination in monochorionic twins. J Perinat Med 27:327, 1999

Chang E, Park M, Kim Y, et al: A case of successful selective abortion using radio-frequency ablation in twin pregnancy sufering from severe twin to twin transfusion syndrome. J Korean Med Sci 24:513, 2009

Chasen ST, Luo G, Perni SC, et al: Are in vitro fertilization pregnancies with early spontaneous reduction high risk? Am J Obstet Gynecol 195:814,t2006

Chauhan SP, Roberts WE, McLaren A, et al: Delivery of the nonvertex second twin: breech extraction versus external cephalic version. m J Obstet GynecoIt173:1015,t1995

Chauhan SP, Scardo JA, Hayes E, et al: Twins: prevalence, problems, and preterm births. Am J Obstet Gynecol 203(4):305, 2010

Cheng W, Yee LM, Caughey AB: Intertwin delivery interval and associated maternal and neonatal outcomes. Abstract No. 848, Am J Obstet Gynecol 216(1):5485,t2017

Chervenak FA, McCullough LB: Ethical challenges in the management of multiple pregnancies: the professional responsibility model of perinatal ethics. J Perinat Med 41:61,t2013 Choi Y, Bishai 0, Minkovitz CS: Multiple births are a risk factor for postpartum maternal depressive symptoms. Pediatrics 123(4):1147,t2009

Christensen K, Petersen I, Skytthe A, et al: Comparison of academic performance of twins and singletons in adolescence: follow-up study. BMJ 333: 1095, 2006

Cohen M, Kohl SG, Rosenthal AH: Fetal interlocking complicating twin gestation. Am J Obstet Gynecol 91t:407, 1965

Combs CA, Garite T, Maurel K, et al: 17-Hydroxyprogesterone caproate for twin pregnancy: a double-blind, randomized clinical trial. Am J Obstet Gynecol 204(3):221.e1, 2011

Conde-Agudelo A, Romero R, Hassan 55, et al: Transvaginal sonographic cervical length for the prediction of spontaneous preterm birth in twin pregnancies: a systematic review and metaanalysis. Am J Obstet Gynecol 203:128.e1,2010

Corcoran S, Breathnach F, Burke G, et al: Dichorionic twin ultrasound surveillance: sonography every 4 weeks signiicantly underperforms sonography every 2 weeks: results of the Prospective Multicenter ESPRiT Study. Am ] Obstet GynecoIt213(4):551.el, 2015

Corsello G, Piro E: The world of twins: an update. ] Matern Fetal Neonatal Med 23(S3):59, 2010

Crombleholme TM, Shera 0, Lee H, et a1: A prospective, randomized, multicenter trial of amnioreduction vs selective fetoscopic laser photocoagulation for the treatment of severe twin-twin transfusion syndrome. Am ] Obstet GynecoIt197:396.el,t200

Crowther CA, Han S: Hospitalization and bed rest for multiple pregnancy.

Cochrane Database Syst Rev 7:CDOOOII0, 2010

Curnow K], Wilkins-Haug L, Ryan A, et al: Detection of triploid, molar, and vanishing twin pregnancies by a single-nucleotide polymorphism-based noninvasive prenatal test. Am ] Obstet Gynecol 212(1):79.el, 2015

D'Alton ME: Delivery of the second twin. Obstet GynecoItI15(2):221, 2010 Danon D, Sekar R, Hack E, et a1: Increased stillbirth in uncomplicated monochorionic twin pregnancies: a systematic review and meta-analysis.

Obstet GynecoIt121(6):1318, 2013

Dashe ]S, Fernandez CO, Twickler DM: Utiliry of Doppler velocimetry in predicting outcome in twin reversed-arterial perfusion sequence. m ] Obstet Gynecol 185(1):135,t2001

Davidson L, Easterling TR, Jackson ]C, et a1: Breech extraction of low-birthweight second twins. Amt] Obstet Gynecol 166:497, 1992 de Castro H, Haas ], Schif E, et al: Trial of labour in twin pregnancies: a retrospective cohort study. B]OG 126(6):940,t2016

Denker HW: Comment on G. Herranz: The timing of monozygotic twinning: a criticism of the common model. Zygote (2013). Zygote 23(2):312,t2015 De Paepe ME, DeKoninck P, Friedman M:Vascular distribution patterns in monochorionic twin placentas. Placenta 26(6):471,t2005

Derbent A, Simavli S, Gumus I, et a1: Nifedipine for the treatment of preterm labor in twin and singleton pregnancies. Arch Gynecol Obstet 284:821, 2011 DeVoe LD: Antenatal fetal assessment: multi fetal gestation-an overview.

Semin Perinatol 32:281, 2008

Diamond MP, Legro RS, Coutifaris C, et al: Assessment of multiple intrauterine gestations from ovarian stimulation (AMIGOS) trial: baseline characteristics. Fertil Steril 103(4):962,t2015

Dickey RP, Taylor SN, Lu PY, et al: Spontaneous reduction of multiple pregnancy: incidence and efect on outcome. Am] Obstet GynecoIt186:77, 2002 Dodd ], Crowther C: Multifetal pregnancy reduction of triplet and higher order multiple pregnancies to twins. Fertil Steril 81 (5): 1420, 2004

Dodd ]M, Crowther CA: Reduction of the number of fetuses for women with a multiple pregnancy. Cochrane Database Syst Rev 10:CD003932, 2012

Dolapcioglu K, Gungoren A, Hakverdi S, et al: Twin pregnancy with a complete hydatidiform mole and co-existent live fetus: two case reportS and review of the literature. Arch Gynecol Obstet 279:431, 2009

Durnwald CP, Momirova V, Rouse D], et al: Second trimester cervical length and risk of preterm birth in women with twin gestations treated with 17-x hydroxyprogesterone caproate.t] Matern Fetal Neonatal Med 23(12):1360, 2010

Duryea EL, Happe SK, McIntire DO, et a1: Sonography interval and the diagnosis of twin-twin transfusion syndrome. ] Matern Fetal Neonatal Med 30(6):640,t2017

Duryea EL, Happe SK, McIntire DD, et al: The natural history of twin-twin transfusion syndrome stratiied by Quintero stage. ] Matern Fetal Neonatal Med 29(21):3411,t2016

Easter SR, Robinson ]N, Lieberman E, et a1: Association of intended route of delivery and maternal morbidiry in twin pregnancy. Obstet Gynecol 129(2):305,t2017

Eddib A, Rodgers B, Lawler ], et al: Monochorionic pseudomonoamniotic twin pregnancy with fetal demise of one twin and development of maternal consumptive coagulopathy. Ultrasound Obstet Gynecol 28:735, 2006

Edris F, Oppenheimer L, Yang Q, et al: Relationship between intertwin delivery interval and metabolic acidosis in the second twin. Am ] Perinatol 23(8):481, 2006

Ehsanipoor R, Arora N, Lagrew DC, et a1: Twin versus singleton pregnancies complicated by preterm premature rupture of membranes. ] Matern Fetal Neonatal Med 25(6):658,t2012

Ekelund CK, Skibsted L, Sogaard K, et a1: Dizygotic monochorionic twin pregnancy conceived following intracytoplasmic sperm injection treatment and complicated by twin-twin transfusion syndrome and blood chimerism. Ultrasound Obstet Gynecol 32:282, 2008

Elliott ]P: Preterm labor in twins and high-order multiples. Clin Perinatol 34:599, 2007

Elliott ]P, Finberg H]: Biophysical proile testing as an indicator of fetal wellbeing in high-order multiple gestations. Am] Obstet Gynecoltl72:508, 1995

Emery SP, Bahriyar MO, Dashe ]S, et 1: The North American Fetal Therapy Network Consensus Statement: prenatal management of uncomplicated monochorionic gestations. Obstet GynecoIt125(5):1236, 2015

Ericson A, Kallen B, Aberg A: Use of multivitamins and folic acid in early pregnancy and multiple births in Sweden. Twin Res 4(2):63, 2001

Evans MI, Ciorica 0, Britt DW, et a1: Update on selective reduction. Prenat Diagn 25:807, 2005

Evans MI, Goldberg]D, Horenstein], et a1: Elective termination for structural, chromosomal, and mendelian anomalies: international experience. Am ] Obstet Gynecol 181 :893, 1999

Faye-Petersen OM, Heller OS, Joshi V: Handbook of Placental Pathology, 2nd ed, London, Taylor & Francis, 2006

Fellman ], Eriksson A W: Secondary sex ratio in multiple births. Twin Res Hum Genet 13(1):101,2010

Ford A, Bateman BT, Simpson LL: Vaginal birth after cesarean delivery in twin gestations: a large, nationwide sample of deliveries. Am] Obstet Gynecol 195:1138, 2006

Fox H, Sebire N]: Pathology of the Placenta, 3rd ed. Philadelphia, Saunders, 2007

Fox NS, Roman AS, Saltzman DH, et al: Risk factors for preeclampsia in twin pregnancies. Am] PerinatoI31(2):163, 2014

Fox NS, Silverstein M, Bender S, et al: Active second-stage management in twin pregnancies undergoing planned vaginal delivery in a U.S. population. Obstet GynecoIt115:229, 2010

Francisco C, Wright D, Benko Z, et al: Hidden high rate of pre-eclampsia in twin compared with singleton pregnancy. Ultrasound Obstet Gynecol 50(1):88,t2017

Francois K, Ortiz], Harris C, et al: Is peripartum hysterectomy more common in multiple gestations? Obstet Gynecoltl05:1369, 2005

Fusi L, Gordon H: Twin pregnancy complicated by single intrauterine death.

Problems and outcome with conservative management. B]OG 97:511, 1990

Fusi L, McParland P, Fisk N, et 1: Acute twin-twin transfusion: a possible mechanism for brain-damaged survivors after intrauterine death of a monochorionic twin. Obstet Gynecol 78: 517, 1991

Futch T, Spinosa], Bhatt S, et a1: Initial clinical laboratory experience in noninvasive prenatal testing for fetal aneuploidy from maternal plasma DNA samples. Prenat Diagn 33(6):569, 2013

Gabriel R, Harika G, Saniez D, et a1: Prolonged intravenous ritodrine therapy: a comparison between multiple and singleton pregnancies. Eur ] Obstet Gynecol Reprod BioI 57:65, 1994

Ghi T, degli Esposti 0, Montaguti E, et al: Maternal cardiac evaluation during uncomplicated twin pregnancy with emphasis on the diastolic function. Am ] Obstet Gynecol 213(3):376, 2015

Ghi T, Nanni M, Pierantoni L, et al: Neonatal respiratory morbidiry in twins versus singletons after elective prelabor caesarean section. Eur ] Obstet Gynecol Reprod BioI 166:156, 2013

Giles W, Bisits A, O'Callaghan S, et 1: he Doppler assessment in multiple pregnancy randomized controlled trial of ultrasound biometry versus umbilical artery Doppler ultrasound and biometry in twin pregnancy. B]OG 110:593,t2003

Girela E, Lorente ]A, Alvarezt]C, et a1: Indisputable double paterniry in dizygous twins. Fertil Steril 67(6):1159, 1997

Giufre M, Piro E, Corsello G: Prematuriry and twinning. ] Matern Fetal Neonatal Med 25(53):6, 2012

Gjerris AC, Loft A, Pinborg A, et al: The efect of a "vanishing twin" on biochemical and ultrasound irst trimester screening markers for Down's syndrome in pregnancies conceived by assisted reproductive technology. Hum Reprod 24(1):55, 2009

Glinianaia SV, Obeysekera MA, Sturgiss S, et al: Stillbirth and neonatal mortaliry in monochorionic and dichorionic twins: a population-based study. Hum Reprod 26(9):2549,t2011

Glinianaia SV, Rankint], Wright C: Congenital anomalies in twins: a registerbased study. Hum Reprod 23:1306, 2008

Gonzalez NL, Goya M, Bellart ], et al: Obstetric and perinatal outcome in women with twin pregnancy and gestational diabetes. ] Matern Fetal Neonatal Med 25(7):1084, 2012

Goodnight W, Newman R: Optimal nutrition for improved twin pregnancy outcome. Obstet Gynecol 114:1121,2009

Gordon MC, McKenna DS, Stewart TL, et a1: Transvaginal cervical length scans to prevent prematuriry in twins: a randomized controlled trial. Am ] Obstet GynecoIt214(2):277.el, 2016

Gourheux N, Deruelle P, Houiin-Debarge V, et a1: Twin-to-twin delivery interval: is a time limit justiied? Gynecol Obstet Fertil 35(10):982, 2007

Goya M, de la Calle M, Pratcorona L, et al: Cervical pessary to prevent preterm birth in women with twin gestation and sonographic short cervix: a multicenter randomized controlled trial (PECEP-Twins). Amt] Obstet Gynecol 214(2):145,t2016

Grant ], Vladutiu C, Manuck TA: Racial disparities in gestational age at delivery among twin gestations. Abstract No. 149, Amt] Obstet Gynecol 216(1):SI00, 2017

Gratacos E, Lewi L, Munoz B, et al: A classification system for selective intrauterine growth restriction in monochorionic pregnancies according to umbilical artery Doppler low in the smaller twin. Ultrasound Obstet Gynecol 30(1):28, 2007

Gratacos E, Ortiz JU, Martinez JM: A systematic approach to the diferential and management of the complications of monochorionic twin pregnancies. Fetal Diagn Ther 32(3):145,t2012

Greene MF: Comment on: A randomized trial of planned cesarean or vaginal delivery for twin pregnancy. N Engl J Med 369(14):1365, 2013

Grobman WA, Peaceman AM, Haney EI, et al: Neonatal outcomes in triplet gestations ater a trial of labor. Am] Obstet Gynecol 179:942, 1998

Gyami C, Mele L, Wapner R, et al: The efect of plurality and obesity on betamethasone concentrations in women at risk for preterm delivery. Am J Obstet Gynecol 203:219.el, 2010

Gyervai K, Hannah ME, Hodnett ED, et al: Tocolytics for preterm labor: a systematic review. Obstet Gynecol 94:869, 1999

Hack E, Derks JB, Elias SG, et al: Increased perinatal mortality and morbidity in monochorionic versus dichorionic twin pregnancies: clinical implications of a large Dutch cohort study. B]OG 115:58, 2008

Hack E, Derks JB, Schaap AH: Perinatal outcome of monoamniotic twin pregnancies. Obstet Gynecol 113(2 Pt 1):353, 2009a

Hack E, van Gemert MJ, Lopriore E, et al: Placental characteristics of monoamniotic twin pregnancies in relation to perinatal outcome. Placenta 30(1):62, 2009b

Hackmon R, Jormark S, Cheng V, et al: Monochorionic dizygotic twins in spontaneous pregnancy: a rare case report. ] Matern Fetal Neonatal Med 22(8):708,t2009

Haggarty P, McCallum H, McBain H, et al: Efect of B vitamins and genetics on success of in-vitro fertilization: prospective cohort study. Lancet 367(9521):1513,t2006

Hall ]G:'Twinning. Lancet 362:735,t2003

Harris OW: Superfecundation: letter. J Reprod Med 27:39, 1982

Hernandez ]S, Twickler DM, McIntire DO, et al: Hydramnios in twin gestations. Obstet Gynecol 120(4):759,t2012

Herranz G: he timing of monozygotic twinning: a criticism of the common model. Zygote 23(1):27, 2015

Heyborne KD, Porreco RP, Garite TJ, et al: Improved perinatal survival of monoamniotic twins with intensive inpatient monitoring. Am J Obstet Gynecol 192(1):96,t2005

Hibbeln JF, Shors SM, Byrd SE: MRI: is there a role in obstetrics? Clin Obstet Gynecol 55(1):352, 2012

Hillman SC, Morris RK, Kilby MD: Co-twin prognosis after single fetal death.

A systematic review and meta-analysis. Obstet Gynecol 118(4):928,t2011 Hoekstra C, Zhao ZZ, Lambalk CB, et al: Dizygotic twinning. Hum Reprod Update 14:37,t2008

Hofmann E, Oldenburg A, Rode L, et al: Twin births: cesarean section or vaginal delivery? Acta Obstet Gynecol Scand 91 (4):463,t2012

Hogle KL, Hutton EK, McBrien A, et al: Cesarean delivery for twins: a systematic review and meta-analysis. Am J Obstet Gynecol 188:220,2003 Hollier LM, McIntire DO, Leveno K]: Outcome of twin pregnancies according to intrapair birth weight diferences. Obstet Gynecol 94: 1 006, 1999

Houlihan C, Poon LC, Ciarlo M, et al: Cervical cerclage for preterm birth prevention in twin gestation with short cervix: a retrospective cohort study. Ultrasound Obstet GynecoIt48(6):752, 2016

Hu LS, Cairet], Twickler OM: MR indings of complicated multi fetal gestations. Pediatr Radiol 36:76, 2006

Huang T, Boucher K, Aul R, et al: First and second trimester maternal serum markers in pregnancies with a vanishing twin. Prenat Diagn 35(1):90, 2015

Huber A, Diehl W, Zikulnig L, et al: Perinatal outcome in monochorionic twin pregnancies complicated by amniotic luid discordance without severe twin-twin transfusion syndrome. Ultrasound Obstet Gynecol 27:45, 2006

Institute of Medicine and National Research Council: Weight Gain During Pregnancy: Reexamining the Guidelines. Washington, DC, National Academies Press, 2009

Jelin E, Hirose S, Rand L, et al: Perinatal outcome of conservative management versus fetal intervention for twin reversed arterial perfusion sequence with a small acardiac twin. Fetal Diagn Ther 27(3):138,t2010

Jenna AB, Goldman DP, Joyce G: Association between the birth of twins and parental divorce. Obstet GynecoIt117(4):892, 2011

Joo JG, Csaba A, Szigeti Z, et al: Spontaneous abortion in multiple pregnancy: focus on fetal pathology. Pathol Res Pract 208(8):458,t2012

Kahn B, Lumey LH, Zybert PA, et al: Prospective risk oftfetal death in singleton, twin, and triplet gestations: implications for practice. Obstet Gynecol 102:685,t2003

Kametas NA, McAulife F, Krampl E, et al: Maternal cardiac function in twin pregnancy. Obstet Gynecol 102:806,t2003

Kaufman D, Du L, Velcek F, et l: Fetus-in-fetu. J m Coli Surg 205(2):378,t2007

Kent EM, Breathnach FM, Gillan JE, et al: Placental pathology, birthweight discordance, and growth restriction in twin pregnancy: results of the ESPRIT Study. Am J Obstet 207(3):220.el, 2012

Kilpatrick SJ, Jackson R, Croughan-Minihane MS: Perinatal mortality in twins and singletons matched for gestational age at delivery at > or = 30 weeks. Am J Obstet Gynecol 174(1 Pt 1):66, 1996

Kim HS, Kim MK, Oh JW, et al: Placental transfer of dexamethasone in twin pregnancy compared to singleton pregnancy. Abstract No. 662. Am J Obstet GynecoIt216(1):S388, 2017

Kim JH, Park SW, Lee JJ: Birth weight reference for triples in Korea. J Korean Med Sci 25:900, 2010

Kindinger LM, Poon LC, Cacciatore S, et al: he efect on gestational age and cervical length measurements in the prediction of spontaneous preterm birth in twin pregnancies: an individual patient level meta-analysis. BJOG 123(6):877,t2016

Klein K, Rode L, Nicolaides KH, et al: Vaginal micronized progesterone and risk of preterm delivery in high-risk twin pregnancies: secondary analysis of a placebo-controlled randomized trial and meta-analysis. Ultrasound Obstet Gynecol 38(3):281, 2011

Knox G, Morley 0: Twinning in Yoruba women. J Obstet Gynaecol Br Emp 67:981,t1960

Kuleva M, Youssef A, Maroni E, et al: Maternal cardiac unction in normal twin pregnancy: a longitudinal study. Ultrasound Obstet Gynecol 38:575, 2011 Kulkarni AD, Jamieson DJ, Jones HW ]r, et al: Fertility treatments and multiple births in the United States. N Engl J Med 369(23):2218,t2013 Langer B, Boudier E, Gasser B, et al: Antenatal diagnosis of brain damage in the survivor after the second trimester death of a monochorionic monoamniotic co-twin: case report and literature review. Fetal Diagn her 12:286, 1997

Lantieri T, Revelli A, Gaglioti P, et al: Superfetation after ovulation induction and intrauterine insemination performed during an unknown ectopic pregnancy. Reprod Biomed Online 20(5):664, 2010 Lappen JR, Hackney ON, Bailit JL: Maternal and neonatal outcomes of attempted vaginal compared with planned cesarean delivery in triplet gestations. Am J Obstet Gynecol 215(4):493.e1, 2016 Lee H, Bebbington M, Crombleholme TM, et al: The North American Fetal herapy Network Registry data on outcomes of radiofrequency ablation for twin-reversed arterial perfusion sequence. Fetal Diagn her 33(4):224, 2013

Lee HC, Gould JB, Boscardin W], et al: Trends in cesarean delivery for twin births in the United State 1995-2008. Obstet Gynecol 118(5):1095,2011 Lee YM, Clery-Goldman J, haker HM, et al: ntenatal sonographic predic tion of twin chorionicity. Am J Obstet Gynecol 195(3):863,t2006 Lee YM, Wylie BJ, Simpson LL, et al: Twin chorionicity and the risk of stillbirth. Obstet Gynecol III:30 1, 2008

LeFevre ML, Bain RP, Ewigman BG, et al: A randomized trial of prenatal ultrasonographic screening: impact on maternal management and outcomes. RADIUS (Routine Antenatal Diagnostic Imaging with Ultrasound) Study Group. Am J Obstet Gynecol 169(3):483, 1993

Leftwich HK, Zaki MN, Wilkins 1, et al: Labor patterns in twin gestations. Am J Obstet Gynecol 209(3):254.e1, 2013

Legro RS, Brzyski RG, Diamond MP, et al: The Pregnancy in Polycystic Ovary Syndrome II study: baseline characteristics and efects of obesity from a multicenter randomized clinical trial. Ferti! Sterilt101(1):258e.8, 2014 Leung Y, Tam H, Leung TN, et al: Efect of twin-to-twin delivery interval on umbilical cord blood gas in the second twins. BJOG 109(1):63,t2002 Leveno KJ, Quirk JG, Whalley P], et al: Fetal lung maturation in twin gestation. Amt] Obstet Gynecol 148:405, 1984 Lewi L, Deprest J, Hecher K: The vascular anastomoses in monochorionic twin pregnancies and their clinical consequences. Am J Obstet Gynecol 208(1):19,t2013 Lewi L, Gratacos E, Ortibus E, et al: Pregnancy and infant outcome of 80 consecutive cord coagulations in complicated monochorionic multiple pregnancies. Am J Obstet Gynecol 194(3):782, 2006 Liem S, Schuit E, Hegerman M, et al: Cervical pessaries for prevention of preterm birth in women with a multiple pregnancy (Pro TWIN): a multicenter, open-label randomised controlled trial. Lancet 382(9901): 1341, 2013

Livingston JC, Livingston L W, Ramsey R, et al: Second-trimester asynchronous multi fetal delivery results in poor perinatal outcome. Obstet Gynecol 103:77,t2004 Lopriore E, Oepkes D: Neonatal morbidity in twin-twin transfusion syndrome. Early Hum Dev 87:595,t2011

Lorenz JM: Neurodevelopmental outcomes of twins. Semin Perinatol 36(3):201,t2012 Lucovnik M, Blickstein I, Lasic M, et al: Hypertensive disorders during monozygotic and dizygotic twin gestations: a population-based study. Hypertens Pregnancy 135(4):542, 2016

Luke B, Brown MB: Maternal morbidity and infant death in twin vs triplet and quadruplet pregnancies. Am J Obstet Gynecol 198:40 l.e 1, 2008

MacDonald-Wallis C, Lawlor DA, Fraser A, et al: Blood pressure change in normotensive, gestational hypertensive, preeclamptic, and essential hypertensive pregnancies. Hypertension 59:1241, 2012

Magann EF, Chauhan SP, Whitworth NS, et al: Determination of amniotic luid volume in twin pregnancies: ultrasonographic evaluation versus operator estimation. Am J Obstet Gynecol 182: 1606, 2000

Mahony BS, Mulcahy C, McCaulife F, et al: Fetal death in twins. Acta Obstet Gynecol Scand 90(11):1274, 2011

Manning FA (ed): Fetal biophysical profile scoring. In Fetal Medicine: Principles and Practices. Notwalk, Appleton & Lange, 1995

Martin JA, Hamilton BE, Osterman MJ, et al: Births: inal data for 2015. Nat!

Vital Stat Rep 66(1):1,t2017

MassardierJ, Golfner F, Journet 0, et al: Twin pregnancy with complete hydatidiform mole and coexistent fetus obstetrical and oncological outcomes in a series of 14 cases. Eur J Obstet Gynecol Reprod Bioi 143:84,t2009

Iatthews T], MacDorman MF, Thoma ME: Infant mortality statistics from the 20t13 period linked birth/infant death data set. Narl Vital Stat Rep 64(91):1,t2015

Maynard SE, Moore Simas TA, Solitro MJ, et al: Circulating angiogenic factors in singleton vs multiple gestation pregnancies. Am J Obstet 198:200. el,t2008

McClamrock HD, Jones HW, Adashi EY: Ovarian stimulation and intrauterine insemination at the quarter centennial: implications for the multiple births epidemic. Ferril Steril 97(4):802, 2012

McElrath TF, Notwitz ER, Robinson IN, et al: Diferences in TDx fetal lung maturity assay values between twin and singleton pregnancies. Am J Obstet Gynecol 182: 11t10, 2000

McHugh K, Kiely EM, Spitz L: Imaging of conjoined twins. Pediatr Radiol 36:899, 2006 McLennan AS, Gyami-Bannerman C, Ananth CV, et al: The role of maternal age in twin pregnancy outcomes. Am J Obstet Gynecol 217(l):80.el, 2017

McMahon KS, Neerhof MG, Haney EI, et al: Prematurity in multiple gestations: identiication of patients who are at low risk. Am J Obstet Gynecol 186:1137,t2002

McNamara HC, Kane SC, Craig JM, et al: A review of the mechanisms and evidence for typical and atypical twinning. Am ] Obstet Gynecol 214(2):172,t2016

McPherson JA, Odibo 0, Shanks AL, et al: Impact of chorionicity on risk and timing of intrauterine fetal demise in twin pregnancies. Am ] Obstet GynecoIt207:190.e1,t2012

Melamed N, Pittini A, Hiersch L, et al: Do serial measurements of cervical length improve the prediction of preterm birth in asymptomatic women with twin gestations? Am J Obstet GynecoIt215(5):616.e1, 2016a

Melamed N, Shah ], Yoon EW, et al: he role of antenatal corticosteroids in twin pregnancies complicated by preterm birth. Am J Obstet Gynecol 215(4):482.el,t2016b

Mhyre ]M: Maternal mortality. Curr Opin Anesthesiol 25:277, 2012

Michelfelder E, Gotrliebson W, Border W, et al: Early manifestations and spectrum of recipient twin cardiomyopathy in twin-twin transfusion syndrome: relation to Quintero stage. Ultrasound Obstet Gynecol 30:965, 2007

Miller J, Chauhan SP, Abuhamad AZ: Discordant twins: diagnosis, evaluation and management. Am J Obstet GynecoIt206(l):10, 2012

Morikawa M, Yamada T, Yamada T, et al: Prospective risk of stillbirth: monochorionic diamniotic twins vs dichorionic twins. J Perinat Med 40:245, 20t12

Moroz LA, Brock CO, Govidappagari 5, et al: Association between change in cervical length and spontaneous preterm birth in twin pregnancies. Am J Obstet Gynecol 216(2): 159.el, 2017

Muggli EE, Halliday]L: Folic acid and risk of twinning: a systematic review of the recent literature, July 1994 to July 2006. MJA 186(5):243,t2007

Muleba N, Dashe N, Yost 0, et al: Respiratory morbidity among second-born twins. Presented at the 25th Annual Meeting of the Sociey for Maternal Fetal Medicine, February 7-12, 2005

Mutchinick OM, Luna-Munoz L, Amar E, et al: Conjoined twins: a worldwide collaborative epidemiological study of the international clearinghouse for birth defects surveillance and research. Am J Med Genet C Semin Med Genet 15 7C( 4) :274, 201t1

Newman RB, Krombach 5, Myers MC, et al: Efect of cerclage on obstetrical outcome in twin gestations with a shortened cervical length. Am J Obstet Gynecol 186:634, 2002

Nicolaides KH, Syngelaki A, Poon LC, et al: Cervical pessary placement for prevention of preterm birth in unselected twin pregnancies: a randomized controlled trial. Am J Obstet Gynecol 214(l):3.el, 2016

Norman ]E, Mackenzie F, Owen P, et al: Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a randomised, double-blind, placebo-controlled study and meta-analysis. Lancet 373:2034, 2009

Nylander PP: Biosocial aspects of multiple births.t] Biosoc Sci 3:29, 1971 Nylander PP: Serum levels of gonadotropins in relation to multiple pregnancy in Nigeria. B]OG 80:65t1,t1973

O'Brien P, Nugent M, Khalil A: Prenatal diagnosis and obstetric management.

Semin Pediatr Surg 24(5):203,t2015

Odibo AO, Cahill AG, Goetzinger KR, et al: Customized growth charts for twin gestations to optimize identiication of small-for-gestational age fetuses at risk of intrauterine fetal death. Ultrasound Obstet GynecoI41:637, 2013

Oh K], Hong ]S, Romero R, et al: The frequency and clinical significance of intra-amniotic inlammation in twin pregnancies with preterm labor and intact membranes. J Matern Fetal Neonatal Med October 1,t20t17 [Epub ahead of print]

Olusanya BO, Solanke OA: Perinatal correlates of delayed childbearing in a developing country. Arch Gynecol Obstet 285(4):951,t2012

Ong 55, Zamora J, Khan KS, et al: Prognosis for the co-twin following singletwin death: a systematic review. BJOG 113:992, 2006

Painter IN, Willemsen G, Nyholt 0, et al: A genome wide linkage scan for dizygotic twinning in 525 families of mothers of dizygotic twins. Human Reprod 25(6):1569,t2010

Pakrashi T, Defranco A: The relative proportion of preterm births complicated by premature rupture of membranes in multifetal gestations: a population-based study. Am J PerinatoIt30:69, 2013

Parra-Cordero M, Bennasar M, Martinez ]M, et al: Cord occlusion in monochorionic twins with early selective intrauterine growth restriction and abnormal umbilical artery doppler: a consecutive series of 90 cases. Fetal Diagn Ther 39(3):186,t2016

Peigne M, Andrieux ], Deruelle P, et al: Quintuplets after a transfer of two embryos following in vitro fertilization: a proved superfecundation. Fertil Steril 95(6):2124.e13, 201t1

Pettit KE, Merchant 1, Machin GA, et al: Congenital heart defects in a large, unselected cohort of monochorionic twins. J Perinatol 33:467, 2013

Post A, Heyborne K: Managing monoamniotic twin pregnancies. C1in Obstet Gynecol 58(3):643, 2015

Prefumo F, Cabassa P, Fichera A, et al: Preliminary experience with microwave ablation for selective feticide in monochorionic twin pregnancies. Ultrasound Obstet GynecoIt41:469, 2013

Prefumo F, Fichera A, Pagani G, et al: The natural history of monoamniotic twin pregnancies: a case series and systematic review of the literature. Prenat Diagn 35(3):274, 2015

Pritchard JA: Changes in blood volume during pregnancy. Anesthesiology 26: 393, 1965

PROSPECT: A trial of pessary and progesterone for preterm prevention in twin gestation with a short cervix, May 2017. Available at: https:llclinicaltrials.gov/ct2/show/NCT02518594. Accessed October 30, 2017

Quarello E, Molho M, Ville Y: Incidence, mechanisms, and patterns of fetal cerebral lesions in twin-to-twin transfusion syndrome. ] Matern Fetal Neonatal Med 20:589, 2007

Quigley MM, Cruikshank DP: Polyhydramnios and acute renal failure. ] Reprod Med 19:92, 1977

Quinn KH, Cao CT, Lacoursiere Y, et al: Monoamniotic twin pregnancy: continuous inpatient electronic fetal monitoring-an impossible goal? Am J Obstet Gynecol 204:t161, 20t11

Quintero A, Morales ), Allen MH, et al: Staging of twin-twin transfusion syndrome. J Perinatol 19:550, 1999

Rana 5, Hacker MR, Modest AM, et al: Circulating angiogenic factors and risk of adverse maternal and perinatal outcomes in twin pregnancies with suspected preeclampsia: novelty and signiicance. Hypertension 60:45t1,t2012

Ray B, Platt MP: Mortality of twin and singleton livebirths under 30 weeks' gestation: a population-based study. Arch Dis Child Fetal Neonatal Ed 94(2):F140, 2009

Rayburn WF, Lavin]P Jr, Miodovnik M, et al: Multiple gestation: time interval between delivery of the irst and second twins. Obstet Gynecol 63:502, 1984

Razavi AS, Chasen ST, Chambers F, et al: Maternal morbidity associated with labor induction in twin gestations. Abstract No. 733 Amt] Obstet Gynecol 216:5427,t2017

Rebarber A, Roman AS, Istwan N, et al: Prophylactic cerclage in the management of triplet pregnancies. Am] Obstet Gynecol 193: 1193, 2005

Record RG, McKeown T, Edwards ]H: An investigation of the diference in measured intelligence between twins and single births. Ann Hum Genet 34(1):11, 1970

Reddy UM, Abuhamad AZ, Levine 0, et al: Fetal imaging: executive summary of a joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Institute of Ultrasound in Medicine, American College of Obstetricians and Gynecologists, American College of Radiology, Society for Pediatric Radiology, and Society of Radiologists in Ultrasound Fetal Imaging workshop. Obstet Gynecol 123(5):1070,t2014

Reddy UM, Branum M, KlebanofA:Relationship of maternal body mass index and height to twinning. Obstet GynecoIt105(3):593, 2005

Roberts D, Dalziel 5: Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 3:CD004454, 2006

Roberts D, Gates 5, Kilby M, et aI: Interventions for twin-twin transfusion syndrome: a Cochrane review. Ultrasound Obstet GynecoIt31:701, 2008

Robyr R, Lewi L, Salomon LJ, et I: Prevdence and management of late fetal complications following successful selective laser coagulation of chorionic plate anastomoses in twin-to-twin transfusion syndrome. Am J Obstet Gynecol 194:796, 2006

Rode L, Klein K, Nicolaides KH, et al: Prevention of preterm delivery in twin gestations (PREDICT): a multicenter, randomized, placebo-controlled trial on the efect of vaginal micronized progesterone. Ultrasound Obstet Gynecol 38:272, 2011

Roman A, Papanna R, Johnson A, et aI: Selective reduction in complicated monochorionic pregnancies: radiofrequency ablation vs bipolar cord coagulation. Ultrasound Obstet Gynecol 36:37, 2010

Roman A, Rochelson B, Martinelli P, et aI: Cerclage in twin pregnancy with dilated cervix between 16 to 24 weeks of gestation: retrospective cohort study. mJ Obstet GynecoIt215(1):98.e1, 2016

Roman AS, Saltzman DH, Fox N, et al: Prophylactic cerclage in the management of twin pregnancies. mJ PerinatoIt30(9):751, 2013

Romero R, Conde-Agudelo A, EI-Refaie W, et aI: Vaginal progesterone decreases preterm birth and neonatal morbidity and mortality in women with a twin gestation and a short cervix: an updated meta-analysis of individual patient data. Ultrasound Obstet GynecoIt49(3):303, 2017

Ronalds GA, De Stavola BL, Leon DA: he cognitive cost of being a twin: evidence from comparisons within families in the Aberdeen children of the 1950s cohort study. BMJ 331(7528):1306, 2005

Rossi AC, D'Addario V: Laser therapy and serial amnioreduction as treatment for twin-twin transfusion syndrome: a metaanalysis and review of literature. mJ Obstet Gynecol 198:147,t2008

Rossi AC, D'Addario V: Umbilical cord occlusion for selective feticide in complicated monochorionic twins: a systematic review of literature. Am J Obstet GynecoIt200(2):123,t2009

Rossi AC, Mullin PM, Chmait RH: Neonatal outcomes of twins according to birth order, presentation and mode of delivery: a systematic review and meta-analysis. BJOG 118(5):523,t2011

Rothman KJ: Fetal loss, twinning and birthweight ater orl contraceptive use.

N Engl J Med 297:468, 1977

Rouse DJ, Caritis SN, Peaceman M, et al: A trial of 17alpha-hydroxyprogesterone caproate to prevent prematurity in twins. N Engl J Med 357:454,t2007

Rouse DJ, Skopec GS, Zlatnik FJ: Fundal height as a predictor of preterm twin delivery. Obstet GynecoI81:211, 1993

Salem SY, Kibel M, Asztalos E, et al: Neonatal outcomes of low-risk, latepreterm twins compared with late-preterm singletons. Obstet Gynecol 130(3):582,t2017

Salomon LJ, Ortqviast L, Aegerter P, et aI: Long-term developmental follow-up of infants who participated in a randomized clinical trial of amniocentesis vs laser photocoagulation for the treatment of twin-to-twin transfusion syndrome. mJ Obstet Gynecol 203(5):444.el, 2010

Schmitz T, Prunet C, Azria E, et aI: Association between planned cesarean delivery and neonatal mortality and morbidity in twin pregnancies. Obstet GynecoIt129(6):986,t2017

Sebire NJ, Foskett M, Paradinas FJ, et al: Outcome of twin pregnancies with complete hydatidiform mole and healthy co-twin. Lancet 359:2165,t2002

Senat MV, Deprest J, Boulvain M, et al: Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome. N Engl J Med 351: 136, 2004

Senat MV, Porcher R, Winer N, et al: Prevention of preterm delivery by 17a1pha-hydroxyprogesterone caproate in asymptomatic twin pregnancies with a short cervix: a randomized controlled trial. Am J Obstet Gynecol 208(3):194.e1,t2013

Shen 0, Samuelof A, Beller U, et I: Number of yolk sacs does not predict amnionicity in early first-trimester monochorionic multiple gestations. Ultrasound Obstet Gynecol 27(1):53, 2006

Shub A, Walker SP: Planned early delivery versus expectant management of monoamniotic twins. Cochran Database Syst Rev 4:CD008820, 2015 Simpson LL: Ultrasound in twins: dichorionic and monochorionic. Semin PerinatoIt37(5):348,t2013

Slaghekke F, Kist ], Oepkes D, et al: Twin anemia-polycythemia sequence: diagnostic criteria, classiication, perinatal management and outcome. Fetal Diagn Ther 27(4):181,t2010

Smith Gc, Fleming M, White IR: Birth order of twins and risk of perinatal death related to delivety in England, Northern Ireland, and Wales, 19942003: retrospective cohort study. BMJ 334(7593):576, 2007

Society for Maternl-Fetal Medicine, Simpson LL: Twin-twin transusion syndrome. Am J Obstet Gynecol 208(1):3, 2013 Sparks TN, Norton ME, Flessel M, et aI: Observed rate of Down syndrome in twin pregnancies. Obstet GynecoIt128(5):1127, 2016

Spencer R: Parasitic conjoined twins: externl, internal (fetuses in fetu and teratomas), and detached (acardiacs). Clin Anat 14:428,2001

Spencer R: Theoretical and analytical embryology of conjoined twins: part I: embryogenesis. Clin Anat 13:36, 2000

Sperling L, Kiil C, Larsen LU, et I: Naturlly conceived twins with monochorionic placentation have the highest risk of fetal loss. Ultrasound Obstet Gynecol 28:644, 2006

Spitz L: Seminars in pediatric surgery: The management of conjoined twins: the great Ormond Street experience. Preface. Semin Pediatr Surg 24(5):201, 2015

Stein W, Misselwitz B, Schmidt 5: Twin-to-twin delivery time interval: influencing factors and efect on short term outcome of the second twin. Acta Obstet Gynecol Scand 87(3):346, 2008

Strandskov HH, Edelen EW, Siemens GJ: Analysis of the sex ratios among single and plural births in the total white and colored U.S. populations. m J Phys Anthropol 4:491, 1946

Sugibayashi R, Ozawa K, Sumie M: et aI: Forty cases of twin reversed arterial perfusion sequence treated with radio frequency ablation using the multistep coagulation method: a single-center experience. Prenat Diagn 36(5):437, 2016

Sunderam 5, Kissin DM, Crawford SB, et al: Assisted reproductive technology surveillance-United States, 2014. MMWR 66(6):1,t2017

Szymusik I, Kosinska-Kaczynska K, Bomba-Opon D, et al: IVG versus spontaneous twin pregnancies-which are at higher risk of complications? J Matern Fetal Neonatal Med 25(12):2725,t2012

Talauliker VS, Arulkumaran 5: Reproductive outcomes after assisted conception. Obstet Gynecol Surv 67(9):566, 2012

Tan L, Goon SM, Salmon Y, et I: Conjoined twins. Acta Obstet Gynecol Scand 50:373, 1971

Tannuri A, Batatinha J, Velhote M, et aI: Conjoined twins-twenty years' experience at a reference center in Brazil. Clinics 68(3):371, 2013

Taylor M, Rebarber A, Saltzman DH, et aI: Induction of labor in twin compared with singleton pregnancies. Obstet Gynecol 120(2):297,t2012 horngren-Jerneck K, Herbst A: Low 5-minute Apgar score: a populationbased register study of 1 million term births. Obstet GynecoI98(1):65, 2001 horson HL, Ramaeker DM, Emery ST: Optimal interval for ultrasound surveillance in monochorionic twin gestations. Obstet Gynecol 117(1):131, 2011

To MS, Fonseca EB, Molina FS, et al: Maternal characteristics and cervical length in the prediction of spontaneous early preterm delivery in twins. m J Obstet GynecoIt194(5):1360, 2006

Trivedi N, GillettR: he retained twinltriplet following a preterm deliveryan analysis of the literature. Aust N Z J Obstet GynaecoI38:461, 1998

Turpin R, Lejeune J, Lafourcade J, et I: Presumption of monozygotism in spite of sexul dimorphism: Y male subject and haploid X neuter subject. C R Hebd Seances Acad Sci 252:2945, 1961

Varner MW, Leindecker S, Spong CY, et al: he Maternal-Fetal Medicine Unit Cesarean Registry: trial of labor with a twin gestation. mJ Obstet Gynecol 193:135,t2005

Vintzileos AM, Ananth CV, Kontopoulos E, et al: Mode of delivety and risk of stillbirth and infant mortality in triplet gestations: United States, 1995 through 1998. m J Obstet Gynecol 192:464,t2005

Vora NL, Ruthazer R, House M, et al: Triplet ultrasound growth parameters.

Obstet GynecoIt107:694, 2006

Wada H, Nunogami K, Wada T, et aI: Difuse brain damage caused by acute twin-twin transfusion during late pregnancy. Acta Paediatr Jpn 40:370, 1998

Walker MC, Murphy E, Pan 5, et I: Adverse maternal outcomes in multifetal pregnancies. BJOG Ill:1294, 2004

Waller DK, Tita TN, Annegers JF: Rates of twinning before and ater fortiication of foods in the U.S. with folic acid, Texas, 1996 to 1998. Paediatr Perinat EpidemioIt17(4):378, 2003

Wen SW, Demissie K, Yang , et al: Maternal morbidity and obstetric complications in triplet pregnancies and quadruplet and higher-order multiple pregnancies. mJ Obstet Gynecol 191 :254, 2004 White C, Wyshak G: Inheritance in human dizygotic twinning. N Engl J Med 271:1003, 1964

Wolfe MD, de la Torre L, Moore LE, et al: Is the protocol for induction of labor in singletons applicable to twin gestations? J Reprod Med 58(304): 137, 2013

Yamasmit W, Chaithongwongwatthana 5, Tolosa JE, et al: Prophylactic oral betamimetics for reducing preterm birth in women with a twin pregnancy. Cochrane Database Syst Rev 12:CD004733, 2015

Yang Q, Wen SW, Chen Y, et al: Occurrence and clinical predictors of operative delivery for the vertex second twin after normal vaginal delivery of the irst twin. Am J Obstet Gynecol 192(1): 178, 2005a

Yang Q, Wen SW, Chen Y, et al: Neonatal death and morbidity in vertexnonvertex second twins according to mode of delivery and birth weight. Am J Obstet GynecoIt192(3):840, 2005b

Yeomans ER: Delivery of twin gestations. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hill Education, 2017

Yinon Y, Mazkereth R, Rosentzweig N, et l: Growth restriction as a determinant of outcome in preterm discordant twins. Obstet Gynecol 105(1):80,t2005

Young BC, Wylie BJ: Efects of twin gestation on maternal morbidity. Semin Perinatol 36(3):162, 2012 Zech NH, Wisser J, Natalucci G, et al: Monochorionic-diamniotic twins discordant in gender form a naturally conceived pregnancy through postzygotic sex chromosome loss in a

Y zygote. Prenat Diagn 28:759, 2008

Zhao DP, de Villiers SF, Slaghekke F, et al: Prevalence, size, number and localization of vascular anastomoses in monochorionic placentas. Placenta 34:589,t2013

Zwijnenburg PJ, Meijiers-Heijboer H, Boomsma DI: Identical but not the same: the value of discordant monozygotic twins in genetic research. Am J Med Genet B Neuropsychiatr Genet 153B(6):1134, 2010

MEDICATIONS AND SURGERIES ................... 901

LAPAROSCOPIC SURGERY ....................... 901

RADIOGRAPHY ................................. 904

DIAGNOSTIC RADIATION . . . . . . . . . . . . . . . . . . . . . . . . 906

SONOGRAPHY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 909 MAGNETIC RESONANCE IMAGING ................. 909

As a rule, al diseases which subject the organism to a considerable strain are much more serious when occurring in a pregnant woman.

-J. Whitridge Williams (1903)

As reviewed by Williams in 1903, pregnant women are susceptible to any medical and surgical disorder that can afect childbearing-aged women. Some of these, especially those that are chronic, more often precede pregnancy. But, they can acutely complicate an otherwise normal pregnancy. Of estimates, one managed-care population had an overall antenatal hospitalization rate of 10.1 per 100 deliveries (Gazmararian, 2002). Approximately one third was for nonobstetrical conditions that included renal, pulmonary, and infectious diseases. In another study from the 2002 Nationwide Inpatient Sample, the injury hospitalization rate was 4.1 women per 1000 deliveries (Kuo, 2007). Last, approximately 1 in every 635 pregnant women will undergo a nonobstetrical surgical procedure (Corneille, 2010; Kizer, 2011).

Obstetricians should have a working knowledge of the wide-ranging medical disorders common to childbearing-aged women. Many of these are within the purview of the general obstetrician. Other disorders, however, will warrant consultation, and still others require a multidisciplinary team. The latter may include maternal-fetal medicine specialists, hospitalists, internists and medical subspecialists, surgeons, anesthesiologists, and numerous other disciplines (Levine, 2016). The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine (2014, 2017b) has redefined aspects of maternal care and proposed required levels of specialized care.

It should be axiomatic that a woman must never be penalized because she is pregnant. To ensure this, several questions should be addressed:

What management would be recommended if the woman were not pregnant?

If the proposed management is diferent because the woman is pregnant, can this be justiied?

What are the risks versus benefits to the mother and her fetus, and are they counter to each other?

Can an individualized management plan be devised that balances beneits versus risks of any alterations?

Such an approach allows individualized care for women with most medical and surgical disorders complicating pregnancy.

Pregnancy induces physiological changes in virtually all organ systems. In turn, results of numerous laboratory tests are altered, and some values would, in the nonpregnant woman, be considered abnorml. Conversely, some may appear to be within a normal range but are decidedly abnormal for the gravida. These changes may ampliy or obuscate evaluation of coexisting conditions. he wide range of pregnany efects on normal physiology and laboratory values are discussed in the chapters that follow in this section and are listed in the Appendix (p. 1255).

Fortunately, most medications needed to treat frequently with relative safety. That said, notable exceptions are considered in Chapter 12 and throughout this text.

Regarding surgery, the risk of an adverse pregnancy out come is not appreciably increased in most women who undergo an uncomplicated operative procedure. With complications, however, risks likely are increased. For example, perforative appendicitis with feculent peritonitis has significant maternal and anesthetic techniques are flawless. Conversely, procedure related complications may adversely afect outcomes. For exam ple, a woman who has uncomplicated removal of an inflamed appendix may sufer aspiration of acidic gastric contents dur ing tracheal intubation or extubation. Still, compared with nonpregnant women undergoing similar procedures, pregnant women do not appear to have excessive complications (Silvestri, 2011). In a study of the American College of Surgeons'

National Surgical Quality Improvement Program, outcomes in pregnant women were compared with matched nonpregnant controls (Moore, 2015). The investigators reported similar out comes in the two cohorts, each with 2539 patients. In a smaller study, however, women undergoing nonobstetrical surgery after 23 weeks' gestation had a high rate of subsequent preterm delivery (Baldwin, 2015).

The most extensive data regarding anesthetic and surgical risks for the gravida and her fetus are from the Swedish Birth and described by Mazze and Kallen (1989). The efects on pregnancy outcomes of 5405 nonobstetrical surgical procedures performed in 720,000 pregnant women from 1973 to 1981 were analyzed. For approximately half of these procedures, general anesthesia was used and commonly involved nitrous oxide supplemented by another inhalation agent or intravenous medications. These procedures were performed in 41 percent of women in the first trimester, 35 percent in the second, and 24 percent in the third. Overall, 25 percent were abdominal operations, and 20 percent were gynecological or urological procedures. Laparoscopy was the most frequently performed operation, and appendectomy was the most common second-trimester procedure.

Excessive perinatal morbidity associated with nonobstetrical surgery is attributable in many cases to the disease itself rather than to adverse efects of surgery and anesthesia. he Swedish Birth Registry again provides valuable data (Table Importantly, the incidences of congenital malformations or of stillbirths were not significantly diferent from those of nonexposed control newborns. However, incidences of low birthweight, preterm birth, and neonatal death in infants born to women who had undergone surgery were significantly greater.

TABLE 46-1. Birth Outcomes in 5405 Pregnant Women Undergoing Nonobstetrical Surgery

Major malformation 1.9% NS Stillbirth 7 per 1000 NS

Neonatal death by 7 days 10.5 per 1 000 <0.05

Preterm <37 wk 7.5% <0.05

Birthweight < 1500 g 1.2% <0.05 Birthweight <2500 g 6.6% <0.05 aCompared with 720,000 pregnancies in women without surgery.

NS = not significant. Data from Mazze, 1989.

Increased neonatal death rates were largely due to preterm birth. In two other studies, the preterm delivery rate in women undergoing nonobstetrical surgery was also elevated (Baldwin, 2015; Hong, 2006).

Rates of fetal abnormalities with maternal surgery in early pregnancy do not appear increased. Kallen and Mazze (1990) scrutinized 572 operations performed at 4 to 5 weeks' gestation and reported a nonsignificant relationship with elevated neural-tube defect rates. In a similar study from a Hungarian database, Czeizel and colleagues (1998) found no evidence that anesthetic agents were teratogenic.

Laparoscopy has become the most common first-trimester procedure used for diagnosis and management of several surgical disorders. In 2017, the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) updated its recommendations concerning laparoscopy use in pregnant women (Table 46-2).

Information regarding surgical approach selection in pregnancy comes from the American College of Surgeons database (Silvestri, 2011). During the 5-year period ending in 2009, almost 1300 pregnant women were studied who had undergone either appendectomy or cholecystectomy. Open appendectomy was performed in 36 percent of 857 gravidas compared with only 17 percent of those not pregnant. Of those undergoing cholecystectomy, an open procedure was used in 10 percent of 436 pregnant women compared with 5 percent of nonpregnant women. No randomized trials compare laparoscopic with open surgery, however, most reviews report equally satisfactory outcomes (Bunyavejchevin, 2013; Cox, 2015; Fatum, 2001). The most frequently performed procedures were cholecystectomy, adnexal surgery, and appendectomy. For adnexal mass surgery in pregnancy, laparoscopy is preferred, and several studies conirm its relative safety (Daykan, 2016; Hoover, 2011; Webb, 2015). At first, 26 to 28 weeks became the upper gestational-age limit recommended, but as experience has accrued, many now describe laparoscopic surgery performed in the third trimester (Kizer, 2011). In one report of 59 gravidas undergoing laparoscopic cholecystectomy or appendectomy, a third were > 26 weeks'

TABLE 46-2. Some Guidelines from the Society of American Gastrointestinal Endoscopic Surgeons (SAGES) for Laparoscopic Surgery in Pregnant Women

Indications-same as for nonpregnant women

Investigation of acute abdominal processes

Appendectomy, cholecystectomy, nephrectomy, adrenalectomy, splenectomy

Position: lateral recumbent

Entry: open technique, careful Veress needle, or optical trocar; fundal height may alter insertion site selection Trocars: direct visualization for placement; fundal height may alter insertion site selection

CO2 insuflation pressures: 10-15 mm Hg

Monitoring: capnography intraoperatively, FHR assessment pre-and postoperatively Perioperative pneumatic compression devices and early postoperative ambulation

CO2 = carbon dioxide; FHR = fetal heart rate. Data from Pearl, 2017.

gestation (Rollins, 2004). No serious adverse sequelae are In women, cardiorespiratory changes are generally not linked to these procedures. In addition, laparoscopic splesevere if insulation pressures are kept below 15 mm Hg. With nectomy, adrenalectomy, and nephrectomy have also been noninvasive hemodynamic monitoring in women at midpregdescribed in pregnant women (Asizare, 2014; Dong, 2014; nancy, the cardiac index decreased 26 percent by 5 minutes of Gernsheimer, 2007; Miller, 2012; Stroup, 2007). insulation and 21 percent by 15 minutes (Steinbrook, 2001).

Despite this, mean arterial pressures, systemic vascular resistance, and heart rate did not change significantly.

changes that are summarized in Table 46-3. Reedy and associ ates (1995) studied baboons at the human equivalent of 22 to Laparoscopic surgery frequently is ideal for the obese woman 26 weeks' gestation. No substantive physiological changes were (Sisodia, 2015). However, some outcomes may be adversely found with insulation pressures of 10 mm Hg, but 20 mm afected in obese gravidas compared with normal-weight

Hg caused significant maternal cardiovascular and respiratory patients. Of these, higher conversion rates to laparotomy, changes after 20 minutes. hese included increased respiratory longer operating times, and longer hospitalizations have rate, respiratory acidosis, diminished cardiac output, and been reported. Also, adequate ventilation is more diicult, increased pulmonary artery and capillary wedge pressures. and greater pneumoperitoneal pressures are needed to create aEffects intensified when insufflation pressure >20 mm Hg in baboons (Reedy, 1995). bData primarily from animal studies.

CO2 =carbon dioxide; CSF = cerebrospinal fluid; PC02 = patial pressure of CO2, Data from O'Rourke, 2006; Reynolds, 2003.

suitable operating space. here is anatomical distortion of the abdominal wall with displaced landmarks. Finally, the risk of developing hernias at port sites is greater.

Because precise efects of laparoscopy in the human fetus are unknown, animal studies are informative. In early studies of pregnant ewes, various investigators reported that uteroplacental blood low declines when intraperitoneal insulation pressure exceeded 15 mm Hg (Barnard, 1995; Hunter, 1995). This was the result of decreased perfusion pressure and increased placental vessel resistance (see Table 46-3). The previously cited baboon studies by Reedy and coworkers (1995) produced similar findings.

Perinatal outcomes in women are limited to observational studies. Reedy and colleagues (1997) used the updated Swedish Birth Registry database to analyze a 20-year period with more than 2 million deliveries. Of 2181 laparoscopic procedures, most were performed during the irst trimester. Perinatal outcomes for these women were compared with those of all women in the database and those undergoing open surgical procedures. These investigators confirmed the earlier indings of an increased risk of low birthweight, preterm delivery, and fetal-growth restriction. Diferences were not found, however, in outcomes of women undergoing laparoscopy versus laparotomy. n observational study of 262 women undergoing surgery for an adnexal mass noted similar findings (Koo, 2012).

The following description is an overview of laparoscopic techniques in pregnancy. For a detailed description refer to Chapter 15 in Cunningham and Gistrap s Operative Obstetrics, 3rd edition (Kho, 2016).

Preparation for laparoscopy difers little from that used for laparotomy. Bowel cleansing is not needed but may aid visualization and manipulations by emptying the large intestine. N asogastric or orogastric decompression reduces the risk of stomach trocar puncture and aspiration. Aortocaval compression is avoided by a left-lateral tilt. Positioning of the lower extremities in boot-type stirrups maintains access to the vagina for fetal sonographic assessment or manual uterine displacement. Intrauterine manipulators are logically avoided.

Most reports describe the use of general anesthesia after tracheal intubation with monitoring of end-tidal carbon dioxideEtC02 (Hong, 2006; Ribic-Pucelj, 2007). With controlled ventilation, EtC02 is maintained at 30 to 35 mm Hg.

Beyond the irst trimester, technical modifications of standard pelvic laparoscopic entry are required to avoid uterine puncture or laceration (Fig. 46-1). Many recommend open enuy techniques to avoid perforations of the uterus, pelvic vessels, and adnexa (Kizer, 2011; Koo, 2012). The abdomen is incised at or above the umbilicus, and the peritoneal cavity entered under direct visualization (Fig. 46-2). At this point, the cannula is then connected to the insulation system, and a 12-mm Hg pneumoperitoneum is created. The initial insulation should be conducted slowly to allow for prompt assessment and reversal of any untoward pressure-related efects. Gas leakage around the cannula is managed by tightening the surrounding skin with a towel clamp. Insertion of secondary trocars into the abdomen is most safely performed under direct laparoscopic viewing. Single-port surgery has also been described (Dursun, 20l3).

In more advanced pregnancies, direct entry through a left upper quadrant port in the midclavicular line, 2 cm beneath the costal margin, may better avoid the fundus (Donkervoort, 2011; Stepp, 2004). Known as Palmer point, this entry site is also used in gynecological laparoscopy because visceroparietal adhesions infrequently form here (Vilos, 2007).

FIGURE 46-1 Pregnant uterus at 10,o20, and 36 weeks' gestation depicting distortion of other intraperitoneal organs. (Reproduced with permission from Kho KA: Diagnostic and operative laparoscopy. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics 3rd ed, New York McGraw-Hili Education, 201o7.)

FIGURE 46-2 Open entry technique for laparoscopic instrument placement. A. Fascia grasped with two Allis clamps and elevated prior to sharp incision. B.Two fascial stitches incorporate the peritoneum and fascia. C. These fascial sutures are wrapped around holders of the Hasson cannula to anchor it in place. (Reproduced with permission from Kho KA: Diagnostic and operative laparoscopy. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics 3rd ed, New York McGraw-Hili Education, 201o7.)

Gasless laparoscopy is a less commonly selected alternative approach that uses a rod with intraabdominal fan-blade-shaped retractors. When opened, these allow the abdominal wall to be lifted upward. It avoids the typical laparoscopic cardiovascular changes because the pneumoperitoneum is created by retraction rather than insuiation (Phupong, 2007).

Risks inherent to any abdominal endoscopic procedure are probably increased slightly during pregnancy. The obvious unique complication is perforation of the pregnant uterus with either a trocar or Veress needle (Azevedo, 2009; Kizer, 2011; Mala, 2014). hat said, reported complications are infrequent (Fatum, 2001; Koo, 2012). One Cochrane database review noted a need for randomized trials to deduce comparative benefits and risks of laparoscopy versus laparotomy during pregnancy (Bunyavejchevin, 2013). Pragmatically, this seems unfeasible, and common sense should dictate the approach.

Imaging modalities are used as adjuncts for diagnosis and therapy during pregnancy. Options include sonography, radiography, and magnetic resonance (MR) imaging. Of these, radiography is the most problematic. Inevitably, some radiographic procedures are performed before recognition of early pregnancy, usually because of trauma or serious illness. Fortunately, most diagnostic radiographic procedures are associated with minimal fetal risks. As with drugs and medications, however, these procedures may lead to litigation if pregnancy outcome is adverse. And, x-ray exposure may lead to a needless therapeutic abortion because of patient or physician anxiety.

Since 2007, the American College of Radiology (ACR) has addressed the growing concern of radiation dose in all ields of medicine (Amis, 2007). Some of its goals were to limit exposure through radiation safety practices and promote lifelong accumulated records of exposures in any given patient. Task Force recommendations included additional considerations for special radiosensitive populations, such as children and pregnant and potentially pregnant women. At our institutions, special recommendations are made for gravidas. Radiation exposure values and duration are recorded and monitored in high-exposure areas such as computed tomography (CT) and luoroscopy.

he term radiation literally refers to energy transmission and thus is often applied not only to x-rays, but also to microwaves, ultrasound, diathermy, and radio waves. Of these, x-rays and gamma rays have short wavelengths with very high energy and are ionizing radiation forms. The other four energy forms have rather long wavelengths and low energy (Brent, 1999b, 2009).

Ionizing radiation refers to waves or particles-photons-of signiicant energy that can change the structure of molecules such as those in DNA or that can create free radical or ions capable of secondarily damaging tissue (Hall, 1991; National Research Council, 1990). Methods of measuring the efects of x-rays are summarized in Table 46-4. The standard terms used are exposure

TABLE 46-4. Some Measures of Ionizing Radiation

Exposure Number of ions produced by x-rays per kg

Dose Amount of energy deposited per kg of tissue

Relative Amount of energy deposited per kg effective of tissue normalized for biological (in air), dose (to tissue), and reative fictive dose (to tissue). In the range of energies for diagnostic x-rays, the dose is now expressed in grays (Gy) , and the relative efective dose is expressed in sieverts (Sv). hese can be used interchangeably. For consistency, all doses discussed subsequently are expressed in contemporane ously used units of gray (1 Gy = 100 rad) or sievert (1 Sv = 100 rem) . To convert, 1 Sv = 100 rem = 100 rad.

As noted, the biological efects of x-rays are caused by an electrochemical reaction that can damage tissue. According to

Brent (1999a, 2009), x-and gamma-radiation at high doses can create two types of biological efects and reproductive risks in the fetus. These are deterministic eicts and stochastic focts, which are both described in the next sections.

One potential harmful efect of radiation exposure is determin istic, which may result in abortion, growth restriction, congeni tal malformations, microcephaly, or mental retardation. hese deterministic efects are threshold efects, and the threshold level is the NOAEL-No Observed Adverse Eict Level (Brent, 2009). lthough controversial, the NOEL concept supports that there is no risk below a threshold dose (0.05 Gy or 5 rad).

It also suggests that the threshold for gross fetal malformations is more likely to be 0.2 Gy (20 rad).

The harmful deterministic efects of ionizing radiation have been extensively studied for cell damage with resultant disordered embryogenesis. These have been assessed in animal models, as well as in Japanese atomic bomb survivors and the Oxford Survey of Childhood Cancers (Sorahan, 1995). Additional sources have confirmed prior observations and provided more information (Groen, 2012). One is a 2003 International Commission on Radiological Protection publication that describes biological fetal efects from prenatal irradiation. Another is the Biological Efects of Ionizing Radiation-BEIR II Phase 2 report of the National Research Council (2006), which discusses health risks from exposure to low levels of ionizing radiation.

In the mouse model, the lethality risk is highest during the preimplantation period-up to 10 days postconception (Kanter, 2014). This is likely due to blastomere destruction caused by chromosomal damage (Hall, 1991). During organogenesis, high-dose radiation-1 Gy or 100 rad-is more likely to cause malformations and growth restriction and less likely to have lethal efects in the mouse. Studies of brain development suggest efects on neuronal development and a window of cortical sensitivity in early and midfetal periods. That said, acute lowdose ionizing radiation appears to have no deleterious efects (Howell,r2013).

Data on adverse human efects of high-dose ionizing radiation mostly derive from the atomic bomb survivors of Hiroshima and Nagasaki (Greskovich, 2000; Otake, 1987). The International Commission on Radiological Protection (2003) confirmed initial studies showing that the increased risk of severe mental retardation was greatest between 8 and 15 weeks' gestation.

There may be a lower-threshold dose of 0.3 Gy (30 rad), which is a range similar to the window of cortical sensitivity in the mouse model discussed earlier. he mean decrease in intelligence quo tient (IQ) scores was 25 points per Gy or 100 rad. here appears to be linear dose response, but it is not clear whether there is a threshold dose. Most estimates err on the conservative side by assuming a linear nonthreshold hypothesis. In a study of fetuses exposed to low radiation doses, Choi and colleagues (2012) did not find an increased risk for congenital anomalies.

Finally, an increased risk of mental retardation in humans < 8 weeks' or > 25 weeks' gestation has not been documented, even with doses exceeding 0.5 Gy or 50 rad (International

Commission on Radiological Protection, 2003). Reports have described high-dose radiation used to treat women for malig nancy, menorrhagia, and uterine myomas. Dekaban (1r968) described 22 infants with microcephaly, mental retardation, or both following exposure in the first half of pregnancy to an estimated 2.5 Gy or 250 rad.

Summary of Fetal Radiation Exposure

From 8 to 15 weeks, the fetus is most susceptible to radiation induced mental retardation. It has not been resolved whether this is a threshold or nonthreshold linear function of dose. he

Committee on Biological Efects (1990) estimates the risk of severe mental retardation to be as low as 4 percent for 0.1 Gy (10 rad) and as high as 60 percent for 1.5 Gy (150 rad). But recall that these doses are 2 to 100 times higher than those considered maximal from diagnostic radiation. Importantly, cumulative doses from multiple procedures may reach the harmful range, especially at 8 to 15 weeks' gestation. At 16 to 25 weeks, the risk is less. And again, there is no proven risk before 8 weeks or after 25 weeks.

Importantly, embryofetal risks from low-dose diagnostic radiation appear to be minimal. Current evidence suggests that risks for malformations, growth restriction, or abortion are not increased from a radiation dose of less than 0.05 Gy (5 rad). Indeed, Brent (2009) concluded that gross congenital malformations would not be increased with exposure to less than 0.2 Gy (20 rad). Because diagnostic x-rays seldom exceed 0.1 Gy (10 rad) , Strzelczyk and associates (2007) concluded that these procedures are unlikely to cause deterministic efects. As emphasized by Groen and coworkers (2012), 0.1 Gy is the radiation equivalent to that from more than 1000 chest x-rays!

These efects refer to random, presumably unpredictable oncogenic or mutagenic efects of radiation exposure. Stochastic efects concern associations between fetal diagnostic radiation exposure and increased risk of childhood cancers or genetic diseases. According to Doll and Wakeford (1997), as well as the National Research Council (2006) BEIR VII Phase 2 report, excess cancers can result from in utero exposure to doses as low as 0.01 Svror 1 rad. Stated another way by Hurwitz and colleagues (2006), the estimated risk of childhood cancer following fetal exposure to 0.03 Gy or 3 rad doubles the background risk of 1 in 600 to that of 2 in 600.

In one report, in utero radiation exposure was determined for 10 solid cancers in adults from age 17 to 45 years. here was a dose-response relationship as previously noted at the 0.r1 Sv or 10 rem threshold. hese cancers likely are associated with a complex series of interactions between DNA and ionizing radiation. They also make it more problematic to predict cancer risk from low-dose radiation of less than 0.1 Sv or 10 rem. Importantly, below doses of 0.1 to 0.2 Sv, there is no convincing evidence of a carcinogenic efect (Brent, 2009, 2014; Preston, 2008; Strzelczyk, 2007).

Estimates of dose to the uterus and embryo for various frequently used radiographic examinations are summarized in Table 46-5. Imaging of maternal body parts farthest from the uterus results in a very small dose of radiation scatter to the embryo or fetus. The size of the woman, radiographic technique, and equipment performance are other variables (Wagner, 1997). hus, data in the table serve only as guidelines. When the radiation dose for a specific individual is required, a medical physicist should be consulted. Brent (2009) recommends consulting the Health Physics Society website (ww.hps.org) to view some examples of questions and answers posed by patients exposed to radiation.

he Radiation Therapy Committee Task Group of the American Association of Physics in Medicine (Stovall, 1995) emphasizes careful individualization of radiotherapy for the pregnant woman (Chap. 63, p. 1191). For example, in some cases, shielding of the fetus and other safeguards can be employed (Fenig, 2001; Nuyttens, 2002). In other instances, the fetus will be exposed to dangerous radiation doses, and a carefully designed plan must be improvised (Prado, 2000). Examples include models that estimate the fetal dose given during maternal brain radiotherapy or tangential breast irradiation (Mazonakis, 1999, 2003). The harmful efects of radiotherapy on future fertility and pregnancy outcomes were reviewed by Wo and Viswanathan (2009) and others and are detailed in Chapter 63 (p. 1192).

To estimate fetal risk, approximate x-ray dosimetry must be known. According to the merican College of Radiology, no single diagnostic procedure results in a radiation dose signiicant enough to threaten embryo-fetal well-being (Hall, 1991).

For standard radiographs, dosimetry is presented in Table 46-5. In pregnancy, the AP-view chest radiograph is the most commonly used study, and fetal exposure is exceptionally small-0.0007 Gy or 70 mrad. With one abdominal radiograph, because the embryo or fetus is directly in the x-ray beam, the dose is higher-O.OO 1 Gy or 100 mrad. he standard intravenous pyelogram may exceed 0.005 Gy or 500 mrad because of several exposures. The one-shot pyelogram described in Chapter 53 (p. 1030) is useful when urolithiasis or other causes of obstruction are unproven by sonography but still suspected. Most "trauma series," such as radiographs of an extremity, skull, or rib series, deliver low doses because of the fetal distance from the target area (Shakerian, 2015).

Dosimetry calculations are much more diicult with these procedures because of variations in the number of radiographs obtained, total fluoroscopy time, and luoroscopy time in which the fetus is in the radiation field. As shown in Table 46-6, the range is variable. he Food and Drug Administration (FDA) limits the exposure rate for conventional fluoroscopy such as barium studies, however, special-purpose systems such as angiography units have the potential for much higher exposure.

Dosea per View Study View (mGy) No. Filmsb Dose (mGy)

TABLE 6-5. Dose to the Uterus for Common Radiologic Procedures

SkuW AP, PA, Lat <0.0001

Chest AP, PN, Latd <0.0001n-0.0008 <0.0005 1.5 0.0002-0.0007

Mammogramd Cc, Lat <0.0003-0.0005 4.0 0.0007 -0.002 Lumbosacral spinee AP, Lat 1.14-2.2 3.4 1.76-3.6 Abdomene AP 1.0 0.8-1n.63 Intravenous pyelograme 3 views 5.5 6.9-14

Hipb (single) AP 0.7-1.4 2.0 1-2

Lat 0.18-0.51 aCalculated for x-ray beams with half-value layers ranging from 2 to 4 mm aluminum equivalent using the methodology of Rosenstein, 1988.

bBased on data and methods reported by Laws, 1978. (Entrance exposure data from Conway, 1989. dEstimates based on compilation of above data.

eBased on NEXT data reported in National Council on Radiation Protection and Measurements, 1989.

AP = anterior-posterior; CC = cranial-caudal; Lat = lateral; PA = posterior-anterior.

TABLE 46-6. Estimated X-Ray Doses to the Uterus/ Embryo from Common Fluoroscopic Procedures

Dose to Fluoroscopic

Cerebral angiographl <0.1

Cardiac angiographyb,( 0.65 223 (± 11n8)

Single-vessel PTCAb,c 0.60 1023 (± 952)

Double-vessel PTCAb,c 0.90 1186 (± 593)

Upper gastrointestinal seriesd 0.56 136 ,e 0.06 192

Barium enemab,f,9 20-40 289-311 aWagner, 1997.

Calculations based on data of Gorson, 1984.

cFinci, 1987.

dSuleiman, 1991n.

eBased on female data from Rowley, 1987.

fAssumes embryo in radiation field for entire examination.

9Bednarek, 1983.

SD = standard deviation.

Angiography and vascular embolization may occasionally be necessary for trauma and for serious maternal disorders, especially renal disease (Wortman, 2013). As before, a greater distance from the embryo or fetus lowers the exposure and risk.

These x-ray images are usually performed by obtaining a spiral of 360-degree images that are postprocessed in multiple planes. Of these, the axial image remains the most commonly obtained

CT (MDCT) images are now standard for common clinical indications. The most recent detectors have 16 or 64 channels, and multidetector protocols may result in increased dosimetry compared with traditional CT imaging. Several imaging parameters have an efect on exposure (Brenner, 2007). These include pitch, kilovoltage, tube current, collimation, number of slices, tube rotation, and total acquisition time. If a study is performed with and without contrast, the dose is doubled because twice as many images are obtained. Fetal exposure is also dependent on factors such as maternal size as well as fetal size and position. And as with plain radiography, the closer the target area is to the fetus, the greater the delivered dose.

Cranial CT scanning is the most commonly performed study in gravidas. It is used for neurological disorders as discussed in Chapter 60 (p. 1156) and with eclampsia as noted in Chapter 40 (p. 724). Nonenhanced CT scanning is commonly used to detect acute hemorrhage within the epidural, subdural, or subarachnoid spaces (Fig. 46-3). Because of the distance from the fetus, radiation dosage is negligible (Goldberg-Stein, 2012).

Abdominal procedures are more problematic. Hurwitz and associates (2006) employed a 16-channel multidetector

FIGURE 46-3 A 37-year-old with intrapartum eclampsia at term.

renchymal hematoma (H) with intraventricular extension (arrow heads). The midline (arrow) is shifted to the right due to mass effect from the hematoma. (Reproduced with permission from Kho KA:

Diagnostic and operative laparoscopy. In Yeomans ER, Hoffman

BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative

Obstetrics 3rd ed, New York McGraw-Hili Education, 2017.) scanner to calculate fetal exposure at 0 and 3 months' gestation using a phantom model. Calculations were made for three commonly requested procedures in pregnant women (Table 46-7). he pulmonary embolism protocol has the same dosimetry exposure as the ventilation-perfusion (V/Q) lung scan discussed on page 908. Because of the pitch used, the appendicitis protocol has the highest radiation exposure, however, it is very useful clinically when MR imaging is not available. Using a similar protocol in 67 women with suspected appendicitis, Lazarus and coworkers (2007) reported sensitivity of 92 percent, specificity of 99 percent, and a negative-predictive value of 99 percent. Here, dosimetry was markedly decreased compared with standard appendiceal imaging because of a different pitch. his is discussed further in Chapter 54 (p. 1052). Last, for suspected urolithiasis, the multidetector-scan protocol is used if sonography is nondiagnostic. Using a similar protocol, White and colleagues (2007) identified urolithiasis in 13 of 20 women at an average of 26.5 weeks. Finally, as shown in

TABLE 46-7. Estimated Radiation Dosimetry with , 6-Channel Multidetector Computed

Pulmonary embolism 0.20-0.47 0.61-0.66

Data from Hurwitz, 2006.

FIGURE 46-4 This woman in her third trimester was involved in a high-speed motor vehicle accident. A. Maximum intensity projection acquired for maternal indications readily identifies fetal skull fractures (arrows). B.3-D reformatted CT image in a bone algorithm demonstrates the fetal skeleton from data acquired during the maternal examination. Again, the arrow marks one fracture site. (Reproduced with permission from Bailey AA, Twickler OM: Perioperative imaging. In Yeomans ER, Hoffman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap'S Operative Obstetrics 3rd ed. New York: McGraw-Hili Education; 201o7. Photo contributor: Dr. Travis Browning.)

Figure 46-4, abdominal tomography is performed if indicated in the pregnant woman with severe trauma (Matzon, 2015; Shakerian, 2015).

Most experience with chest CT scanning is with suspected pulmonary embolism. The most recent recommendations for its use in pregnancy from the Prospective Investigation of Pulmonary Embolism Diagnosis-PIOPED-II investigators were summarized by Stein and associates (2007). They found that pulmonary scintigraphy-the V/Q scan-was recommended at that time for pregnant women by 70 percent of radiologists and chest CT angiography by 30 percent. Indeed, scintigraphy is still recommended by the American Thoracic Society for gravidas with a normal chest x-ray (Leung, 2012). hat said, most agree that multidetector-CT angiography has improved accuracy because of increasingly faster acquisition times (Brown, 2014). Others have reported a higher use rate for CT angiography and emphasize that dosimetry is similar to that with V/Q scintigraphy (Brenner, 2007; Greer, 2015; Hurwitz, 2006). Controversies on this topic continue, recognizing that fetal radiation doses are lower with CT angiography compared with the V/Q scan, but maternal chest radiation doses are substantially higher with CT scanning (van Mens, 2017). We prefer MDCT scanning initially for suspected pulmonary embolism (Chap. 52, p. 1016).

CT pelvimetry is used by some before attempting breech vaginal delivery (Chap. 28, p. 542). he fetal dose approaches 0.015 Gyor 1.5 rad, but use of a low-exposure technique may reduce this to 0.0025 Gy or 0.25 rad.

hese can be given intravenously or taken orally. Intravenous contrast agents are considered category B by the FDA. The types of intravenous contrast employed for imaging today are iodinated and low osmolality, thus, they cross the placenta to the fetus. With water-soluble iodinated contrast, no cases of neonatal hypothyroidism or other adverse efects have been documented (American College of Radiology, 2015). Oral contrast preparations, typically containing iodine or barium, have minimal systemic absorption and are unlikely to afect the fetus.

hese studies are performed by "tagging" a radioactive element to a carrier that can be injected, inhaled, or swallowed. For example, the radioisotope technetium-99m may be tagged to red blood cells, sulfur colloid, or pertechnetate. he method used to tag the agent determines fetal radiation exposure. he amount of placental transfer is obviously important, but so is renal clearance because of fetal proximity to the maternal bladder. Measurement of radioactive technetium is based on its decay, and the units used are the curie (Ci) or the becquerel (Bq). Dosimetry is usually expressed in millicuries (mCi). he efective tissue dose is expressed in sievert units (Sv) with conversion as discussed in Table 46-4: 1 Sv = 100 rem = 100 rad.

Depending on the physical and biochemical properties of a radioisotope, an average fetal exposure can be calculated (Wagner, 1997; Zanzonico, 2000). Commonly used radiopharmaceuticals and estimated absorbed fetal doses are given in Table 46-8. The radionuclide dose should be kept as low as possible (Adelstein, 1999; Zanotti-Fregonara, 2017). Exposures vary with gestational age and are greatest earlier in pregnancy for most radiopharmaceuticals. One exception is the later efect ofiodine-131 on the fetal thyroid (Wagner, 1997).

Discussed earlier, some still use the ventilation-perfusion lung scan for suspected pulmonary embolism. It is also used if CT angiography is nondiagnostic. Perfusion is measured with injected 99T c-macroaggregated albumin, and ventilation is measured with inhaled xenon-127 or xenon-133. Fetal exposure with either is negligible (Chan, 2002; 110untford, 1997).

Thyroid scanning with iodine-123 or iodine-131 seldom is indicated in pregnancy. With trace diagnostic doses used, however, fetal risk is minimal. Importantly, therapeutic radioiodine in doses to treat Graves disease or thyroid cancer may cause fetal thyroid ablation and cretinism.

amCi = millicuries. To convertto mrad, mUltiply by 100.

bExposures are generally greater prior to 12 weeks compared with increasing gestational ages.

cSome measurements account for placental transfer.

dThe uptake and exposure of 1 increases with gestational age.

Tc04 = pertechnetate; TI = thallium.

Data from Adelstein, 1999; Schwartz, 2003; Stather, 2002; Wagner, 1997; Zanzonico, 2000.

he sentinel lymphoscintigram, which uses 99mT c-sulfur indispensable in everyday practice. Its wide-ranging clinical colloid to detect the axillary lymph node most likely to have uses are further discussed in Chapter 10 and in most other secmetastases from breast cancer, is a commonly used preoperative tions of this book. study in nonpregnant women (Newman, 2007; Spanheimer, 2009; Wang, 2007). As shown in Table 46-8, the calculated dose is approximately 0.014 mSv or 1.4 mrad, which should MAGNETIC RESONANCE IMAGING not preclude its use during pregnancy.

Magnetic resonance technology does not use ionizing radiation, and its application is cited throughout this book. Advantages include high soft-tissue contrast, ability to characterize tissue, Of all of the major advances in obstetrics, the development of and acquisition of images in any plane-particularly axial, sagsonography for study of the fetus and mother certainly is one of ittal, and coronal. An entire section in Chapter 10 (p. 215) is the greater achievements. The technique has become virtually devoted to mechanisms that generate MR images.

The most recent update of the expert panel on MR safety of the American College of Radiology was summarized by Kanal and colleagues (20l3). The panel concluded that no harmful human efects are reported from MR imaging. Similar conclusions were reached by the Canadian Task Force on Preventive Health Care (Patenaude, 2014).

Early studies found diferences in blastocyst formation of early murine embryos exposed to MR imaging with 1.5 T (T = tesla) (Chew, 2001). When operated within standardized limits, maternal and fetal imaging can be safely performed at clinical magnet strengths-3 T and below. MR imaging can be used, regardless of trimester: (1) if the information cannot be obtained with another nonionizing modality, namely sonography, (2) if the results of the study will guide maternal or fetal management during pregnancy, and (3) if the imaging cannot be delayed until the woman is no longer pregnant. he decision to use a magnetic field strengthr> 1.5 T may be made for specific maternal indications. Early work also suggests imaging at 3 T can improve fetal assessment (Victoria, 2016). A magnetic ield strength up to 4 T appears safe in animals (Magin, 2000). Vadeyar and associates (2000) reported no demonstrable fetal heart rate pattern changes during MR imaging of gravidas. Studies evaluating children exposed in utero have shown no deleterious efects (Clements, 2000; Kok, 2004; Reeves, 2010).

Contraindications to MR imaging include internal cardiac pacemakers, neurostimulators, implanted defibrillators and infusion pumps, cochlear implants, shrapnel or other metal in biologically sensitive areas, some intracranial aneurysm clips, and any metallic foreign body in the eye. Of more than 51,000 nonpregnant patients scheduled for MR imaging, Dewey and colleagues (2007) found that only 0.4 percent had an absolute contraindication to the procedure.

Elemental gadolinium cheates are used to create paramagnetic contrast. hese cross the placenta and are found in the fetus, placenta, and nnionic fluid (Oh, 2015). In doses approximately 10 times the human

FIGURE 46-5 Multipara at 29 weeks' gestation with suspected appendicitis. A. Coronal T2-weighted magnetic resonance image demonstrates severe hydronephrosis (arrow) and perinephric fluid (white arrowhead) suggesting caliceal rupture. The normal appendix is seen laterally (black arrowhead). B. Coronal computed tomography (CT) better defines the source of obstruction as an 8-mm radiopaque stone at the ureteropelvic junction (blue arrow) and distal to the hydronephrosis (white arrow). C and D. In the same woman, more anterior coronal and sagittal CT images show the expected displacement of a noninflamed appendix yellow arrow) into the upper abdomen with advancing gestation.

FIGURE 46-6 Nullipara at 27 weeks' gestation. A. Axial T2-weighted MR image demonstrates mild fetal unilateral ventriculomegaly involving the left lateral ventricle (arrow).

B. Sagittal T2-weighted MR image demonstrates normal development of the corpus callosum (arrowheads) and vermis (arrow).

TABLE 6-9. Guidelines for Diagnostic Imaging During Pregnancy and Lactation

Sonography and magnetic resonance (MR) imaging are not associated with fetal risk and are preferred options for imaging in pregnancy

In general, radiation exposure during radiography, computed tomography (C), or nuclear medicine imaging delivers a dose much lower than that associated with fetal harm. If needed to supplement sonography or MR imaging or if more readily available, these should not be withheld

With MR imaging, gadolinium contrast use should be restricted unless it significantly improves diagnostic accuracy to benefit fetal or matenal outcome

Data from American College of Obstetricians and Gynecologists, 20ln7a.

dose, a gadolinium-based contrast agent caused slight developmental delay in rabbit fetuses. De Santis and associates described 26 women given a gadolinium derivative in the first trimester without adverse fetal efects (Kanal, 2013). According to Briggs and colleagues (2015), the American College of Obstetricians and Gynecologists (2017a), and the American College of Radiology (2015), routine use of gadolinium is not recommended unless there are potential benefits that outweigh fetal risks. his recommendation stems from a possible dissociation of the toxic gadolinium ion from its ligand in amnionic Ruid and potential prolonged exposure of the fetus.

In some cases, MR imaging may be complementary to CT, and in others, MR imaging is preferable. Maternal central nervous system abnormalities, such as brain tumors or spinal trauma, are more clearly seen with MR imaging. As discussed in Chapter 40 (p. 723), MR imaging has provided valuable insights into the pathophysiology of preeclampsia (Twickler, 2007; Zeeman, 2003, 2014). It is invaluable in the diagnosis of neurological emergencies (Edlow, 2013). To evaluate the maternal abdomen and retroperitoneal space, MR imaging is a superb technique. It is chosen by many to determine the degree and extent of placenta accreta and its variants (Chap. 41, p. 780). It has been employed for detection and localization of adrenal tumors, renal lesions, gastrointestinal lesions, and pelvic masses in pregnancy. For evaluating neoplasms of the chest, abdomen, and pelvis in pregnancy, it has particular value (Boyd, 2012; Tica, 2013). MR urography has been used successfully for renal urolithiasis (Mullins, 2012). As discussed in Chapter 37 (p. 672), CT and MR imaging are useful for evaluation of puerperal infections, but MR imaging provides better visualization of the bladder Rap area following cesarean delivery (Brown, 1999; Twickler, 1997). MR imaging now includes evaluation of right lower quadrant pain in pregnancy, specifically appendicitis (Fig. 46-5) (Baron, 2012; Dewhurst, 2013; Furey, 2014; Pedrosa, 2009; Tsai, 2017). Investigators have also found other disorders of the gastrointestinal tract to be easily diagnosed with MR imaging (Chap. 54, p. 1043). Finally, cardiac MR imaging has shown promise in investigating normal physiology, complex defects, and cardiomyopathies (Kramer, 2015; Nelson, 2015; Stewart, 2016).

Fetal MR imaging provides a complement to sonography (LaiferNarin, 2007; Sandrasegaran, 2006). According to Zaretsky and associates (2003a), MR imaging can be used to image almost all elements of the standard fetal anatomical survey. The most frequent fetal indications for MR imaging are evaluation of complex abnormalities of the brain, chest, and genitourinary system (Williams, 2017). Reichel (2003), Twickler (2002), and others have validated its use for fetal central nervous system anomalies and biometry (Fig. 46-6). Caire and coworkers (2003) reported its merits for fetal genitourinary anomalies. Hawkins and colleagues (2008) described MR imaging in 21 fetuses with renal anomalies and oligohydramnios. Zaretsky and associates (2003b) noted that fetal-weight estimation was more accurate using MR imaging than with sonography. Fetal movement is less problematic with faster acquisitions. Morphology is primarily assessed with fast T2-weighted sequences such as HASTE-Half-Fourier Acquisition Single Shot Turbo Spin Echo, or SSFSE-Single hot Fast Spin Echo. Fetal indications and indings of MR imaging are discussed more extensively in Chapter 10 (p. 217) and throughout this book.

he American College of Obstetricians and Gynecologists (2017 a) has reviewed the efects of radiographic, sonographic, and magnetic-resonance exposure during pregnancy. Its suggested guidelines are shown in Table 46-9.

Adelstein 5J: Administered radionuclides in pregnancy. Teratology 59:236, 1999

American College of Obstetricians and Gynecologists: Guidelines for diagnostic imaging during pregnancy and lactation. Committee Opinion No. 723, October 2017a

American College of Obstetricians and Gynecologists: Nonobstetric surgery during pregnancy. Committee Opinion No. 696, April 2017b

American College of Radiology: ACR manual on contrast media. Version 10.1, 20t15

Amis E5 Jr, Butler PF, Applegate E, et al: American College of Radiology white paper on radiation dose in medicine. J Am Coll Radiol 4(5):272, 2007

Asizare M, 2015; A1ipour M, Taghavi M, et al: Bilateraltlaparoscopic adrenalectomy in a pregnant women with Cushing's syndrome. Urol J II(5): 191t1, 2014

Azevedo JL, Azevedo Oe, Miyahira SA, et al: Injuries caused by Veress needle insertion for creation of pneumoperitoneum: a systematic literature review. Surg Endosc 23(7):1428,t2009

Bailey M, Twickler OM: Perioperative imaging. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed, New York, McGraw-Hill Education, 2017

Baldwin A, Borowski KS, Brost Be, et al: Antepartum nonobstetrical surgery at :23 weeks' gestation and risk for preterm delivery. Am J Obstet Gynecol 212:232.e1,t2015

Barnard JM, Chain 0, Droste 5, et al: Fetal response to carbon dioxide pneumoperitoneum in the pregnant ewe. Obstet Gynecol 85:669, 1995

Baron KT, Arleo EK, Robinson C, et al: Comparing the diagnostic performance of MRI versus CT in the evaluation of acute nontraumatic abdominal pain during pregnancy. Emerg RadioIt19(6):519, 2012 Bednarek DR, Rudin 5, Wong, et al: Reduction of fluoroscopic exposure for the air-contrast barium enema. Br J Radiol 56:823, 1983

Boyd CA, Benarroch-Gampel J, Kilic G, et al: Pancreatic neoplasms in pregnancy: diagnosis, complications, and management. J Gastrointest Surg 16(5):1064,t2012 Brenner OJ, Hall JH, Phil 0: Computed tomography-an increasing source of radiation exposure. N Engl J Med 357:2277, 2007 Brent L: Carcinogenic risks of prenatal ionizing radiation. Semin Fetal Neonatal Med 19(3):203,t2014 Brent L: Developmental and reproductive risks of radiological procedures utilizing ionizing radiation during pregnancy. Proceedings No. 21 in Radiation Protection in Medicine: Contemporary Issues. Proceedings of the ThirtyFifth Annual Meeting of the National Council on Radiation Protection and Measurements. Arlington, VA, April 7-8, 1999a Brent L: Saving lives and changing family histories: appropriate counseling of pregnant women and men and women of reproductive age, concerning risk of diagnostic radiation exposure during and before pregnancy. Am J Obstet Gynecol 200(1):4, 2009 Brent L: Utilization of developmental basic science principles in the evaluation of reproductive risks from pre-and postconception environmental radiation exposures. Teratology 59: 182, 1999b Briggs GG, Freeman RK: Drugs in Pregnancy and Lactation, 10th ed. Philadelphia, Lippincott Williams & Wilkins, 2015 Brown AM, Cronin CG, NiMhuircheartaigh J, et al: Evaluation of imaging quality of pulmonary 64-vlDCT angiography in pregnancy and puerperium. AJR An1 J Roentgenol 202(1):60, 2014 Brown CE, Stettler RW, Twickler 0, et al: Puerperal septic pelvic thrombophlebitis: incidence and response to heparin therapy. Am J Obstet Gynecol 181:143, 1999 Bunyavejchevin 5, Phupong V: Laparoscopic surgery for presumed benign ovarian tumor during pregnancy. Cochrane Database Syst Rev 1:CD005459, 2013 Caire JT, Ramus RM, Magee KP, et al: MRI of fetal genitourinary anomalies. AJR Am J Roentgenol 181:1381,t2003 Chan WS, Ray JG, Murray 5, et al: Suspected pulmonary embolism in pregnancy. Arch Intern Med 152: 1170, 2002 Chew 5, Ahmadi A, Goh PS, et al: The efects of 1.5T magnetic resonance imaging on early murine in-vitro embryo development. J Magn Reson Imaging 13:417, 2001 Choi JS, Han JY, Ahn HK, et al: Fetal and neonatal outcomes in irst-trimester pregnant women exposed to abdominal or lumbar radiodiagnostic procedures without administration of radionucleotides. Intern Med J 43(5):513, 2012 Clements H, Duncan KR, Fielding K, et al: Infants exposed to MRI in utero have a normal paediatric assessment at 9 months of age. Br J Radiol 73 (866):190,t2000 Committee on Biological Efects of Ionizing Radiation: Other somatic and fetal efects. In BEIR V: Efects of Exposure to Low Levels ofIonizing Radiation. Washington, National Academy Press, 1990 Corneille MG, Gallup TM, Bening T, et al: he use of laparoscopic surgery in pregnancy: evaluation of safety and eicacy. Am J Surg 200:363,t2010 Cox TC, Huntington CR, Blair LJ, et al: Laparoscopic appendectomy and cholecystectomy versus open: a study in 1999 pregnant patients. Surg Endosc 30(2):593,t2016 Czeizel E, Pataki T, Rockenbauer M: Reproductive outcome ater exposure to surgery under anesthesia during pregnany. Arch Gynecol Obstet 261: 193, 1998 Daykan Y, Klein Z, Bugin R, et al: Ovarian torsion during pregnancy-perinatal and delivery outcome after surgical treatment. Am J Obstet Gynecol 214:5110,t2016 Dekaban AS: Abnormalities in children exposed to x-irradiation during various stages of gestation: tentative timetable of radiation injury to the human fetus. J Nucl Med 9:471, 1968 De Santis M, Straface G, Cavaliere AF, et al: Gadolinium periconceptional exposure: pregnancy and neonatal outcome. Acta Obstet Gynecol Scand 86:99,t2007

Dewey M, Schink T, Dewey CF: Frequency of referral of patients with safetyrelated contraindications to magnetic resonance imaging. Eur J RadioI63(1): 124, 2007

Dewhurst C, Beddy P, Pedrosa I: MRI evaluation of acute appendicitis in pregnancy. J Magn Reson Imaging 37(3):566,t2013

Doll R, Wakeford R: Risk of childhood cancer from fetal irradiation. Br J Radiol 70:130, 1997

Dong 0, Li H: Diagnosis and treatment of pheochromocytoma during pregnancy. J Matern Neonatal Med 27(18):1930,t2014

Donkervoort, SC, Boerma 0: Suspicion of acute appendicitis in the third trimester of pregnancy: pros and cons of a laparoscopic procedure. JSLS 15(3):379,t201t1

Dursun P, Giiliimser e, Caglar M, et al: Laparoendoscopic single-site surgery for acute adnexal pathology during pregnancy: preliminary experience. J Matern Fetal Neonatal Med 26(13):1282,t2013

Edlow JA, Caplan LR, O'Brien K, et al: Diagnosis of acute neurological emergencies in pregnant and postpartum women. Lancet Neurol 12(2): 175, 2013

Fatum M, Rojansky N: Laparoscopic surgery during pregnancy. Obstet Gynecol Surv 56:50,t2001

Fenig E, Mishaeli M, Kalish Y, et al: Pregnancy and radiation. Cancer Treat Rev 27:1,t2001

Finci L, Meier B, Stefenino G, et al: Radiation exposure during diagnostic catheterization and single-and double-vessel percutaneous transluminal coronary angioplasty. Am J Cardiol 60: 1401, 1987

Furey A, Bailey M, Pedrosa I: Magnetic resonance imaging of acute abdominal and pelvic pain in pregnancy. Top Magn Reson Imaging 23(4):225,t2014 Gazmararian JA, Petersen R, Jamieson OJ, et al: Hospitalizations during preg nancy among managed care enrollees. Obstet Gynecol 100:94, 2002 Gernsheimer T, .McCrae R: Immune thrombocytopenic purpura in pregnancy. Curr Opin Hematol 14:574,t2007

Goldberg-Stein SA, Liu B, Hahn PF, et al: Radiation dose management: part 2, estimating fetal radiation risk from CT during pregnancy. AJR Am J Roentgenol 198(4):W352, 2012

Gorson RO, Lassen M, Rosenstein M: Patient dosimetry in diagnostic radiology. In Waggener RG, Kereiakes JG, Shalek R (eds): Handbook of Medical Physics, Vol II. Boca Raton, CRC Press, 1984

Greer IA: Clinical Practice. Pregnancy complicated by venous thrombosis. N Engl J Med 373(6):540,t2015

Greskovich JF, Macklis M:Radiation therapy in pregnancy: risk calculation and risk minimization. Semin Oncol 27:633, 2000

Groen RS, Bae JY, Lim K]: Fear of the unknown: ionizing radiation exposure during pregnancy. Am J Obstet Gynecol 206(6):456, 2012

Hall E]: Scientific view of low-level radiation risks. RadioGraphics 11t:509, 1991

Hawkins JS, Dashe JS, Twickler OM: Magnetic resonance imaging diagnosis of severe fetal renal anomalies. Am J Obstet Gynecol 198:328.el, 2008 Hong JY: Adnexal mass surgery and anesthesia during pregnancy: a 10-year retrospective review. Int J Obstet Anesth 15:212, 2006

Hoover K, Jenkins TR: Evaluation and management of adnexal mass in pregnancy. Am J Obstet Gynecol 205(2):97, 2011

Howell EK, Gaschak SP, Griith KD: Radioadaptive response following in utero low-dose irradiation. Radiat Res 179(1):29, 2013

Hunter JG, Swanstrom L, Thornburg K: Carbon dioxide pneumoperitoneum induces fetal acidosis in a pregnant ewe model. Surg Endosc 9:272, 1995 Hurwitz LM, Yoshizumi T, Reiman E, et al: Radiation dose to the fetus from body MDCT during early gestation. Am J Roentgenol 186:871,2006 International Commission on Radiological Protection: Biological efects after prenatal irradiation (embryo and fetus). IRCP Publication 90. Ann IRCP:

Kallen B, Mazze RI: Neural tube defects and irst trimester operations. Teratology 41:717,t1990

Kanal E, Barkovich AJ, Bell C, et al: American College of Radiology guidance document on MR safe practices: 2013. J Magn Reson Imaging 37:501,t2013 Kanter OJ, O'Brien MB, Shi XH, et al: The impact of ionizing radiation on placental trophoblasts. Placenta 35(2):85,t2014

Kho A: Diagnostic and operative laparoscopy. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed, New York, McGraw-Hill Education, 2017

Kizer NT, Powell MA: Surgery in the pregnant patient. Clin Obstet Gynecol 54(4):633,t2011

Kok D, de Vries MM, Heerschap A, et al: Absence of harmful efects of magnetic resonance exposure at 1.5 T in utero during the third trimester of pregnancy: a follow-up study. Magn Reson Imaging 22(6):851,t2004

Koo y], Kim HJ, Lim KT, et al: Laparotomy versus laparoscopy for the treatment of adnexal masses during pregnancy. Aust N Z J Obstet Gynecol 52:34,t2012

Kramer CM: Role of cardiac MR imaging in cardiomyopathies. J Nucl Med 56 SuppIt4):39S, 2015 Kuo e, Jamieson DJ, McPheeters ML, et al: Injury hospitalizations of pregnant women in the United States, 2002. Am J Obstet Gynecoltl96:t161, 2007 Laifer-Narin S, Budorick NE, Simpson LL, et al: Fetal magnetic resonance imaging: a review. Curr Opin Obstet Gynecol 19: 151, 2007 Lazarus E, Mayo-Smith W, Mainiero MB, et al: CT in the evaluation of nontraumatic abdominal pain in pregnant women. Radiology 244:784,t2007 Leung AN, Bull TM, Jaeschke R, et al: American Thoracic Sociery documents: an oicial American horacic Sociery/Sociery of Thoracic Radiology Clinical Practice Guidelines-evaluation of suspected pulmonary embolism in pregnancy. Radiology 262(2):635,t20t12 Levine LD, Schulkin J, Mercer BM, et al: Role of the hospital and maternal fetal medicine physician in obstetrical inpatient care. Am J Perinatol 33(2):123,t2016 Magin L, Le JK, Klintsova A, et al: Biological efects of long duration, highfield (4T) MRI on growth and development in the mouse. J Magn Res Imaging 12(1):t140,t2000 Mala T, Harsem NK, Rostad S, et al: Perforation of the pregnant uterus during laparoscopy for suspected internal herniation after gastric bypass. Case Rep Obstet Gynecol 20t181, 2014 Matzon JL, Lutsky KF, Ricci EK, et al: Considerations in the radiologic evaluation of the pregnant orthopaedic patient. J Am Acad Orthop Surg 23(8):485, 20t15 Mazonakis M, Damilakis J, Varveris H, et al: A method of estimating fetal dose during brain radiation therapy. Int J Radiat Oncol Bioi Phys 44:455, 1999 Mazonakis M, Varveris H, Damilakis J, et al: Radiation dose to conceptus resulting from tangentil breast irradiation. Int J Radiat Oncol Bioi Phys 55:386, 2003 Mazze RI, Kallen B: Reproductive ourcome after anesthesia and operation during pregnancy: a registry study of 5405 cases. Am J Obstet Gynecol 161:1t178, 1989 Miller MA, Mazzaglia PJ, Larson L, et al: Laparoscopic adrenalectomy for phaeochromocytoma in a twin gestation. J Obstet Gynaecol 32(2): 186, 2012 Moore HB, Juarez-Colunga E, Bronsert M, et al: Efect of pregnancy on adverse outcomes after general surgery. JAMA Surg 150(7):637,t2015 Mountford PJ: Risk assessment of the nuclear medicine patient. Br J Radiol 100:671, 199 Mullins JK, Semins MJ, Hayams ES, et al: Half Fourier single-shot turbo-echo magnetic resonance urography for the evaluation of suspected renal colic in pregnancy. Urology 79(6):1252,t20t12 National Council on Radiation Protection and Measurements: Medical X-ray, electron beam and gamma-ray protection for energies up to 50 MeV. Report No. 102, Bethesda, 1989 National Research Council: Health efects of exposure to low levels of ionizing radiation BEIR V. Committee on the Biological Efects of Ionizing Radiations. Board on Radiation Efects Research Commission on Life Sciences. Washington, National Academy Press, 1990 National Research Council: Health risks from exposure to low levels of ionizing radiation BEIR VII Phase 2. Committee to assess health risks from exposure to low levels of ionizing radiation. Board on Radiation Efects Research Division on Earth and Life Studies. Washington, National Academies Press, 2006 Nelson DB, Stewart RD, Matulevicius SA, et al: he efects of maternal position and habitus on maternal cardiovascular parameters as measured by cardiac magnetic resonance. Am J PerinatoIt32(14):t1318, 2015 Newman EA, Newman LA: Lymphatic mapping techniques and sentinel lymph node biopsy in breast cancer. Surg Clin North Am 87:353, 2007 Nuyttens J], Prado L, Jenrette JM, et al: Fetal dose during radiotherapy: clinical implementation and review of the literature. Cancer Radiother 6:352, 2002 Oh Y, RobertS H, Schabel Me, et al: Gadolinium chelate contrast material in pregnancy: fetal biodistribution in the nonhuman primate. Radiology 276(1):t110,t2015 O'Rourke N, Kodali BS: Laparoscopic surgery during pregnancy. Curr Opin Anaesthesiol 19:254, 2006 Otake M, Yoshimaru H, Schull WJ: Severe mental retardation among the prenatally exposed survivors of the atomic bombing of Hiroshima and Nagasaki: a comparison of the old and new dosimetry systems. Radiation Efects Research Foundation, Technical Report No. 16-8 , 198 Patenaude Y, Pugash 0, Lim K, el al: Sociery of Obstetricians and Gynaecologists of Canada. he use of magnetic resonance imaging in the obstetric patient. J Obstet Gynaecol Can 36(4):349, 2014 Pearl JP, Price RR, Tonkin E, et al: SAGES guidelines for the use of laparoscopy during pregnancy. Surg Endosc 31t(10):3767,t20t1 Pedrosa I, Lafornara M, Pandharipande PV, et al: Pregnant patients suspected of having acute appendicitis: efect of MR imaging on negative laparotomy rate and appendiceal rate. Radiology 250(3):749, 2009

General Considerations and Maternal Evaluation 913 Phupong V, Bunyavejchewin S: Gasless laparoscopic surgery for ovarian cyst in a second trimester pregnant patient with a ventricular septal defect. Surg Laparosc Endosc Percutan Tech 17:565,t2007 Prado L, Nelson SJ, Nuyttens J], et al: Clinicl implementation of the AAPM Task Group 36 recommendations on fetal dose from radiotherapy with photon beams: a head and neck irradiation case report. J Appl Clin Med Phys 1(1):t1,t2000 Preston DL, Cullings H, Suyama A, et al: Solid cancer incidence in atomic bomb survivors exposed in utero or as young children. J Natl Cancer Inst 100:428,t2008 Reedy MB, Galan HL, Bean-Lijewski JD, et al: Maternal and fetal efects of laparoscopic insuiation in the gravid baboon. J Am Assoc Gynecol Laparose 2:399, 1995 Reedy MB, Kallen B, Kuehl TJ: Laparoscopy during pregnancy: a study of ive fetal outcome parameters with use of the Swedish Health Registry. Am J Obstet Gynecol 177:673, 1997 Reeves MJ, Brandreth M, Whitby EH, et al: Neonatal cochlear function: measurement after exposure to acoustic noise during in utero MR imaging. Radiology 257(3):802,t2010 Reichel TF, Ramus RM, Caire JT, et al: Fetal central nervous system biometry on MR imaging. AJR Am J RoentgenoIt180:1t155, 2003 Reynolds JD, Booth JV, de la Fuente S, et al: A review of laparoscopy for nonobstetric-related surgery during pregnancy. Curr Surg 60: 164, 2003 Ribic-Pucelj M, Kobal B, Peternelj-Marinsek S: Surgical treatment of adnexal masses in pregnancy: indications, surgical approach and pregnancy ourcome. J Reprod Med 3, 2007 Rollins MD, Chan KJ, Price R: Laparoscopy for appendicitis and cholelithiasis during pregnancy. Surg Endosc 18:237, 2004 Rowley A, Hill SJ, Watkins A, et al: An investigation into the levels of radiation exposure in diagnostic examinations involving luoroscopy. Br J ,1t98 Sandrasegaran K, Lall CG, Aisen AA: Fetal magnetic resonance imaging. Curr Opin Obstet Gynecol 18:605,t2006 Schwartz JL, vfozurkewich EL, Johnson TM: Current management of patients with melanoma who are pregnant, want to get pregnant, or do not want to get pregnant. Cancer 97:2130, 2003 Shakerian R, Thomson BN, Judson R, el al: Radiation fear: impact on compliance with trauma imaging guidelines in the pregnant patient. J Trauma Acute Care Surg 78(1):88, 20t15 Silvestri MT, Pettker CM, Brousseau EC, et al: Morbidiry of appendectomy and cholecystectomy in pregnant and nonpregnant women. Obstet Gynecol 11t8(6):1261,t201t1 Sisodia M1, Del Carmen MG, Boruta OM: Role of minimally invasive surgery in the management of adnexal masses. Clin Obstet Gynecol 58(1t):66, 2015 Sociery for Maternal-Fetal Medicine (SMFM), Sciscione A, Berghella V, et al: Society for Maternal-Fetal Medicine (SMFM) Special Report: the maternalfetal medicine subspecialists' role within a health care system. Am J Obstet Gynecolt21 (6):607,t2014 Sorahan T, Lancashire RJ, Temperton DH, et al: Childhood cancer and paternal exposure to ionizing radiation: a second report from the Oxford Survey of Childhood Cancers. Am J Ind Med 1,t1995 Spanheimer PM, Graham MM, Sugg SL, et al: Measurement of urerine radiation exposure from lymphoscintigraphy indicates safety of sentinel lymph node biopsy during pregnancy. Ann Surg Oncol 16(5):t1143,t2009 Stather JW, Phipps A W, Harrison JD, et al: Dose coeicients for the embryo and fetus following intakes of radio nuclides by the mother. J Radiol Prot 22: 1, 2002 Stein, PO, Woodard PK, Weg JG, et al: Diagnostic pathways in acute pulmonary embolism: recommendations of the PIOPED II investigators. Radiology 242(1):15,t200 Steinbrook A, Bhavani-Shankar K: Hemodynamics during laparoscopic surgery in pregnancy. Anesth Analg 93: 15 0, 2001 Stepp K, Falcone T: Laparoscopy in the second trimester of pregnancy. Obstet Gynecol Clin North Am 31:485, 2004 Stewart RD, Nelson DB, Matulevicius SA, et al: Cardiac magnetic resonance to assess the impact of maternal habitus on cardiac remodeling during pregnancy. Am J Obstet Gynecol 214(5):640.el, 2016 Stovall M, Blackwell CR, Cundif J, et al: Fetal dose from radiotherapy with photon beams: report of AAPM Radiation Therapy Committee Task Group No. 36. Med Phys 22:63, 1995 Stroup SP, Altamar HO, L'Esperance JO, et al: Retroperitoneoscopic radical nephrectomy for renal-cell carcinoma during twin pregnancy. J Endourol 21t:735,t2007 Strzelczyk, J, Damilakis J, Marx MV, et al: Facts and controversies abour radiation exposure, part 2: low-level exposures and cancer risk. J Am Coil Radiol 4:32,t200 Suleiman OH, Anderson J, Jones B, et al: Tissue doses in the upper gastrointestinal examination. Radiology 178(3):653, 1991

Tica A, Tica os, Satoiu A, et al: Large pancreatic mucinous cystic neoplasm during pregnancy: what should be done? Gynecol Obstet Invest 5(2): 132, 2013

Tsai R, Raptis C, Fowler KJ, et al: MRI of suspected appendicitis during pregnancy: interradiologist agreement, indeterminate interpetation, and the meaning of non-visualization of the appendix. Br J Radiol 90: 1079, 2017

Twickler OM, Cunningham FG: Central nervous system indings in preeclampsia and eclampsia. In Lyall F, Belfort M (eds): Pre-eclampsiaEtiology, and Clinical Practice. Cambridge, Cambridge University Press, 2007, p 424

Twickler OM, Reichel T, McIntire DO, et al: Fetal central nervous system ventricle and cisterna magna measurements by magnetic resonance imaging. Am J Obstet Gynecol 187:927, 2002

Twickler OM, Setiawan AT, Evans R, et al: Imaging of puerperal septic thrombophlebitis: a prospective comparison ofMR imaging, CT, and sonography. AJR Am J RoentgenoIt169:t1t039, 1997

Vadeyar SH, Moore RJ, Strachan BK, et al: Efect of fetal magnetic resonance imaging on fetal heart rate patterns. Am J Obstet Gynecol 182:666, 2000 van Mens TE, Scheres LJ, de Jong PG, et al: Imaging for the exclusion of pulmonary embolism in pregnancy. Cochrane Database Syst Rev 1:CD011053, 2017

Victoria T, Johnson AM, Edgar JC, et al: Comparison berween 1.5-T and 3-T MRI for fetal imaging: is there an advantage to imaging with a higher field strength? AJR Am J Roentgenol 206: 195, 2016

Vilos GA, Ternamian A, Dempster J, et al: Laparoscopic entry: a review of techniques, technologies, and complications. J Obstet Gynaecol Can 29:433,t2007 Wagner LK, Lester RG, Saldana LR: Exposure of the Pregnant Patient to Diag nostic Radiation. Philadelphia, Medical Physics Publishing, 1997

Wang L, YutJM, Wang YS, et al: Preoperative lymphoscintigraphy predicts the successful identification but is not necessary in sentinel lymph nodes biopsy in breast cancer. Ann Surg Oncol 14(8):2215,t200

Webb KE, Sakhel K, Chauhan SP, el al: Adnexal mass during pregnancy: a review. Am J Perinatol 32(11):1010, 2015

White WlvI, Zite NB, Gash J, et l:Low-dose computer tomography for the evaluation ofAank pain in the pregnant population. J EndoutoI21:1255, 2007 WO JY, Viswanathan AN: Impact of radiotherapy on fertility, pregnancy, and neonatal outcomes in female cancer patients. Int J Radiat Oncol Bioi Phys 3(5):1304,t2009

Wortman A, Miller DL, Donahue TF, et al: Embolization of renal hemorrhage in pregnancy. Obstet Gynecol 121(Pt 2 Supplt1):480, 2013 Zanotti-Fregonara P, Hindie E: Performing nuclear medicine examinations in pregnant women. Phys Med 43:159,t2017 Zanzonico PB: Internal radionuclide radiation dosimetry: a review of basic concepts and recent developments. J Nucl Med 41t:297,t2000 Zaretsky M, McIntire 0, Twickler OM: Feasibility of the fetal anatomic and maternal pelvic survey by magnetic resonance imaging at term. Am J Obstet Gynecol 189:997, 2003a

Zaretsky M, Reichel TF, McIntire DO, et al: Comparison of magnetic resonance imaging to ultrasound in the estimation of birth weight at term. Am J Obstet GynecoIt189:1017, 2003b

Zeeman GG, Cipolla MJ, Cunningham FG: Cerebrovascular (patho)physiology in preeclampsia. In Taylor RN, Roberts JM, Cunningham FG, et al (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Elsevier, 2014, p 269

Zeeman GG, Hatab M, Twickler D: Maternal cerebral blood Row changes in pregnancy. Am J Obstet Gynecol 189:968,t2003

OBSTETRICALINTENSIVE CARE ....................915

ACUTE PULMONARY EDEMA ......................917

ACUTE RESPIRATORY DISTRESS SYNDROME ........918

SEPSIS SYNDROME.............................. 921

TRAUMA....................................... 925

THERMAL INJURY............................... 930

CARDIOPULMONARY RESUSCITATION.............931

The pregnant women is exposed to the same possibiliy of injuy as at other times, the prognosis not being naturaly altered except that abortion tequenty occurs.

-J. Whitridge Williams (1903) hese observations made more than a century ago are less applicable toda) to critically ill pregnant women because of current intensive care capabilities. For example, severe medical, surgical, and obstetrical disorders complicating pregnancy are frequently managed by a multidisciplinary team for optimal care. It is axiomatic that obstetricians and other members of the health-care team must have a working knowledge of the unique considerations for pregnant women. Some of those discussed in Chapter 46 include pregnancy-induced physiological changes, alterations in normal laboratory values, and consideration for the second patient-the fetus. Because these critically ill women are usually young and in good health, their prognosis is generally better than that of many other patients admitted to intensive care units (ICUs) (Gafney, 2014).

In the United States each year, 1 to 3 percent of pregnant women require critical care services, and the risk of death during such admissions ranges from 2 to 11 percent (American College of Obstetricians and Gynecologists, 2017b). hose with pregnancy-associated complications-especiall) hemorrhage and hypertension-have the greatest need for intensive care (Chantry, 2015; Gafney, 2014; Guntupalli, 2015a,b). That said, many antepartum admissions are for nonobstetrical reasons, and these include diabetes, pneumonia or asthma, heart disease, chronic hypertension, pyelonephritis, and thyrotoxicosis (Guntupalli, 2015b; Zeeman, 2006). Additionally, intrapartum and postpartum critical care for hypertensive disorders, hemorrhage, sepsis, or cardiopulmonary complications is often required. In instances of life-threatening hemorrhage, surgical procedures may be necessary, and close proximity to a delivery-operating room is paramount. For women who are undelivered, fetal well-being is also better served by this close proximity, especially because many are delivered preterm (Kilpatrick,r2016).

• Organization of Critical Care he concept and development of critical care for all aspects of medicine and surgery began in the 1960s. The National Institutes of Health held a Consensus Conference (1983) and the Society of Critical Care Medicine (1988, 1999) subsequently established guidelines for ICUs. Especially pertinent to obstetrics, these costly units prompted the evolution of a step-down intermediate care unit. hese latter units were designed for patients who did not require intensive care, but who needed a higher level of care than that provided on a general ward. The American College of Critical Care Medicine and the Society of Critical Care Medicine (1998) have published guidelines for these units (Table

TABLE 47-1 . Guidelines for Conditions That Could Qualify for Intermediate Care

Cardiac: for possible infarction, stable infarction, stable arrhythmias, mild-to-moderate congestive heart failure, hypertensive urgency without end-organ damage Pulmonary: stable patients for weaning and chronic ventilation, patients potential for respiratory failure who are otherwise stable Neurological: stable central nervous system, neuromuscular, or neurosurgical conditions that close monitoring Drug overdose: hemodynamically stable Gastrointestinal: stable bleeding, liver failure with stable vital signs Endocrine: diabetic ketoacidosis, thyrotoxicosis that requires frequent monitoring Surgical: postoperative from major procedures or complications that require close monitoring Miscellaneous: early sepsis, patients who require closely titrated intravenous fluids, pregnant women with severe

Data from Nasraway, 1998 .

Although the evolution of critical care for obstetrical patients has generally followed developments just described, there are no speciic guidelines. Most hospitals employ a blend of these concepts, and in general, units can be divided into three types.

First, in most hospitals, severely ill women are transferred to medical or surgical ICUs that are operated by specialists oten certified in critical care medicine. Admissions or transfers to these units are situation-speciic and based on the acuity of care needed and on the ability of the facility to provide it. For example, pregnant women who require ventilatory support, invasive monitoring, or pharmacological support of circulation are typically transferred to an ICU (Chantry, 2015). Another example is the neurological ICU (Sheth, 2012). In an earlier review of more than 25 tertiarycare referral institutions, approximately 0.5 percent of obstetrical patients were transferred to these types ofICUs (Zeeman, 2006).

A second type is the obstetrical intermediate care unit, sometimes referred to as a high-dependency care unit (HDU). One example is found at Parkland Hospital. Located within the labor and delivery unit, it has designated rooms stafed by experienced personnel. The two-tiered system incorporates the guidelines for intermediate and intensive care. Care is provided by maternal-fetal medicine specialists and nurses with experience in critical care obstetrics. As needed, this team is expanded to include other obstetricians and anesthesiologists, hospitalists, gynecological oncologists, pulmonologists, cardiologists, surgeons, and other medical and surgical subspecialists (Stevens, 2015). Many tertiary-care centers have developed similar intermediate care units and use selected triage to ICUs. Guidelines

Last, obstetrical ICUs are full-care ICUs but are operated by obstetrical and anesthesia personnel in the labor and delivery unit. Only a few obstetrical sevices have these capabilities (Zeeman, 2003, 2006).

For smaller hospitls, transfer to a medical or surgical ICU is usually preferable, and sometimes transfer to another hospital is necessary. s discussed, indications for admission to these types of critical care units vary, however, patient mix for these units is similar (Table 47-2). he American College of Obstetricians and Gynecologists (2017b) has summarized criticl obstetrical care implementation depending on hospital size and technical facilities.

Data obtained during pregnancy with pulmonary artery catheterization (PAC) have contributed immensely to the understanding of normal pregnancy hemodynamics and pathophysiology of common obstetrical conditions. These include preeclampsia-eclampsia, acute respiratory distress syndrome,

TABLE 47-2. Comparison of Acuity of Patient Mix for Obstetrical Critical Care Shown in Percent

Care Unit Surgical.lCU

Factor {n = 483)a {n = 81.3)b for such transfers must follow the federal Emergency Medical Hypertension

Treatment and Labor Act (EMTALA) guidelines. According to the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017), the minimal monitoring required for a critically ill patient during transport includes continuous pulse oximetry, electrocardiography, and regular assessment of vital signs. They must have secure venous access, and those who are mechanically ventilated must have endotracheal tube position confirmed and secured. Left uterine displacement and supplemental oxygen is applied routinely during transport of antepartum patients. Continuous fetal heart rate or tocodynamic monitoring is individualized.

Preg na ncy-Related 0.2 2 aData from Zeeman, 2003.

bData from Baskett, 2009; Keizer, 2006; Paxton, 2014; Small, 201n2; Stevens, 2006; Vasquez, 2007.

(Columns of indications do not total 100 percent because some diagnoses are not listed.

and amnionic-fluid embolism (Clark, 1988, 1995, 1997; Cunningham, 1986, 1987; Hankins, 1984, 1985). Also, because of these studies, most have concluded that such monitoring is seldom necessary (American College of Obstetricians and Gynecologists, 2013; Gidwani, 2013; Magder, 2015).

In nonobstetrical patients, randomized trials of nearly 5000 subjects have shown no benefits with PAC (Harvey, 2005; National Heart, Lung, and Blood Institute, 2006; Sandham, 2003). According to a Cochrane Database review, no randomized trials have used PAC for preeclampsia management (Li, 2012). he overall mechanisms, benefits, and risks were recently reviewed by Magder (2015).

Formulas for deriving some hemodynamic parameters are shown in Table 47-3. hese measurements can be indexed for body size by dividing by body surface area (BSA). Normal values for nonpregnant adults are used, but with the caveat that these may not necessarily reflect changes induced by the more "passive" uteroplacental perfusion.

In a landmark investigation, Clark and colleagues (1989) used PAC to obtain cardiovascular measurements in healthy pregnant women and again in these same women when nonpregnant (Chap. 4, p. 62). Because increased blood volume and cardiac output are compensated by decreased vascular resistance and increased pulse rate, ventricular performance remains within the normal range at term.

Cardiac complications are a common indication for ICU admission of pregnant women (Guntupalli, 2015b). Evaluation of cardiac unction is frequently performed using echo cardiography. his technology is indispensable in interrogating cardiac anatomy and especially right-ventricular unction (Krishnan, 2015; hiele, 2015). It is considered in more detail in Chapter 49 (p. 951), and some norml values are listed in the Appendix (p. 1261). A working knowledge of cardiovascular physiology in pregnancy is paramount to understanding the pathophysiology of gestational complications discussed later in this chapter and throughout the book.

TABLE 47-3. Formulas for Deriving Various Cardiopulmonary Parameters

BSA = body surface area (m2); CVP = central venous pressure (mm Hg); DBP = diastolic blood pressure; HR = heart rate (beats/min); MAP = mean systemic arterial pressure (mm Hg); MPAP = mean pulmonary artery pressure (mm Hg); PCWP = pulmonary capillary wedge pressure (mm Hg); SBP = systolic blood pressure.

Critical Care and Trauma 91.7

The incidence of pulmonary edema complicating pregnancy averages 1 in 500 deliveries at tertiary referral centers. The two general causes are: (1) cardiogenic, namely, hydrostatic edema caused by high pulmonary capillary hydraulic pressures, and (2) noncardiogenic, that is, permeability edema caused by capillary endothelial and alveolar epithelial damage. In pregnancy, noncardiogenic pulmonary edema is more common. Taken in toto, studies in gravidas indicate that more than half who develop pulmonary edema have some degree of sepsis syndrome in conjunction with tocolysis, severe preeclampsia, or obstetrical hemorrhage combined with vigorous luid therapy (O'Dwyer, 2014; hornton, 2011).

lthough cardiogenic pulmonary edema is less frequent, common precipitating causes include resuscitation for hemorrhage and vigorous treatment of preterm labor. In one study, the causes in 51 women with pulmonary edema were cardiac failure, tocolytic therapy, iatrogenic luid overload, and preeclampsia (Sciscione, 2003). In another study, more than half of cases were associated with preeclampsia, and the other three causes had equal distribution (Hough, 2007). In still another study of 53 cases, 83 percent were caused by hypertensive disorders, 11 percent cardiac, and 6 percent sepsis (O'Dwyer, 2015). Although used less commonly today, tocolytic therapy with �-mimetic drugs at one time was the cause of up to 40 percent of pulmonary edema cases (DiFederico, 1998; Gandhi, 2014; Jenkins, 2003).

Endothelial activation is the common denominator that is associated with preeclampsia, sepsis syndrome, and acute hemorrhage-or frequently combinations thereof-and they are the most common predisposing factors to pulmonary edema (T able 47-4). As discussed, these clinical scenarios are often associated with corticosteroids given to induce fetal lung

TABLE 47-4. Some Causes and Associated Factors for Pulmonary Edema in Pregnancy

Noncardiogenic permeability edema: endothelial activation with capillary-alveolar leakage

Sepsis syndrome: pyelonephritis, metritis

Tocolytic therapy: �-mimetics, MgS04

Cardiogenic pulmonary edema: myocardial failure with maturation along with vigorous luid replacement and tocolytic therapy (Thornton, 2011). Parenteral 3-agonists are indisputably linked to pulmonary edema. Studies have also associated magnesium sulfate given for preeclampsia (Gandhi, 2014; Wilson, 2014; Xiao, 2014). Combined therapy is also causative. In one study of nearly 800 women given magnesium sulfate for preterm labor, 8 percent developed pulmonary edema, and half of this afected group had also received terbutaline (Samol, 2005).

Ventricular failure causing pulmonary edema in pregnancy is usually associated with some form of gestational hypertension. Although it can be due to congenital or acquired anatomical defects, diastolic dysfunction is frequently from chronic hypertension, obesity, or both (Jessup, 2003; Kenchaiah, 2002). In these women, acute systolic hypertension exacerbates diastolic dysfunction and causes pulmonary edema (Dennis, 2012; Gandhi, 2001). Of note, concentric and eccentric hypertrophy is two-to threefold more common in black women compared with white women (Drazner, 2005). In a case-control study of 28 gravidas with preeclampsia and pulmonary edema, half of them were undelivered (Gandhi, 2014).

In women with an underlying cardiomyopathy, heart failure is commonly precipitated by preeclampsia, hypertension, hemorrhage and anemia, and puerperal sepsis (Cunningham, 1986; Sibai, 1987). In many of these, when echocardiography is done later, systolic function is normal as measured by ejection fraction, but evidence for diastolic dysunction can often be found (Aurigemma, 2004). The use of brain natriuretic peptide (BNP) has not been evaluated extensively in pregnancy (Seror, 2014). his neurohormone is secreted from ventricle myocytes and fibroblasts with distention seen in heart failure. In nonpregnant patients, values < 100 pgl mL have an excellent negative-predictive value, and levels >500 pg/mL have an excellent positivepredictive value. It is problematic that levels frequently are 100 to 500 pg/mL, and thus nondiagnostic (Ware, 2005). Values for N-terminal BNP and atrial natriuretic peptide (ANP) are both elevated with preeclampsia (Szabo, 2014; Tihtonen, 2007). his is discussed in greater detail in Chapter 4 (p. 63), and normal values for pregnancy are given in the Appendix (p. 1259).

Acute pulmonary edema requires emergency care. Furosemide is given in 20-to 40-mg intravenous doses along with therapy to control severe hypertension. Further treatment depends on whether a woman is ante-or postpartum. A live fetus prohibits the use of cardioactive drugs that might rapidly lower peripheral resistance and in turn severely diminish uteroplacental circulation. he cause of cardiogenic failure is determined by echocardiography, which will help direct further therapy. Acute pulmonary edema is not, per se, an indication for emergency cesarean delivery.

Acute lung injury that causes a form of severe permeability pulmonary edema and respiratory failure is termed acute respiratory distress syndrome (ARDS). This is a pathophysiological continuum from mild pulmonary insuiciency to dependence on high inspired oxygen concentrations and mechanical ventilation. Uniform criteria for its diagnosis are lacking, and thus the incidence is variably reported for pregnancy. In one survey of the Nationwide Inpatient Sample, 2808 pregnant women with ARDS were identified (Rush, 2017). he incidence ranged from 36 to 60 cases per 100,000 births, and the maternal mortality rate was 9 percent. In its most extreme form, requiring ventilatory support, the associated mortality rate is 45 percent. This rate can be as high as 90 percent if caused or complicated by sepsis (Phua, 2009). Although gravidas are younger and usully healthier thn the overall population, they still have mortality rates of 25 to 40 percent (Catanzarite, 2001; Cole, 2005). Finally, if ARDS develops antepartum, the perinatal mortality rate is correspondingly high.

Most investigators define ARDS as radiographically documented pulmonary iniltrates, a ratio of arterial oxygen tension to the fraction of inspired oxygen (Pao2:Fio2) <200, and no evidence of heart failure (Mallampalli, 2010; hompson, 2017). Revised by international consensus, the Berlin Dinition was described by the ARDS Definition Task Force (2012) and includes categories of mild, moderate and severe. To date, for most interventional studies, a working diagnosis of acute lung injuy is made when the Pao2:Fio2 ratio is <300 and is coupled with dyspnea, tachypnea, oxygen desaturation, and radiographic pulmonary infiltrates (Wheeler, 2007).

ARDS is a pathophysiological description that begins with an acute lung injury from various causes (Table 47-5). In pregnant

TABLE 47-5. Some Causes of Acute Lung Injury and Respiratory Failure in Pregnant Women

Pneumonia: bacterial, viral, aspiration

Sepsis syndrome: chorioamnionitis, pyelonephritis, puerperal infection, septic abortion

Hemorrhage: shock, massive transfusion, transfusion-

Embolism: amnionic fluid, trophoblastic disease, air, fat

Data from Cole, 2005; Duarte, 2014; Golombeck, 2006; Lapinsky, 2015; Martin, 2006; Sheffield, 2005; Sibai, 20104; Snyder, 201n3; Zeeman, 2003, 2006.

women, sepsis and difuse infectious pneumonia are the two most common single-agent ARDS causes. Pyelonephritis, puer peral pelvic infection, and chorioamnionitis are the most frequent causes of sepsis. As discussed on page 917, severe preeclampsia and obstetrical hemorrhage are also commonly associated with permeability edema. Importantly, more than half of pregnant women with ARDS have some combination of sepsis, hemor rhage, shock, and luid overload. The contribution of tranosion related acute lung injuy (TAIl) is unclear (Chap. 41, p. 791).

Endothelial injury in the lung capillaries releases cytokines that recruit neutrophils to the inflammation site. Here, they elaborate more cytokines to worsen tissue injury. There are three stages of ARDS development. First, the exudative phase follows widespread injury to microvascular endothelium, including the pulmonary vasculature, and there is also alveolar epithelial injury. These result in increased pulmonary capillary perme ability, surfactant loss or inactivation, diminished lung volume, and vascular shunting with resultant arterial hypoxemia. Next, the ibroprolierative phase usually begins 3 to 4 days later and lasts up to day 21. Last, theibrotic phase results from healing, and despite this, the long-term prognosis for pulmonary func tion is surprisingly good (Herridge, 2003; Levy, 2015).

With pulmonary injury, the clinical condition depends largely on the insult magnitude, the ability to compensate for it, and the disease stage. For example, soon after the initial injury, physical findings are absent except perhaps hyperventilation. And at irst, arterial oxygenation usually is adequate. Pregnancy-induced mild metabolic alkalosis may be accentuated by hyperventilation. With worsening, clinical and radiological evidence for pulmonary edema, decreased lung compliance, and increased intrapulmonary blood shunting become apparent. Progressive alveolar and interstitial edema develop with extravasation of inflammatory cells and erythrocytes.

Ideally, pulmonary injury is identified at this early stage, and speciic therapy is directed at the underlying insult. Further progression to acute respiratory failure is characterized by marked dyspnea, tachypnea, and hypoxemia. Additional lung volume loss results in worsening of pulmonary compliance and increased shunting. Difuse abnormalities are heard by auscultation, and a chest radiograph characteristically demonstrates bilateral lung involvement (Fig.

At this phase, the injury ordinarily would be lethal in the absence of ventilatory support. When shunting exceeds 30 percent, severe refractory hypoxemia develops along with metabolic and respiratory acidosis that can result in myocardial irritability, dysfunction, and cardiac arrest.

Reduced ARDS mortality rates have resulted from advances in care of the critically ill (Levy, 2015). his requires close attention to: (1) recognizing and treating underlying medical and surgical disorders, (2) minimizing procedures and their complications, (3) administering prophylaxis against venous thromboembolism, gastrointestinal bleeding, aspiration, and central venous catheter infection, (4) promptly diagnosing nosocomial infections, and (5) providing adequate nutrition.

FIGURE 47-1 Anteroposterior chest radiograph of a secondtrimester pregnant woman with marked bilateral parenchymal and pleural opacification secondary to acute respiratory distress syndrome (ARDS) due to pyelonephritis.

In cases of severe acute lung injury, providing adequate oxygenation of peripheral tissues is balanced against maneuvers that further aggravate lung injury. At least intuitively, increasing oxygen delivery should produce a corresponding increase in tissue uptake, but this is diicult to measure. Support of systemic perfusion with intravenous crystalloid and blood is imperative. As discussed earlier, the trial conducted by the National Heart, Lung, and Blood Institute (2006) showed that pulmonary artery catheter use did not improve outcomes. Because sepsis is commonplace in lung injury, vigorous antimicrobial therapy is given for infection, and any necrotic tissues are debrided. Oxygen delivery can be greatly improved by correction of anemia. Speciically, each gram of hemoglobin carries 1.25 mL of oxygen when 90-percent saturated. By comparison, increasing the arterial P02 from 100 to 200 mm Hg results in the transport of only 0.1 mL of additional oxygen for each 100 mL of blood.

Reasonable goals in caring for the woman with severe lung injury are to attain a Pao2 of 60 mm Hg or 90-percent oxygen saturation using an inspired oxygen content < 50 percent and positive end-expiratory pressures < 15 mm Hg. With regard to the pregnancy, it remains controversial whether delivery of the fetus improves maternal oxygenation (Mallampalli, 2010). In a study of 29 women undergoing mechanical ventilation, 10 were delivered while intubated (Lapinsky, 2015). This was associated with a modest improvement in respiratory function in perhaps half, but no factors were identiied that predicted a better outcome.

Noninvasive ventilation, that is, positive pressure ventilation by face mask, may be efective in some women in early stages of pulmonary insuiciency (Duarte, 2014). Early intubation is preferred in the gravida if respiratory failure is more likely than not, and especially if it appears imminent. Many successful formulas for mechanical ventilation are employed, and initially a tidal volume :;6 mLlkg is optimal (Levy, 2015; Schwaiberger, 2016). High-frequency oscillation ventilation (HFOV) is controversial in ARDS (Ferguson, 2013; Slutsy, 2013). Adjustments are made to obtain a Paoz>60 mm Hg or a hemoglobin oxygen saturation 290 percent and a Pacoz of 35 to 45 mm Hg. Lower levels for Paoz are avoided, because placental perfusion may be impaired (Levinson, 1974).

For women who require ventilation for any length of time, the maternal mortality rate is 10 to 20 percent. In a study of 51 such women, almost half had severe preeclampsia, and most required intubation postpartum. Eleven were delivered while being ventilated, and another six were discharged undelivered (Jenkins, 2003). here were two maternal deaths, including a woman who died as a complication of tocolytic treatment. In three other reports, maternal mortality rates ranged from 10 to 25 percent (Chen, 2003; Lapinsky, 2015; Schneider, 2003). In most cases, delivery did not improve maternal outcome.

With severe lung injury and high intrapulmonary shunt fractions, it may not be possible to provide adequate oxygenation with usual ventilatory pressures, even with 100-percent oxygen. Positive end-expiratory pressure is usually successful in decreasing the shunt by recruiting collapsed alveoli. At low levels of 5 to 15 mm Hg, positive pressure can typically be used safely. At higher levels, impaired right-sided venous return can result in decreased cardiac output, lowered uteroplacental perfusion, alveolar overdistention, falling compliance, and barotrauma (Schwaiberger, 2016; Slutsky, 2013).

As discussed in Chapter 33 (p. 620), extracorporeal membrane oxygenation (ECM 0) has been successfully used for neonatal meconium aspiration syndrome. Preliminary observation suggests that it may be useful in adults with ARDS (Brodie, 2011; Levy, 2015; Peek, 2009). ECMO use has been reported in pregnant women. In one study, 12 patients with inluenza-induced lung failure were treated with ECMO, and of four maternal deaths, three were due to anticoagulation-related hemorrhage (Nair, 2011). In another study, the duration of support in four survivors was 2 to 28 days (Cunningham, 2006). In a review of 29 treated gravidas, 80 percent of cases were due to ARDS, and the maternal and perinatal mortality rate was 28 percent (Anselmi, 2015). Technical aspects of ECMO were reviewed by Brodie and Bacchetta (2011).

he propensity of the hemoglobin molecule to release oxygen is described by the oyhemoglobin dissociation curve (Fig. 47-2). For clinical purposes, the curve can be divided into an upper oxygen association curve representing the alveolar-capillary environment and a lower oxygen dissociation portion representing the tissue-capillary environment. Shifts of the curve have their greatest efect at the steep portion because they afect oxygen delivery. A rightward shit is associated with decreased hemoglobin ainity for oxygen and hence increased tissue-capillary oxygen :0 60= :l

FIGURE 47-2 Oxyhemoglobin dissociation curve. With higher oxygen tension (Pao2) in the pulmonary alveoli, adult hemoglobin is maximally saturated compared with that at the lower oxygen tension in the tissue capillaries. Note that at any given oxygen tension, fetal hemoglobin carries more oxygen than adult hemoglobin, as indicated by percent saturation.

interchange. Rightward shifts are produced by hypercapnia, metabolic acidosis, fever, and increased 2,3-diphosphoglycerate levels. During pregnancy, the erythrocyte concentration of 2,3-diphosphoglycerate is increased by approximately 30 percent. This favors oxygen delivery to both the fetus and maternal peripheral tissues.

Fetal hemoglobin has a higher oxygen ainity than adult hemoglobin. As seen in Figure 47-2, its curve is positioned to the left of the adult curve. To achieve 50-percent hemoglobin saturation, the Paoz must be 27 mm Hg in the mother compared with only 19 mm Hg in the fetus. Under normal physiological conditions, the fetus is constantly on the dissociation, or tissue, portion of the curve. Even with severe maternal lung disease and very low Paoz levels, oxygen displacement to fetal tissues is favored. Another example of this comes from pregnant women who live at high altitudes. Here, despite a maternal Paoz of only 60 mm Hg, the fetal Paoz is equivalent to that of fetuses at sea level (Subrevilla, 1971).

Although mortality outcomes are similar, conservative rather than liberal fluid management is associated with fewer days of mechanical ventilation (Wiedemann, 2006). Some pregnancyinduced physiological changes predispose to a greater risk of permeability edema from vigorous fluid therapy. Colloid oncotic pressure (COP) is determined by serum albumin concentration, and 1 gl dL exerts approximately 6 mm Hg pressure. As discussed in Chapter 4 (p. 68), serum albumin concentrations normally drop in pregnancy. This results in a decline in oncotic pressure from 28 mm Hg in the nonpregnant woman to 23 mm Hg at term and to 17 mm Hg in the puerperium (Benedetti, 1979; Dennis, 2012). With preeclampsia, endothelial activation with leakage causes extravascular albumin loss and lowered serum albumin levels. As a result in these cases, 14 mm Hg postpartum (Zinaman, 1985). hese changes have a significant clinical efect on the colloid oncotic pressure/wedge pressure gradient. Normally, this gradient exceeds 8 mm Hg. However, when it is 4 mm Hg or less, the risk for pulmonary edema rises. No benefits are gained by albumin rather than crystalloid infusions in these women (Uhlig, 2014). hese associations were reviewed by Dennis and Solnordal (2012).

No long-term follow-up studies address gravidas who recover from ARDS. In nonpregnant subjects, risks for impaired global cognitive function at 3 and 12 months are significant (Pandharipande, 2013). Data from nonpregnant patients indicate a 1-to 2-year hiatus before basic normal activity is restored in all. In a 5-year follow-up study, Herridge and associates (201r1) reported normal lung function but signiicant exercise limitation, physical and psychological sequelae, decreased physical quality of life, and increased use of health-care services.

This syndrome is induced by a systemic inlammatory response to bacteria or viruses or their by-products such as endotoxins or exotoxins. The severity of the syndrome is a continuum or spectrum 47-3). According to the Centers for Disease Control and Prevention (CDC), sepsis caused 6.2 percent of pregnancy-related deaths in the United States from 201r1 to 2013 (Creanga, 2017). It was also a signiicant cause of maternal mortality in Michigan and the United Kingdom (Bauer, 2015; 110hamed-Ahmed, 2015; Nair, 2015).

Infections that most commonly cause sepsis syndrome in obstetrics are pyelonephritis (Chap. 53, p. 1028), chorioamnionitis and puerperal sepsis (Chap. 37, p. 667), septic abortion (Chap. 18, p. 351), and necrotizing fasciitis (Chap. 37, p. 671). With severe sepsis, the mortality rate in nonpregnant patients is 20 to 35 percent and is 40 to 60 percent with septic shock (Angus, 2013; Munford, 2015). With shock, the mortality rate in pregnancy has been reported to be 30 percent (Mabie, 1997; Snyder, 2013). That said, the maternal mortality risk from sepsis is significantly underestimated (Bauer, 2015; Chebbo, 2016; Mohamed-Ahmed,r2015).

Most of what is known concerning sepsis pathogenesis comes from study of lipopolysaccharide-LPS or endotoxin (Munford, 2015). The lipid A moiety is bound by mononuclear blood cells, becomes internalized, and stimulates release of mediators and a series of complex downstream perturbations. Clinical aspects of the sepsis syndrome are manifest when cytokines are released that have endocrine, paracrine, and autocrine actions (Angus, 2013; Singer, 2016).

Although the sepsis syndrome in obstetrics may be caused by several pathogens, most cases represent a small group. For example, pyelonephritis complicating pregnancy caused by Escherichia coli and Klebsiela species commonly is associated with bacteremia and sepsis syndrome (Cunningham, 1987; Snyder, 2013). And although pelvic infections are usually polymicrobial, bacteria that cause severe sepsis syndrome are frequently endotoxin-producing Enterobacteriaceae, most commonly E coli (Eschenbach, 2015). Other pelvic pathogens are aerobic and anaerobic streptococci, Bacteroides species, and Clostridium species. Some strains of group A 3-hemolytic ) SIRS-fever, tachycardia, tachypnea, leukocytosis, leukopenia t::,

Organ system dysfunctionacidosis, encephalopathy, oliguria, hypoxemia, coagulopathy

Spectrum of Severity

FIGURE 47-3 The sepsis syndrome begins with a systemic inflammatory response syndrome (SIRS) in response to infection that may progress to septic shock.

streptococci and Staphylococcus aureus-including communityacquired methicillin-resistant strains (CA-MRSA)-produce a superantigen that activates T cells to rapidly cause all features of the sepsis syndrome-toxic shock syndrome (Moellering, 2011; Soper, 2011). his is discussed further in Chapter 37 (p. 675).

drome. Examples include exotoxins from Clostridium pertingens or sordellii, toxic-shock-syndrome toxin-1 (TSST -1) from S au reus, and toxic shock-like exotoxin from group A 3-hemolytic streptococci (Daif, 2009; Soper, 2011). These last exotoxins cause rapid and extensive tissue necrosis and gangrene, especially of the postpartum uterus, and may cause profound cardiovascular collapse and maternal death (Nathan, 1993; Sugiyama, 2010). In a review discussed subsequently, the maternal mortality rate from these infections was 58 percent (Yamada, 2010).

Thus, the sepsis syndrome begins with an inflammatory response that is directed against microbial endotoxins and exotoxins (Angus, 2013). CD4 T cells and leukocytes are stimulated to produce proinflammatory compounds that include tumor necrosis factor-a (TNF-a), several interleukins, other cytokines, proteases, oxidants, and bradykinin that result in a "cytokine storm" (Russell, 2006). Many other cellular reactions then follow that include stimulation of pro-and antiinflammatory compounds, procoagulant activity, gene activation, receptor regulation, and immune suppression (Filbin, 2009; Moellering, 2011). It is also likely that interleukin-6 (IL-6) mediates myocardial suppression (Pathan, 2004).

he pathophysiological response to this cascade is selective vasodilation with maldistribution of blood low. Leukocyte and platelet aggregation cause capillary plugging. Worsening endothelial injury causes profound permeability, capillary leakage, and interstitial fluid accumulation (Fig. 47-4). Depending on the degree of injury and inflammatory response, a pathophysiological and clinical continuum evolves as depicted in Figure 47-3. The clinical syndrome begins with subtle signs of

Cytokines and other inflammatory mediators lead to endothelial junction separation

FIGURE 47-4 Endothelial permeability. The normal interendothelial interface is shown in the left inset. Cytokines and other inflammatory mediators disassemble the cellular junctions, resulting in microvascular leaks (right).

sepsis from infection and terminates with septic shock, which is defined by hypotension unresponsive to intravenous hydration. In its early stages, clinical shock results primarily from decreased systemic vascular resistance that is not compensated fully by increased cardiac output. Hypoperfusion results in lactic acidosis, decreased tissue oxygen extraction, and end-organ dysfunction that includes acute lung and kidney injury.

he sepsis syndrome has myriad clinical manifestations that, at least in part, are dependent on the specific invading microorganism and its particular endo-or exotoxins. Some of the general efects of LPS are as follows: 1.

Central nervous system: confusion, delirium, somnolence, coma, combativeness, fever 2.

Cardiovascular: tachycardia, hypotension 3.

Pulmonary: tachypnea, arteriovenous shunting with dysoxia and hypoxemia, exudative iniltrates from endothelialalveolar damage, pulmonary hypertension 4.

Gastrointestinal: gastroenteritis-nausea, vomiting, and diarrhea; ileus; hepatocellular necrosis-jaundice, transaminitis 5.

Renal: prerenal oliguria, azotemia, acute kidney injury, proteinuria 6.

Hematological: leukocytosis or leukopenia, thrombocytopenia, activation of coagulation with disseminated intravascular coagulopathy 7.

Endocrine: hyperglycemia, adrenal insuiciency 8.

Cutaneous: acrocyanosis, erythroderma, bullae, digital gangrene.

Thus, although capillary leakage initially causes hypovolemia, if intravenous crystalloid is given at this point, then sepsis hemodynamically can be described as a high cardiac output, low systemic vascular resistance condition (Fig. 47-5). Concomitantly, pulmonary hypertension develops, and despite the high cardiac output, severe sepsis also causes myocardial depression (Munford, 2015; Ognibene, 1988). This is often referred to as the warm phase of septic shock. hese indings are the most common cardiovascular manifestations of early sepsis, but they can be accompanied by some of the other clinical or laboratory aberrations listed above.

The response to initial intravenous hydration may be prognostic. Most pregnant women who have early sepsis show a salutary response with crystalloid and antimicrobial therapy, and if indicated, debridement of infected tissue. Conversely, if hypotension is not corrected following vigorous luid infusion, then the prognosis is more guarded. At this juncture, if there also is no response to 3-adrenergic inotropic agents, this indicates severe and unresponsive extracellular luid extravasation with vascular insuiciency, overwhelming myocardial depression, or both. Oliguria and continued peripheral vasoconstriction characterize a secondary, cold phase of septic shock that is rarely survived. Another poor prognostic sign is continued renal, pulmonary, and cerebral dysfunction once hypotension has been corrected (Angus, 2013; Chebbo, 2016). The average risk of death increases by 15 to 20 percent with failure of each organ system. With three systems, mortality rates are 70 percent (Martin, 2003; Wheeler, 1999).

FIGURE 47-5 Hemodynamic efects of sepsis syndrome. Values for normal women at term are shown by dots. With early sepsis, there is high cardiac output and low vascular resistance. With fluid resuscitation, cardiac output increases even more, but so does capillary hydraulic pressure. With continued sepsis, there may be myocardial depression to further increase capillary hydraulic pressure. Decreased plasma oncotic pressure (serum albumin [g] x 6 mm Hg) contributes to interstitial lung fluid and endo/epithelialoleak causes alveolar flooding. LVSWI = left ventricular stroke work index; PCWP = pulmonary capillary wedge pressure.

In 2004, an international consensus efort was launched as the Surviving Sepsis Campaign (Dellinger, 2013). he cornerstone of management is eary goal-directed management, and it stresses prompt recognition of serious bacterial infection and close monitoring of vital signs and urine flow. It remains controversial if institution of this protocol has improved survival rates (ARISE Investigators, 2014; Mouncey, 2015; ProCESS Investigators, 2014). Similar conclusions were reached with sets of early warning systems in obstetrics (Edwards, 2015; Mhyre, 2014). Albright and associates (2017) have validated the Sepsis in Obstetrics Score to identiy the risk ofICU admission for sepsis.

An algorithm for management of sepsis syndrome is shown in 47-6. The three basic steps are performed as simultaneously as possible and include evaluation of the sepsis source and its sequelae, cardiopulmonary function assessment, and immediate management. The most important step in sepsis management is rapid infusion of 2 L and sometimes as many as 4 to 6 L of crystalloid luids to restore renal perfusion in severely afected women (Vincent, 2013). Simultaneously, appropriately chosen broad-spectrum antimicrobials are begun. Because hemoconcentration is caused by the capillary leak, if anemia coexists, then blood is given. Maintaining the hemoglobin concentration at : 9 g/ dL did not have superior outcomes compared with that of :7 g/dL (Holst, 2014). hat said, fetal oxygenation is improved by the higher concentration.

The use of colloid solution such as hetastarch is controversial (Angus, 2013; Ware, 2000). One randomized trial comparing tality rate with the starch solution (Perner, 2012). Another study found equivalent results with 6-percent hydroxyethyl starch compared with normal saline (Myburgh, 2012). Albumin was not found to be superior to crystalloids (Caironi, 2014).

Aggressive volume replacement ideally is promptly followed by urinary output of at least 30 and preferably 50 mL/hr, as well as other indicators of improved perfusion. If not, then con sideration is given for vasoactive dtug therapy (Pacheco, 2014).

Mortality rates are high when sepsis is further complicated by respiratory or renal failure. With severe sepsis, damage to pul alveolar looding and pulmonary edema. This may occur even with low or normal pulmonary capillary wedge pressures, as with the ARDS discussed on page 918 and depicted in Figure 47-1.

Broad-spectrum antimicrobials are chosen empirically based on the probable source of infection. They are given promptly in maximal doses after appropriate cultures are taken of blood, urine, or exudates not contaminated by normal flora. In severe sepsis, appropriate empirical coverage results in better survival rates (Barochia, 2010; MacArthur, 2004). In obstetrics acute pyelonephritis is usually caused by Enterobacteriaceae, as discussed in Chapter 53 (p. 1028). For pelvic infections, empirical coverage with regimens such as ampicillin plus gentamicin plus clindamycin generally suices (Chap. 37, p. 668). Associated incisional and other soft-tissue infections are increasingly likely to be caused by methicillin-resistant S aureus, thus vancomycin therapy may be added (Klevens, 2007; Rotas, 2007). With a septic abortion, a Gram-stained smear may be helpful in identiying Clostridium species or group A streptococcal organisms. his is also true for deep fascial infections.

Continuing sepsis may prove fatal, and debridement of necrotic tissue or drainage of purulent material is crucial (Nelson, 2015; Pacheco, 2014). In obstetrics, the major causes of sepsis are infected abortion, pyelonephritis, and puerperal pelvic infections, which include metritis and infections of perineal lacerations or of hysterotomy or laparotomy incisions. With a septic abortion, uterine contents must be removed promptly by curettage as described in Chapter 18 (p. 351) . Hysterectomy is seldom indicated unless gangrene has resulted.

For women with pyelonephritis, continuing sepsis should prompt a search for obstruction caused by calculi or by a perinephric or intrarenal phlegmon or abscess. Renal sonography or "one-shot" pyelography can help diagnose obstruction and calculi. With obstruction, ureteral catheterization, percutaneous nephrostomy, or flank exploration may be lifesaving (Chap. 53, p. 1029). Computed tomography (CT) or magneticresonance imaging aids in identiying a phlegmon or abscess.

Puerperal Infections. Most cases of puerperal pelvic sepsis are clinically manifested in the first several days postpartum, and

FIGURE 47-6 Algorithm for evaluation and management of sepsis syndrome. Rapid and aggressive implementation is paramount for success. The three steps-Evaluate, Assess, and Manage-are carried out as simultaneously as possible.

intravenous antimicrobial therapy without tissue debridement cases, there is bacteremia and widespread tissue invasion, but with is generally curative. here are at least three exceptions. an intact uterus and abdominal incision. If uterine necrosis can

First, massive uterine myonecrosis can be caused by group A be excluded-usually by CT scanning-then in our experiences, 3-hemolytic streptococcal or clostridial infections (Soper, 2011; as well as in others, hysterectomy may not be necessary (Soper, Sugiyama, 2010; Yamada, 2010). hose with early-onset disease 2011). Still, these infections are highly lethal (Yamada, 2010). present with findings listed in Table 47-6. The mortality rate in As a second exception, necrotizing fasciitis of the episiotomy these women with gangrene s shown in Figure 47-7 is high, and site or of the abdominal surgical incision is a surgical emergency. prompt hysterectomy may be lifesaving (Mabie, 1997; Nathan, As described by Gallup and coworkers (2002), these infections 1993). Group A 3-hemolytic streptococci and clostridial coloare aggressively managed as discussed in Chapter 37 (p. 671). nization or infection also cause toxic-shock syndrome without Sinha and colleagues (2015) described a woman with Fournier obvious gangrene (Mason, 2012). These are due to either strepgangrene who required radical debridement and colostomy. tococcal toxic-shock-syndrome-like toxin or clostridial exotoxin As a inal exception, persistent or aggressive postpartum that evolved from 5 aureus (Chap. 37, p. 675). In many of these uterine infection with necrosis, uterine incision dehiscence, and severe peritonitis may lead to sepsis (Chap. 37, p. 672). In this regard, women following cesarean delivery who are suspected of having peritonitis should be carefully evaluated for uterine incisional necrosis or bowel perforation. These infections tend to be less aggressive than necrotizing group A streptococcal infections and develop later postpartum. CT imaging of the abdomen and pelvis can frequently disclose these. If either is suspected, then prompt surgical exploration is indicated. With incisional necrosis, hysterectomy is usually necessary (Fig. 37-5, p. 673). Finally, peritonitis and sepsis much less commonly may result from a ruptured parametrial, intraabdominal, or ovarian abscess (Chap. 37, p. 671).

As shown in Figure 47-6, a woman with severe sepsis syndrome is supported with continuing crystalloid infusion, blood

FIGURE 47-7 A fatal case of group A 3-hemolytic Streptococcus pyogenes puerperal infection following an uncomplicated vaginal delivery at term. The infection caused uterine gangrene and overwhelming sepsis syndrome. Arrows point to overtly "balloonedout" black gangrenous areas of the postpartum uterus at the time of laparotomy for hysterectomy.

transusions, and ventilation. In some cases, other measures may be necessary. Vasoactive drugs are not given unless aggressive luid treatment fails to correct hypotension and perfusion abnor malities. First-line vasopressors are norepinephrine, epinephrine, dopamine, dobutamine, or phenylephrine (Vincent, 2013).

he use of corticosteroids remains controversial. Some stud ies, but not all, show a salutary efect of corticosteroid admin istration. It is thought that critical ilness-related corticosteroid sion. hus, corticosteroids may be considered for use in vaso pressor-dependent patients (Angus, 2013; Munford, 2015).

Endotoxin stimulates endothelial cells to up regulate tis sue factor and thus procoagulant production (Cunningham, 2015). Consumptive coagulopathy associated with sepsis is dis cussed in Chapter 41 (p. 782). At the same time, it decreases the anticoagulant action of activated protein C. Several agents developed to block coagulation, however, did not improve outcomes. Some include recombinant activated protein C, anti thrombin II, platelet-activating actor antagonist, and tissue ac tor pathway inhibitor (Munford, 2015; Wenzel, 2012).

Depending on deinitions used, 10 to 20 percent of gravidas suffer physical trauma (Jain, 2015; Lucia, 2016). Moreover, injuryrelated deaths are the most commonly identiied nonobstetrical cause of maternal mortality (Brown, 2013a; Horon, 2001). In a California study of4.8 million pregnancies, almost 1 in 350 women were hospitalized for injuries from assaults (El Kady, 2005). From Parkland Hospital, motor vehicle accidents and falls accounted for 85 percent of injuries sustained by 1682 pregnant women (Hawkins, 2007). From the National Violent Death Reporting System, Palladino and colleagues (2011) found 2.0 pregnancyassociated suicides per 100,000 live births. he rate was 2.9 per 100,000 for pregnancy-associated homicides. Notably, intimatepartner violence may be linked to these suicides (Martin, 2007). Finally, injury prevention and education of high-risk patients may help to decrease morbidity (Chisolm, 2017; Lucia, 2016).

According to the CDC, llltlmate-partner violence describes physical, sexual, or psychological harm by a current or former partner or spouse (Breiding, 2015). Such violence afects 1 in 5 women each year. One goal in violence prevention for Healthy People 2010 was the reduction of physical abuse directed at women by male partners. The Pregnancy Risk Assessment Monitoring Systems (PRAMS) report showed some improvement in these areas (Suellentrop, 2006).

Even more appalling is that physical violence directed at women continues during pregnancy. Abuse is linked to poverty, poor education, and use of tobacco, alcohol, and illicit drugs (Centers for Disease Control and Prevention, 2008). Unfortunately, abused women tend to remain with their abusers, and the major risk factor for intimate-partner homicide is prior domestic violence (Campbell, 2007). Finally, women seeking pregnancy termination have a higher incidence of intimatepartner violence (Bourassa, 2007).

exposure is high aFor nonpregnant women, doxycycline, 100 mg orally twice daily for 7 days, can be given instead. bpregnancy category C.

HIV = human immunodeficiency virus; 1M = intramuscularly. Data from Centers for Disease Control and Prevention, 2015.

The woman who is physically abused tends to present late, if at all, for prenatal care. In one study, pregnant women hospitalized in California as a result of assault had signiicantly increased perinatal morbidity rates (El Kady, 2005). Immediate sequelae included uterine rupture, preterm delivery, and maternal and perinatal death. Subsequent outcomes included increased rates of placental abruption, preterm and low-birthweight newborns, and other adverse outcomes. Silverman and associates (2006) reported similar results from PRAMS, which included more than 118,000 pregnancies in 26 states.

Preventatively, the American College of Obstetricians and Gynecologists (2012) recommend universal screening for intimate-partner violence at the initial prenatal visit, during each trimester, and again at the postpartum visit (Chap. 9, p. 162). Others recommend a case-finding approach based on clinical suspicion (Robertson-Blackmore, 2013).

According to the National Intimate Partner and Sexual Violence Survey (Black, 2014), an estimated 1.2 million women will be sexually assaulted each year. Satin and coworkers (1992) reviewed more than 5700 female sexual assault victims in Dallas County and reported that 2 percent were pregnant. Associated physical trauma is common (Sugar, 2004). From a forensic standpoint, the evidence collection protocol is not altered (Linden, 2011).

In addition to attention to physical injuries, exposure to sexually transmitted diseases must be considered. The CDC (2015) recommends antimicrobial prophylaxis against gonorrhea, chlamydial infection, bacterial vaginosis, and trichomoniasis (Table 47-7). If the woman is not pregnant, another very important aspect is emergency contraception, as recommended by the American College of Obstetricians and Gynecologists (2016; 2017a) and discussed in Chapter 38 (p. 696).

Finally, the importance of psychological counseling for the rape victim and her family cannot be overemphasized. A 30-to 35-percent lifetime risk each for posttraumatic stress disorder, major depression, and suicide contemplation follows sexual assault (Linden, 201r1) .

At least 3 percent of pregnant women are involved in motor vehicle accidents each year in the United States. Using data from PRAMS, Sirin and colleagues (2007) estimated that 92,500 gravidas are injured annually. Motor-vehicle crashes are the most common causes of serious, life-threatening, or fatal blunt

FIGURE 47-8 Illustration showing correct use of three-point automobile restraint. The upper belt is above the uterus, and the lower belt fits snugly across the upper thighs and well below the uterus.

trauma during pregnancy (Brown, 2013a; Mendez-Figueroa, 2013,r2016; Vladutiu, 2013). Mattox and Goetzl (2005) report these accidents to be the leading cause of traumatic fetal deaths as well. This was also true from our experiences from Parkland Hospital (Hawkins, 2007). Traic crashes are most frequent in the second trimester (Redel meier, 2014). As with all motor vehicle crashes, alcohol use is often associated. But sadly, as many as half of accidents occur without seat-belt use, and many of these deaths would likely be preventable by the three-point restraints shown in Figure 47 8 (Luley, 2013; Schuster, 2016). Seat belts prevent contact with the steering wheel, and they reduce abdominal impact pressure (Motozawa, 2010).

Original concerns regarding injuries caused by airbag deployment have been somewhat allayed (Luley, 2013; Matsushita, 2014). One study included 30 such women from 20 to 37 weeks' gestation whose airbag deployed in accidents with a median speed of35 mph (Metz, 2006). A third did not use seat belts, and there was one fetal death from the single case of placental abruption. In a retrospective cohort study that included 2207 pregnant women in crashes with airbag deployment, perinatal outcomes were not clinically diferent from 1141 controls without airbags (Schif, 2010). Importantly, 96 percent of both groups used seat belts. Thus, it appears that injuries with airbag deployment are related to the severity of the crash (Mendez-Figueroa, 2016).

Some other common causes of blunt trauma are falls and aggra vated assaults. In the California review reported by El Kady and associates (2005), intentionally inflicted injuries were present in approximately a third of pregnant women who were hospitalized for trauma. Less common are blast or crush injury (Sela, 2008). With blunt trauma, intraabdominal injuries can be serious. Even so, bowel injuries are less frequent because of the protective efect of a large uterus. Still, diaphragmatic, splenic, liver, and kidney damage may also be sustained. Par ticularly worrisome is the specter of amnionic-fluid embolism, which has been reported with even mild trauma (Ellingsen, 2007; Pluymakers, 2007). Retroperitoneal hemorrhage is pos sibly more common than in nonpregnant women (T akehana, 2011).

Orthopedic injuries are also encountered with some regular ity (Desai, 2007). From the Parkland Hospital trauma unit, 6 percent of 1682 pregnant women evaluated had orthope dic injuries. his subset was also at increased risk for placen tal abruption, preterm delivery, and perinatal mortality. In a review of 101 pelvic fractures during pregnancy, there was a 9-percent maternal and 35-percent fetal mortality rate (Leggon, 2002). In another study of pelvic and acetabular fractures dur ing 15 pregnancies, there was one maternal death, and four of 16 fetuses died (Almog, 2007). Finally, head trauma and neu rosurgical care raise unique issues (Qaiser, 2007).

Perinatal death rates increase with the severity of maternal injuries. Fetal death is more likely with direct fetoplacental injury, maternal shock, pelvic fracture, maternal head injury, or hypoxia (Ikossi, 2005; Pearlman, 2008). Motor vehicle accidents caused 82 percent of fetal deaths from trauma. Death was caused by placental injury in half and by uterine rupture in 4 percent (Weiss, 2001).

Although uncommon, fetal skull and brain injuries are more likely if the head is engaged and the maternal pelvis is fractured (Palmer, 1994). Conversely, fetal head injuries, presumably from a contrecoup efect, may be sustained in unengaged vertex or nonvertex presentations. Fetal skull fractures are rare and best seen using CT imaging (Sadro, 2012). One example is Figure 46-8 (p. 908). Other sequelae include intracranial hemorrhage (Gherman, 2014; Green-hompson, 2005). A newborn with paraplegia and contractures associated with a motor vehicle accident sustained several months before birth was described by Weyerts and colleagues (1992). Other injuries have included fetal decapitation or incomplete midabdominal fetal transection at midpregnancy (Rowe, 1996; Weir, 2008).

Catastrophic events that occur with blunt trauma include placental injuries-abruption or placental tears (Fig. 47-9). Placental separation from trauma is likely caused by deformation of the elastic myometrium around the relatively inelastic placenta (Crosby, 1968). his may result from a deceleration injury as the large uterus meets the immovable steering wheel or seat belt. Some degree of abruption complicates 1 to 6 percent of p. 768). Kettel and coworkers (1988) emphasized that traumatic abruption may be occult and unaccompanied by uterine pain, tenderness, or bleeding. In our experiences with 13 such women at Parkland Hospital, 11 had uterine tenderness, but only five had vaginal bleeding. Because traumatic abruption is more likely to be concealed and generate higher intrauterine pressures, associated coagulopathy is more likely than with nontraumatic abruption (Cunningham, 2015). Partial separation may also generate uterine activity, which is described more fully on page 930. Other features are evidence of fetal compromise such as fetal tachycardia, sinusoidal pattern, late decelerations, acidosis, and fetal death.

FIGURE 47-9 Mechanism of placental tear or "fracture" caused by a deformationreformation injury. Placental abruption is seen as blood collecting in the retroplacental space. Inset. From here, blood can be forced into placental bed venules and enter maternal circulation. Such fetomaternal hemorrhage may be identified with Kleihauer-Betke testing.

If the abdominal force associated with trauma is considerable, then the placenta can be torn or "fractured" (see Fig. 47-9). If so, then life-threatening fetal hemorrhage may be encountered either into the amnionic sac or by fetomaternal hemorrhage (Pritchard, 1991). he tear is linear or stellate and is caused by rapid deformation and reformation (Fig. 47-10). Especially if there is ABO compatibility, fetomaternal hemorrhage is quantified using a Kleihauer-Betke stain of maternal blood. A small amount of fetal-maternal bleeding has been described in up to a third of trauma cases, and in 90 percent of these, the volume is < 15 mL (Goodwin, 1990; Pearlman, 1990). Parenthetically, nontraumatic placental abruption is much less often associated with signifi minor injuries and up to 50 percent of major injuries (Pearlcant fetomaternal hemorrhage because only minimal fetal blood man, 1990; Schif, 2002). Abruption was found to be more enters into the intervillous space. With traumatic abruption, likely if vehicle speed exceeded 30 mph (Reis, 2000). however, massive fetomaternal hemorrhage may follow. In one Clinical indings with traumatic abruption may be simistudy, the risk of associated uterine contractions and preterm lar to those for spontaneous placental abruption (Chap. 41, labor was a 20-fold if there was evidence for a fetomaternal

FIGURE 47-10 A. Partial placental abruption in which the adherent blood clot has been removed. Note the laceration of the placenta (arrow), which caused fetal death from massive fetomaternal hemorrhage. B. Kleihauer-Betke stain of a peripheral smear of maternal blood.

The dark cells that constituted 4.5 percent of red blood cells are fetal in origin, whereas the empty cells are maternal.

bleed (Muench, 2004). With severe fetal bleeding, long-term adverse neurological outcomes are frequent (Kadooka, 2014).

Blunt trauma leads to uterine rupture in < 1 percent of severe cases (American College of Obstetricians and Gynecologists, 20 17b). Rupture is more likely in a previously scarred uterus and is usually associated with a direct impact of substantial force. Decelerative forces following a 25-mph collision can generate up to 500 mm Hg of intrauterine pressure in a properly restrained woman (Crosby, 1968). Clinical indings may be identical to those for placental abruption with an intact uterus, and maternal and fetal deterioration are soon inevitable. Pearlman and Cunningham (1996) described uterine fundal "blowout" with fetal decapitation in a 20-week pregnancy following a high-speed collision. Similarly, Weir and colleagues (2008) described supracervical uterine avulsion and fetal transection at 22 weeks. CT scanning may be useful to diagnose uterine rupture with a dead fetus or placental separation (Kopelman, 2013; Manriquez, 2010; Sadro, 2012).

In a study of 321 pregnant women with abdominal trauma, Petrone (2011) reported a 9-percent incidence of penetrating injuries. Of these, 77 percent were gunshot wounds and 23 percent were stab wounds. he incidence of maternal visceral injury with penetrating trauma is only 15 to 40 percent compared with 80 to 90 percent in nonpregnant individuals (Stone, 1999). When the uterus sustains penetrating wounds, the fetus is more likely than the mother to be seriously injured. Indeed, although the fetus sustains injury in two thirds of cases with penetrating uterine injuries, maternal visceral injuries are seen in only 20 percent. Still, their seriousness is underscored in that maternal-fetal mortality rates are signiicantly higher than those seen with blunt abdominal injuries in pregnancy. Specifically, maternal mortality rates were 7 versus 2 percent, and fetal mortality rates were 73 versus 10 percent, respectively .

• Management of Trauma

Maternal and fetal outcomes are directly related to the severity of injury. That said, commonly used methods of severity scoring do not take into account significant morbidity and mortality rates related to placental abruption and thus to pregnancy outcomes. In a study of 582 pregnant women hospitalized for injuries, the injury severity score did not accurately predict adverse pregnancy outcomes (Schif, 2005). Importantly, relatively minor injuries were associated with preterm labor and placental abruption. Others have reached similar conclusions (Biester, 1997; Ikossi, 2005). In a study of 317 women at 24 weeks' gestation or more who had "minor trauma," 14 percent had clinically significant urerine contractions requiring extended fetal evaluation past 4 hours (Cahill, 2008).

With few exceptions, treatment priorities in injured pregnant women are multidisciplinary (Barraco, 2010; Mendez-Figueroa, 2016). Primary goals are evaluation and stabilization of maternal injuries. Attention to fetal assessment during the acute evaluation (merican College of Obstetricians and Gynecologists, 2017b;

Brown, 2009). Basic rules of resuscitation include ventilation, arrest of hemorrhage, and treatment of hypovolemia with crys talloid and blood products. After midpregnancy, the large uterus is positioned of the great vessels to diminish its efect on vessel compression and cardiac output (Nelson, 2015).

Following emergency resuscitation, evaluation is continued for fractures, internal injuries, bleeding sites, and placental, uterine, and fetal trauma. Radiography is not proscribed, but special attention is given each indication. Not surprisingly, one report observed that pregnant trauma victims had less radiation exposure than nonpregnant controls (Ylagan, 2008). Some advocate screening abdominal sonography followed by CT scanning for positive sonographic findings (Brown, 2005; Saphier, 2014). Procedures used include the FAST scan ocused 4ssessment with �onography or t.rauma. his examination is ars-minute, four-to six-view imaging study that evaluates perihepatic, perisplenic, pelvic, and pericardial views (MendezFigueroa, 2016). In general, if fluid is seen in any of these views, then the volume is >500 mL (Fig. 47-11). Importantly, this amount has not been corroborated for pregnancy. In some cases, open peritoneal lavage may be informative (Tsuei, 2006).

Penetrating injuries in most cases must be evaluated using radiography. Because clinical response to peritoneal irritation is blunted during pregnancy, an aggressive approach to exploratory laparotomy is pursued. Whereas exploration is mandatory for abdominal gunshot wounds, some clinicians advocate close observation for selected stab wounds. Diagnostic laparoscopy has also been used (Chap. 46, p. 901).

The necessity for cesarean delivery depends on several factors. Laparotomy itself is not an indication for hysterotomy.

FIGURE 47-1 1 Fast scan. Upper quadrant scan shows anechoic free fluid (asterisk) between the liver edge (arrow) and kidney (Morison pouch). The patient had 2500 mL of blood in the peritoneal cavity. (Reproduced with permission from Mendez-Figueroa H, Rouse OJ: Trauma in pregnancy. In Yeomans ER, Hoffman BL, Gilstrap, III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili, 2017.)

Some considerations include gestational age, fetal condition, extent of uterine injury, and whether the large uterus hinders adequate management of other intraabdominal injuries (Tsuei, 2006).

Because fetal well-being may relect the status of the mother, fetal monitoring is another "vital sign" that helps evaluate the extent of maternal injuries. Even if the mother is stable, electronic monitoring may suggest placental abruption. In a study by Pearlman and coworkers (1990), no woman had an abruption if uterine contractions were less often than every 10 minutes within the 4 hours after trauma was sustained. lmost 20 percent ofwomen who had contractions more frequently than every 10 minutes in the irst 4 hours had an associated placental abruption. In these cases, abnormal tracings were common and included fetal tachycardia and late decelerations. Conversely, no adverse outcomes were reported in women who had normal monitor tracings (Connolly, 1997). Importantly, if tocolytics are used for these contractions, they may obfuscate findings, and we do not recommend them.

Because placental abruption usually develops early following trauma, fetal monitoring is begun as soon as the mother is stable. The ideal duration ofposttrauma monitoring is not precisely known. From data cited above, observation for 4 hours is reasonable with a normal tracing and no other sentinel indings such as contractions, uterine tenderness, or bleeding. Certainly, monitoring should be continued as long as there are uterine contractions, nonreassuring fetal heart patterns, vaginal bleeding, uterine tenderness or irritability, serious maternal injury, or ruptured membranes (American College ofObstetricians and Gynecologists, 2017b). In rare cases, placental abruption has developed days after trauma (Higgins, 1984).

It is unclear whether routine use of the Kleihauer-Betke or an equivalent test in pregnant trauma victims might modiy adverse outcomes associated with fetal anemia, cardiac arrhythmias, and death (Pak, 1998). In a retrospective review of 125 pregnant women with blunt injuries, the Kleihauer-Betke test was judged to be of little value during acute trauma management (Towery, 1993). Others have reached similar conclusions, although a positive test with fetal cells of0.1 percent was predictive of uterine contractions or preterm labor (Connolly, 1997; Muench, 2003, 2004).

For the woman who is D-negative, administration ofanti-D immunoglobulin should be considered. his may be omitted if a test for fetal bleeding is negative. Even with anti-D immunoglobulin, alloimmunization may still develop if the fetalmaternal hemorrhage exceeds 15 mL of fetal cells (Chap. 15, p.r306).

For the pregnant trauma patient, confirmation of current tetanus immunization status is pertinent. When indicated, a dose oftetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) is preferred for its neonatal pertussis immunity beneits (Chap. 9, p. 171).

Fetal* Maternal...

FIGURE 47-1 2 Maternal and fetal mortality rates by burn severity in nearly 400 women. (Data from Akhtar, 1994; Amy, 1985; Mabrouk, 1977; Maghsoudi, 2006; Parikh, 2015; Rayburn, 1984; Rode, 1990.)

Treatment ofthe burned gravida is similar to that for nonpregnant patients (Mendez-Figueroa, 2016). With treatment, it is generally agreed that pregnancy does not alter maternal outcome from thermal injury compared with that of nonpregnant women ofsimilar age. As perhaps expected, maternal and fetal survival parallels the percentage of burned surface area (Parikh, 2015). Karimi and colleagues (2009) reported higher mortality rates for both with suicidal attempts and with inhalational injuries. The composite mortality rate for nearly 400 women from seven studies increased in a linear fashion as the percent of burned body surface area increased 47-12). For 20-, 40-, and 60-percent burns, the maternal mortality rates were approximately 4, 30, and 93 percent, respectively. he corresponding fetal mortality rates were 20, 48, and 96 percent, respectively. With severe burns, the woman usually enters labor spontaneously within a few days to a week and often delivers a stillborn. Contributory factors are hypovolemia, pulmonary injury, septicemia, and the intensely catabolic state (Radosevich, 2013).

Following serious abdominal burns, skin contractures that develop may be painful during a subsequent pregnancy and may even require surgical decompression and split-skin autografts (Mitsukawa, 2015; Radosevich, 2013). Loss or distortion of nipples may cause problems in breastfeeding. Mitsukawa and associates (2015) reported that contracture release was indicated with scars spanning more thanr>75 percent of the total abdominal area. Alternatively, normal abdominal tissue expansion due to pregnancy appears to be an excellent source for obtaining skin grafts postpartum to correct scar deformities at other body sites (Del Frari, 2004).

Earlier case reports suggested a high fetal mortality rate with electric shock (Fatovich, 1993). In a prospective cohort study, however, Einarson and coworkers (1997) showed similar perinatal outcomes in 31 injured women compared with those of noninjured controls. They concluded that traditional 110volt North American electrical current likely is less dangerous than the 220-volt currents available in Europe. A woman with been related to a mild electrical shock at 22 weeks was described (Sozen, 2004). Another woman with brain death from cardiac arrest was reported (Sparic, 2014). Thermal burns with electro cution may be extensive.

The pathophysiological efects of lightning injuries can be devastating. Garda Gutierrez and coworkers (2005) reviewed a 50-percent stillbirth rate.

According to estimates from the Nationwide Inpatient Sample, cardiac arrest complicates approximately 1 in 12,000 delivery admissions (Mhyre, 2014) . The most common underlying causes were hemorrhage, heart failure, amnionic-Buid embolism, and sepsis. General topics regarding planning and equipment have been reviewed by the American College of Obstetricians and Gynecologists (20 17b) and the Society for Obstetric Anesthesia and Perinatology (Lipman, 2014). Special considerations for cardiopulmonary resuscitation (CPR) conducted in the second half of pregnancy are outlined in the American Heart Association 2010 guidelines (Jeejeebhoy, 2015). he committee acknowledges the following as standards for critically ill gravidas: (1) relieve possible vena caval compression by left lateral uterine displacement, (2) administer 100-percent oxygen, (3) establish intravenous access above the diaphragm, (4) assess for hypotension that warrants therapy, which is defined as systolic blood pressure < 100 mm Hg or < 80 percent of baseline, and (5) review possible causes of critical illness and treat conditions as early as possible.

he position of the heart for external compressions is not diferent from that in nonpregnant women (Holmes, 2015). In nonpregnant women, external chest compression results in a cardiac output approximately 30 percent of normal. In late pregnancy, this may be even less with compressions because of uterine aortocaval compression (Clark, 1997; Nelson, 2015). Thus, it is paramount to accompany other resuscitative eforts with uterine displacement. This can be accomplished by tilting the operating table laterally, by placing a wedge under the patient's right hip, or by pushing the uterus to the left manually (Rees, 1988; Rose, 2015). If no equipment is available, an individual may kneel on the Boor with the maternal back on his or her thighs to form a "human wedge" (Whitty, 2002).

During maternal resuscitation, because of pregnancy-induced hindrances on CPR eforts, emergent perimortem cesarean delivey for fetal salvage and improved maternal resuscitation may be considered. Some have stated that cesarean delivery is indicated within 4 to 5 minutes of beginning CPR if the fetus is viable (Drukker, 2014). In women delivered by perimortem cesarean, neurologically intact neonatal survival and the cardiac arrest-todelivery interval are inversely related (Katz, 2012). Speciically, of newborns delivered within 5 minutes of arrest, 98 percent are neurologically intact; within 6 to 15 minutes, 83 percent are intact; within 16 to 25 minutes, 33 percent are intact; and within 26 to 35 minutes, only 25 percent are intact (Clark, 1997). This, coupled with some evidence that delivery may also enhance maternal resuscitation, has led the American College of Obstetricians and Gynecologists (2017b) to recommend consideration for cesarean delivery to begin within 4 minutes of cardiac arrest in these cases.

his serious and sometimes contentious issue is far from evi dence based. To wit, Katz and associates (2005) reviewed 38 perimortem cesarean deliveries with a "large selection bias." of maternal cardiac arrest improves maternal and fetal outcomes.

Even so, as emphasized by Clark (1997) and Rose (2015) and their coworkers, and in our experiences, these goals rarely can be met in actual practice. For example, most cases of cardiac arrest occur in uncontrolled circumstances, and thus, the time to CPR initiation alone would require the irst 5 minutes. hus "crash" cesarean delivery would supersede resuscitative eforts, would necessarily be done without appropriate anesthesia or surgical equipment, and more likely than not, would lead to maternal death. Moreover, the distinction between a peri mortem versus postmortem cesarean operation is imperative (Katz, 2012; Rose, 2015). Last, in the balance, any choice may favor survival of the mother over the fetus, or vice versa, and thus there are immediate unresolvable ethical concerns. Katz (2012) has provided a scholarly review of peri mortem cesarean delivery.

Occasionally, a pregnant woman with a supposedly healthy intact fetus will be kept on somatic support to await fetal viability or maturity. This is discussed in Chapter 60 (p. 1168).

According to their review, Brown and coworkers (2013b) reported that clinically significant envenomations in pregnant women are from snakes, spiders, scorpions, jellyish, and hymenoptera such as bees, wasps, hornets, and ants. Adverse outcomes are related to maternal efects. These investigators conclude that limited evidence supports the use of a venomspeciic approach that includes symptomatic care, antivenom administration when appropriate, anaphylaxis treatment, and fetal assessment. One management scheme for North American snakebites was provided by Lei and associates (2015).

Akhtar MA, Mulawkar PM, Kulkani HR: Burns in pregnancy: efect on maternal and fetal outcomes. Buns 20:351,t1994 Albright CM, Has P, Rouse OJ, et al: Intenal validation of the sepsis in obstetric score to identiY risk of morbidity from sepsis in pregnancy. Obstet Gynecolt130:74 ,2017 Almog G, Liebergall M, Tsafrir A, et al: Management of pelvic fractures during pregnancy. Am J Orthop 36:E153, 2007 American Academy ofPediarrics, American College of Obstetricians and Gyne cologists: Guidelines for Perinatal Care, 8th ed. Elk Grove Village, 2017 American College of Critical Care Medicine and the Society of Critical Care

Medicine: Guidelines on admission and discharge for adult intermediate care units. Crit Care Med 26:607, 1998 American College of Obstetricians and Gynecologists: Intimate partner vio lence. Committee Opinion No. 518, February 2012

American College of Obstetricians and Gynecologists: Hypertension in pregnancy: report of the American College of Obstetricians and Gynecologists' task force on hypertension in pregnancy. Executive summary. Obstet Gynecol 122:1122, 2013

American College of Obstetricians and Gynecologists: Sexual assault. Committee Opinion No. 592, April 2014, Reairmed 2016

American College of Obstetricians and Gynecologists: Access to emergency contraception. Committee Opinion No. 707, ] uly 2017 a

American College of Obstetricians and Gynecologists: Critical care in pregnancy. Practice Bulletin No. 170, October 2016, Reairmed 2017b

Amy BW, McManus F, Goodwin CW, et al: Thermal injury in the pregnant patient. Surg Gynecol Obstet 161:209, 1985

Angus DC, van der Poll T: Severe sepsis and septic shock. N Engl ] Med 369:840,t2013

Anselmi A, Ruggieri VG, Letheulle], et al: Extracorporeal membrane oxygenation in pregnancy.] Card Surg 30(10):781,2015

ARDS Deinition Task Force: Acute respiratory distress syndrome. The Berlin deinition.t]AMA 307(23):2526,t2012

ARISE Investigators, ANZICS Clinical Trials Group, Peake SL: Goal-directed resuscitation for patients with septic shock. N Engl] Med 371(16)1496, 2014

Aurigemma GP, Gaasch H: Diastolic heart failure. N Englt] Med 35t1:1097, 2004

Barochia AV, Cui X, Vilberg D, et al: Bundled care for septic shock: an analysis of clinical trials. Crit Care Med 38:668,t2010

Barraco RD, Chiu WC, Clancy V, et al: Practice management guidelines for the diagnosis and management of injury in the pregnant patient: the EAST Practice Management Guidelines Work Group.] Trauma 69(1):211, 2010

Baskett TF, O'Connell CM: Maternal critical care in obstetrics.t] Obstet Gynaecol Can 31(3):218, 2009

Bauer ME, Lorenz RP, Bauer ST, et al: Maternal deaths due to sepsis in the state of Michigan, 1999-2006. Obstet GynecoI126(4):747, 2015 Benedetti T], Carlson RW: Studies of colloid osmotic pressure in pregnancyinduced hypertension. Am] Obstet GynecoIt135:308, 1979

Biester EM, Tomich PG, Esposito T], et al: Trauma in pregnancy: normal revised trauma score in relation to other markers of maternofetal statuspreliminary study. Am] Obstet Gynecol 176: 1206, 1997

Black Me, Basile Ke, Breiding M], et al: The National Intimate Partner and Sexual Violence Survey. 2014. Available at: http://www.cdc.gov/violenceprevention/nisvs.l Accessed May 7,t2016

Bourassa D, Berube ]: The prevalence of intimate partner violence among women and teenagers seeking abortion compared with those continuing pregnancy.] Obstet Gynaecol Can 29:415, 2007

Breiding M], Basile KC, Smith SG, et al: Intimate partner violence surveillance: uniform definitions and recommended data elements. Version 2.0, 2015. Available at: http://www.cdc.gov/violenceprevention/pdf/intimatepartnerviolence.pdf. Accessed Ivlay 7,t2016

Brodie D, Bacchetta M: Extracorporeal membrane oxygenation for ARDS in adults. N Englt] Med 365(20):1905,t2011

Brown HL: Trauma in pregnancy. Obstet GynecoIt114:147, 2009

Brown MA, Sirlin CB, Farahmand N, et al: Screening sonography in pregnant patients with blunt abdominal trauma. ] Ultrasound Med 24: 175, 2005 Brown S, Mozurkewich E: Trauma during pregnancy. Obstet Gynecol Clin

North Am 40(1):47, 2013a

Brown SA, Seifert SA, Rayburn F: Management of envenomations during pregnancy. Clin Toxicol 51:3, 2013b

Cahill AG, Bastek ]A, Stamilio DM. et al: Minor trauma in pregnancy-is the evaluation unwarranted? Am] Obstet GynecoIt198:208.e1, 2008

Caironi P, Tognoni G, Masson S, et al: Albumin replacement in patients with severe sepsis or septic shock. N Engl] Med 370(15):1412,t2014 Campbell ]C, Glass N, Sharps PW, et al: Intimate partner homicide: review and implications of research and policy. Trauma Violence Abuse 8:246,t2007

Catanzarite V, Willms D, Wong D, et al: Acute respiratory distress syndrome in pregnancy and the puerperium: causes, courses, and outcomes. Obstet Gynecol 97:760, 200t1

Centers for Disease Control and Prevention: Adverse health conditions and health risk behaviors associated with intimate partner violence-United States, 2005. MMWR 57(5):113,t2008

Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines, 2015. MMWR 64(3):1,2015

Chantry A, Deneux-haraux e, Bonnet MP, et al: Pregnancy-related ICU admissions in France: trends in rate and severity, 2006-2009. Crit Care Med 43:78,t2015

Chebbo A, Tan S, Kassis C, et al: Maternal sepsis and septic shock. Crit Care Clin 32(1):119, 2016

Chen CY, Chen CP, Wang KG, et al: Factors implicated in the outcome of pregnancies complicated by acute respiratoty failure.] Reprod Med 48:641,2003

Chisholm CA, Bullock L, Ferguson ]E: Intimate partner violence and pregnancy: screening and intervention. Am] Obstet Gynecol 217: 145, 2017 Clark SL, Cotton DB: Clinical indications for pulmonary artery catheterization in the patient with severe preeclampsia. Am] Obstet Gynecol 158:453, 1988 Clark SL, Cotton DB, Hankins GDV, et al: Critical Care Obstetrics, 3rd ed.

Boston, Blackwell Science, 1997

Clark SL, Cotton DB, Lee W, et al: Central hemodynamic assessment of normal term pregnancy. Am] Obstet Gynecol 161:1439, 1989

Clark SL, Hankins GD, Dudley DA, et al: Amniotic fluid embolism: analysis of a national registry. Am] Obstet Gynecol 172: 1158, 1995 Cole DE, Taylor TL, McCullough DM, et al: Acute respiratory distress syndrome in pregnancy. Crit Care Med 33:S269, 2005

Connolly M, Katz L, Bash L, et al: Trauma and pregnancy. Amt] PerinatoIt14:331, 1997

Creanga A, Syverson C, Seed K, et al: Pregnancy-related mortality in the United States, 2011-2013. Obstet GynecoIt130(2):366, 2017

Crosby Wvl, Snyder RG, Snow Ce, et al: Impact injuries in pregnancy, 1.

Experimental studies. Am ] Obstet Gynecol 101: 1 00, 1968

Cunningham FG, Lucas M], Hankins GD: Pulmonary injury complicating antepartum pyelonephritis. Am] Obstet Gynecol 156:797, 1987 Cunningham FG, Nelson DB: Disseminated intravascular coagulation syndromes in obstetrics. Obstet Gynecol 126:999,t2015

Cunningham FG, Pritchard ]A, Hankins GDV, et al: Peripartum heart failure: a speciic pregnancy-induced cardiomyopathy or the consequence of coincidental compounding cardiovascular events? Obstet GynecoIt67:t157, 1986

Cunningham ]A, Devine PC, ]elic S: Extracorporeal membrane oxygenation in pregnancy. Obstet Gynecol 108:792, 2006

Daif ]L, Levie M, Chudnof S, et al: Group A Streptococcus causing necrotizing fasciitis and toxic shock syndrome after medical termination of pregnancy. Obstet Gynecol 113:504,t2009

Del Frari B, Pulzl P, Schoeller T, et al: Pregnancy as a tissue expander in the correction of a scar deformity. Amt] Obstet Gynecol 190:579,t2004

Dellinger RP, Levy MM, Rhodes A, et al: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 41t(580), 2013

Dennis AT, Solnordal CB: Acute pulmonary oedema in pregnant women.

Anaesthesia 67(6):646,t2012

Desai P, Suk M: Orthopedic trauma in pregnancy. Amt] Orthop 36:E160, 2007

DiFederico EM, Burlingame ]M, Kilpatrick S], et al: Pulmonary edema in obstetric patients is rapidly resolved except in the presence of infection or of nitroglycerine tocolysis after open fetal surgery. Am ] Obstet Gynecol 179:925,t1998

Drazner MH, Dries DJ, Peshock RM, et al: Left ventricular hypertrophy is more prevalent in blacks than whites in the general population. he Dallas Heart Study. Hypertension 45:124, 2005

Drukker L, Hants Y, Sharon E, et al: Perimortem cesarean section for maternal and fetal salvage: concise review and protocol. Acta Obstet Gynecol Scand 93(10):965,t2014

Duarte AG: ARDS in pregnancy. Clin Obstet Gynecol 57(4):862, 2014

Edwards SE, Grobman WA, Lappen ]R, et al: Modified obstetric early warning scoring systems (MOEWS): validating the diagnostic performance for severe sepsis in women with chorioamnionitis. Amt] Obstet Gynecol 212(4):536. e1, 2015

Einarson A, Bailey B, Inocencion G, et al: Accidental electric shock in pregnancy: a prospective cohort study. Amt] Obstet Gynecol 176:678, 1997

El Kady D, Gilbert WM, ing G, et al: Maternal and neonatal outcomes of assaults during pregnancy. Obstet Gynecolt105:357, 2005

Ellingsen CL, Eggebo TM, Lexow K: Amniotic fluid embolism after blunt abdominal trauma. Resuscitation 75(1):180, 2007

Eschenbach DA: Treating spontaneous and induced septic abortions. Obstet

Gynecol 125(5):1042,t2015 Fatovich DM: Electric shock in pregnancy. ] Emerg Med 11: 175, 1993 Ferguson ND, Cook D], Guyatt GH, et al: High-frequency oscillation in early acute respiratory distress syndrome. N Engl] Med 368(9):795, 2013

Filbin MR, Ring DC, Wessels MR, et al: Case 2-2009: a 25-year-old man with pain and swelling of the right hand and hypotension. N Engl ] Med 360:281, 2009

Gafney A: Critical care in pregnancy-is it diferent? Semin Perinatol 38(6):329,t2014

Gallup DG, Freedman MA, Meguiar RV, et al: Necrotizing fasciitis in gynecologic and obstetric patients: a surgical emergency. Am ] Obstet Gynecol 187:305,t2002

Gandhi S, Sun 0, Park L, et al: he Pulmonary Edema Preeclampsia Evaluation (PEPE) Study.t] Obstet GynaecoIt36(l2):1065, 2014

Gandhi SK, Powers ]e, Nomeir M, et al: he pathogenesis of acute pulmonary edema associated with hypertension. N Engl ] Med 344: 17, 2001

Garcia Gutierrez JJ, Melendez J, T orrero JV, et al: Lightning injuries in a pregnant woman: a case report and review of the literature. Burns 31: 1045,2005

Gherman RB, Chauhan SP: Placental abruption and fetal intraventricular hemorrhage after airbag deployment: a case report. J Reprod fed 59(9-10):501, 20t14

Gidwani UK, Mohanty B, Chatterjee K: he pulmonaty artery catheter: a critical reappraisal. Cardiol Clin 31(4):545, 2013

Golombeck K, Ball RH, Lee H, et al: Maternal morbidity after maternal-fetal surgery. Am J Obstet Gynecol 194:834, 2006

Goodwin TM, Breen MT: Pregnancy outcome and fetomaternal hemorrhage after noncatastrophic trauma. Am J Obstet GynecoIt162:665, 1990

Green-Thompson R, Moodley J: In-utero intracranial haemorrhage probably secondary to domestic violence: case report and literatute review. J Obstet Gynaecol 25:816, 2005

Guntupalli KK, Hall N, Karnard DR, et al: Critical illness in pregnancy: part I: an approach to a pregnant patient in the ICU and common obstetric disorders. Chest 148(4):1093, 2015a

Guntupalli KK, Karnad DR, Bandi V, et al: Critical illness in pregnancy: part II: common medical conditions complicating pregnancy and puerperium. Chest 148(5):1333, 2015b

Hankins GO, Wendel GO, Cunningham FG, et al: Longitudinal evaluation of hemodynamic changes in eclampsia. Am J Obstet Gynecol 150:506, 1984 Hankins GO, Wendel GO, Leveno KJ, et al: Myocardial infarction during pregnancy. A review. Obstet Gynecol 65:139, 1985

Harvey S, Harrison DA, Singer M, et al: Assessment of the clinical efectiveness of pulmonary artery catheters in management of patients in intensive care (PAC-Man): a randomized controlled trial. Lancet 366:472,t2005

Hawkins JS, Casey BM, Minei J, et al: Outcomes after trauma in pregnancy.

Am J Obstet Gynecol 197:S92, 2007

Herridge MS, Cheung M, Tansey CM, et al: One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 348:683, 2003 Herridge MS, Tansey CM, Matte A, et al: Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med 364(14): 1293,t2011 Higgins SO, Garite TJ: Late abruptio placentae in trauma patients: implications for monitoring. Obstet Gynecol 63: lOS, 1984

Holmes S, Kirkpatrick IDC, Zelop CM, et al: MRI evaluation of maternal cardiac displacement in pregnancy: implications for cardiopulmonary resuscitation. Am J Obstet Gynecol 213:40 l.el, 2015

Holst LB, Haase N, Wetterslev J, et al: Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med 371(15):1381, 2014 Horon IL, Cheng 0: Enhanced surveillance for pregnancy-associated mortality-Maryland, 1993-1998. JAMA 285:1455,t2001 Hough ME, Katz V: Pulmonary edema: a case series in a community hospital.

Obstet Gynecol 109: 115S, 200

Ikossi DG, Lazar A, Morabito 0, et al: Profile of mothers at risk: an analysis of injury and pregnancy loss in 1, 195 trauma patients. J Am Coli Surg 200:49, 2005

Jain V, Chari R, Maslovitz S, et al: Guidelines for the management of a pregnant trauma patient. J Obstet Gynaecol Can 3 (6):553,t2015

Jeejeebhoy FM, Zelop CM, Lipman S, et al: Cardiac arrest in pregnancy. AHA J 47,t2015

Jenkins TM, Troiano NH, Graves CR, et al: Mechanical ventilation in an obstetric population: characteristics and delivery rates. Am J Obstet Gynecol 188:439,t2003

Jessup M, Brozena S: Heart failure. N Engl J Med 348:200 ,t2003

Kadooka M, Kato H, Kato A, et al: Efects of neonatal hemoglobin concentration on long-term outcome of infants afected by fetomaternal hemorrhage. Early Hum Dev 90(9):431,t2014

Karimi H, Momeni M, Momeni M, et al: Burn injuries during pregnancy in Iran. Int J Gynaecol Obstet 104(2):132,t2009

Katz V, Balderston K, DeFreest M: Perimortem cesarean delivery: were our assumptions correct? Am J Obstet Gynecol 192: 1916, 2005

Katz L: Peri mortem cesarean delivery: its role in maternal mortality. Semin PerinatoIt36(1):68,t2012

Keizer JL, Zwart JJ, Meerman RH, et al: Obstetric intensive care admission: a 12-year review in a tertiary care centre. Eur J Obstet Gynecol Reprod BioI 128:152,t2006

Kenchaiah S, Evans Jc, Levy 0, et al: Obesity and the risk of heart failure. N Engl J Med 347:305, 2002

Kettel LM, Branch OW, SCOtt JR: Occult placental abruption after maternal trauma. Obstet Gynecol 71:449, 1988

Kilpatrick SJ, Abreo A, Gould J, et al: Confirmed severe maternal morbidity is associated with high rate of preterm delivery. Am J Obstet Gynecol 215(2): 233.el,2016

K1evens RM, Morrison MA, Nadle J, et al: Invasive methicillin-resistant Staphylococcus au reus infections in the United States. JMfA 298 (15): 1 63, Kopelman TR, Manriquez NE, Gridley M, et al: The ability of computed tomography to diagnose placental abruption in the trauma patient. J Trauma Acute Care Surg 74(1):236,t2013

Krishnan S, Schmidt GA: Acute right ventricular dysfunction: real-time management with echocardiography. Chest 147(3):835,t2015

Lapinsky SE, Rojas-Suarez JA, Crozier TM, et al: Mechanical ventilation in critically-ill pregnanr women: a case series. Int J Obstet Anesth 24:323, 2015 Lee L, Slutsky AS: Sepsis and endothelial permeability. N Engl J Med ):689,t2010

Leggon E, Wood Gc, Indeck MC: Pelvic fractures in pregnancy: factors inBuencing maternal and fetal outcomes. J Trauma 96,t2002

Lei C, Badowski NJ, Auerbach PS, et al: Disorders caused by venomous snakebites and marine animal exposures. In Kasper DL, 8auci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill, 2015, p 2736

Levinson G, Shnider SM, DeLorimier A, et al: Efects of maternal hyperventilation on uterine blood Bow and fetal oxygenation and acid-base status. Anesthesiology 40:340, 19. 4

Levy BD, Choi AMK: Acute respiratoly distress syndrome. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles ofInternal Medicine, 19th ed. New York, McGraw-Hill, 2015, p 1

Li H, Novikova N: Pulmonary artery Bow catheters for directing management in pre-eclampsia. Cochrane Database Syst Rev 6:CD008882, 2012 Linden JA: Care of the adult patient after sexual assault. N Engl J Med 365(9): 834,t2011

Lipman S; Cohen S; Einav S; et al: he Sociery for Obstetric Anesthesia and Perinatology consensus statement on the management of cardiac arrest in pregnancy. Anesth Analg 118(5) 1003, 2014

Lucia A, Dantoni SE: Trauma management of the pregnant patient. Crit Care Clin 32(1):109, 2016

Luley T, Fitzpatrick CB, Grotegut CA, et al: Perinatal implications of motor vehicle accident trauma during pregnancy: identiying populations at risk. Am J Obstet GynecoI208:466.e1, 2013

Mabie WC, Barton JR, Sibai BM: Septic shock in pregnancy. Obstet Gynecol 90:553, 1997

Mabrouk AR, el-Feky AE: Burns during pregnancy: a gloomy outcome. Burns 23:596, 197

MacArthur RD, .Miller M, Albertson T, et al: Adequacy of early empiric antibiotic treatment and survival in severe sepsis: Experience from the MONARCS trial. Clin Infect Dis 38:284, 2004

Magder S: Invasive hemodynamic monitoring. Crit Care Clin 31(1)67,t2015 Maghsoudi H, Samnia R, Garadaghi A, et aI: Burns in pregnancy. Burns 32:246, 2006

Mallampalli A, Hanania A, Guntupalli KK: Acute lung injury and acute respiratory distress syndrome. In Belfort .A, Saade GR, Foley MR, et al (eds):

Critical Care Obstetrics, 5th ed. Wiley-Blackwell, 2010, p 338

Manriquez M, Srinivas G, Bollepalli S, et al: Is computed tomography a reliable diagnostic modality in detecting placental injuries in the setting of acute trauma? Am J Obstet GynecoIt202(6):611.e1, 2010

Martin GS, Mannino OM, Eaton S, et al: he epidemiology of sepsis in the United States from 1979 through 2000. N Eng! J Med 348:1546, 2003 Martin SR, Foley MR: Intensive care in obstetrics: an evidence-based review.

3,t2006

Martin SL, Macy j, Sullivan K, et al: Pregnancy-associated violent deaths: the role of intimate partner violence. Trauma Violence Abuse 8: 135, 2007 Mason KL, Aronof OM: Postpartum group A Streptococcus sepsis and maternal immunology. Am J Reprod Immunol 67(2):91, 2012

Matsushita H, Harada A, Sato T, et al: Fetal intracranial injuries following motor vehicle accidents with airbag deployment. J Obstet Gynaecol Res 40(2):599,t2014

Mattox L, Goetzl L: Trauma in pregnancy. Crit Care Med 33:S385, 2005 Mendez-Figueroa H, Dahlke JD, Vress A, et al: Trauma in pregnancy: an updated systematic review. Am J Obstet Gynecol 209(1): 1, 2013

Mendez-Figueroa H, Rouse OJ: Trauma in pregnancy. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed, New York, McGraw-Hill Education, 2016, In press

Metz TO, Abbott JT: Uterine trauma in pregnancy after motor vehicle crashes with airbag deployment: a 30-case series. J Trauma 61:658, 2006

Mhyre JM, Tsen LC, Einav S, et al: Cardiac arrest during hospitalization for delivery in the United States, 1998-2011. Anesthesiology 120(4):810, 2014

Mitsukawa N, Saiga A, Satoh K: Protocol of surgical indications for scar contracture release before childbirth: women with severe abdominal scars after burn injuries. J Plast Surg Hand Surg 49(1):32, 2015

Moellering RC Jr, Abbott GF, Ferraro vIJ: Case 2-2011: a 30-year-old woman with shock after treatment for a furuncle. N Engl J Med 364(3): 266,t2011

Mohamed-Ahmed 0, Nair M, Acosta C, et al: Progression from severe sepsis in pregnancy to death: a UK population-based case-control analysis. BJOG 122:1506,t2015

Motozawa Y, Hitosugi M, Abe T, et al: Efects of seat belts worn by pregnant drivers during low-impact collisions. Am J Obstet Gynecol 203(1):62.e1, 2010

Mouncey PR, Osbon TM, Power GS, et al: Trial of early, goal-directed resuscitation for septic shock. N Engl J Med 3 2(14):1301,t2015

Muench M, Baschat A, Kush M, et al: Maternal fetal hemorrhage of greater than or equal to 0.t1 percent predicts preterm labor in blunt maternal trauma. Am J Obstet GynecoIt189:S119, 2003

Muench MV, Baschat A, Reddy UM, et a1: K1eihauer-Betke testing is important in all cases of maternal trauma. J Trauma 57: 1 094, 2004

Munford RS: Severe sepsis and septic shock. In Kasper DL, Fauci AS, Hauser SL, et al: Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill, 2015, p 1751

Myburgh JA, Finfer S, Bellomo R, et a1: Hydroxyethyl starch or saline for luid resuscitation in intensive ca.re. N Engl J Med (20):1901,t2012

Nair M, Kurinczukt]J, Brocklehurst P, et al: Factors associated with maternal death from direct pregnancy complications: a UK national case-control study. BJOG 122(5):653,t2015

Nair P, Davies AR, Beca J, et al: Extracorporeal membrane oxygenation for severe ARDS in pregnant and postpartum women during the 2009 H1N1 pandemic. Intensive Care Med 37(4):648,t201t1

Nasraway SA, Cohen IL, Dennis RC, et al: Guidelines on admission and discharge for adult intermediate care units. Crit Care Med 26(3):607, 1998

Nathan L, Peters MT, Ahmed AM, et al: he return of Iife-threateningtpuerperal sepsis caused by group A streptococci. Am J Obstet Gynecol 169:571, 1993

National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network: Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med 354:2213,t2006

National Institutes of Health: Critical Care Medicine Consensus Conference. JAMA 250:798, 1983

Nelson DB, Stewart RD, Matulevicius SA, et al: he efects of maternal position and habitus on maternal cardiovascular parameters as measured by cardiac magnetic resonance. Am J Perinatol 32: 1318, 2015

O'Dwyer SL, Gupta M, Anthony J: Pulmonary edema in pregnancy and the puerperium: a cohort study of 53 cases. J Perinat Med 43:675, 2015

Ognibene FP, Parker MM, Natanson C, et al: Depressed left ventricular performance. Response to volume infusion in patients with sepsis and septic shock. Chest 93:903, 1988

Pacheco LD, Saade GR, Hankins GD: Severe sepsis during pregnancy. Clin Obstet Gynecol 57(4):827, 2014

Pak LL, Reece A, Chan L: Is adverse pregnancy outcome predictable after blunt abdominal trauma? Am J Obstet Gynecol 9:1140, 1998

Palladino CL, Singh V, Campbell J, et al: Homicide and suicide during the perinatal period. Obstet Gynecol 118(5): 1056,t2011

Palmer JD, Sparrow OC: Extradural haematoma following intrauterine trauma. Injury 1, 1994

Pandharipande PP, Girad TD, Jackson A, et al: Long-term cognitive impairment after critical illness. N Engl J Med 369: 1306, 20t13

Parikh P, Sunesara I, Lutz E, et al: Burns during pregnancy: implications for maternal-perinatal providers and guidelines for practice. Obstet Gynecol Surv 70:633, 2015

Pathan N, Hemingway CA, A1izadeh A, et al: Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock. Lancet 363:203, 2004

Paxton JL, Presneill J, Aitken L: Characteristics of obstetric patients referred to intensive care in an Australian tertiaty hospital. Aust N Z J Obstet Gynaecol 54(5):445,t2014

Pearlman MD, Cunningham FG: Trauma in pregnancy. In Cunningham FG, MacDonald pc, Gant NF, et al (eds): Williams Obstetrics, 19th ed. Supplement No. 21, October/November 1996

Pearlman MD, K1inch KD, Flannagan CAC: Fetal outcome in motor-vehicle crashes: efects of crash characteristics and maternal restraint. Am J Obstet Gynecol 198(4):450.e1, 2008

Pearlman MD, Tintinalli JE, Lorenz RP: A prospective controlled study of outcome after trauma during pregnancy. Am J Obstet Gynecol 162: 1502, 1990

Peek GJ, Mugford M, Tiruvoipati R, et al: Eicacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicenter randomized controlled trial. Lancet 374(9698):1351, 2009

Perner A, Naase N, Guttormsen, et al: Hydroxyethyl starch 130/0.4 versus Ringer's acetate in severe sepsis. N Engl J Med (2):124,t20t12

Petrone P, Talving P, Browder T, et al: Abdominal injuries in pregnancy: a 155-month study at two level 1 trauma centers. Injury 42(1 ,201t1

Phua J, Badia JR, Adhikari NK, et al: Has mortaliry from acute respiratory stress syndrome decreased over time? A systematic review. Am J Respir Crit Care Med 179(3):220, 2009

Pluymakers C, De Weerdt A, Jacquemyn Y, et al: Amniotic fluid embolism after surgical trauma: twO case reports and review of the literature. Resuscitation 72(2):324, 2007

Pritchard JA, Cunningham G, Pritchard SA, et al: On reducing the frequency of severe abruptio placentae. m J Obstet Gynecol 165: 1345, 1991 ProCESS Investigators, Yealy DM, Kellum JA, et a1: A randomized trial of pro tocol-based care for early septic shock. N Engl J Med 370(18): 1683,t2014 Qaiser R, Black P: Neurosurgery in pregnancy. Semin Neurol 27:476, 2007 Radosevich A, Finegold H, Goldfarb W, et al: nesthetic management of the pregnant burn patient: excision and grafting to emergency cesarean section. J Clin Anesth 25(7):582,t2013

Rayburn W, Smith B, Feller I, et al: Major burns during pregnancy: efects on fetal well-being. Surg Gynecol Obstet 63:392, 1984

Redelmeier DA, May SC, Thiruchelvam D, et a1: Pregnancy and the risk of a traic crash. CMAJ 186(10):742,t2014

Rees GA, Willis BA: Resuscitation in late pregnancy. Anaesthesia 43(5):347, 1988

Reis PM, Sander CM, Pearlman MD: Abruptio placentae after auto accidents.

A case control study. J Reprod Med 45:6, 2000

Robertson-Blackmore E, Putnam FW, Rubinow DR, et al: Antecedent trauma exposure and risk of depression in the perinatal period. J Clin Psychiatry 74:e942,t2013

Rode H, Millar AJ, Cywes S, et al: hermal injury in pregnancy-the neglected tragedy. S Afr Med J 77:346, 1990

Rose CH, Faksh A, Traynor KD, et al: Challenging the 4-to 5-minute rule: from peri mortem cesarean to resuscitative hysterotomy. Am J Obstet Gynecol 213(5):653, 2015

Rotas M, McCalla S, Liu C, et al: Methicillin-resistant Staphylococcus aureus necrotizing pneumonia arising from an infected episiotomy site. Obstet Gynecol 109:533, 2007

Rowe TF, Lafayette S, Cox S: An unusual fetal complication of traumatic uterine rupture. J Emerg Med 14:173, 1996

Rush B, Martinka P, Kilb B, et al: Acute respiratory distress syndrome in pregnant women. Obstet Gynecol 129:530,t2017

Russell JA: Management of sepsis. N Engl J Med 355: 1699,t2006

Sadro CT, Zins M, Debiec K, et a1: Case report: lethal fetal head injury and placental abruption in a pregnant trauma patient. Emerg Radiol 19(2): 175, 2012

Samol JM, Lambers DS: Magnesium sulfate tocolysis and pulmonary edema: the drug or the vehicle? Am J Obstet Gynecol 192: 1430, 2005

Sandham ]D, Hull RD, Brant RF, et al: A randomized, controlled trial of the use of pulmonary-artery catheters in high-risk surgical patients. N Engl J Med 348:5,t2003

Saphier NB, Kopelman TR: Traumatic Abruptio Placenta Scale (TAPS): a proposed grading system of computed tomography evaluation of placental abruption in the trauma patient. Emerg RadioIt21(l):17, 2014

Satin AJ, Ramin JM, Paicurich J, et al: The prevalence of sexual assault: a survey of 2404 puerperal women. Am J Obstet Gynecol 167:973, 1992

Schif viA, Holt L: Pregnancy outcomes following hospitalization for motor vehicle crashes in Washington State from 1989 to 2001. Am J Epidemiol 161:503,t2005

Schif MA, Holt L, Daling JR: Maternal and infant outcomes after injury during pregnancy in Washington state from 1989 to 1997. J Trauma 53:939, 2002

Schif vA, Mack CD, Kaufman P, et al: The efect of air bags on pregnancy outcomes in Washington state: 2002-2005. Obstet GynecoIt115(l):85, 2010

Schneider MB, Ivester TS, Mabie WC, et al: Maternal and fetal outcomes in women requiring amepartum mechanical ventilation. Abstract No. 45. Obstet Gynecol 101 :69S, 2003

Schuster M, Becker N, Mackeen AD: Blum trauma in pregnancy. Abstract No. 363. mJ Obstet Gynecol 214:S203, 2016

Schwaiberger D, Karcz M, Menk M, et al: Respiratory failure and mechanical ventilation in the pregnant patient. Crit Care Clin 32(1):85, 2016 Sciscione A, Invester T, Largoza M, et al: Acute pulmonary edema in pregnancy. Obstet Gynecol 101 :511, 2003

Sela HY, Shveiky D, Laufer N, et 1: Pregnant women injured in terror-related multiple casualty incidems: injuries and outcomes. J Trauma ,t2008

Seror J, Lefevre G, Berkane N, et a1: B-type natriuretic peptide measurement for early diagnosis of acute pulmonary edema during pregnancy. Acta Obstet Gynecol Scand 93(12):1317,t2014

Sheield ]S, Cunningham FG: Urinary tract infection in women. Obstet Gynecol 106:1085,t2005

Sheth SS, Sheth KN: Treatment of neurocritical care emergencies in pregnancy. Curr Treat Options Neurol 14:197,t2012

Sibai BM, Mabie BC, Harvey q, et al: Pulmonary edema in severe preeclampsia-eclampsia: analysis of thiny-seven consecutive cases. Am J Obstet Gynecol 156: 1174, 1987

Sibai BM, Viteri OA: Diabetic ketoacidosis in pregnancy. Obstet Gynecol 123:167,t2014

Silverman JG, Decker MR, Reed E, et al: Intimate partner violence victimization prior to and during pregnancy among women residing in 26 U.S. states: associations with maternal and neonatal death. Am J Obstet Gynecol 195: 140,t2006

Singer M, Deutschman CS, Seymour CW, et l: he hird International Consensus Deinitions for Sepsis and Septic Shock (Sepis-3). JAMA 315:801, 2016 Sinha R, Arachchi A, Lee P, et al: Fournier gangrene in pregnancy. Obstet

Gynecol 125(6):1342,t2015

Sirin H, Weiss HB, Sauber-Schatz EK, et al: Seat belt use, counseling and motorvehicle injury during pregnancy: results from a multi-state population-based survey. Matern Child Health J 11:505,2007

Slutsky AD, Ranieri VM: Ventilator-induced lung injury. N Engl J Med 369: 2126,t2013

Small MK, James AH, Kershaw T, et al: Near-miss maternal mortality: cardiac dysfunction as the principal cause of obstetric intensive care unit admissions. Obstet Gynecolt119(2 pt 1):250,t2012

Snyder CC, Barton JR, Habli M, et al: Severe sepsis and septic shock in pregnancy: indications for delivery and maternal and perinatal outcomes. J Matern Fetal Neonatal Med 26(5):503, 2013

Society of Critical Care Medicine: Recommendations for intensive care unit admission and discharge criteria. Crit Care Med 16(8):807, 1988

Society of Critical Care Medicine: Guidelines for intensive care unit admission, discharge, and triage. Crit Care Med (3):633, 1999

Soper DE, Lee 51, Kim JY, et al: Case 35-2011: a 33-year-old woman with postpartum leukocytosis and gram-positive bacteremia. N Engl J Med 365(20): 1916,t2011

Sozen I, Nesin N: Accidental electric shock in pregnancy and antenatal occurrence of maternal deep vein thrombosis. A case report. J Reprod Med 49:58, 2004 Sparic R, Berisavac I, Kadija 5, et al: Accidental electrocution in pregnancy. Int J Gynaecol Obstet 126(2):181, 2014

Stevens TA, Carroll MA, Promecene PA, et al: Utility of acute physiology, age, and chronic health evaluation (APACHE III) score in maternal admissions to the intensive care unit. Am J Obstet Gynecol 194:e13, 2006

Stevens T A, Swaim LS, Clark SL: he role of obstetrics/gynecology hospitalists in reducing maternal mortality. Obstet Gynecol Clin North m42(3):463, 2015 Stone IK: Trauma in the obstetric patient. Obstet Gynecol Clin North Am 26:459, 1999

Subrevilla A, Cassinelli MT, Carcelen A, et al: Human fetal and maternal oxygen tension and acid-base status during delivery at high altitude. Am J Obstet Gynecol Ill: 1111,

Suellentrop K, Morrow B, Williams L, et al: Monitoring progress toward achieving maternal and infant Healthy People 2010 objectives-19 states, Pregnancy Risk Assessment Monitoring System (PRAMS), 2000-2003. MMWR 55(9):1, 2006

Sugar NF, Fine DN, Eckert LO: Physical injury after sexual assault: indings of a large case series. Am J Obstet Gynecol 190:71, 2004

Sugiyama T, Kobayashi T, Nagao K, et al: Group A streptococcal toxic shock syndrome with extremely aggressive course in the third trimester. J Obstet Gynaecol Res 36(4):852, 2010

Szabo G, Molvarec A, Nagy B, et al: Increased B-type natriuretic peptide levels in early-onset versus late-onset preeclampsia. Clin Chen Lab Med 52:281, 2014

Takehana CS, Kang YS: Acute traumatic gonadal vein rupture in a pregnant patient involved in a major motor vehicle collision. Emerg Radiol 18(4): 349,t2011 hiele RH, Bartels K, Gan TJ: Cardiac output monitoring: a contemporary assessment and review. Crit Care Med 43(1):177,t2015

Thompson BT, Chambers RC, Liu KD: Acute respiratory distress syndrome.

N Engl J Med 377:562, 201

Thornton CE, von Dadelszen P, Makris A, et al: Acute pulmonary oedema as a complication of hypertension during pregnancy. Hypertens Pregnancy 30(2):169,t2011

Tihtonen M, Koobi T, Vuolteenaho 0, et al: Natriuretic peptides and hemodynamics in preeclampsia. Am J Obstet Gynecol 196:328, 200

Towery R, English TP, Wisner 0: Evaluation of pregnant women after blunt injury. J Trauma 35:731, 1993

Tsuei BJ: Assessment of the pregnant trauma patient. Injuty Int J Care Injured 37:367, 2006

Uhlig C, Silva PL, Deckert 5, et al: Albumin versus crystalloid solutions in patients with the acute respiratory distress syndrome: a systematic review and meta-analysis. Crit Care 18(1):R10, 2014

Vasquez ON, Estenssoror E, Canales HS, et l: Clinical characteristics and out comes of obstetric patients requiring ICU admission. Chest 131 (3):718, 2007 Vincent JL, De Backer 0: Circulatory shock. N Engl J Med 369: 1726, 2013 Vladutiu CJ, Marshall SW, Poole C, et al: Adverse pregnancy outcomes follow ing motor vehicle crashes. Am J Prev Med 45:629, 2013

Ware LB, Matthay MA: Acute pulmonary edema. N Engl J Med 353:2788, 2005

Ware LB, Matthay MA: The acute respiratory distress syndrome. N Engl J Med 342: 1334, 2000

Weir LF, Pierce BT, Vazquez JO: Complete fetal transection after a motor vehicle collision. Obstet Gynecol III (2):530, 2008

Weiss HB, Songer TJ, Fabio A: Fetal deaths related to maternal injury. JAMA 286: 1863, 2001

Wenzel RP, Edmond MB: Septic shock-evaluating another failed treatment.

N Engl J Med 366(22):2122,t2012

Weyerts LK, Jones MC, James HE: Paraplegia and congenital contractures as a consequence of intrauterine trauma. Am J Med Genet 43:751, 1992 Wheeler AP, Bernard GR: Acute lung injuly and the acute respiratory distress syndrome: a clinical review. Lancet 369: 1553, 2007

Wheeler AP, Bernard GR: Treating patients with severe sepsis. N Engl J Med 340:207, 1999

Whitty JE: Maternal cardiac arrest in pregnancy. Clin Obstet Gynecol 45:377, 2002

Wiedemann HP, Wheeler AP, Bernard GR, et al: Comparison of two Ruidmanagement strategies in acute lung injury. N Engl J Med 354(24):2213, 2006

Wilson MS, Ingersoll M, Meschter E, et al: Evaluating the side efects of treatment for preterm labor in a center that uses "high-dose" magnesium sulfate. Am J PerinatoI31(8):711, 2014

Xiao C, Gangal M, Abenhaim HA: Efect of magnesium sulfate and nifedipine on the risk of developing pulmonaty edema in preterm births. J Perinat Med 42(5):585,t2014

Yamada T, Yamada T, Yamamura MK, et al: Invasive group A streptococcal infection in pregnancy. J Infect 60(6):417,t2010

Ylagan MV, Trivedi N, Basu T, et al: Radiation exposure in the pregnant trauma patient: implications for fetal risk counseling. Abstract No. 320. Am J Obstet Gynecol 199(6):5100,t2008

Zeeman GG: Obstetric critical care: a blueprint for improved outcomes. Crit Care Med 34:5208, 2006

Zeeman GG, Wendel GO Jr, Cunningham FG: A blueprint for obstetric critical care. Am J Obstet Gynecol 188:532, 2003

Zinaman M, Rubin J, Lindheimer MD: Serial plasma oncotic pressure levels and echoencephalography during and after delivery in severe preeclampsia. Lancet 1:1245, 1985

I recenty saw a patient who imagined hersef in the last month of pregnancy, and who, while talking to me, exclaimed at the violence of the movements, but on examination I ound that her uterus was normal in size, and that her enlarged abdomen was due to a rapidy increasing deposit of at.

-J. Whitridge Williams (1903)

At the beginning of the last century, obesity was not terribly problematic, and with few exceptions, Williams did not refer to its adverse obstetricl efects. Fast forward to today when excessive weight is a major health problem in many aiuent societies (GBD 2015 Obesity Collaborators, 2017). Indeed, by 2014, more than a third of all adults in the United States were obese (Ogden, 2015).

The adverse health aspects of obesity are staggering and include risks for diabetes mellitus, heart disease, hypertension, stroke, and osteoarthritis. Obese gravidas and their fetuses are predisposed to various serious pregnancy-related complications and to higher long-term morbidity and mortality rates.

Of systems to classiy obesity, the body mass index (EM), also known as the Quetelet index, is most oten used. The BMI is calculated as weight in kilograms divided by the square of the height in meters (kg/mr). Calculated BMI values are available in various chart and graphic forms (Fig. 48-1). The National Institutes of Health (2000) classiies adults according to BMI as follows: normal is 18.5 to 24.9 kg/mr, overweight is 25 to 29.9 kg/mr, and obese is �30 kg/mr. Obesity is urther divided into: class 1 is 30 to 34.9 kg/mr, cass 2 is 35 to 39.9 kg/mr, and cass 3 is �40 kg/mr. Class 3 obesity is oten referred to as morbid obesity, with super-morbid obesiy describing a BMI �50 kg/mr.

Using these deinitions, from 2011 to 2014, slightly more women than men were designated obese-36 versus 34 percent (Ogden, 2015). Among girls and women, the prevalence of obesity rises with age and varies among ethnicities 48-2). lthough obesity is now common among all socioeconomic levels, the overall severity advances with increasing poverty (Bilger, 2017). Also, a genetic predisposition has been identiied from several gene loci (Locke, 2015; Shungin, 2015).

Fat tissue is much more complex than merely its energy storage function. Many fat tissue cells communicate with all other tissues via endocrine and paracrine factors, which are cytokines speciically termed adipocytokines. Also simply called adipokines, some of these with metabolic functions include adiponectin, leptin, tumor necrosis factor-a (TNF-a), interleukin 6 (IL-6), resistin, visfatin, apelin, vascular endothelium growth factor (VEGF), lipoprotein lipase, and insulin-like growth factor. A principal adipokine is adiponectin, which is a 30-kDa protein. It enhances insulin sensitivity, blocks hepatic glucose release, and has cardioprotective efects on circulating plasma lipids. An adiponectin deficit is linked with diabetes, hypertension, endothelial cell activation, and cardiovascular disease.

Cytokines that result in insulin resistance are leptin, resistin, TNF-a, and IL-6, and higher levels of these are found during pregnancy. Indeed, adipokines, especially the inflammatory cytokines, may be the primary stimulant of insulin resistance

Weight (pounds) 90 110 130 150 170 190 210 230 250 270 290 310 330 350 2 , 1 1 6'6, 1 I, , 1 I I II ' , 1 I I II 1 1 I, , 1 I I I, , I 1 I I Underwei�ht 11BMI < 185 I /•BMI > I 1.9 I _ 1 I 6'3., 1 1 1 I , i 1 I 1 I, , 1 1 1, , 1 1 I I , , . 1 1 1I, , I 1 1 I1 1 , , 1 1 1 I n, , 1 1 1 1 , , 1 1 1 1 )1.8 5'1e1 c n 1 1 0, , 1 1 1 Cm 1 I, , 1 1 1 I3 1 1 1 1 01 1 C s I 1 1 1 l1 1 : ' 1 I 3, 1 I �) , 1 I') 1.7 1,-, 1 5'71 :I ''i 1 1I )I '), , I , , I, , 1 , , I , , 11 1.6 ' , 1 5'3t --, 1 , 1 , I1, 11I11 1.5 4'1e1 I· 40 50 60 70 80 90 100 110 120 130 140 150 160 Weight (kg) FIGURE 48-1 Chart for estimating body mass index (8M I). To find the 8Ml category for a particular subject, locate the point at which the height and weight intersect. (Al-Badri, 2015; Yang, 20r16). Conversely, adiponectin has antiinflammatory and insulin-sensitizing roles and is negatively regulated by fat mass. As one example of the discordant efects of these adipokines, gestational diabetes is associated with lower adiponectin but higher leptin levels. Placental production of these adipokines is also important and related to fetal growth • Metabolic Syndrome Given its multifaceted endocrine and paracrine functions, the detrimental efects of excessive adipose tissue are not surprising (Cornier, 201r1; Gilmore, 2015). Obesity interacts with inherited factors to cause insulin resistance. This resistance is characterized by impaired glucose metabolism and a predisposition to type 2 diabetes. Insulin resistance also causes several subclinical abnormalities that predispose to cardiovascular disease and accelerate its onset. The most important among these are type 2 diabetes, dyslipidemia, and hypertension, which are constituents of the metabolic syndrome. Criteria to define this syndrome are found in Table 48-1 (Alberti, 2009). Waist circumference is the preferred measurement for screening, but any three of five factors listed are suicient to diagnosis the metabolic syndrome. N otably, most patients with type 2 diabetes have metabolic syndrome according to these criteria. Also, obese women with hypertension typically demonstrate elevated plasma insulin levels. hese are even higher in women with central obesity (Fu, 2015). he National Health Nutrition Examination Survey (NHANES) of the Centers for Disease Control and Prevention documented an overall 34-percent prevalence of the metabolic syndrome in the United States by 2012 (Moore, 2017). As expected, the prevalence rose with age. It was 20 percent for those aged 18 to 29 years and was 36 percent for those aged 30 to 49 years.

and adiposity by mechanisms yet to be defined (Sartori, 2016). 60 46 36 Girls Women FIGURE 48-2 Prevalence of obesity in girls and women in the United States for 2009-201o4. (Data from Ogden, 201o5.)

FIGURE 48-3 Estimated hazard ratios (95% (I) for death due to cardiovascular disease according to body mass index among 1.46 million white adult men and women. (Data from de Gonzalez, 2010.)

TABLE 48-1 . Criteria for Diagnosis of the Metabolic Syndrome

Patients with three or more of the following:

Elevated triglyceridesb: ::150 mg/dL

Reduced high-density lipoprotein cholesterolb: <50 mg/dL in Elevated blood pressureb: systolicn::130 mm Hg and/or diastolic ::85 mm Hg Elevated fasting glucoseb: ::100 mg/dL country-and population-specific thresholds.

bThose with normal values while taking medications are considered to meet these criteria.

Data from Alberti, 2009.

Generally speaking, visceral adiposity correlates with hepatic fat content (Cornier, 201l). With obesity, excessive fat accumulates in the liver-hepatic steatosis, which is also called nonalcoholic fatty liver disease (NAFLD). In persons with the metabolic syndrome, steatosis can progress to nonalcoholic steatohepatitis (NASH) and cirrhosis, as well as hepatocellular carcinoma. Indeed, one fourth of chronic liver disease cases worldwide are caused by NAFLD (Younossi, 2016). \10reover, NAFLD is strongly associated with both fatal and nonfatal cardiovascular disease (T argher, 2016).

Obese individuals sufer well-known consequences such as glucose intolerance, hypertension, dyslipidemia, and metabolic syndrome. Furthermore, metabolic syndrome and obesity are linked with cardiovascular disease, including myocardial infarction, atrial ibrillation, heart failure, and stroke (Long, 2016). Insulin resistance and metabolic syndrome cause structural cerebral changes and lower executive functioning and memory in adults. Similar consequences are also found in adolescents, suggesting that metabolic syndrome's efects on neurocognitive function are independent of signiicant occlusive vascular disease (Rusinek, 2014).

Obesity is associated with higher rates of all-cause early mortality (Fontaine, 2003; Peeters, 2003). Cardiovascular mortality data from 19 prospective studies are shown in Figure 48-3. In these and other studies, mortality risk from cardiovascular disease and cancer grew proportionally with increasing BM!. Importantly, however, an obesiy paradox-whereby certain groups actually derive a survival advantage from being obese-has been hypothesized (Hainer, 2013). Despite this, the health beneits of weight normalization are well documented (Cheung, 2017).

Weight loss is tremendously diicult for obese individuals. If achieved, long-term maintenance poses equally daunting challenges. Obstetrician-gynecologists are encouraged to aid weight 4.42 loss in obese adult women. Successful approaches include behavioral, pharmacological, and surgical techniques or a combination of these methods (Dixon, 2016). Dietary changes and exercise reduce weight and rates of the associated metabolic syndrome (Garvey, 2016; Martin, 2016). When used in conjunction with bariatric surgery, glucose control in those with type 2 diabetes is improved (Schauer, 2014). However, both surgical and medical interventions are associated with appreciable long-term failure rates-up to 50 percent in patients with type 2 diabetes undergoing bariatric surgery (Mingrone, 2015).

Obese women unequivocally have reproductive disadvantages (American Society for Reproductive Medicine, 2015).r1his translates into diiculty in achieving pregnancy, early and recurrent pregnancy loss, preterm delivery, and several obstetrical, medical, and surgical complications with pregnancy, labor, delivery, and the puerperium (American College of Obstetricians and Gynecologists, 2015). Also, oral contraceptive failure may be more likely in overweight women (Chap. 38, p. 691). Last, infantsand later, adult children-of obese mothers have correspondingly higher morbidity rates (Godfrey, 2017; Reynolds, 2013).

Obesity complicating pregnancy has grown substantially in this country. Our experience at Parkland Hospital over three epochs is shown in Figure 48-4.

For overweight women, higher rates of adverse outcomes complicate pregnancy (Schummers, 2015). Shown in Table 48-2 are results from ive studies including more than 1 million singleton pregnancies. Although not as magniied as in the obese cohort, rates of almost all complications are signiicantly greater in overweight women than in those whose BMI is normal.

obesity and the metabolic syndrome are charac terized by insulin resistance, which causes low grade inlammation and endothelial activation (Ma, 2016). hese latter efects playra central role in preeclampsia (Chap. 40, p. 715). he overwhelming evidence between rising maternal BMI and the incidence of preeclampsia is depicted in Figure 48-6. Similar observations were reported from a large Canadian study and by the Safe Labor Consortium (im, 2016; Schummers, 2015).

Obesity and hypertension are common cofactors in peripartum heart failure (Cunningham, 1986,r2012). Stewart and colleagues (2016) prospectively studied the efect of obesity on cardiac remodeling in pregnancy among 14 normal and 9 overweight or obese women (Fig. 4-8, p. 61).

FIGURE 48-4 Increasing prevalence of obesity during four epochs in pregnant women classified at the time of their first prenatal visit at Parkland Hospital. regressed to normal by 3 months postpartum.

or women (Fig. 48-7). This, however,

For obese women, deinitions used in studies of adverse out comes vary widely, and BMIs from >30 kg/mrto >50 kg/mrhave served as thresholds (Crane, 2013; Denison, 2008; Stamilio, 2014). Of outcomes, Mariona (2017) reviewed maternal deaths in Michigan and found that the risk of a maternal death was nearly fourfold higher in obese women. Women with supermorbid obesity experience very high rates of maternal and neonatal complications including preeclampsia, fetal overgrowth, and cesarean delivery, with even higher rates of meconium aspiration, ventilator support, and neonatal death (Marshall, 2014; Smid, 2016). Data from one large study is shown in Figure 48-5.

Especially striking are the markedly elevated rates of hypertension and gestational diabetes. As discussed previously,

Obesity and gestational diabetes are inextricably linked as shown in Table 48-2. heir coexistence with and adverse efects on pregnancy outcomes are discussed in Chapter 57 (pp. 1097 and 1111).

Nonalcoholic fatty liver disease is associated with several adverse pregnancy outcomes. In a cohort of 110 women with NAFLD, risks for preeclampsia, preterm birth, low-birthweight neonates, cesarean delivery, and gestational diabetes were elevated (Hagstrom, 2016). In one prospective study of 476 pregnancies, first-trimester sonographic evidence of maternal NAFLD was strongly associated with gestational diabetes (De Souza, 2016a,b). Meyer and associates (2013) found that overweight and obese gravidas had a higher proportion of low-density lipoprotein III (LDL-III) compared with that of

TABLE 48-2. Adverse Pregnancy Effects in Overweight and Obese Women 18.5-24.9 n = 621,048 2.3 2.7 3.u 20.9 6.6 25.2 2.0

Prevalence (%) with Odds Ratio

Overweight 8MI 25-29.9 Obese 8MI > 30 n = 228,945 4.3 (OR 1n.91n, 1.86-1n.96) 4.3 (OR 1n.60, 1.56-1n.64) 4.1 (OR 1.09, 1.05-1.13) 23.8 (OR 1.19, 1.17-1n.21) 8.3 (OR 1.28, 1.26-1n.31) 31.5 (OR 1.37, 1.34-1.39) 2.4 (OR 1.22, 1n.17-1.28) n = 78,043 8.6 (OR 4.04,n3.94-4.15) 8.1 (OR 3.17, 3.0u-3.25) 4.8 (OR 1.28, 1.23--1n.34) 29.7 (OR 1.60, 1.57--1.64) 11.5 (OR 1.85, 1.81-1.89) 39.3 (OR 1.92, 1.88-1n.96) 2.3 (OR 1.14, 1.08-1.21) 8.4 (OR 1.29, 1.26-1.31) 8.7 (OR 1.34, 1.31-1.37)

Pelvic infection 0.6 0.7 (OR 1.16, 1.06-1.26) 0.8 (OR 1.28, 1.15-1n.43)

Wound infection or complication 0.4 0.5 (OR 1.42, 1.28-1.58) 1.0 (OR 2.70, 2.42-3.01)

Large for gestational age 8.7 13.1 (OR 1.57, 1.54-1.61) 16.3 (OR 2.04, 1.99-2.10)

Macrosomia 2.0 3.6 (OR 1.81, 1.74-1.88) 5.1 (OR 2.60, 2.50-2.71) Stillbirth 0.3 1.8 (OR 5.89, 5.57-6.22) 0.5 (OR 1.71, 1.56-1.87) aOdds ratios with 95% CI are significant when compared to normal BMI group. BMI = body mass index.

Data from Kim, 2016; Lisonkova, 2017; Ovesen, 20n1n1; Schummers, 2015; Sebire, 2001n.

normal-weight women. LDL-III predominance is a hallmark of ectopic liver fat accumulation that is typical of NAFLD. At Parkland Hospital, we are now frequently encountering obese gravidas who have NAFLD and evidence of steatohepatitis manifest by elevated serum hepatic transaminase levels. In rare cases, liver biopsy is necessary to exclude other causes.

In addition to these metabolic complications, quality-of-life measures are also negatively afected by obesity during pregnancy (Amador, 2008; Ruhstaller, 2017). One systematic review found significantly higher risks ofdepression in overweight and obese women during and after pregnancy (Molyneaux, 2014). Obese women were also significantly more likely to experience anxiety during pregnancy.

Stillbirths are more prevalent as the degree of obesity accrues (Ovesen, 2011; Schummers, 2015). In a review of almost 100 -15-:))..)S 10)):)0'3E 5 0 30 20

FIGURE 48-6 Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study: frequency of preeclampsia according to BMI. (Data from the HAPO Study Cooperative Research Group, 2008.)

D Controls (BMI <30) (n 3752) D Obese (BMI 30-35) (n = 1473) • Morbidly obese (BMI >35) (n = 877) 4.8 8.3

FIGURE 48-5 Incidence of selected pregnancy outcomes in 16,102 women enrolled in the FASTER (First-and Second-Trimester Evaluation of Risk) trial according to BMI. (Data from Weiss, 2004.) studies, obesity was the highest ranking modifiable risk factor for stillbirth (Flenady, 201l). In super-morbidly obese compared with normal-weight gravidas, Yao and associates (2014) found 5.7 and l3.6-fold higher stillbirth rates at 39 and 41 weeks' gestation, respectively. Remarkably, 25 percent of term stillbirths in this study involved obese women. Chronic hypertension with superimposed preeclampsia associated with obesity is one cause of excessive stillbirths.

Evaluating perinatal death rates, Lindam and coworkers (2016) reported that high maternal BMI in early pregnancy was a risk factor. The risk ofneonatal death is also greater for obese women 0ohansson, 2014; Meehan, 2014). Finally, Cnattingius and Villamor (2016) noted that accruingweight between pregnancies is a risk factor for perinatal mortality, whereas weight loss between pregnancies for overweightwomen lowers this risk.

Both fetal and neonatal complications are increased in obese women. Two important and interrelated cofactors that 0.85 • Obese

J 0.80 0.75 .J,0.70 .J,0.65 0.60

FIGURE 48-7 Geometric changes of ventricular remodeling across pregnancy in obese and normal-weight women. LVM = left ventricular mass, LVEDV = left ventricular end-diastolic volume. (Data from Stewart, 2016.) contribute to excessive rates of perinatal morbidity are chronic hypertension and diabetes, both of which are associated with maternal obesity. hese comorbidities each may playra role in the higher rates of fetal-growth restriction and indicated pre term birth that are seen in obese women (Schummers, 2015).

Pregestational diabetes also raises the birth defect rate, and ges tational diabetes is complicated by excessive numbers of large for-gestational-age and macrosomic fetuses (Chap. 44, p. 857).

Even when diabetes is not considered, the prevalence of macrosomic newborns is greater in obese women (Kim, 2016;

Ovesen, 2011; Schummers, 2015). he group from Metro prepregnancy obesity, gestational weight gain, and diabetes and their relationship to adverse pregnancy outcomes and to greater newborn weight and fat mass (Catalano, 2009, 2015; Lassance, 2015; Ma, 2016; Yang, 2016). Although each of these variables is associated with larger and more corpulent newborns, pre gene expression has the strongest influence on the prevalence of macrosomic neonates.

Rates of birth defects are also higher with comorbid obesity (Stothard, 2009). For neural-tube defects, elevated risks of 1.2-, 1.7-, and 3. I-fold are found in overweight, obese, and severely obese women, respectively (Rasmussen, 2008). he National Birth Defect Prevention Study reported a correlation between BMI and congenital heart defects (Gilboa, 2010). However, this may be related to diabetes as a cofactor (Biggio, 2010). Importantly, obesity is detrimental to the accuracy of obstetrical sonographic examination and to antepartum identiication of birth defects (Adekola, 2015; Dashe, 2009; Weichart, 2011).

Obese women beget obese children, who themselves become obese adults. Catalano and coworkers (2009) studied ofspring at a mean age of 9 years and found a direct association with maternal prepregnancy obesity and childhood obesity. hey also reported associations with central obesity, elevated systolic blood pressure, increased insulin resistance, and lipid abnormalities-all elements of the metabolic syndrome. Reynolds and associates (2013) reported higher rates of cardiovascular disease and all-cause mortality in 37,709 adult ofspring of overweight and obese mothers. Similar cardiometabolic health efects in ofspring were echoed by Gaillard and colleagues (2016). Other data support that excessive maternal weight gain in pregnancy may predict obesity in adult ofspring (Lawrence, 2014; Reynolds, 2010). Last, rates of glucose intolerance and metabolic syndrome are higher among ofspring of obese women (Gaillard, 2016; Tan, 2015).

he potential biological mechanisms of these associations are unclear. But such studies raise the possibility ofetal programming, that is, the fetal environment may lead to adverse adult health outcomes. Elucidation is limited by insuicient data on potential maternal and genetic predisposing factors and on the environment of the infant and child in relation to diet and activity. he science of epigenetics has provided some support for the possibility that perturbations of the maternal-fetal environment can adversely alter postdelivery events (Kitsiou-T zeli, 2017). Also possible are contributions of the maternal-child environment subsequent to birth (Gluck, 2009). These and other factors regarding fetal programming are discussed in Chapter 44 (p. 849).

The Institute of Medicine (2009) has updated its previous maternal weight gain determinants (Table 9-4, p. 166). For overweight women, weight gain of 15 to 25 pounds is sug gested. For obese women, the Institute advocates a gain of 11 to 20 pounds. Intuitively, maternal weight must increase suf iciently to provide for fetal and placental tissue accrual and for amnionic fluid and maternal blood volume expansion. Thus, maternal weight loss is during pregnancy is discouraged. The

American College of Obstetricians and Gynecologists (2015) endorses these Institute guidelines.

However, these recommendations were issued without irm scientific evidence to support them, and their value remains unproven (Rasmussen, 2010). For example, recent studies differ with respect to the efect of insuicient weight gain for obese women. Bodnar and colleagues (2016) reported no greater risk for low-birthweight or small-for-gestational-age newborns among 47,494 obese women who had inadequate weight gain during pregnancy. Bogaerts and associates (2015) found that even weight loss among obese women did not yield poor fetal growth. In contrast, however, Hannaford and coworkers (2017) reported that obese women who gained less than the Institute recommendations were almost three times more likely to deliver a small-for-gestational-age neonate. Another study similarly found an almost twofold greater risk among obese women who lost weight during pregnancy (Cox Bauer, 2016).

Apart from inadequate weight gain, excessive gestational weight gain may portend greater risks for the obese mother. Berggren and coworkers (2016) noted that overweight and obese women accrued maternal fat rather than lean mass with excessive gestational weight gain. From another analysis, overall higher rates of hypertensive disorders, cesarean delivery, and fetal overgrowth as well as lower rates of spontaneous preterm birth and fetal undergrowth were found among women gaining more than recommended Oohnson, 2013). However, when analyzed according to BMI category, significantly higher rates of preeclampsia, cesarean delivery, and fetal overgrowth were identified among the 1937 overweight women, but not for the 1445 obese women, who gained excess weight.

During pregnancy, overweight and obese women gain more weight than recommended compared with normal-weight gravidas (Endres, 2015). Moreover, overweight and obese women have excessive postpartum weight retention at 1 year, and one third retain at least 20 pounds more than their prep regnancy weight.

Several dietary interventions can help limit and achieve the weight-gain targets listed in the previous section. Options include lifestyle interventions and physical activity. In one randomized trial of exercise in 300 overweight women, risks for gestational diabetes were lowered (Wang, 2017). That said, in another trial, 75 overweight women were randomly assigned to routine care or to a 16-week moderate-intensity stationary cycling program starting after midpregnancy. NIaternal and neonatal outcomes did not difer between groups (Seneviratne, 2016). Also, a Cochrane database analysis of 11,444 women suggests that lifestyle interventions confer only a modest reduction in maternal weight gain, and their benefits for fetal overgrowth, cesarean delivery rate, and adverse neonatal outcome are not significant (Muktabhant, 2015). Regarding neonatal outcomes, the poor success of lifestyle interventions during pregnancy has been attributed to their late introduction, that is, after early gene expression within the placenta has already been programmed (Catalano, 2015).

Close prenatal monitoring detects most early signs of diabetes or hypertension. Standard screening tests for fetal anomalies are suicient, while remembering the sonographic limitations for fetal anomaly detection in this group. Accurate fetal growth surveillance in obese women usually requires serial sonographic assessment. Antepartum external fetal heart rate monitoring is likewise more diicult.

Obese women are at increased risk for multiple labor or intrapartum complications. These include postterm pregnancy or labor abnormalities (Carpenter, 2016). In one study of 143,519 women, the odds of spontaneous labor at term in obese women was approximately half that of normal-weight women (Denison, 2008). In an analysis of more than 5000 parturients, women with a Bh11 >30 kg/mrhad a longer duration of and slower early progression in first-stage labor (Norman, 2012).

Compared with normal-weight women, obese women are twice as likely to undergo labor induction (Denison, 2008). Unfortunately, obese women are also twice as likely to experience a failed induction, and this risk rises with greater degrees of obesity (Wolfe, 2011). In a retrospective analysis of 470 nul liparous women with a BMI >30 kg/mrand an unfavorable cervix, those who underwent labor induction at 39 weeks' gestation were compared with those expectantly managed beyond 39 weeks (Wolfe, 2014). Two thirds of pregnancies expectantly managed either labored or had spontaneously ruptured membranes. Compared with this cohort, those who underwent planned labor induction had an elevated cesarean delivery rate-26 versus 40 percent. Moreover, their newborns were more frequently admitted to the neonatal intensive care unit-6 versus 18 percent. Conversely, Lee and associates (2016) reviewed statistics from 74,725 deliveries in obese women and reported that elective induction at 37 to 39 weeks in nulliparas and especially multiparas was actually associated with a lower cesarean delivery rate. hese conflicting results highlight the diiculties faced by obstetrical providers as they contemplate the seemingly competing interests of the fetus and the obese mother. To address this, the Maternal-Fetal Medicine Units Network is conducting a randomized trial of planned labor induction at 39 weeks' gestation in nulliparous women.

Obese women present anesthesia challenges that include diicult epidural and spinal analgesia placement and complications from failed or diicult intubations. Evaluation of super-morbidly obese gravidas by the anesthesiologist is recommended during prenatal care or upon arrival to the labor unit (American College of Obstetricians and Gynecologists, 2017). Although the rationale for antepartum anesthesia consultation and early epidural analgesia access seems logical, little published data truly demonstrates benefits from these practices (Eley, 2016) .

Regional analgesia for morbidly obese women is associated with longer neuraxial procedure times and more failed placement attempts (Tonidandel, 2014). Importantly, however, spinal analgesia in obese women for cesarean delivery does not appear to have benefits over combined spinal-epidural. For example, Ross and colleagues (2014) compared single-shot spinal analgesia with combined spinal-epidural analgesia and found that both methods could be placed with equal expediency and function similarly in morbidly obese patients.

Obese women who undergo regional analgesia that is complicated by relative hypotension more frequently have neonates with umbilical artery cord blood acidemia, probably due to delayed delivery. Edwards and colleagues (2013) studied 5742 obese women and found that pH significantly dropped, and base deficit rose, with increasing BMI. The rate of pH <7.1 doubled from 3.5 percent for a BMI <25 kg/mrto 7.1 percent for a BMI ::40 kg/mr. Anesthetic risks and complications are discussed in more detail in Chapter 25.

These rates are significantly greater in obese women. In one study, the primary rate was 33.8 percent for obese and 47.4 percent for morbidly obese women. These values compare strikingly with the rate of only 20.7 percent for normal-weight gravidas (Weiss, 2004). In an analysis of 226,958 women, cesarean delivery rates rose signiicantly for overweight (34 percent), class I (38 percent), class II (43 percent), and class III (50 percent) obesity (Schummers, 2015). In the same study, rates of gestational diabetes, itself a risk factor for cesarean delivery, increased from 6 percent for women with a BMI <25 kg/mrto 21 percent for those with a BMI of ::40 kg/mr. More worrisome is that obese women also have higher rates of emergency cesarean delivery, and obesity lengthens times for decision-to-incision and for delivery (O'Dwyer, 2013; Pulman, 2015). Girsen and associates (2014) found significantly increased incision-to-delivery times for both emergent and nonemergent cases.

Discussed in Chapter 31 (p. 596), the incidence of failed trial oflabor after cesarean is higher in obese women (Grasch, 2017; Hibbard, 2006). Women who gain weight between pregnancies also have signiicantly lower rates of vaginal birth after cesarean.

IIIII \I.' I

FIGURE 48-8 Abdominal incision for the obese woman. A. Frontal view. The dotted line indicates an appropriate skin incision for abdominal entry relative to the panniculus. As shown by the uterus in the background, selection of this periumbilical site permits access to the lower uterine segment. B. Sagittal view.

For cesarean delivery, forethought is given to optimal placement and type of abdominal incision to allow access to the fetus and to efect the best wound closure. We prefer a vertical incision in obese women to provide the most direct access (Fig. 48-8). Others prefer a low transverse abdominal incision, with or without rostral taping of the pendulous abdomen. Individual diferences in maternal body habitus preclude naming anyrone approach as superior (tfcLean, 2012; Turan, 2016). Some observational studies have compared wound outcomes associated with vertical and transverse skin incisions, but results are conflicting as to a superiority of either (Brocato, 2013; Marrs, 2014; McClean, 2012; Sutton, 2016; Thornburg, 2012).

he frequency of abdominal wound infections is directly related to BM!. Conner and associates (2014) found the risk of wound infection is threefold higher for super-morbidly obese women compared with nonobese women-23 versus 7 percent. Among women with a BMI >45 kg/mr, wound complication rates range from 14 to 19 percent (Smid, 2015;

Stamilio, 2014). Comorbid diabetes apparently raises this risk (Leth, 201l). Other studies describe wound complication rates ranging from 2 to >40 percent in obese women (Conner, 2014; vIarrs, 2014; Smid, 2015; Thornburg, 2012).

Several interventions maybe preventive. Closure ofsubcuta tion rates (Tipton, 2011). Studies have also examined the use of higher doses of perioperative prophylactic antibiotics. Phar macokinetic studies indicate that tissue concentrations of pro phylactic antibiotics are lower with increasing BMI (Pevzner, 2011; Young, 2015). One prospective study showed that a 3-g dose of cefazolin resulted in higher tissue concentrations com pared with a 2-g dose (Swank, 2015). hat said, a retrospective analysis of 335 women with a median weight of 310 pounds found that the higher dose of cefazolin did not result in few surgical site infections (Ahmadzia, 2015). In one recent study, phylaxis had a surgical infection rate of 13.4 percent compared with a rate of 6.4 percent for those given a 2-day course of oral cephalexin and metronidazole in addition to perioperative prophylaxis (Valent, 2017).

used prophylactically (Mark, 2014). To address this, Hussamy and colleagues (2018) designed a randomized trial of NPWT going cesarean delivery. Such therapy did not signiicantly lower the postoperative wound complication rate compared with routine care-19 versus 17 percent, respectively.

To lower thromboembolic complications, graduated compression stockings, hydration, and early mobilization after cesarean delivery in obese women are recommended by the American College of Obstetricians and Gynecologists (2015). Some also recommend "mini-dose" heparin prophylaxis, but we do not routinely use this (Chap. 52, p. 1019).

Several surgical procedures are designed to treat morbid obesity either by diminishing gastric volume-restrictive, or by bypassing gastrointestinal absorption-restrictive nalabsorptive. In nonpregnant patients, these procedures improve or resolve diabetes, hyperlipidemia, hypertension, and obstructive sleep apnea and reduce risks of myocardial infarction and death (Beamish, 2016).

Of options, the two approved laparoscopic adjustable silicone gastric banding (LASGB) procedures-LAPBAND and REALIZE-place a band 2 cm below the gastroesophageal junction to create a small stomach pouch above the ring. he ring diameter is controlled by a saline reservoir in the band.

hese procedures can have positive efects on pregnancy outcomes. For example, Dixon and colleagues (2005) compared

TABLE 8-3. Pregnancy Outcomes Following Bariatric Surgery

Outcomea (n = 651) (n = 361.) aData not reported identically-frequencies are approxi mations.

bData from Adams, 201n5; Bar-Zohar, 2006; Carelli, 201n1;

Dixon, 2005; Ducarme, 2013; Facchiano, 2012; Lapolla, 2010; Pilone, 2014; Sheiner, 2009; Skull, 2004.

(Data from Adams, 2015; Ducarme, 2013; Facchiano, 2012;

Gonzalez, 2015; Sheiner, 2009.

pregnancy outcomes in bariatric surgery patients against their preprocedural outcomes and those of a matched cohort of obese women. Following banding, the incidences of gestational hypertension-1 0 versus 45 percent-and gestational diabetes-6 versus 15 percent-were significantly lower in the bariatric surgery patients compared with their preprocedural pregnancies. The results from these and other studies are shown in Table 48-3.

Deflation of the band during pregnancy afects maternal and fetal weight gain. Pilone and coworkers (2014) studied 22 pregnancies after band placement and reported that all women underwent full delation of the band in the first trimester and gained an average of 14.7 kg during pregnancy. In another study, 42 women underwent deflation of the band, whereas 54 women maintained band inlation. A deflated band was associated with higher mean weight gain-15.4 kg versus 7.6 kg, increased birthweight-3712 versus 3380 g, and a twofold greater risk of macrosomia compared with an inflated one (Cornthwaite, 2015). Rarely, the band may slip from nausea and vomiting, especially with advancing gestation or postpartum (Pilone, 2014; Schmitt, 2016; Sufee, 2012). One fatal fetal cerebral hemorrhage developed from maternal vitamin K deiciency secondary to prolonged vomiting due to band slippage that created a gastric outlet obstruction (Van lieghem, 2008).

The laparoscopically performed Roux-en-Y gastric bypass is the most commonly used procedure for gastric restriction and selective malabsorption. Its surgical steps are described in

Figure 48-9.

As with other bariatric procedures, pregnancy outcomes are changed remarkably following Roux-en-Y bypass (Adams, 2015). As shown in Table 48-3, rates of hypertension, gestational diabetes, and fetal macrosomia are reduced. Serious complications are uncommon, however, upper abdominal pain is frequent in pregnancy and often associated with internal

FIGURE 48-9 Roux-en-Y bypass. With this, the proximal stomach is completely transected to leave a 30-mL pouch. The proximal end of the distal jejunum is then connected to the small pouch. This bypasses a large part of the stomach and duodenum. At a site 60 cm distal to this gastrojejunostomy, a Roux-en-Y enteroenterostomy is also completed to allow drainage of secretions from the unused stomach and duodenum.

herniation, which is protrusion of the bowel through a mesentery defect. Petersen and associates (2017) described outcomes in a birth cohort including 139 pregnancies. Upper abdominal pain complicated 46 percent, and a third of these had internal herniation. The preterm birth rate was 14 of 64 among those with upper abdominal pain versus 1 of75 in those without pain. Intussusception and small bowel obstruction can develop from internal herniation, and maternal deaths from herniation and obstruction have been reported (Moore, 2004; Renault, 2012). Bowel obstruction is notoriously diicult to diagnose (Vannevel, 2016; Wx, 2013).

Because of its associated health successes, bariatric surgery is popular, and many women subsequently become pregnant (Narayanan, 2016). From observational studies, fertility rates improve and obstetrical complication rates decline in women after bariatric surgery compared with morbidly obese controls (Kominiarek, 2017; Yi, 2015). In one these studies, despite surgical treatment, almost half of 670 women were still obese at the time of their first pregnancy after bypass Qohansson, 2015). Nevertheless, the frequency of large-for-gestational-age newborns dropped from 22 to 8.6 percent and of small-forgestational-age neonates rose from 7.6 to 15.6 percent. In a systematic review, Yi and colleagues (2015) conirmed these fetal weight trends after bariatric surgery. Also, risks for diabetes and preeclampsia were reduced.

Currently, the American College of Obstetricians and Gynecologists (2015) recommends that women who have undergone bariatric surgery be assessed for vitamin and nutritional suiciency. When indicated, vitamins Bl2 and D, folic acid, and calcium supplementation are given. Vitamin A deficiency is also possible (Chagas, 2013). Women with a gastric band should be monitored by their bariatric team during pregnancy because adjustments of the band may be necessary. Finally, special vigilance is appropriate for signs of internal herniation with intestinal obstruction (Stuart, 2017; Wx, 2013).

Adams TD, Hammoud AO, Davidson LE, et al: Maternal and neonatal outcomes for pregnancies before and after gastric bypass surgery. Int JtObes (Lond) 39:686, 2015

Adekola H, Soto E, Dai J, et al: Optimal visualization of the fetal four-chamber and outlow tract views with transabdominal ultrasound in the morbidly obese: are we there yet? J Clin Ultrasound 43:548, 2015

Ahmadzia HK, Patel EM, Joshi D, et al: Obstetric surgical site infections: 2 grams compared with 3 grams of cefazolin in morbidly obese women. Obstet GynecoIt126:708, 2015

Al-Badri MR, Zantout MS, Azar ST: he role of adipokines in gestational diabetes mellitus. her Adv Endocrinol Metab 6:103, 2015

Alberti KG, Eckel RH, Gtundy SM et al: Harmonizing the metabolic syndrome. A joint interim statement of the International Diabetes Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120(16):1640,t2009

Amador N, Juarez JM, Guizar JM, et al: Quality of life in obese pregnant women: a longitudinal study. Am J Obstet Gynecol 198:203.e1, 2008 American College of Obstetricians and Gynecologists: Obesity in pregnancy.

Practice Bulletin 156, December 20t15

American College of Obstetricians and Gynecologists: Obstetric analgesia and anesthesia. Practice Bulletin No. 177, April 2017

American Society for Reproductive Medicine: Obesity and reproduction: a committee opinion. Fertil Steril lO4: 116, 2015

Bar-Zohar D, Azem F, Klausner J, et al: Pregnancy after laparoscopic adjustable gastric banding: perinatal outcome is favorable also for women with relatively high gestational weight gain. Surg Endosc 20: 1580, 2006

Beamish AJ, Olbers T, Kelly AS, et al: Cardiovascular efects of bariatric surgery. Nat Rev Cardiol 13:730,t2016

Berggren EK, Groh-Wargo S, Presley L, et al: Maternal fat, but not lean, mass is increased among overweight/obese women with excess gestational weight gain. Am J Obstet Gynecol 214:745.e1, 2016

Biggio JR J r, Chapman V, Neely C, et al: Fetal anomalies in obese women: the contribution of diabetes. Obstet Gynecol 115:290,t2010

Bilger M, Kruger EJ, Finkelstein A: Measuring socioeconomic inequality in obesity: looking beyond the obesity threshold. Health Econ 26(8): 1052, 2017

Bodnar LM, Pugh SJ, Lash TL, et al: Low gestational weight gain and risk of adverse perinatal outcomes in obese and severely obese women. Epidemiology 27:894,t2016

Bogaerts A, Ameye L, Martens E, et al: Weight loss in obese pregnant women and risk for adverse perinatal outcomes. Obstet Gynecol 125:566, 2015

Brocato BE, horpe EM Jr, Gomez LM, et al: The efect of cesarean delivery skin incision approach in morbidly obese women on the rate of classical hysterotomy. J Pregnancy 2013:890296,t2013

Carelli AMI, Ren C], Youn A,et al: Impact oflaparoscopic adjustable gastric banding on pregnancy, maternal weight, and neonatal health. Obes Surg 21:1552,t2011

Carpenter JR: Intrapartum management of the obese gravida. Clin Obstet Gynecol 59:172, 2016

Catalano P, deMouzon SH: Maternal obesity and metabolic risk to the ofspring: why lifestyle interventions have not achieved the desired outcomes. Int JtObes (Lond) 39:642, 20t15

Catalano PM, Farrell K, Thomas A, et al: Perinatal risk factors for childhood obesity and metabolic dysregulation. Am J Clin Nutr 90:1303, 2009 Chagas CB, Saunders C, Pereira S, et al: Vitamin A deiciency in pregnancy: perspectives after bariatric surgery. Obes Surg 23:249, 2013

Cheung YM, Joham A, Marks S, et al: he obesity paradox: an endocrine perspective. Intern MedJ 47(7):72 ,2017

Cnattingius S, Villamor E: Weight change between successive pregnancies and risks of stillbirth and infant mortality: a nationwide cohort study. Lancet 387:558,t2016

Conner SN, Verticchio JC, Tuuli MG, et al: Maternal obesity and risk of postcesarean wound complications. Am J Perinatol 31 :299, 2014

Cornier A, Despres JP, Davis N, et al: Assessing adiposity: a scientiic statement from the American Heart Association. Circulation 124:1996,t2011

Cornthwaite K, Jeferys A, Lenguerrand E, et al: One size does not fit all. Management of the laparoscopic adjustable gastric band in pregnancy: a national prospective cohort study. Lancet 385 Suppl 1 :S32, 2015

Cox Bauer CM, Bernhard A, Greer DM, et al: Maternal and neonatal outcomes in obese women who lose weight during pregnancy. J Perinatol 36:278,t2016

Crane JM, Murphy P, Burrage L, et al: Maternal and perinatal outcomes of extreme obesity in pregnancy. J Obstet Gynaecol Can 35: 606, 20t13 Cunningham FG: Peripartum cardiomyopathy: we've come a long way, but. ... Obstet Gynecol 120(5):992, 2012

Cunningham FG, Pritchard JA, Hankins GV, et al: Idiopathic cardiomyopathy or compounding cardiovascular events? Obstet GynecoI67:157, 1986 Dashe JS, McIntire DD, Twickler DM: Efect of maternal obesity on the ultrasound detection of anomalous fetuses. Obstet Gynecol 113: 1001, 2009

De Gonzalez AB, Hartge P, Cherhan JR, et al: Body mass index and mortality among 1.46 million white adults. N Engl J Med 363:23, 2010

De Souza LR, Berger H, Rernakaran R, et al: Hepatic fat and abdominal adiposity in early pregnancy together predict impaired glucose homeostasis in mid-pregnancy. Nutr Diabetes 6:e229, 2016a

De Souza LR, Berger H, Retnakaran R, et al: Non-alcoholic fatty liver disease in early pregnancy predicts dysglycemia in mid-pregnancy: prospective study. Am J Gastroenterol 111:665, 2016b

Denison FC, Price J, Graham C, et al: faternal obesity, length of gestation, risk of postdates pregnancy and spontaneous onset of labour at term. B JOG 115:720,t2008

Dixon JB: Obesity in 2015: advances in managing obesity. Nat Rev Endocrinol 12:65,t2016

Dixon JB, Dixon ME, O'Brien PE: Birth outcomes in obese women after laparoscopic adjustable gastric banding. Obstet Gynecol lO6:965, 2005

Ducarme G, Parisio L, Santulli P, et al: Neonatal outcomes in pregnancies after bariatric surgery: a retrospective multi-centric cohort study in three French referral centers. J Matern Fetal Neonatal Med 26:275,

Edwards RK, Cantu J, Cliver S, et al: The association of maternal obesity with fetal pH and base deicit at cesarean delivery. Obstet Gynecol 122(2 Pt 1): 262, 2013

Eley VA, van Zundert A, Lipman J, et al: Anaesthetic management of obese parturients: what is the evidence supporting practice guidelines? Anaesth Intensive Care 44:552,t2016

Endres LK, Straub H, McKinney C, et al: Postpartum weight retention risk factors and relationship to obesity at one year. Obstet Gynecol 125: 144, 2015

Facchiano E, Iannelli A, Santulli P, et al: Pregnancy after laparoscopic bariatric surgery: comparative study of adjustable gastric banding and Roux-en-Y gastric bypass. Sutg Obes Relat Dis 8:429, 2012

Flenady V, Koopmans L, Middleton P, et al: Major risk factors for stillbirth in high-income countries: a systematic review and meta-analysis. Lancet 377:1331,t2011

Fontaine R, Redden DT, Wang C, et al: Years of life lost due to obesity.

JAMA 289:187,t2003

Ford ES, Giles H, Dietz H: Prevalence of the metabolic syndrome among

U.S. adults. Findings from the hird National Health and Nutrition Examination Survey. JAMA 287:356, 2002

Fu J, Hofker M, Wijmenga C: Apple or pear: size and shape matter. Cell Metab 7:507,t2015

Gaillard R, Welten M, Oddy H, et al: Associations of maternal prepregnancy body mass index and gestational weight gain with cardio-metabolic risk factors in adolescent ofspring: a prospective cohort study. BJOG 123:207, 2016

Garvey T, Mechanick JI, Brett EM, et al: American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr Pract 22:842, 2016

GBD 2015 Obesity Collaborators: Health efects of overweight and obesity in 195 countries over 25 years. N Engl J Med 377: 13, 2017

Gilboa SM, Correa A, Botto LD, et al: Association between prepregnancy body mass index and congenital heart defects. Am J Obstet Gynecol 202:51.e1, 2010

Gilmore A, Klempel-Donchenko M, Redman LM: Pregnancy as a window to future health: excessive gestational weight gain and obesity. Semin Perinarol 39:296, 2015

Girsen AI, Osmundson SS, Naqvi M, et al: Body mass index and operative times at cesarean delivery. Obstet Gynecol 124:684,t2014

Gluck ME, Venti CA, Lindsay RS, et al: Maternal influence, not diabetic intrauterine environment, predicts children's energy intake. Obesity 17:772, 2009

Godfrey M, Reynolds M, Prescott SL, et al: Influence of maternal obesity on the long-term health of ofspring. Lancet Diabetes EndocrinoIt5:53,201 Gonzalez I, Rubio MA, Cordido F, et al: Maternal and perinatal outcomes after bar iatric surgery: a Spanish multicenter study. Obes Surg 25:436, 2015 Grasch JL, Thompson JL, Newton JM, et al: Trial of labor compared with cesarean delivery in superobese women. Obstet Gynecol 130:994, 2017 Hagstrom H, Hoijer J, Ludvigsson JF, et al: Adverse outcomes of pregnancy in women with non-alcoholic fatty liver disease. Liver Int 36:268, 2016 Hainer V, Aldhoon-Hainerova I: Obesity paradox does exist. Diabetes Care 36 SuppIt2:S276,t2013

Hannaford E, Tuuli MG, Odibo L, et al: Gestational weight gain: association with adverse pregnancy outcomes. Am J Perinatol 34: 147,t2017

HAPO Study Cooperative Research Group, Metzger BE, Lowe LP, et al: Hyperglycemia and adverse pregnancy outcomes. N EnglJ Med 358(19):1991,2008

Hibbard JU, Gilbert S, Landon MB, et al: Trial of labor or repeat cesarean delivery in women with morbid obesity and previous cesarean delivery. Obstet Gynecol 108(1): 125, 2006

Hofman BL, Horsager R, RobertS SW et al: Obesity. In Williams Obstetrics, 23rd edition Study Guide, New York, McGraw-Hill, 2011

Hussamy OJ, Wortman AC, McIntire DO, et al: A randomized trial of closed incision negative pressure therapy in morbidly obese women undergoing cesarean delivery. Presented at the 38th Annual Meeting of the Society for Maternal-Fetal Medicine, January 29-Februaty 3, 2018

Institute of Medicine, National Research Council, Rasmussen M, et al (eds): Weight Gain during Pregnancy: Reexamining the Guidelines. Washington, National Academy of Sciences, 2009

Johansson K, Cnattingius S, Naslund I, et al: Outcomes of pregnancy ater bariatric surgery. N Engl J Med 372:814, 2015

Johansson S, Villamor E, Altman M, et al: Maternal overweight and obesity in early pregnancy and risk of infant mortality: a population based cohort study in Sweden. BMJ 349:g6572, 2014

Johnson J, Clifton RG, RobertS JM, et al: Pregnancy outcomes with weight gain above or below the 2009 Institute of Medicine guidelines. Obstet Gynecol 121:969,t2013 Kim SS, Zhu Y, Grantz KL, et al: Obstetric and neonatal risks among obese women without chronic disease. Obstet Gynecol 128: 104, 2016 Kitsiou-Tzeli S, Tzetis M. Maternal epigenetics and fetal and neonatal growth. Curr Opin Endocrinol Diabetes Obes 24:43, 2017 Kominiarek A, Jungheim ES, Hoeger M, et al: American Society for Metabolic and Bariatric Surgery position statement on the impact of obesity and obesity treatment on fertility and fertility therapy. Endorsed by the American College of Obstetricians and Gynecologists and the Obesity Society. Surg Obes Relat Dis 13(5):750,t2017 Lapolla A, Marangon M, Dalfra MG, et al: Pregnancy outcome in morbidly obese women before and after laparoscopic gastric banding. Obes Surg 20:1251,t2010 Lassance L, Haghiac M, Leahy P, et al: Identiication of early transcriptome signatures in placenta exposed to insulin and obesity. Am J Obstet Gynecol 212:647.e1,t2015 Lawrence GM, Shulman S, Friedlander Y, et al: Associations of maternal prepregnancy and gestational body size with ofspring longitudinal change in BM!. Obesity (Silver Spring) 22: 1165, 2014 Lee VR, Darney BG, Snowden JM, et al: Term elective induction of labour and perinatal outcomes in obese women: retrospective cohort study. BJOG 123:271,2016 Leth A, Uldbjerg N, Norgaard M, et al: Obesity, diabetes, and the risk ofinfections diagnosed in hospital and post-discharge infections ter cesarean section: a prospective cohort study. Acta Obstet Gynecol Scand 90(5) :501, 2011 Lindam A, Johansson S, Stephansson 0, et al: High maternal body mass index in early pregnancy and risks of stillbirth and infant mortality-a populationbased sibling study in Sweden. Am] EpidemioIt184:98, 2016 Lisonkova S, Muraca GM, Potts J, et al: Association berween prepregnancy body mass index and severe maternal morbidity. JAMA 318:1777,t2017 Locke AE, Kahali B, Berndt SI, et al: Genetic studies of body mass index yield new insights for obesity biology. Nature 518:197, 2015 Long MT, Fox CS: The Framingham Heart Study-67 years of discovery in metabolic disease. Nat Rev Endocrinol 12:177,t2016 Ma RC, Schmidt MI, Tam WH, et al: Clinical management of pregnancy in the obese mother: before conception, during pregnancy, and postpartum. Lancet Diabetes EndocrinoIt4:1037, 2016 Mariona FG: Does maternal obesity impact pregnancy-related deaths? Michigan experience. J Matern Fetal Neonatal Med 30(9):1060, 2017

Mark KS, Alger L, Terplan :M: Incisional negative pressure therapy to prevent wound complications following cesarean section in morbidly obese women: a pilot study. Surg Innov 21:345,t2014

Marrs CC, Moussa HN, Sibai BM, et al: The relationship between primary cesarean delivery skin incision type and wound complications in women with morbid obesity. Am J Obstet Gynecolt210:319.e1, 2014

Marshall NE, Guild C, Cheng W, et al: he efect of maternal body mass index on perinatal outcomes in women with diabetes. Am ] Perinatol 31:249,t2014

Martin CA, Gowda U, Smith B] et al: Systematic review of the efect oflifestyle interventions on the components of the metabolic syndrome in South Asian migrants. J Immigr Minor Health October 21, 2016 [Epub ahead of print]

McLean M, Hines R, Polinkovsky M, et al: Type of skin incision and wound complications in the obese parturient. Am J Perinatol 29:301, 2012 Meehan S, Beck CR, Mair-]enkins J, et al: Maternal obesity and infant mortality: a meta-analysis. Pediatrics 133:863,t2014

Meyer B], Stewart FM, Brown EA, et al: Maternal obesity is associated with the formation of small dense LDL and hypoadiponectinemia in the third trimester. J Clin Endocrinol Metab 98:643, 2013

Mingrone G, Panunzi S, De Gaetano A, et al: Bariatric-metabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label, single-centre, randomised controlled trial. Lancet 386:964, 2015

Molyneaux E, Poston L, Ashurst-Williams S, et al: Obesity and mental disorders during pregnancy and postpartum: a systematic review and metaanalysis. Obstet GynecoIt123:857, 2014

Moore lX, Chaudhary N, Akinyemiju T, et al: Metabolic syndrome prevalence by race/ethnicity and sex in the United States, National Health and Nutrition Examination Survey, 1988-2012. Prev Chronic Dis 14: 160287, 2017

Moore A, Ouyang OW, Whang EE: Maternal and fetal deaths after gastric bypass surgery for morbid obesity. N Engl] Med 351:721, 2004

Muktabhant B, Lawrie TA, Lumbiganon P, et al: Diet or exercise, or both, for preventing excessive weight gain in pregnancy. Cochrane Database Syst Rev 6:CD007145,t2015

Narayanan RP, Syed A: Pregnancy following bariatric surgery-medical complications and management. Obes Surg 26:2523, 2016

National Institutes of Health: The practical guide: identiication, evaluation, and treatment of overweight and obesity in adults. NIH Publication 00-4084. Bethesda, National Institutes of Health, 2000

Norman SM, Tuuli MG, Obido AO, et al: he efects of obesity on the irst stage of labor. Obstet Gynecol 120: 130, 2012

O'Dwyer V, O'Kelly S, Monaghan B, et al: Maternal obesity and induction of labor. Acta Obstet Gynecol Scand 92: 1414, 2013

Ogden CL, Carroll MD, Fryar CD, et al: Prevalence of obesity in the United States, 2011-2014. NCHS data brief No. 219, Hyattsville, National Center for Health Statistics, 2015

Ovesen P, Rasmussen S, Kesmodel U: Efect of prepregnancy maternal overweight and obesity on pregnancy outcome. Obstet Gynecol 118(2 Pt 1): 305,t2011

Peeters A, Barendregt J), Willekens F, et al: Obesity in adulthood and its consequences for life expectancy: a life-table analysis. Ann Inten Med 138:24, 2003

Petersen L, Lauenborg J, Svare J, et al: he impact of upper abdominal pain during pregnancy following a gastric bypass. Obes Surg 27(3):688,t2017

Pevzner L, Swank M, Krepel C, et al: Efects of maternal obesity on tissue concentrations of prophylactic cefazolin during cesarean delivery. Obstet GynecoIt117:877,t2011 Pilone V, Hasani A, Di Micco R, et al: Pregnancy after laparoscopic gastric banding: maternal and neonatal outcomes. Int J Surg 12 Suppl l:S 136, 2014 Pulman ), Tohidi M, Pudwellt], et al: Emergency caesarean section in obese parturients: Is a 30-minute decision-to-incision interval feasible? J Obstet Gynaecol Can 37:988, 2015 Rasmussen KM, Abrams B, Bodnar LM, et al: Recommendations for weight gain during pregnancy in the context of the obesity epidemic. Obstet Gynecol 116:1191,t2010 Rasmussen SA, Chu SY, Kim SY, et al: Maternal obesity and risk of neural tube defects: a metaanalysis. Am J Obstet Gynecol 198(6):611,t2008

Renault K, Gyrtrup H], Damgaard K, et al: Pregnant women with fatal complication after laparoscopic Roux-en-Y gastric bypass. Acta Obstet Gynecol Scand 91:873, 2012 Reynolds RM, Allan KM, Raja EA, et al: Maternal obesity during pregnancy and premature mortality from cardiovascular event in adult ofspring: follow-up of 1 323275 person years. BM] 347:f4539, 2013 Reynolds RM, Osmond C, Phillips 01, et al: Maternal BMI, parity, and pregnancy weight gain: influences on ofspring adiposity in young adulthood. ] Clin Endocrinol Metab 95:5365,t2010

Ross VH, Dean LS, Thomas ]A, et al: A randomized controlled comparison between combined spinal-epidural and single-shot spinal techniques in morbidly obese parturients undergoing cesarean delivery: time for initiation of anesthesia. Anesth Analg 118: 168, 2014

Ruhstaller E, Elovitz A, Stringer M, et al: Obesiry and the association with maternal mental health sym ptoms. ] Matern Fetal Neonatal Med 10: 1, 2017 Rusinek H, Convit A: Obesity: cerebral damage in obesity-associated metabolic syndrome. Nat Rev Endocrinol 10:642,t2014

Sartori C, Lazzeroni P, Merli S: From placenta to polycystic ovarian syndrome: the role of adipokines. Mediators Inlamm 2016:4981916, 2016

Schauer PR, Bhatt DL, Kitwan ]P, et al: Bariatric surgery versus intensive medical therapy for diabetes-3 year outcomes. N Engl ] Med 370:2002, 20t14

Schmitt F, Topart P, Salle A, et a1: Early postpartum gastric band slippage after bariatric surgety in an adolescent obese girl.] Surg Case Rep 2016(9), 2016

Schummers L, Hutcheon ]A, Bodnar LM, et al: Risk of adverse pregnancy outcomes by prep regnancy body mass index: a population-based study to inform prep regnancy weight loss counseling. Obstet Gynecol 125: 133,2015

Sebire N], ]olly M, Harris JP, et al: Maternal obesity and pregnancy outcome: a study of 287,213 pregnancies in London. Int] Obes Relat Metab Disord 25:1175,t2001

Seneviratne SN, Jiang Y, Derraik], et al: Efects of antenatal exercise in overweight and obese pregnant women on maternal and perinatal outcomes: a randomised controlled trial. B]OG 123:588,t2016

Sheiner E, Balaban E, Dreiher], et al: Pregnancy outcome in patients following diferent types of bar iatric surgeries. Obes Surg 19:1286, 2009

Shungin 0, Winkler TW, Croteau-Chonka De, et al: New genetic loci link adipose and insulin biology to body fat distribution. Nature 518:187, 2015

Skull A], Slater GH, Duncombe ]E, et al: Laparoscopic adjustable banding in pregnancy: safety, patient tolerance and efect on obesity-related pregnancy outcomes. Obes Surg 14:230, 2004

Smid MC, Kearney MS, Stamilio OM: Extreme obesity and postcesarean wound complications in the Maternal-Fetal Medicine Unit cesarean registry. Am] PerinatoI32:1336, 2015

Smid Me, Vladutiu q, Dotters-Katz SK, et al: Maternal super obesity and neonatal morbidity ater term cesarean delivery. Am] Perinatol 33:1198, 2016 Stamilio OM, Scifres CM: Extreme obesity and postcesarean maternal complications. Obstet Gynecol 124(2 Pt 1):227,t2014

Stewart RD, Nelson DB, Matulevicius SA, et al: Cardiac magnetic resonance imaging to assess the impact of maternal habitus on cardiac remodeling during pregnancy. An1] Obstet Gynecol 214:640.e1, 2016

Stothard K], Tennant PW, Bell R, et al: Maternal overweight and obesity and the risk of congenital anomalies: a systematic review and meta-analysis. ]AMA 30t1t:636, 2009

Stuart A, Kallen K: Risk of abdominal surgery in pregnancy among women who have undergone bariatric surgery. Obstet Gynecol 129:887,t2017

Sufee MT, Poncelet e, Barrat C: Gastric band slippage at 30 weeks' gestation: diagnosis and laparoscopic management. Surg Obes Relar Dis 8(3):366, 2012

Sutton AL, Sanders LB, Subramaniam A, et al: Abdominal incision selection for cesarean delivery of women with class III obesity. Am] PerinatoI33:547, 2016

Swank ML, Wing DA, Nicolau DP, et al: Increased 3-gram cefazolin dosing for cesarean delivery prophylaxis in obese women. Am ] Obstet Gynecol 213:415.e1,t2015

Tan HC, Roberts ], Catovt]: Mother's pre-pregnancy BMI is an important determinant of adverse cardiometabolic risk in childhood. Pediatr Diabetes 16:419,t2015

Targher G, Byrne CD, Lonardo A, et a1: Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: a meta-anlysis.t] Hepatol 65:589, 2016

Thornburg LL, Linder A, Durie DE, et al: Risk factors for wound complications in morbidly obese women undergoing primary cesarean delivery. ] Matern Fetal Neonatal Med 25:1544, 2012

Tipton M, Cohen SA, Chelmow 0: Wound infection in the obese pregnant woman. Semin Perinatol 35:345, 2011

Tonidandel A, Bootht], D'Angelo R, et al: Anesthetic and obstetric outcomes in morbidly obese parturients: a 20-year follow-up retrospective cohort study. Int] Obstet Anesth 23:357, 2014

Turan OM, Rosenbloom ], Galeyt]L, et al: he relationship between rostral retraction of the pannus and outcomes at cesarean section. Amt] Perinatol 33:951,t2016

Valent M, DeArmond e, Houston ]M, et al: Efect of post-cesarean delivery cephalexin and metronidazole on surgical site infection among obese women. A randomized trial. ]AMA 318: 1026, 2017

Van Mieghem T, Van Schoubroeck 0, Depiere M, et al: Fetal cerebral hemorrhage caused by vitamin K deiciency after complicated bariatric surgety. Obstet Gynecol 11t2:434, 2008

Vannevel V, Jans G, Bialecka M, et al: Internal herniation in pregnancy after gastric bypass. A systematic review. Obstet Gynecol 127: 10 13, 2016

Wang e, Wei Y, Zhang X, et al: A randomized clinical trial of exercise during pregnancy to prevent gestational diabetes mellitus and improve pregnancy outcome in ovetweight and obese women. Am ] Obstet Gynecol 21t6:340, 2017

Wax ]F, Pinette MG, Cartin A: Roux-en-Y gastric bypass-associated bowel obstruction complicating pregnancy-an obstetrician's map to the clinical mineield. Am] Obstet GynecoIt208:265, 2013

Weichartt] and Hartge DR: Obstetrical sonography in obese women: a review. ] Clin Ultrasound 39:209, 2011

Weisst]L, Malon FD, Emig 0, et al: Obesity, obstetric complications and cesarean delivery rate-a population based screening study. FASTER Research Consortium. Am J Obstet Gynecol 190: 1 091, 2004

Wolfe H, Timofeev ], Tefera E, et al: Risk of cesarean in obese nulliparous women with unfavorable cervix: elective induction vs expectant management at term. Am] Obstet Gynecol 211:53.e1, 2014

Wolfe KB, Rossi A, Warshak CR: he efect of maternal obesity on the rate of failed induction oflabor. Am] Obstet Gynecol 205:128.el, 2011

Yang X, Li M, Haghiac M, et a1: Causal relationship between obesity-related traits and TLR-4-driven responses at the maternal-fetal interface. Diabetologia 59:2459,t2016

Yao R, Ananth CV, Park BY, et al: Obesity and the risk of still birth: a population-based cohort study. Am] Obstet Gynecol 210:457.e1, 2014

YiY, Li QF, Zhang], et al: A meta-analysis of maternal and fetal outcomes of pregnancy after bariatric surgery. Int] Gynaecol Obstet 130:3, 2015

Young OM, Shaik IH, Twedt R, et al: Pharmacokinetics of cefazolin prophylaxis in obese gravidae at time of cesarean delivery. Am ] Obstet Gynecol 213:541.el,t2015

Younossi ZM, Koenig AB, Abdelarif 0, et al: Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64:73,t2016

PHYSIOLOGICAL CONSIDERATIONS IN PREGNANCY.. . 948

DISEASE ................... 949

PERIPARTUM MANAGEMENT CONSIDERATIONS ..... 951 SURGICALLY DISEASE.. . . . . . . . . . 954 VALVULAR HEART DISEASE ...................... 955

CONGENITAL HEART DISEASE . . . . . . . . . . . . . . . . . . . . 958 PULMONARY HYPERTENSION . . . . . . . . . . . . . . . . . . . . 960

CARDIOMYOPATHIES ........................... 962

HEART FAILURE ................................ 964

INFECTIVE ENDOCARDITIS ....................... 965

ARRHYTHMIAS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 965

DISEASES OF THE AORTA ........................ 967

ISCHEMIC HEART DISEASE . . . . . . . . . . . . . . . . . . . . . . . 968

Some authorities recommend that women suering rom heart lesions be dissuaded rom marriage. This, however, appears to be an extreme view, though, of course, when the lesion is serious and the compensation auly, the dangers of childbearing should be caruly explaine.

-J. Whitridge Williams (1903)

As Williams recognized more than a century ago, pregnancy in those with signiicant heart disease can be extremely hazardous and may lead to decompensation and death. In an analysis of maternal mortality in the United States between 2011 and 2013, the causes previously responsible for most maternal deaths-hemorrhage, hypertensive disorders, and embolism-continued to show declining rates. In contrast, deaths attributable to cardiovascular diseases were responsible for approximately 26 percent of all pregnancy-related deaths (Creanga, 2017). Cardiovascular diseases also account for significant maternal morbidity and are a prominent reason for obstetrical intensive care unit admissions (Small, 2012).

The rising prevalence of cardiovascular diseases complicating pregnancy is likely multifactorial and includes the higher rates of obesity, hypertension, and diabetes (Klingberg, 2017). Indeed, according to the National Center for Health Statistics, almost half of adults aged 20 and older have at least one risk factor for cardiovascular disease (Fryar, 2012). Another related reason is delayed childbearing. Last, as discussed subsequently (p. 958), an increasing number of women with congenital heart disease are now becoming pregnant.

he marked pregnancy-induced anatomical and functional changes in cardiac physiology can have a profound efect on underlying heart disease (Chap. 4, p. 60). Some of these changes are listed in Table 49-1. Importantly, cardiac output increases approximately 40 percent during pregnancy. Almost half of this total takes place by 8 weeks' gestation and is maximal by midpregnancy (Capeless, 1989). his early rise stems from augmented stroke volume, which results from lowered vascular resistance. Later in pregnancy, resting pulse and stroke volume are even higher because of greater end-diastolic ventricular volume that results from pregnancy hypervolemia. hese changes translate to a cardiac output that enlarges across pregnancy to

TABLE 49-'. Hemodynamic Changes in 10 Normal Pregnant Women at Term Compared with Repeat Values Obtained 12 Weeks pregnant women because they do not take into account the spherical remodeling characteristic of normal pregnancy (Savu, 2012; Stewart, 2016).

Adjusting for these geometrical changes, Melchiorre and coworkers (2016) studied normal cardiac echocardiographic indings in 559 nulliparas at four points during pregnancy and again at 1 year postpartum. At term, signiicant chamber diastolic dysfunction and impaired myocardial relaxation were evident in approximately 18 and 28 percent of the women

Data from Clark, 1989.

average 40 percent higher at term. hese adaptations are even more profound in multifetal pregnancies (Kametas, 2003; Kuleva, 2011). Importantly, intrinsic left ventricular contractility does not change. hus, normal left ventricular function is maintained during pregnancy. Namely, pregnancy is not characterized by hyperdynamic function or a high cardiac-output state.

Women with underlying cardiac disease may not always accommodate these changes, and ventricular dysfunction leads to cardiogenic heart failure. A few women with severe cardiac dysfunction can experience evidence of heart failure before midpregnancy. In others, heart failure may develop after 28 weeks' gestation, when pregnancy-induced hypervolemia and cardiac output reach their maximum. In most, however, heart failure develops peripartum, when labor, delivery, and several common obstetrical conditions add undue cardiac burdens. Some of these include preeclampsia, hemorrhage and anemia, and sepsis.

Ventricular volumes and mass accrue to accommodate pregnancy-induced hypervolemia. his is reflected by greater end-systolic and end-diastolic dimensions. At the same time, however, septal thickness and ejection fraction are unchanged. his is because these alterations are accompanied by substantive ventricular remodeling-plasticiy-which is characterized by eccentric expansion of left-ventricular mass that averages 30 to 35 percent near term. All of these adaptations return to prepregnancy values within a few months postpartum.

Certainly for clinical purposes, ventricular function during pregnancy is normal as estimated by the Braunwald ventricular function graph depicted in Figure 4-9 (p. 61). For given illing pressures, there is appropriate cardiac output so that cardiac function during pregnancy is eudynamic. In nonpregnant subjects with a normal heart who sustain a high-output state, the left ventricle undergoes longitudinal remodeling, and echocardiographic functional indices of its deformation provide normal values. In pregnancy, there instead appears to be spherical remodeling, and these calculated indices that measure longitudinal deformation are depressed. Thus, normal nonpregnant indices are likely inaccurate when used to assess function in studied, respectively. Moreover, a significant proportion of women studied demonstrated a drop in stroke volume index and a tendency toward eccentric remodeling. hese indings suggest cardiovascular maladaptation to the increased volume demands in a substantial proportion of apparently normal pregnancies. Of note, signiicant dyspnea at rest was reported by 7.4 percent of the women at term, most of whom had chamber diastolic dysfunction. Cardiac function and all signs of dyspnea fully recovered at 1 year postpartum.

Cardiac magnetic resonance (MR) imaging increasingly is used to evaluate cardiac structure and function. Stewart and associates (2016) performed cardiac MR imaging studies in 23 women longitudinally across pregnancy and at 12 weeks postpartum. Compared with studies performed at 12 to 16 weeks' gestation, left ventricular mass grew significantly for both normal-weight and overweight women. he calculated geometrical ratio of left ventricular mass to left ventricular end-diastolic volume demonstrated concentric remodeling throughout gestation, which resolved by 12 weeks' postpartum. he right ventricle also remodels (Martin, 2017) . Taken together, these observations likely mean that pregnancy causes a mixture of eccentric and concentric ventricular remodeling.

he physiological adaptations of normal pregnancy can induce symptoms and alter clinical indings that may confound the diagnosis of heart disease. For example, in normal pregnancy, functional systolic heart murmurs are common, respiratory efort is accentuated, edema frequently accrues in lower extremities after midpregnancy, and fatigue and exercise intolerance often develop. Some systolic flow murmurs can be loud, and normal changes in the various heart sounds depicted in

Figure 49-1 may erroneously suggest cardiac disease. In con trast, clinical findings that are more likely to suggest heart disease are listed in Table 49-2.

Noninvasive cardiovascular studies such as electrocardiography, chest radiography, and echocardiography will provide the data necessary for evaluation in most women.

In the electrocardiogram (ECG) , an average 15-degree leftaxis deviation is found as the diaphragm is elevated in advancing pregnancy. Other indings, depicted in Figure 49-2, include a reduced PR interval, inverted or flattened T waves, and a Q wave in lead DIll (Angeli, 2014). Pregnancy does not alter voltage indings. Atrial and ventricular premature contractions are relatively frequent (Carruth, 1981).

FIGURE 49-1 Normal cardiac examination findings in the pregnant woman. Sl = first sound; M1 = mitral first sound; S2 = second sound; P2 = pulmonary second sound. (Data from Gei, 2001; Hytten, 1991o.)

TABLE 49-2. Clinical Indicators of Heart Disease During Pregnancy �� +

Syncope Leftward deviation of the mean QRS axis .' I,,l,

Clubbing of fingers

Q wave in lead 0'1" (Reproduced with permission from Angeli F, Angeli E, Verdecchia P: Electrocardiographic changes in hypertensive disorders of pregnancy, Hypertens Res. 2014 Nov;37(11 ):973-975.) 0001 ...0001 ",'

FIGURE 49-2 Normal electrocardiograph (ECG) adaptations durPersistent tachycardia and/or arrhythmia ing pregnancy, including a reduced mean PR interval, increased Persistent split second sound heart rate, left axis deviation, inverted or flattened T waves and a

With radiography, anteroposterior (AP) and lateral chest radiographs are useful, and when a lead apron shield is used, fetal radiation exposure is minimal. Gross cardiomegaly can usually be excluded, but slight heart enlargement cannot be detected accurately because the heart silhouette normally is larger in pregnancy. his is accentuated further with a portable

AP chest radiograph.

Echocardiography is now widely used and permits accurate diagnosis of most heart diseases during pregnancy. Some nor the dimensions of all cardiac chambers, a slight but signii cant growth in left ventricular mass, and greater tricuspid and mitral valve regurgitation (Grewal, 2014). Of note, systolic function normally does not change. Savu (2012) and Vitarelli diographic parameters for pregnancy, which are listed in the

Appendix (p. 1261). In some situations, such as complex con genital heart disease, transesophageal echo cardiography may be useful.

Cardiovascular MR imaging, compared with echocardiography, is associated with higher reproducibility and is less hindered by ventricular geometry and body habitus. The right ventricle can also be assessed (Nelson, 2017). Ducas and associates (2014) have published normal reference values for pregnancy.

Of other studies, albumin or red cells tagged with technetium-99m are rarely needed during pregnancy to evaluate ventricular function. That said, the estimated fetal radiation exposure from nuclear medicine studies of myocardial perfusion is negligible. It is safe to perform cardiac catheterization with limited fluoroscopy time. During coronary angiography, the mean radiation exposure to the unshielded abdomen is 1.5 mGy, and less than 20 percent of this reaches the fetus (European Society of Cardiology, 2011). Shortening the fluoroscopic time may help to minimize radiation exposure (Raman, 2015; Tuzcu, 2015). In women with clear indications, any minimal theoretical fetal risk is outweighed by maternal beneits (Chap. 46, p. 906).

• Classification of Functional Heart Disease

No clinically applicable test accurately measures functional cardiac capacity. The clinical classification of the New York Heart Association (NYHA) is based on past and present disability and is uninfluenced by physical signs: • Class I. Uncompromised-no limitation of physical activiy:

These women do not have symptoms of cardiac insuiciency or experience anginal pain.

Class II. Slight limitation of physical activiy: These women are comfortable at rest, but if ordinary physical activity is undertaken, discomfort in the form of excessive fatigue, palpitation, dyspnea, or anginal pain results.

Class III. Marked limitation of physical activiy: These women are comfortable at rest, but less than ordinary activity causes excessive fatigue, palpitation, dyspnea, or anginal pain.

Class IV. Severey compromised-inabiliy to peorm any physical activity without discomort: Symptoms of cardiac insufficiency or angina may develop even at rest. If any physical activity is undertaken, discomfort is increased.

Cardiovascular Disorders 95.1

Siu and associates (2001 b) expanded the NYHA classification and developed a scoring system for predicting cardiac complications during pregnancy. The system derives from a Canadian prospective analysis of 562 pregnant women with heart disease during 617 pregnancies. Predictors of cardiac complications included: (1) prior heart failure, transient ischemic attack, arrhythmia, or stroke; (2) baseline NYHA class III or IV or cyanosis; (3) left-sided obstruction defined as mitral valve area <2 cmr, aortic valve area < 1.5 cmr, or peak left tion fraction <40 percent. The risk of pulmonary edema, sus tained arrhythmia, stroke, cardiac arrest, or cardiac death was substantially elevated with one of these factors and even more so with two or more. Khairy and colleagues (2006) reported similar indings.

An even more comprehensive risk stratification system is the tion of Cardiovascular Disease and Pregnancy (Table 49-3). It ceptional counseling. Lu (2015) and Pijuan-Domenech (2015) and their associates in their analyses concluded that the modi ied WHO classification provides the greatest predictive accu racy for cardiac complications during pregnancy.

Women with severe heart disease will beneit immensely from counseling before pregnancy, and they usually are referred for maternal-fetal medicine or cardiology consultation (Clark, 2012; Seshadri, 2012). Maternal mortality rates generally correlate directly with functional classification, and this relationship may change as pregnancy progresses. From the previously described Canadian study, Siu and colleagues (2001 b) observed signiicant worsening of NHA class in 4.4 percent of 579 pregnancies in which the baseline class was I or II. As described later, some women have life-threatening cardiac abnormalities that can be reversed by corrective surgery, and subsequent pregnancy becomes less dangerous. In other cases, such as women with mechanical valves taking warfarin, fetal teratogenic concerns predominate. Last, many congenital heart lesions are inherited as polygenic characteristics (Chap. 13, p. 268). Because of this, some women with congenital heart lesions give birth to similarly afected neonates, and the risk varies widely (Table 49-4).

In most instances, management involves a team approach with an obstetrician, cardiologist, anesthesiologist, and other specialists as needed. With complex lesions or other high-risk cases, evaluation by a multidisciplinary team is recommended early in pregnancy. Within this framework, both prognosis and management are influenced by the type and severity of the speciic lesion and by the maternal functional classiication. In some, pregnancy termination may be advisable.

With rare exceptions, women in NYHA class I and most in class II negotiate pregnancy without morbidity. Special

TABLE 49-3. World Health Organization (WHO) Risk Classification of Cardiovascular Disease and Pregnancy with Management Recommendations

WHO l-Risk no higher than general population Uncomplicated, small, or mild:

Mitral valve prolapse with no more than trivial mitral regurgitation

Successfully repaired simple lesions:

WHO 2-Small increase in risk of maternal mortality If otherwise uncomplicated: • Individualized care similar to WHO categories 2 or 3 depending on lesion and disease severity

WHO 3-Significantly increased risk of maternal Mechanical valve mortality or expert cardiac and obstetrical care Systemic right ventricle-congenitally corrected transposition, required simple transposition post Mustard or Senning repair

WHO 4-Very high risk of maternal mortality or Pulmonary arterial hypertension termination discussed Previous peripartum cardiomyopathy with any residual impairment

Marfan syndrome with aorta dilated >40 mm

Pregnancy contraindicated.

If pregnancy occurs, monthly or bimonthly cardiac and obstetrical monitoring

Summarized from European Society of Gynecology, 201a1; Nanna, 2014; Thorne, 2006; World Health Organization, 201a0.

attention is directed toward both prevention and early recogCigarette smoking is prohibited. Illicit drug use may be parnition of heart failure. Of speciic risks, infection with sepsis ticularly harmful, an example being the cardiovascular efects syndrome can precipitate this. Moreover, bacterial endocardiof cocaine or amphetamines. In addition, intravenous drug use tis is a deadly complication of valvular heart disease (p. 965). raises the risk of infective endocarditis. Each woman is instructed to avoid contact with persons who Fortunately, women in NA class III and IV are uncomhave respiratory infections, including the common cold, and to mon today. In the prior Canadian study, only 3 percent of the report at once any evidence for infection. Pneumococcal and approximately 600 pregnancies were complicated by NA inluenza vaccines are recommended (Chap. 9, p. 172). class III heart disease, and no women had class IV when irst

TABLE 49-4. Risks for Fetal Heart Lesions Related to Afected Family Members

Atrial septal defect 2.5 1.5 5-11

Patent ductus arteriosus 3 2.5 4

Coarctation of the aorta NS NS 14

Fallot tetralogy 2.5 1.5 2-3

NS = not stated.

Data from Lupton, 2002.

seen (Siu, 2001b). If a woman chooses pregnancy, she must understand the risks and is encouraged to be compliant with planned care. In some women, prolonged hospitalization or bed rest is often necessary.

In general, vaginal delivery is preferred, and labor induction is usually safe (Thurman, 2017). From the large Registry on

Pregnancy and Cardiac Disease, Ruys and coworkers (2015) planned cesarean delivery. Planned cesarean delivery conferred no advantage for maternal or neonatal outcome.

Cesarean delivery is usually limited to obstetrical indications, and considerations are given for the speciic cardiac lesion, overall maternal condition, and availability of experienced anesthesia personnel and hospital capabilities. Some of these women tolerate major surgical procedures poorly and are best delivered in a unit experienced with management of complicated cardiac disease. Occasionally, pulmonary artery catheterization may be needed for hemodynamic monitoring (Chap. 47, p. 916). In our experiences, however, invasive monitoring is rarely indicated.

Based on her review, Simpson (2012) recommends cesarean delivery for women with the following: (1) dilated aortic root >4 cm or aortic aneurysm; (2) acute severe congestive heart failure; (3) recent myocardial infarction; (4) severe symptomatic aortic stenosis; (5) warfarin administration within 2 weeks of delivery; and (6) need for emergency valve replacement immediately after delivery. Although we agree with most of these, we have some caveats. For example, we prefer aggressive medical stabilization of pulmonary edema followed by vaginal delivery if possible. Also, warfarin anticoagulation can be reversed with vitamin K, plasma, or prothrombin concentrates.

During labor, the mother with signiicant heart disease should be kept in a semirecumbent position with a lateral tilt. Vital signs are taken frequently between contractions. Increases in pulse rate much above 100 beats per minute (bpm) or respiratory rate above 24 per minute, particularly when associated with dyspnea, may suggest impending ventricular failure. For evidence of cardiac decompensation, intensive medical management must be instituted immediately. Delivery itself does not necessarily improve the maternal condition and, in fact, may worsen it. Moreover, emergency cesarean delivery may be particularly hazardous. Clearly, both maternal and fetal status must be considered in the decision to hasten delivery under these circumstances.

Relief from pain and from apprehension is important. Although women, continuous epidural analgesia is recommended for most. The major problem with conduction analgesia is mater nal hypotension (Chap. 25, p. 491). This is especially danger ous in women with intracardiac shunts in whom low may be reversed. Hypotension can also be life-threatening if there is pulmonaY arterial hypertension or aortic stenosis because ven tricular output is dependent on adequate preload. In women with these conditions, narcotic regional analgesia or general anesthesia may be preferable.

For vaginal delivery in women with only mild cardiovas cular compromise, epidural analgesia given with intravenous sedation oten suices. his has been shown to minimize intra uum-assisted delivery. Subarachnoid blockade is not generally recommended in women with significant heart disease due to associated hypotension. For cesarean delivery, epidural analge sia is preferred by most clinicians with caveats for its use with pulmonary arterial hypertension (p. 962).

Cardiovascular decompensation during labor may manifest as pulmonary edema with hypoxia or as hypotension, or both. The proper therapeutic approach depends on the speciic hemodynamic status and the underlying cardiac lesion. For example, decompensated mitral stenosis with pulmonary edema due to luid overload is often best treated with aggressive diuresis. If precipitated by tachycardia, heart rate control with �-blocking agents is preferred. Conversely, the same treatment in a woman sufering decompensation and hypotension due to aortic stenosis could prove fatal. Unless the underlying pathophysiology is understood and the cause of the decompensation is clear, empirical therapy may be hazardous.

Women who have shown little or no evidence of cardiac compromise during pregnancy, labor, or delivery may still decompensate postpartum. Fluid mobilized into the intravascular compartment and reduced peripheral vascular resistance place higher demands on myocardial performance. Therefore, meticulous care is continued into the puerperium (Keizer, 2006; Zeeman, 2006). Postpartum hemorrhage, anemia, infection, and thromboembolism are much more serious complications with heart disease. Indeed, these factors often act in concert to precipitate postpartum heart failure. In addition, sepsis and severe preeclampsia cause or worsen pulmonary edema because of endothelial activation and capillary-alveolar leakage (Chap. 47, p. 917).

For puerperal tubal sterilization after vaginal delivery, the procedure can be delayed up to several days to ensure that the mother has normalized hemodynamically and that she is afebrile, not anemic, and ambulating normally. Alternatively, for those desiring future fertility, detailed contraceptive advice is available in the u. Medical Eligibiliy Criteria or Contraceptive Use guidelines (Curtis, 2016).

Most clinically signiicant congenital heart lesions are repaired during childhood. Examples of those frequently not diagnosed until adulthood include atrial septal defects, pulmonic stenosis, bicuspid aortic valve, and aortic coarctation (Brickner, 2014). In some cases, the defect is mild and surgery is not required. In others, a significant anomaly is amenable to corrective surgery, performed ideally before pregnancy. In rare instances, surgical corrections are necessary during pregnancy.

Numerous reports describe subsequent pregnancy outcomes in women who have a prosthetic mitral or aortic valve. The type of valve, either mechanical or biological, is paramount. From one review, the overall estimated maternal mortality rate was 1.2 percent. he rate was 1.8 percent in the mechanical valve subgroup and 0.7 percent in the bioprosthetic subgroup (Lawley, 2015). Using the Registry of Pregnancy and Cardiac Disease, the maternal mortality rate was 1.4 percent in women with a mechanical heart valve and 1.5 percent in women with a tissue heart valve (van Hagen, 2015). Mechanical heart valve thrombosis complicated 4.7 percent. In total, only 58 percent with a mechanical heart valve had a pregnancy free of serious adverse events compared with 79 percent of patients with a tissue heart valve (Table 49-5). Because of thrombosis risks, anticoagulation may be requisite, but its complications are described in the next section. Thus, pregnancy is undertaken only ater serious consideration for women with a prosthetic mechanical valve.

Bouhout and coworkers (2014) reported the outcomes of 27 pregnancies in 14 women who underwent an aortic valve replacement prior to pregnancy. Seven of the 27 pregnancies occurred in five women with a mechanical prosthesis. Complications in this group included two embolic myocardial infarctions and one each of miscarriage, postpartum hemorrhage, placental abruption, and preterm birth. In the bioprosthetic group, nine miscarriages, two hospitalizations for syncope, and one preterm birth were noted.

Porcine tissue valves are safer during pregnancy, primarily because thrombosis is rare and anticoagulation is not required (see Table 49-5). Despite this, valvular dysfunction with cardiac deterioration poses a serious risk. Another drawback is that bioprostheses are less durable than mechanical ones, and valve replacement longevity averages 10 to 15 years. Cleuziou and colleagues (2010) concluded that pregnancy does not accelerate the risk for replacement. But, Nappi and associates (2014) found an association between pregnancy and valve deterioration in women with cryopreserved mitral homograft valves.

his is critical for women with mechanical prosthetic valves . Unfortunately, warfarin is the most efective anticoagulant for preventing maternal thromboembolism but causes harmful fetal efects (Chap. 12, p. 247). Anticoagulation with heparin is less hazardous for the fetus, however, the risk of maternal thromboembolic complications is much higher (McLintock, 2011).

Warfarin is teratogenic and causes miscarriage, stillbirths, and fetal malformations. In one study of 71 women given warfarin throughout pregnancy, the rates of miscarriage were 32 percent; stillbirth, 7 percent; and embryopathy, 6 percent (Cotrufo, 2002). The risk was highest when the mean daily dose of warfarin exceeded 5 mg. Similarly, the American College of Cardiology and the American Heart Association estimate that the risk of embryopathy is dose dependent, with a lower risk-less than 3 percent-if the dose of warfarin is :;5 mg/d (Nishimura, 2014). If the dosage is >5 mg/d, the risk of embryopathy exceeds 8 percent.

Anticoagulation for mechanical valves using low-dose unfractionated heparin is definitely inadequate and carries a high associated maternal mortality rate (Chan, 2000; Iturbe-Alessio, 1986). Even ful anticoagulation with either unfractionated heparin (UFH) or one of the low-molecular-weight heparins (LMWH) is associated with valvular thrombosis (Leyh, 2002, 2003; Rowan, 2001). But, compliance with twice-daily dosing and therapeutic monitoring may have contributed (McLintock, 2014). hus, if full anticoagulation with dose-adjusted UFH or LMWH is used, meticulous monitoring is recommended. The activated partial thromboplastin time (aPTT) should be at least 2 times control or anti-Xa levels should be 0.8 to 1.2 U/mL at aData from the Registry of Pregnancy and Cardiac Disease. Data from van Hagen, 2015.

4 to 6 hours postdose (Nishimura, 2014).

Several diferent treatment options-none of which are completely ideal-are principally based on consensus opinion. Two are from the American College of Chest Physicians and the other jointly from the merican College of Cardiology and the American Heart Association (Bates, 2012; Nishimura, 2014). Any of four regimens is recommended. First, adjusted-dose LMWH is given twice daily, with a peak anti-Xa level drawn 4 hours ater dosing. In another, adjusted UFH is dosed every 12 hours to keep the midinterval aPTT twice control or anti Xa level between 0.35 0.70 U/mL. As a third option, LMWH or UFH is given as just described until 13 weeks, and then warfarin is substituted until near delivery, at which time it is replaced by LMWH or UFH. Last, in women judged to carry a high risk of thrombosis and for whom the eicacy and safety of heparins are concerns, warfarin is suggested throughout pregnancy. Heparin is then substituted close to delivery. In addition, aspirin, 75 to 100 mg, is given daily.

Heparin is discontinued just before delivery. If delivery supervenes while the anticoagulant is still efective, and extensive bleeding is encountered, then protamine sulfate is given intravenously. nticoagulant therapy with warfarin or heparin may be restarted 6 hours following vaginal delivery, usually with no problems. Following cesarean delivery, full anticoagulation is withheld, but the optimal duration is not exactly nown. The American College of Obstetricians and Gynecologists (2017) advises resuming unfractionated or low-molecular-weight heparin 6 to 12 hours ater cesarean delivery. It is our practice, however, to wait at least 24 hours following a major surgical procedure.

Because warfarin, LMWH, and UFH do not accumulate in breast milk, they do not induce an anticoagulant efect in the newborn. hese anticoagulants are compatible with breastfeeding (American College of Obstetricians and Gynecologists, 2017).

Although usually postponed until after delivery, valve replacement or other cardiac surgery during pregnancy may be lifesaving. Several reviews conirm that such surgery is associated with major maternal and fetal morbidity and mortality. At the Mayo Clinic between 1976 and 2009,r21 pregnant women underwent cardiothoracic surgery requiring cardiopulmonary bypass Oohn, 2011). The procedures included valve replacements, myxoma excisions, aneurysm repairs, patent foramen ovale closure, prosthetic aortic valve thrombectomy, and septal myectomy. Median cardiopulmonary bypass time was 53 minutes, with a range of 16 to 185 minutes. One woman died 2 days ater surgery, three fetuses died, and 52 percent were delivered before 36 weeks' gestation. Elassy and associates (2014) described 23 women who underwent urgent open cardiac surgery for severe valve malfunction. Two women and 10 fetuses-all at a gestational age below 28 weeks-died before hospital discharge. Only six fetuses were delivered at term. To optimize outcomes, Chandrasekhar and coworkers (2009) recommend that surgery be elective when possible, pump low rate should remain >2.5 Llmin/m2, normothermic perfusion pressure should exceed 70 mm Hg, and hematocrit should be keptr> 28 volumes percent.

Many successful pregnancies have followed cardiac transplantation (Abdalla, 2014; Vos, 2014). The current recommendations from The International Society of Heart and Lung Transplantation do not discourage pregnancy in stable heart transplant recipients who are more than 1 year posttransplant (Costanzo, 2010). Obviously, a highly specialized level of care with a mul tidisciplinary team is necessary.

he transplanted heart appears to responds normally to preg nancy-induced alterations (Key, 1989; Kim, 1996). Despite this, complications are common during pregnancy (Dashe, 1998). Of 53 pregnancies in 37 heart recipients, almost half developed hypertension, and 22 percent sufered at least one rejection episode during pregnancy (Armenti, 2002; Miniero, 2004). They were delivered-usually by cesarean-at a mean of 37 to 38 weeks' gestation. hree fourths of neonates were liveborn. At follow-up, at least ive women had died more than 2 years postpartum. Another analysis of 25 such women with 42 pregnancies found no maternal deaths. Major complica tions included two rejections during the early puerperium, two cases of renal failure, and 11 spontaneous abortions (Estensen, 2011). Five women died 2 to 12 years after delivery. And from the United Kingdom, Mohamed-Ahmed and colleagues (2014) identiied 14 women with transplants between 2007 and 2011r.

Graft rejections occurred in two women, one of whom died.

Rheumatic fever is uncommon in the United States because of less crowded living conditions, penicillin availability, and evolution of nonrheumatogenic streptococcal strains. Still, it remains the chief cause of serious mitral valvular disease in women of childbearing age in the nonindustrialized world (Nanna, 2014; Roeder, 2011) .

Rheumatic endocarditis causes most mitral stenosis lesions. The normal mitral valve surface area is 4.0 cmr, and when stenosis 2 narrows this to <2.5 cmr, symptoms usually develop (Desai, 2000). The contracted valve impedes blood low from the left atrium to the ventricle.

With more severe stenosis, the left atrium dilates, let atrial pressure is chronically elevated, and signiicant passive pulmonary hypertension develops (Table 49-6). These women have a relatively ixed cardiac output, and thus the increased preload of normal pregnancy and other factors that raise cardiac output may cause ventricular failure and pulmonary edema. Indeed, a fourth of women with mitral stenosis have cardiac failure for the irst time during pregnancy (Caulin-Glaser, 1999). he resulting pulmonary venous hypertension and pulmonary edema create symptoms of dyspnea, fatigue, palpitations, cough, and hemoptysis. The classic murmur may not be heard in some women, and this clinical picture at term may be confused with idiopathic peripartum cardiomyopathy (Cunningham, 1986,r2012).

Also with signiicant stenosis, tachycardia shortens ventricular diastolic illing time and elevates the mitral gradient. his too may lead to pulmonary edema. Thus, sinus tachycardia is often treated prophylactically with 3-blocking agents. Atrial tachyarrhythmias, including ibrillation, are common in mitral stenosis and are treated aggressively. Atrial ibrillation also predisposes to mural thrombus formation and cerebrovascular embolization that can cause stroke (Chap. 60, p. 1161). Atrial thrombosis can develop despite a sinus rhythm (Hameed, 2005).

Pregnancy Outcomes 66 newborns who were delivered at term had normal growth and development.

In general, complications are directly associated with the degree2 Labor and delivery are particularly stressful for women withofvalvular stenosis. Women with a mitral-valve area <2 cmrare symptomatic mitral stenosis (Fig. 49-3). Uterine contractionsat greatest risk (Siu, 2001b). In one study of 46 gravidas with increase cardiac output by increasing circulating blood volume.

mitral stenosis, 43 percent developed heart failure, and 20 percent Pain, exertion, and anxiety cause tachycardia with possible ratedeveloped arrhythmias (Hameed, 2001). Fetal-growth restriction 2rrelated heart failure. Epidural analgesia for labor is ideal, but was more common in women with a mitral valve area < 1.0 cmr• fluid overload is avoided. Abrupt expansion in preload mayPrognosis is also related to maternal functional capacity.

raise pulmonary capillary wedge pressure and cause pulmonaryAmong 486 pregnancies complicated by rheumatic heart disedema. Wedge pressures rise immediately postpartum. Oneease-predominantly mitral stenosis-8 of 10 maternal deaths hypothesis for this suggests that the loss of the low-resistance were in women in NYHA classes III or IV (Sawhney, 2003).

placental circulation couples with venous "autotransfusion"

Limited physical activity is generally recommended in women with mitral stenosis. If symptoms of pulmonary congesJ tion develop, activity is further reduced, dietary sodium is restricted, and diuretics are given (Siva, 2005). Also, �-blocker drug therapy slows the ventricular response to activity. If new onset atrial ibrillation develops, intravenous verapamil, 5 to 10 mg, is given, or electrocardioversion is performed. For chronic :) 15 ibrillation, digoxin, a �-blocker, or a calcium-channel blocker ; E can slow ventricular response. Therapeutic anticoagulation is = E 10 indicated with persistent ibrillation, left atrial thrombus, and/ ) A B C or a history of embolism (Nanna, 2014). ..m 5 0 Surgical intervention is considered for women with sympc tomatic severe mitral stenosis and in those with lesser degrees E0 of mitral stenosis-mitral-valve area 1.5 to 2.0 cm2-compli.

hypertension. Balloon valvuloplasty is preferred if the valve is pliable (Bui, 2014). In one review of 71 pregnant women with surements (red graph line) in eight women with mitral valve stenosis. Shaded yellow and blue boxes are mean (± 1 SO) pres neous valvuloplasty, 98 percent were either NYHA class I or sures in nonlaboring normal women at term. A. First-stage labor.

II at delivery (Esteves, 2006). At a mean of 44 months, the

B. Second-stage labor 15 to 30 minutes before delivery. C. Postpartotal event-free maternalsurvival rate was 54 percent. However, tum 5 to 15 minutes. D. Postpartum 4 to 6 hours. E. Postpartum 18 eight women required another surgical intervention. All of the to 24 hours. (Data from Clark, 1985, 1989.) from a now-empty, contracted uterus and from the lower extremities and pelvis (Clark, 1985).

Most prefer vaginal delivery in women with mitral stenosis.

Elective induction is reasonable so that labor and delivery are attended by a scheduled, experienced team. With severe steno sis and chronic heart failure, insertion of a pulmonary artery catheter may help guide management.

A trivial degree of mitral insuiciency is found in most normal patients. But if mitral valve lealets align improperly during systole, abnormal degrees of mitral regurgitation can develop. his is eventually followed by left ventricular dilation and eccentric hypertrophy (see Table 49-6). Acute mitral insuiciency is caused by chordae tendineae rupture, papillary muscle infarction, or leaflet perforation from infective endocarditis. Chronic mitral regurgitation, in contrast, may derive from rheumatic fever, connective tissue diseases, mitral valve prolapse, or left ventricular dilation of any etiology-for example, dilated cardiomyopathy. Less common causes include a calcified mitral annulus, possibly some appetite suppressants, and in older women, ischemic heart disease. Mitral valve vegetations-Libman-Sacks endocarditis-are relatively common in women with antiphospholipid antibodies (Shrof, 2012). These sometimes coexist with systemic lupus erythematosus.

In nonpregnant patients, symptoms from mitral valve insufficiency are rare, and valve replacement is seldom indicated unless infective endocarditis develops. During pregnancy, mitral regurgitation is similarly well tolerated, probably because the lowered systemic vascular resistance yields less regurgitation. Heart failure rarely develops during pregnancy, and occasionally tachyarrhythmias or severely depressed systolic function require treatment.

This diagnosis implies the presence of a pathological connective tissue disorder-often termed myxomatous degenerationwhich may involve the valve lealets themselves, the annulus, or the chordae tendineae. Mitral insuiciency may develop. Most women with mitral valve prolapse are asymptomatic and are diagnosed during routine examination or echocardiography. he few women with symptoms have anxiety, palpitations, atypical chest pain, dyspnea with exertion, and syncope (Guy, 2012).

Pregnant women with mitral valve prolapse rarely have cardiac complications. Hypervolemia may even imptove alignment of the mitral valve, and women without pathological myxomatous degeneration generally have excellent pregnancy outcomes (LdniakSobelga, 2004). For women who are symptomatic, �-blocking drugs diminish sympathetic tone, relieve chest pain and palpitations, and reduce the risk of life-threatening arrhythmias.

Usually a disease of aging, aortic stenosis in younger women is most likely a congenital lesion. Since the decline in rheumatic disease incidence, aortic stenosis is less common, and the most frequent cause in the United States is a bicuspid valve (Friedman, 2008). A normal aortic valve has an area of 3 to 4 cmr, with a pressure gradient <5 mm Hg. If the valve area is < 1 cmr, there is severe obstruction to flow and a progressive pressure overload on the left ventricle (Roeder, 2011). Concentric left ventricular hypertrophy follows, and if it is severe, enddiastolic pressures become elevated, ejection fraction declines, and cardiac output is reduced (see Table 49-6). Characteristic manifestations develop late' and include chest pain, syncope, heart failure, and sudden death from arrhythmias. Life expectancy averages only 5 years after exertional chest pain develops, and valve replacement is indicated for symptomatic patients.

Clinically significant aortic stenosis is infrequent during pregnancy. Mild-to-moderate degrees of stenosis are well tolerated, however, severe disease is life-threatening. he principal underlying hemodynamic problem is the ixed cardiac output associated with severe stenosis. During pregnancy, several common events acutely lower preload further and thus aggravate the ixed cardiac output. hese include vena caval occlusion from the gravid uterus, regional analgesia, and hemorrhage. Importantly, these also decrease cardiac, cerebral, and uterine perfusion. It follows that severe aortic stenosis may be extremely dangerous during pregnancy. From the earlier-cited Canadian study, complication rates were higher if the aortic valve area measured < 1.5 cmr(Siu, 2001 b). And in the report by Hameed and associates (2001), the maternal mortality rate with aortic stenosis was 8 percent. Women with valve pressure gradients > 100 mm Hg appear to be at greatest risk.

For asymptomatic women with aortic stenosis, no treatment except close observation is required. Management of a symptomatic woman includes strict limitation of activity and prompt treatment of infections. If symptoms persist despite bed rest, surgical intervention may be considered. Catheter-based valvuloplasty is associated with risks to both the mother and fetus and is not very efective in the long term (Pessel, 2014; Reich, 2004). The aortic valve can again narrow or new aortic regurgitation may develop. he alternative surgical approach-valve replacement-is associated with significant risk of fetal demise due to the efects of cardiac bypass (Dart, 2010). Accordingly, the American College of Cardiology, the American Heart Association, and the European Society of Cardiology recommend delaying conception until after surgical correction for severe aortic stenosis (Bonow, 2008).

For women with critical aortic stenosis, intensive monitoring during labor is essential. Pulmonary arteY catheterization may be helpful because of the narrow margin separating fluid overload from hypovolemia. Women with aortic stenosis are dependent on adequate end-diastolic ventricular filling pressures to maintain cardiac output and systemic perfusion. Abrupt drops in end-diastolic volume may result in hypotension, syncope, myocardial infarction, and sudden death. hus, avoiding diminished ventricular preload and maintaining cardiac output are key. During labor and delivery, afected women are best managed on the "wet" side. his provides a margin of safety in intravascular volume in anticipation of possible hemorrhage. In women with a competent mitral valve, pulmonary edema is rare.

During labor, narcotic epidural analgesia seems ideal and avoids potentially hazardous hypotension. Easterling and coworkers (1988) studied the efects of epidural analgesia in ive women with severe stenosis and demonstrated immediate and profound efects from decreased illing pressures. Xia and associates (2006) emphasize slow administration of dilute local anesthetic agents into the epidural space. In hemodynamically stable women, forceps or vacuum delivery is used for standard obstetrical indications.

Aortic valve regurgitation or insuiciency allows diastolic Bow of blood from the aorta back into the let ventricle. Frequent causes of abnormal insuiciency are rheumatic fever, connective tissue abnormalities, and congenital lesions. With Marfan syndrome, the aortic root may dilate and create regurgitation (p. 967). Acute insuiciency may also develop with bacterial endocarditis or aortic dissection (pp. 965 and 967). Last, aortic and mitral vlve insuiciency have both been linked to the appetite suppressants fenBuramine and dexfenBuramine and to the ergot-derived dopamine agonists cabergoline and pergolide (Gardin, 2000; Schade, 2007; Zanettini, 2007). With chronic insuiciency, let ventricular hypertrophy and dilation develop and are followed by slow-onset fatigue, dyspnea, and pulmonary edema, although rapid deterioration usually follows (see Table 49-6).

Aortic insuiciency is generally well tolerated during pregnancy. Like mitral valve insuiciency, diminished vascular resistance is thought to improve hemodynamic function. If symptoms of heart failure develop, diuretics are given and bed rest is encouraged.

his lesion is usually congenital and also may be associated with Fallot tetralogy or Noonan syndrome. The greater hemodynamic burden of pregnancy can precipitate right-sided heart failure or atrial arrhythmias in women with severe stenosis. Surgical correction ideally is done before pregnancy, but if symptoms progress, a balloon valvuloplasty may be necessary antepartum (Galal, 2015; Siu, 2001a).

In studying pregnancy outcomes, Drenthen and colleagues (2006) found infrequent cardiac complications in a group of 81 pregnancies in 51 Dutch women with pulmonic stenosis. The NHA classification worsened in two women, and nine experienced palpitations or arrhythmias. No changes in pulmonary valvular function or other adverse cardiac events were reported. However, non cardiac complication rates were significant-17 percent had preterm delivery, 15 percent had hypertension, and 4 percent developed thromboembolism.

The incidence of congenital heart disease in the United States approximates 11 per 1000 liveborn neonates (Egbe, 2014). With modern surgeries, approximately 90 percent of those born with congenital heart disease survive to childbearing age, and it is now the most common type of heart disease encountered during pregnancy (Brickner, 2014; Lindley, 2015). Specifically, analysis from the United States Nationwide Inpatient Sample database shows a linear rise in the prevalence of congenital heart disease between 2000 and 2010-from 6.4 to 9.0 per 10,000 women admitted for delivery (Thompson, 2015).

Of pregnancy outcomes in women with congenital heart disease compared with those without, the odds of cardiovascular and obstetrical complications were 10.5 to 35.5 and 1.2 to 2.1 times higher, respectively (Thompson, 2015). Moreover, maternal mortality rates were greater for women with congenital heart disease than for unafected gravidas-17.8 and 0.7 per 10,000 deliveries, respectively. Opotowsky and coworkers (2012) reported similar risks.

Approximately one fourth of all adults has a patent foramen ovale (Miller, 2015). Most atrial septal defects (ASDs) are asymptomatic until the third or fourth decade. he secundumtype defect accounts for 70 percent, and associated mitral valve myxomatous abnormalities with prolapse are common. Most recommend repair if ASD is discovered in adulthood. Pregnancy is well tolerated unless pulmonary hypertension has developed, but this is uncommon (Geva, 2014). Treatment of ASD during pregnancy is indicated for congestive heart failure or an arrhythmia. Based on their review, liaga and colleagues (2003) concluded that the risk of endocarditis with an ASD is negligible.

With the potential to shunt blood from right to let, aparadoxical embolism, that is, entry of a venous thrombus through the septal defect and into the systemic arterial circulation, is possible and may cause an embolic stroke (Erkut, 2006; Miller, 2015). In asymptomatic women with ASD, thromboembolism prophylaxis is problematic, and the heterogeneous recommendations have been summarized by Kizer and Devereux (2005). Compression stockings and prophylactic heparin have also been recommended for a pregnant woman with an ASD who is immobile or has another risk factor for thromboembolism (Head, 2005).

These lesions close spontaneously during childhood in 90 percent of cases. Most defects are paramembranous, and the degree of left-to-right shunt and associated physiological derangements are related to lesion size. In general, if the defect mea sures < 1.25 cmr, pulmonary hypertension and heart failure do not develop. If the efective defect size exceeds that of the aortic valve orifice, symptoms rapidly develop. For these reasons, most children undergo surgical repair before pulmonary hypertension develops. Adults with unrepaired large defects develop left ventricular failure and pulmonary hypertension and have a high incidence of bacterial endocarditis (Brickner, 2000, 2014).

Pregnancy is well tolerated with small-to-moderate sized shunts. If pulmonary arterial pressures reach systemic levels, however, there is reversal or bidirectional Bow-Eisenmenger syndrome (p. 960). When this develops, the maternal and fetal mortality rates are signiicantly higher, and thus, pregnancy is not generally advisable. Bacterial endocarditis is more common with unrepaired defects, and antimicrobial prophylaxis is often required (p. 965). As shown in Table 49-4, 10 to 16 percent of ofspring born to these women also have a ventricular septal defect.

These account for approximately 3 percent of all congenital cardiac malformations and are distinct from isolated atrial or ventricular septal defects. An atrioventricular (A V) septal defect is characterized by a common, ovoid A V junction. his defect is associated with aneuploidy, Eisenmenger syndrome, and other malformations (Altin, 2015). Compared with simple septal defects, complications are more frequent during pregnancy. In a review of 48 pregnancies in 29 afected women, complications included persistent deterioration of NA class in 23 percent, signiicant arrhythmias in 19 percent, and heart failure in 2 percent (Drenthen, 2005b). Congenital heart disease was identiied in 15 percent of the ofspring.

The ductus connects the proximal left pulmonary artery to the descending aorta just distal to the left subclavian artery. Functional closure of the ductus from vasoconstriction occurs shortly after term birth. he physiological consequences with its persistence are related to its size. Most signiicant lesions are repaired in childhood, but for individuals who do not undergo repair, the mortality rate is high after the ifth decade (Brickner, 2014). In some younger women with an unrepaired ductus during pregnancy, however, pulmonary hypertension, heart failure, or cyanosis will develop if systemic blood pressure falls and leads to shunt reversal of blood from the pulmonary artery into the aorta (Vashisht, 2015). A sudden blood pressure decline at delivery-such as with regional analgesia or hemorrhage-may lead to fatal collapse. Accordingly, hypotension is ideally avoided but treated vigorously if it develops. Prophylaxis for bacterial endocarditis is indicated at delivery for unrepaired defects (p. 965). As shown in Table 49-4, the incidence of inheritance approximates 4 percent.

When congenital heart lesions produce right-to-Ieft shunting of blood past the pulmonary capillary bed, cyanosis develops. The classic and most commonly encountered lesion in adults and during pregnancy is the Fallot tetraloy (Lindley, 2015). his is characterized by a large ventricular septal defect, pulmonary stenosis, right ventricular hypertrophy, and an overriding aorta that receives blood from both the right and left ventricles. The magnitude of the shunt varies inversely with systemic vascular resistance. Hence, during pregnancy, when peripheral resistance declines, the shunt increases and cyanosis worsens.

Generally, women with cyanotic heart disease do poorly during pregnancy. With uncorrected Fallot tetralogy, maternal mortality rates approach 10 percent. here is a relationship between chronic hypoxemia, polycythemia, and pregnancy outcomes such as miscarriage and perinatal morbidity. When hypoxemia is intense enough to stimulate a rise in hematocrit above 65 vol umes percent, pregnancy wastage is virtually 100 percent.

Although not all cyanotic lesions are repairable, with satis factory surgical correction before pregnancy, maternal and fetal outcomes are much improved. In a review of 197 pregnancies in 99 women with surgically corrected Fallot tetralogy, preg nancy was usually well tolerated, and no mothers died. Still, almost 9 percent of pregnancies were complicated by adverse and heart failure (Balci, 2011; Kamiya, 2012). For women with a pulmonary valve replacement, pregnancy does not adversely afect graft function (Oosterhof, 2006). Prior to or after con ception, women with Fallot tetralogy are ofered genetic coun seling and evaluation for 22q 11 deletion syndrome (Lindley, 2015).

Some women with Ebstein anomay, characterized by a mal positioned and malformed tricuspid valve, may reach reproduc tive age. Right ventricular failure from volume overload and cyanosis are common during pregnancy. In the absence of cya nosis, heart failure, or signiicant arrhythmias, afected women usually tolerate pregnancy well (Brickner, 2014).

Transposition of the Great Vessels

Pregnancy following surgical correction of transposition has prominent risks. Canobbio (2006) and Drenthen (2005a), each with their colleagues, described outcomes of 119 pregnancies in 68 women-90 percent had a prior Mustard procedure and 10 percent a previous Senning procedure. During pregnancy, one fourth had arrhythmias, 12 percent developed heart failure, and one subsequently required cardiac transplantation. One woman died suddenly a month after delivery, and another died 4 years later. A third of the newborns were delivered preterm. In another report of 60 pregnancies in 34 women who had undergone transposition repair, approximately a fourth ended in miscarriage or abortion, and another fourth delivered preterm (Trigas, 2014). Deterioration in functional class occurred in seven women, and documented deterioration in systolic function occurred in four women. Finally, two women required resuscitation during delivery, and one experienced supraventricular tachycardia during labor. Of other defects, in women with previously repaired truncus arteriosus and doubleoutlet right ventricle, successful-although eventful-pregnancies have also been described (Drenthen, 2008; Hoendermis, 2008).

With hypoplastic lt heart syndrome, almost 70 percent of afected women are now expected to survive into adulthood and frequently become pregnant (Feinstein, 2012). Those who have undergone a Fontan repair are at particularly high risk for complications. In brief, this procedure involves diverting blood via a surgical anastomosis from the vena cava to the pulmonary artery without passing through the right ventricle. Blood Bows passively to the pulmonary vasculature. Thus, patients with a Fontan palliation are very preload dependent (Lindley, 2015).

lead to pulmonary

FIGURE 49-4 Eisenmenger syndrome due to a ventricular septal defect (VSD). A. Substantialolet-to-right shunting through the VSD leads to morphological changes in the smaller pulmonary arteries and arterioles. Specifically, medial hypertrophy, intimal cellular proliferations, and fibrosis lead to narrowing or closure of the vessel lumen. These vascular changes create pulmonary hypertension and a resultant reversal of the intracardiac shunt (8). With sustained pulmonary hypertension, extensive atherosclerosis and calcification often develop in the large pulmonary arteries. Although a VSD is shown here, Eisenmenger syndrome may also develop in association with a large atrial septal defect or patent ductus arteriosus.

Of outcomes, one review of 14 women conceiving after a Fontan repair found that six spontaneously aborted all pregnancies, and eight others carried 14 pregnancies to viability (Cauldwell, 2016). Cardiac complications included arrhythmias and thromboembolism. Ten newborns delivered preterm, and eight neonates were small for gestational age. Similar complications attend a maternal systemic right ventricle, that is, one in which the right ventricle rather than the left pumps blood to the systemic circulation (Khan, 2015).

his describes secondary pulmonary hypertension that arises from any cardiac lesion. The syndrome develops when pulmonary vascular resistance exceeds systemic resistance and leads to concomitant right-to-Ieft shunting. The most common underlying defects are atrial or ventricular septal defects and persistent ductus arteriosus (Fig. 49-4). Patients are asymptomatic for years, but eventually pulmonary hypertension becomes severe enough to cause this shunting (Greutmann, 2015).

Pregnant women with Eisenmenger syndrome tolerate hypotension poorly, and death usually is caused by right ventricular failure with cardiogenic shock. In a review of 44 cases through 1978, maternal and perinatal mortality rates approximated 50 percent (Gleicher, 1979). In a later review of 73 pregnancies, Weiss and associates (1998) cited a 36-percent maternal death rate. Three of 26 deaths were antepartum, and the remainder of women died intrapartum or within a month of delivey. In a subsequent study of 13 gravidas, one mother died 17 days after delivery, and there were ive perinatal deaths (Wang, 2011).

Given such poor outcomes or both mother and etus, Eisenmenger syndrome is considered to be an absolute contraindication to pregnancy (Brickner, 2014; Lindley, 2015; Meng, 2017; Warnes, 2015). Management of those who do become pregnant has recently been detailed by Broberg (2016) and is discussed in the next section.

Normal resting mean pulmonary artery pressure is 12 to 16 mm Hg. Pulmonary vascular resistance in late pregnancy approximates 80 dyne/sec/cm-5, which is 34-percent less than the nonpregnant value of 120 dyne/sec/cm-5 (Clark, 1989). Pulmonay hypertension is deined in nonpregnant individuals as a resting mean pulmonary pressure >25 mm Hg.

he current clinical classification system, shown in Table 49-7, includes five groups of disorders that cause pulmonary hypertension (Galie, 2016). There are important prognostic and therapeutic distinctions between group 1 pulmonary arterial hypertension and the other groups. Group 1 indicates that a specific disease afects pulmonary arterioles. It includes idiopathic or primary pulmonary arterial hypertension as well as those cases secondary to a known cause such as connective tissue disease. For example, approximately one third of women with scleroderma and 10 percent with systemic lupus erythematosus

TABLE 49-7. Comprehensive Clinical Classification of Pulmonary Hypertension 1. Pulmonary arterial hypertension

Drug and toxin induced Associated with connective tissue disease, HIV infections, portal hypertension, congenital heart diseases, schistosomiasis

Drugs, toxins and radiation induced

Associated with connective tissue disease, HIV infection

I" Persistent pulmonary hypertension of the newborn 2. Pulmonary hypertension due to let heart disease 3. Pulmonary hypertension due to lung diseases and/or hypoxia

Other pulmonary diseases with mixed restrictive and obstructive pattern Sleep-disoriented breathing

Chronic exposure to high altitude 4. Chronic thromboembolic pulmonary hypertension/other pulmonary artery obstructions

Other pulmonary artery obstructions, i.e., tumors, arteritis, pulmonary stenosis, parasites 5. Pulmonary hypertension with unclear and/or multifactorial mechanisms

Hematological disorders: chronic hemolysis, myeloproliferative disorders, splenectomy Systemic disorders: sarcoidosis, pulmonary histiocytosis, neurofibromatosis

Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders Others: fibrosing mediastinitis, chronic renal failure

HIV = human immunodeficiency virus. Adapted from Galie, 2016.

have pulmonary hypertension (Rich, 2005). Other causes in young women are human immunodeiciency virus (HI) infection, sickle-cell disease, and thyrotoxicosis (Newman, 2015; Sheield, 2004).

In pregnant women, group 2 disorders are the most common. hese are secondary to pulmonary venous hypertension caused by left-sided atrial, ventricular, or valvular disorders. A typical example is mitral stenosis discussed earlier (p. 955). In contrast, groups 3 through 5 are seen infrequently in young healthy women .

Symptoms may be vague, and dyspnea with exertion is the most frequent. With group 2 disorders, orthopnea and nocturnal dyspnea are also usually present. Angina and syncope occur when right ventricular output is ixed, and they suggest advanced disease. Chest radiography often shows enlarged pulmonary hilar arteries and attenuated peripheral markings. It also may disclose parenchymal causes of hypertension. N oninvasive echocardiography can provide an estimate of pulmonary artery pressures, although cardiac catheterization remains the standard for measurement. In two studies with a combined 51 pregnant women who underwent both echo cardiography and cardiac catheterization, pulmonary artery pressures were significantly overestimated by echocardiography in approximately one third of cases (Penning, 2001; Wylie, 2007).

Regardless of the etiology, the inal common pathway of pulmonary hypertension is right heart failure and death. he average survival length after diagnosis is <4 years (Krexi, 2015). That said, longevity depends on the severity and cause of pulmonary hypertension at discovery. As discussed later, some disorders respond to medical interventions, which may improve quality of life. Preconceptional and contraceptive counseling are imperative (Gei, 2014).

he maternal mortality rate is appreciable in afected women, and this is especially so with idiopathic pulmonary hypertension. In the past, there were frequently poor distinctions in identiying both causes and severity of hypertension. hus, although most severe cases of idiopathic pulmonary arterial hypertension had the worst prognosis, it was erroneously assumed that all types of pulmonary hypertension were equally dangerous. With widespread use of echocardiography, lesssevere lesions with a better prognosis are now discernible. Bedard and coworkers (2009) reported that maternal mortality rate statistics improved during the decade ending in 2007 (25 percent) compared with those for the decade ending in 1996 (38 percent). Importantly, almost 80 percent of the deaths were during the first month postpartum. More recently, Meng and associates (2017) reported mortality rates of 23 percent with group 1 and 5 percent with the other groups. Mortality was related to pulmonary hypertension severity.

As discussed, pregnancy is contraindicated with severe disease, especially in women with pulmonary arterial changesmost cases in group 1. With milder disease from other causes-group 2 being the most common-the prognosis is better (Meng, 2017). With the more frequent use of echocardiography and pulmonary artery catheterization in young women with heart disease, we have identified women with mild-to-moderate pulmonary hypertension who tolerate pregnancy, labor, and delivery well. One example described by Sheield and Cunningham (2004) is that of pulmonary hypertension that develops with thyrotoxicosis but is reversible with treatment. Similarly, Boggess and colleagues (1995) described nine women with interstitial and restrictive lung disease with varying degrees of pulmonary hypertension, and all tolerated pregnancy reasonably well.

Treatment of symptomatic pregnant women includes activity limitation and avoidance of the supine position later in gestation. Diuretics, supplemental oxygen, and pulmonary vasodilator drugs are standard therapy for symptoms. Some recommend anticoagulation (Hsu, 2011). Several reports describe the successful use of intravenous pulmonary artery vasodilators (Badalian, 2000; Garabedian, 2010; Goya, 2014). Prostacyclin analogues that can be administered parenterally include epoprostenol and treprostinil, whereas iloprost is inhaled. Each has been used in gravidas. Inhaled nitric oxide is an option that has been employed in cases of acute cardiopulmonary decompensation (Lane, 2011). As reviewed by Obiean and Cleary (2014), phosphodiesterase-5 inhibitors, such as sildenail, cause vasodilation of both the pulmonary and systemic vascular beds and have an inotropic efect on the hypertrophic right ventricle. his also has been used to advantage during pregnancy (Goland, 2010; Hsu, 2011; Meng, 2017). Bosentan, an endothelin-receptor antagonist, is teratogenic in mice and contraindicated in pregnancy (Obican, 2014).

During labor and delivery, these women are at greatest risk when venous return and right ventricular filling are diminished. To avoid hypotension, assiduous attention is given to epidural analgesia induction and to blood loss prevention and treatment at delivery (Meng, 2017).

The American Heart Association defines these as a heterogeneous group of myocardial diseases associated with mechanical and/ or electrical dysfunction. Afected women usually-but not invariably-have inappropriate ventricular hypertrophy or dilation. Cardiomyopathies stem from varied causes, some of which are genetic (Maron, 2006). Of the two major divisions, primay cardiomyopathies are solely or predominantly conined to heart muscle. Examples are hypertrophic cardiomyopathy, dilated cardiomyopathies, and peripartum cardiomyopathy. Secondary cardiomyopathies result from generalized systemic disorders that produce pathological myocardial involvement. Diabetes, systemic lupus erythematosus, chronic hypertension, and thyroid disorders are representative conditions.

Epidemiological studies suggest that this disorder is common, afecting approximately 1 in 500 adults (Herrey, 2014; Maron, 2004). Characterized by cardiac hypertrophy, myocyte disarray, and interstitial ibrosis, the condition is caused by mutations in anyrone of more than a dozen genes that encode cardiac sarcomere proteins in up to 60 percent of afected patients. In such cases, inheritance is autosomal dominant, and genetic screening is complex (Elliott, 2014). Other genetic and nongenetic causes account for 5 to 10 percent of cases, and the cause is unknown in approximately 25 percent. The myocardial muscle abnormality is typified by let ventricular myocardial hypertrophy with a pressure gradient against let ventricular outflow. Diagnosis is established by echocardiographic identification of a hypertrophied and nondilated left ventricle in the absence of other cardiovascular conditions.

Most afected women are asymptomatic, but dyspnea, anginal or atypical chest pain, syncope, and arrhythmias may develop. Complex arrhythmias may progress to sudden death, which is the most frequent cause of death. Asymptomatic patients with runs of ventricular tachycardia are especially prone to sudden death. Symptoms usually worsen with exercise.

lthough limited reports suggest that pregnancy is well tolerated, adverse cardiac events are frequent. In one analysis of 271 pregnancies in 127 afected women, there were no maternal deaths. However, more than a fourth had at least one adverse cardiac symptom-including dyspnea, chest pain, or palpitations (Thaman, 2003). Based on one systematic review that included 237 women with hypertrophic cardiomyopathy who had a combined 408 pregnancies, Schinkel (2014) calculated a maternal mortality rate of 0.5 percent. Worsening of symptoms or other complications occurred in 29 percent, and 26 percent delivered preterm.

Management is similar to that for aortic stenosis. Strenuous exercise is prohibited during pregnancy. Abrupt positional changes are avoided to prevent reflex vasodilation and decreased preload. Likewise, drugs that evoke diuresis or diminish vascular resistance are generally not used. If symptoms develop, especially angina, 3-adrenergic or calcium-channel blocking drugs are given. The delivery route of the fetus is determined by obstetrical indications. Choice of anesthesia is controversial, and some authors consider general anesthesia the safest (Pitton, 2007). Neonates rarely demonstrate inherited lesions at birth.

This is characterized by left and/or right ventricular enlargement and reduced systolic function in the absence of coronary, valvular, congenital, or systemic disease known to cause myocardial dysfunction. Although there are many known causes of dilated cardiomyopathy-both inherited and acquired, the etiology remains undefined in approximately half of cases (Stergiopoulos, 2011). Some result from viral infections, including myocarditis and HIV (Barbaro, 1998; Felker, 2000). Other causes, which are potentially reversible, include alcoholism, cocaine abuse, and thyroid disease. Watkins and coworkers (2011) reviewed the many complex genetic mutations associated with inherited forms of dilated cardiomyopathy.

This disorder is similar to other forms of nonischemic dilated cardiomyopathy except for its unique relationship with pregnancy (Pyatt, 2011). Indeed, peripartum cardiomyopathy shares a genetic predisposition with both familial and sporadic idiopathic dilated cardiomyopathy (Ware, 2016). Currently, it is a diagnosis of exclusion following a concurrent evaluation for peripartum heart failure.

Although the term peripartum cardiomyopathy has been used widely, at least until recently, little evidence supported a unique pregnancy-induced cardiomyopathy. Pearson (2000) reported findings of a workshop of the National Heart, Lung, and Blood Institute that established the following diagnostic criteria: 1.

Development of cardiac failure in the last month of pregnancy or within 5 months after delivery, 2.

Absence of an identifiable cause for the cardiac failure, 3.

Absence of recognizable heart disease prior to the last month of pregnancy, and 4.

Left ventricular systolic dysfunction demonstrated by classic echocardiographic criteria, such as depressed ejection fraction or fractional shortening along with a dilated left ventricle (Fig. 49-5).

he etiology of peripartum cardiomyopathy remains unknown, and proposed causes include viral myocarditis, abnormal immune response to pregnancy, aberrant response to the greater hemodynamic burden of pregnancy, hormonal interactions, malnutrition, inflammation, and apoptosis (Elkayam, 2011). Another suggests that oxidative stress during late pregnancy leads to the proteolytic cleavage of prolactin (Hilfiker-Kleiner, 2014). The resulting 16-kDa prolactin

FIGURE 49-5 Peripartum cardiomyopathy with mild pulmonary edema. Anterior-posterior projection chest radiograph of a woman with an abnormally enlarged heart and mild perihilar opacification consistent with dilated cardiomyopathy.

fragment is cardiotoxic and can impair cardiomyocyte metab olism and contractility. Bromocriptine therapy has been suggested because it inhibits prolactin secretion. In one pre liminary study, bromocriptine improved recovery of afected women, and a randomized trial is currently recruiting patients (Haghikia, 2015; Sliwa, 2010).

Hypertensive disorders frequently coexist with peripartum cardiomyopathy, and another proposed mechanism links peripartum cardiomyopathy to preeclampsia (Cunningham, 2012; Fong, 2014; Patten, 2012). Antiangiogenic factors-already known to be associated with preeclampsia-can induce peripartum cardiomyopathy in susceptible mice. hus, cardiomyopathy may be precipitated by antiangiogenic factors in a host made susceptible because of insuicient proangiogenic factors.

Several investigators describe a common pathway linking these suggested etiologies (Arany, 2016; Hiliker-Kleiner, 2014). Specifically, unbalanced oxidative stress and a high level of prolactin leads to production of the 16-kDa prolactin fragment that seems to both initiate and propagate the disease. The fragment, which mainly afects the endothelium, together with additional antiangiogenic factors might disturb the angiogenic balance during the puerperium and thereby impair cardiac function.

With no proven etiology, the diagnosis of peripartum cardiomyopathy currently requires that other causes of cardiac dysfunction be excluded. Biiltmann and coworkers (2005) studied endomyocardial biopsy specimens from 26 women with peripartum cardiomyopathy and reported that more than half had histological evidence of "borderline myocarditis." hey noted viral genomic material for parvovirus B 19, human herpesvirus 6, Epstein-Barr virus, and cytomegalovirus. From Parland Hospital, otherwise "idiopathic" heart failure was found to be caused by hypertensive heart disease, clinically silent mitral stenosis, obesity, or viral myocarditis (Cunningham, 1986). Indeed, 20 percent of women with treated chronic hypertension in pregnancy have concentric hypertrophy (Ambia, 2017).

N tusi and associates (2015) analyzed the clinical features of 30 women with peripartum cardiomyopathy compared with 53 women with hypertensive heart failure. With cardiomyopathy, the symptoms began postpartum in all women, whereas symptoms began antepartum in 85 percent of women with hypertensive heart failure. Peripartum cardiomyopathy was significantly linked with twin gestation, smoking, and echo cardiographic abnormalities. In contrast, hypertensive heart failure patients more often had a family history of hypertension, hypertension and preeclampsia in a prior pregnancy, tachycardia, and left ventricular hypertrophy on echo cardiography.

he incidence of peripartum cardiomyopathy varies considerably and depends on the diligence for the search of a cause. In a review of the Nationwide Inpatient Sample database, the incidence rose from 1 in 1181 live births in 2004 to 1 in 849 in 2011 (Kolte, 2014). Two other large population-based studies cite a frequency of 1 in 2000 to 2800 live births (Gunderson, 2011; Harper, 2012). In an earlier study from Parkland Hospital, we identified idiopathic cardiomyopathy in only approximately 1 in 15,000 deliveries-an incidence similar to that of idiopathic cardiomyopathy in young nonpregnant women (Cunningham, 1986).

Approximately half of women sufering from peripartum cardiomyopathy recover baseline ventricular function within 6 months of delivery. But in those with persistent cardiac failure, the mortality rate approaches 85 percent over 5 years (Moioli, 2010). In a group of 100 women with newly diagnosed peripartum cardiomyopathy, 72 percent had a left ventricular ejection fraction ::50 percent, and 93 percent had event-free survival (McNamara, 2015). However, six women experienced nine major events that included four deaths, four left ventricular assist device implantations, and one heart transplantation. Recovery to a left ventricular ejection fraction ::50 percent occurred in almost 90 percent of women whose baseline ejection fraction was at least 30 percent. This compared with <40 percent in women whose baseline ventricular ejection fraction was < 30 percent. Recovery was also related to the baseline left ventricular end-diastolic diameter. Li and colleagues (2016) also found that a baseline left ventricular ejection fraction <34 percent and a brain natriuretic peptide (BNP) level > 1860 pg/ mL were associated with an approximately threefold greater risk of persistent left ventricular systolic dysfunction.

From the largest studies on the topic, approximately one third of women with a history of peripartum cardiomyopathy will sufer relapse with worsening of symptoms and deterioration of left ventricular function during another pregnancy (Elkayam, 20 14a). The risk of relapse in women with persistent left ventricular dysfunction is substantially higher than in those who have developed normal ventricular function before a subsequent pregnancy (Hiliker-Kleiner, 2017). But, normalization of let ventricular function does not guarantee an uncomplicated pregnancy, because approximately 20 percent of these women are at risk for deterioration in left ventricular function.

Arrhythmogenic right ventricular dysplasia is a unique cardiomyopathy defined histologically by progressive replacement of right ventricular myocardium with adipose and fibrous tissue. It has an estimated population prevalence of 1 in 5000, predisposes to ventricular tachyarrhythmias, and is a cause of sudden death, particularly in younger individuals (Agir, 2014; Elliott, 2008). The additional risk of pregnancy in women with arrhythmogenic right ventricular cardiomyopathy is unknown, however, based on their systematic review, Krul and coworkers (2011) counsel against pregnancy.

Restrictive cardiomyopathy is probably the least common type. This inherited cardiomyopathy is characterized by a ventricular illing pattern in which worsening myocardial stifness raises ventricular pressure precipitously and al�ows only a small filling volume (Elliott, 2008). Because of the severe clinical course and poor prognosis in general, pregnancy is not advised (Krul, 2011). Takotsubo cardiomyopathy is a rare form of acute reversible left ventricular apical wall ballooning (Kraft, 2017).

Regardless of the underlying condition that causes cardiac dysfunction, women who develop peripartum heart failure almost always have obstetrical complications that either contribute to or precipitate heart failure. For example, preeclampsia is common and may precipitate afterload failure. Indeed, indings from the Registry on Pregnancy and Cardiac Disease indicate that women with preexisting heart disease who develop preeclampsia have a 30-percent risk of developing heart failure during pregnancy (Ruys, 2014). Moreover, high-output states caused by hemorrhage and acute anemia elevate cardiac workload and magniy the physiological efects of compromised ventricular function. Similarly, infection and sepsis syndrome raise cardiac output and oxygen utilization and depress myocardial function.

In many populations, chronic hypertension with superimposed preeclampsia is the most frequent cause of heart failure in pregnancy. Many of these women have concentric let ventricular hypertrophy (Ambia, 2017). In some, mild antecedent undiagnosed hypertension causes covert cardiomyopathy, and when superimposed preeclampsia develops, together they may cause otherwise inexplicable peripartum heart failure. Obesity is a frequent cofactor with chronic hypertension, and it too is associated with ventricular hypertrophy (Kenchaiah, 2002).

Congestive heart failure can have a gradual onset or may present as acute "flash" pulmonary edema. Heart failure onset is most likely at the end of the second/beginning of the third trimester and peripartum (Ruys, 2014). Of symptoms, dyspnea is universal and others are orthopnea, palpitations, substernal chest pain, a sudden decline in the ability to complete usual duties, and nocturnal cough. Clinical findings include persistent basilar rales, hemoptysis, progressive edema, tachypnea, and tachycardia (Sheield, 1999). Hallmark radiographic findings usually are cardiomegaly and pulmonary edema (see Fig. 49-5).

Acutely, there is usually systolic failure, and echocardiography shows an ejection fraction <0.45 or a fractional shortening <30 percent, or both, and an end-diastolic dimensionr> 2.7 cm/m2 (Hibbard, 1999). Coincidental diastolic failure may also be found, depending on the underlying cause (Redfield, 2016).

with diuretic administration to reduce preload. Hypertension is common, and afterload reduction is accomplished with hydralazine or another vasodilator. Because of marked fetal efects, angiotensin-converting enzyme inhibitors are withheld until after delivery. With chronic heart failure, the incidence of associated thromboembolism is high, and thus prophylactic heparin is often recommended.

Lt ventricular assist devices are now employed more fre quently for acute and chronic heart failure treatment. A few reports describe their use during pregnancy (LaRue, 2011;

Sims, 2011). Extracorporeal membrane oxygenation (ECMO) was reported to be lifesaving in a woman with fulminating peri partum cardiomyopathy, and it may be used in women with pulmonary hypertension (Meng, 2017; Smith, 2009).

In the United States, those at greatest risk for endocarditis are those with congenital heart lesions, intravenous drug use, degenerative valve disease, and intracardiac devices (Karchmer, 2015). Subacute bacterial endocarditis usually stems from a low-virulence bacterial infection superimposed on an underlying structural lesion. These are usually native valve infections. Organisms that cause indolent endocarditis are most often viridans-group streptococci or Staphylococcus or Enterococcus species. Among intravenous drug abusers and those with catheter-related infections, Staphylococcus aureus predominates. With prosthetic valve infections, Staphylococcus epidermidis is a frequent cause. Streptococcus pneumoniae and Neisseria gonorrhoeae may occasionally cause acute, fulminating disease. Others have reported Neisseria sicca and N mucosa, group B streptococcus, and Escherichia coli endocarditis during pregnancy or peripartum (Cox, 1988; Deger, 1992; Kangavari, 2000; Kulas, 2006).

Infective endocarditis symptoms vary and often develop insidiously. Fever, often with chills, is seen in 80 to 90 percent of cases, a murmur is heard in up to 85 percent, and anorexia, fatigue, and other constitutional symptoms are common (Karchmer, 2015). Clinical clues are anemia, proteinuria, and manifestations of embolic lesions that include petechiae, focal neurological changes, chest or abdominal pain, and ischemia in an extremity. In some cases, heart failure develops. Symptoms may persist for several weeks before the diagnosis is found, and a high index of suspicion is necessary.

Diagnosis is made using the Duke criteria, which include positive blood cultures for typical organisms and evidence of endocardial involvement (Hoen, 2013; Pierce, 2012). Echocardiography may be diagnostic, but lesions <2 mm or those on the tricuspid valve may be missed. If uncertain, transesophageal echocardiog raphy is accurate and informative. Importantly, a negative echo cardiographic study does not exclude endocarditis.

Treatment is primarily medical, and ascertainment of the infecting organism and its sensitivities is imperative for antimi crobial selection. Guidelines for appropriate antibiotic treatment (Habib, 2015; Karchmer, 2015). Recalcitrant bacteremia and heart failure due to valvular dysfunction are but a few reasons that persistent valvular infection may require replacement.

Infective endocarditis is uncommon during pregnancy and the puerperium. During a 7 -year period, the incidence of endocarditis at Parkland Hospital approximated 1 in 16,000 births, and two of seven women died (Cox, 1988). Matenal and fetal mortality rates range from 25 to 35 percent (Habib, 2015; Seaworth, 1986). In a systematic review of infective endocarditis during pregnancy, risk factors were intravenous drug use (14 percent), congenital heart disease (12 percent), and rheumatic heart disease (12 percent) (Kebed, 2014). he most common pathogens were streptococcal (43 percent) and staphylococcal (26 percent) species. Among 51 pregnancies, the maternal mortality rate was 11 percent.

For years, patients with heart valve problems were given peri procedural antibiotics for endocarditis prophylaxis. Currently, however, recommendations are more stringent. The American Heart Association recommends prophylaxis for dental procedures in those with: (1) a prosthetic valve or prosthetic material used in a valve repair, (2) prior endocarditis, (3) unrepaired cyanotic heart defect or repaired lesion with residual defect at prosthetic sites, and (4) valvulopathy ater heart transplantation (Nishimura, 2017). The American College of Obstetricians and Gynecologists (2016) does not recommend endocarditis prophylaxis for either vaginal or cesarean delivery in the absence of pelvic infection except with the lesions cited above. Women at highest risk for endocarditis are those with cyanotic cardiac disease, prosthetic valves, or both. When indicated, and for women not already receiving intrapartum antimicrobial therapy for another indication that would also provide coverage against endocarditis, prophylactic regimens are shown in Table 49-8. hese are administered as close to 30 to 60 minutes before the anticipated delivery time as is feasible.

Both preexisting and new-onset cardiac arrhythmias are often encountered during pregnancy, labor, delivery, and the puerperium Qoglar, 2014; Knotts, 2014). In a study of73 women with a history of supraventricular tachycardia (ST) , paroxysmal atrial flutter or fibrillation, or ventricular tachycardia, recurrence rates during pregnancy were 50, 52, and 27 percent, respectively (Silversides, 2006). The mechanism(s) responsible for the higher incidence of arrhythmias during pregnancy are

TABLE 49-8. Antibiotic Prophylaxis for Infective Endocarditis in High-Risk Patients

American College of Obstetricians and Gynecologist (2016)

Standard (IV): ampicillin 2 9 or cefazolin or ceftriaxone 1 9 Penicillin-allergic (IV): cefazolin or ceftriaxone 1 9 or clindamycin 600 mg Oral: amoxicillin 2 9

American Heart Association/European Society of Cardiology (Karchmer, 201n5)a

Standard: amoxicillin 2 9 PO or ampicillin 2 9 IV or 1M Penicillin-allergic: clarithromycin or azithromycin 500 mg PO; cephalexin 2 gnPO; clindamycin 600 mg PO, IV, or 1M; or cefazolin or ceftriaxone 1 9 IV or 1M 1M = intramuscularly; IV = intravenously.

aCefazolin r ceftriaxone given 30 minutes and all others given 1 hour prior to procedure.

not well elucidated. From some studies, estradiol and progesterone are proarrhythmic. Estrogen augments the number of adrenergic receptors in the myocardium, and adrenergic responsiveness seems to be greater in pregnancy (Enriquez, 2014). Perhaps the normal but mild hypokalemia of pregnancy and/or the physiological rise in heart rate serves to induce arrhythmias. Alternatively, detection of arrhythmias may be greater because of the frequent visits typical of routine prenatal care.

Slow heart rhythms, including complete heart block, are compatible with a successful pregnancy outcome (Keepanasseril, 2015). Some women with complete heart block have syncope during labor and delivery, and occasionally temporary cardiac pacing is necessary (Hidaka, 2006). In our experiences and from others, women with permanent artificial pacemakers usually tolerate pregnancy well (Hidaka, 2011; Jafe, 1987). With ixed-rate devices, cardiac output apparently is increased by augmented stroke volume.

Patients with pacemakers or other electrical implants require special precautions during surgery. Stray current may be interpreted as an intracardiac signal by the implanted device and lead to pacing changes. In addition, myocardial burns may result from conduction of current through the pacing electrode rather than through the grounding pad (Pinski, 2002). With these devices, preventive steps include cardiology consultation; bipolar electrosurgery or Harmonic scalpel use rather than mono polar current; if needed, minimal monopolar settings; continuous cardiac and pulse oximetry monitoring; contingency plans for arrhythmias; and close proximity of electrosurgery active and return electrodes (Crossley, 2011).

The most common arrhythmia seen in reproductive-aged women is paroxysmal SVT. The prevalence during pregnancy is 24 cases per 100,000 hospital admissions, and approximately 20 percent will experience symptomatic exacerbations during pregnancy (Enriquez, 2014). Interestingly, the mean heart rate of pregnant women with paroxysmal SVT is faster compared with nonpregnant women-184 versus 166 bpm, respectively (Yu, 2015). From Hungary, BGnhidy and associates (2015) found that approximately half of women with paroxysmal SVT had an initial onset during pregnancy. Notably, maternal paroxysmal SVT was associated with a twofold greater risk of septal cardiac defects, particularly secundum atrial septal defects, in their ofspring.

In contrast, rarely do atrial ibrilation and atrial lutter present for the irst time during pregnancy. Indeed, new-onset atrial ibrillation should prompt a search for underlying etiologies that include cardiac anomalies, hyperthyroidism, pulmonary embolism, drug toxicity, and electrolyte disturbances (DiCarloMeacham, 2011). Major complications include embolic stroke, and when associated with mitral stenosis, pulmonary edema may develop in later pregnancy if the ventricular rate is increased.

For acute treatment, vagal maneuvers, which include Valsalva maneuver, carotid sinus massage, bearing down, and immersion of the face in ice water, raise vagal tone and block the atrioventricular node (Link, 2012; Page, 2015). Intravenous adenosine is a short-acting endogenous nucleotide that also blocks atrioventricular nodal conduction. Our experiences are similar to those of others in that adenosine is safe and efective for cardioversion in hemodynamically stable gravidas (Page, 2015; Robins, 2004). Transient fetal bradycardia has been described with adenosine (Dunn, 2000).

If pharmacological therapy is inefective or contraindicated, the merican College of Cardiology and the merican Heart Association recommend synchronized cardioversion in pregnant women with hemodynamically unstable SVT (Page, 2015). And although electrical cardioversion with standard energy settings is not contraindicated in pregnancy, vigilance is important. Barnes and colleagues (2002) described a case in which direct current cardioversion led directly to a sustained uterine contraction and fetal bradycardia. As an aside, pregnancy has no efect on the operation of implantable cardioverter-defibrillator devices (Boule, 2014).

If cardioversion fails or is unsafe because of concurrent thrombus, then long-term anticoagulation and heart rate control with medication are necessary (DiCarlo-1eacham, 2011). Other treatment options recommended by the American College of Cardiology and the American Heart Association (Page, 2015) include:

Intravenous metoprolol or propranolol when adenosine is inefective or contraindicated

Intravenous verapamil when adenosine and 3-blocking agents are inefective or contraindicated

Intravenous amiodarone with potentially life-threatening SVT and when other therapies are inefective or contraindicated.

Pregnancy may predispose otherwise asymptomatic women with WoffParkinson-White (WP) syndrome to exhibit arrhythmias. In a study of 25 women who had SVT diagnosed before pregnancy, three of 12 women with WPW syndrome and six of 13 without the condition developed SVT during pregnancy (Pappone, 2003). In some patients, accessory pathway ablation may be indicated. Driver and coworkers (2015) have provided a review.

This form of arrhythmia is uncommon in healthy young women without underlying heart disease. Brodsky and associates (1992) described seven pregnant women with new-onset ventricular tachycardia and reviewed 23 reports. Most of these women were not found to have structural heart disease. In 14 cases, tachycardia was precipitated by physical exercise or psychological stress. Abnormalities found included two cases of myocardial infarction, two of prolonged QT interval, and one of anesthesia-provoked tachycardia. They concluded that pregnancy events precipitated the tachycardia and recommended 3-blocking agents for control. As previously discussed (p. 964), arrhythmogenic right ventricular dysplasia will result occasionally in ventricular tachyarrhythmias (Lee, 2006). If unstable, emergency cardioversion is indicated, and standard adult energy settings are adequate Qeejeebhoy, 2011; Lin, 2015).

This conduction anomaly may predispose individuals to a potentially fatal ventricular arrhythmia known as torsades de pointes (Roden, 2008) . Two studies comprised of 502 pregnant women with long QT syndrome both reported a signiicant increase in cardiac events postpartum but not during pregnancy (Rashba, 1998; Seth, 2007). The normal rise in heart rate during pregnancy may be partially protective. Paradoxically, 3-blocking agents-preferably propranolol-lower the risk of torsades de pointes in patients with long QT syndrome and should be continued throughout pregnancy and the puerperium (Enriquez, 2014; Seth, 2007). Importantly, many medications, including some used during pregnancy such as azithromycin, erythromycin, and clarithromycin, may predispose to QT prolongation (Ray, 2012; Roden, 2004).

vlarfan syndrome and coarctation are two aortic diseases that place the pregnant woman at increased risk for aortic dissection (Russo, 2017). Indeed, half of dissection cases in young women are related to pregnancy (O'Gara, 2004). Other risk factors are bicuspid aortic valve and Turner or Noonan syndrome. A high rate of aortic dissection or rupture is also reported in patients with Ehlers-Danlos syndrome (Murray, 2014; Pepin, 2000). Although the mechanism(s) involved are unclear, the initiating event is a tear in the intimal layer of the aorta, followed by hemorrhage into the media, and finally rupture.

In most cases, aortic dissection presents with severe chest pain described as ripping, tearing, or stabbing. Diminution or loss of peripheral pulses coupled with a recently acquired aor tic insuiciency murmur is an important physical inding. he diferential diagnosis of aortic dissection in pregnancy includes myocardial infarction, pulmonary embolism, pneumothorax, aortic valve rupture, and obstetrical catastrophes, especially placental abruption and uterine rupture.

More than 90 percent of patients with aortic dissection have an abnormal chest radiograph. Aortic angiography is the most definitive method for diagnosis confirmation. However, sonog raphy, computed tomography, and MR imaging are used more frequently depending on the urgency of the clinical situation.

Initial medical treatment is given to lower blood pressure.

Proximal dissections most often need to be resected, and the aortic valve replaced if necessary. Distal dissections are more complex, and many may be treated medically. Among non pregnant patients, survival is not improved by immediate elec tive repair compared with surveillance and delayed repair of abdominal aortic aneurysms <5.5 cm. But, Karthikesalingam and colleagues (2016) suggest that the size threshold for aneu rysm repair should be revisited.

This autosomal dominant connective tissue disorder has an incidence of 2 to 3 cases per 10,000 individuals and is without racial or ethnic predilection (Ammash, 2008). As discussed in Chapter 59 (p. 1151), Marfan syndrome is characterized by generalized tissue weakness that can result in dangerous cardiovascular complications. Because all tissues are involved, other defects are frequent and include joint laxity and scoliosis. Progressive aortic dilation causes aortic valve insuiciency, and there may be infective endocarditis and mitral valve prolapse with insuiciency. Aortic dilation and dissecting aneurysm are the most serious abnormalities. Early death is due either to valvular insuiciency and heart failure or to a dissecting aneurysm.

Of outcomes, a study using the Nationwide Inpatient Sample from 2003 to 2010 found 339 deliveries in women with Marfan syndrome. There was one maternal death and six (1.8 percent) aortic dissections (Hassan, 2015). Russo and associates (2017) used Texas obstetrical discharge data and found that eight of 47 women with aortic dissection had Marfan syndrome. A study from the United ingdom reported similar results (Curry, 2014).

The aortic root usually measures approximately 2 cm, and during normal pregnancy, it expands slightly (Easterling, 1991). With Marfan syndrome, aortic root repair is recommended at diameters of 4.0 to 4.5 cm (Smok, 2014). The guidelines of the American College of Cardiology, the American Heart Association, and the merican Association of horacic Surgeons advise prophylactic aortic repair in women considering pregnancy if the diameter of the ascending aorta exceeds 4 cm (Hiratzka, 2010). The guidelines of the European Society of Cardiology (2011) advise repair of the aorta at diameters :::4.5 cm. Because shorter patients have dissection at a smaller diameter, surgical repair is also considered using a formula indexed to height (Bradley, 2014; Smok, 2014).

For pregnant women with known thoracic aortic root or ascending aortic dilation, monthly or bimonthly echocardiographic measurements of the ascending aortic dimensions are recommended to detect expansion (Hiratzka, 2010). Prophylactic 3-blocking agents have become standard for pregnant women with �1arfan syndrome because they reduce hemodynamic stress on the ascending aorta and slow the dilation rate (Simpson, 2012). Ideally, pregnant women with aortic aneurysms are delivered at facilities in which cardiothoracic surgery is available. Vaginal delivery with regional analgesia and an assisted second stage seem safe for women with an aortic root diameter < 4 cm.

When the aortic root measures 4 to 5 cm or greater, elective cesarean delivery is recommended with consideration of postpartum replacement of the proximal aorta with a prosthetic graft (Simpson, 2012). Successful aortic root replacement during pregnancy has been described, but the surgery has also been associated with fetal hypoxic-ischemic encephalopathy (Mul, 1998; Seeburger, 2007). Several case reports describe emergency cesarean deliveries in women with acute type A dissections that were repaired successfully at the time of delivery (Guo, 2011; Haas, 2011; Papatsonis, 2009).

To evaluate obstetrical outcomes, investigators for one study of 63 women with Marfan syndrome analyzed their 142 pregnancies. Of 111 pregnancies progressing past 20 weeks' gestation, 15 percent delivered preterm, and 5 percent had preterm prematurely ruptured membranes (vleijboom, 2006). here were eight perinatal deaths, and half of the neonatal survivors were subsequently diagnosed with Marfan syndrome.

In this relatively rare lesion, the aorta is abnormally narrowed and is often accompanied by abnormalities of other large arteries. A fourth of afected patients have a bicuspid aortic valve, and another 10 percent have cerebral artery aneurysms. Other associated lesions are persistent ductus arteriosus, septal defects, and Turner syndrome. he collateral circulation arising above the coarctation remodels and expands, often strikingly, to cause localized erosion of rib margins by hypertrophied intercostal arteries. Typical indings include hypertension in the upper extremities but normal or reduced pressures in the lower extremities. Authors have described diagnosis during pregnancy using MR imaging (Sherer, 2002; Zwiers, 2006). Moreover, Jimenez-Juan and associates (2014) found that aortic diameter measured by �1R and the risk of adverse events during pregnancy were inversely correlated. Of note, no adverse outcomes occurred if the minimum diameter at the coarctation exceeded 15 mm.

Major complications with aortic coarctation include congestive heart failure after long-standing severe hypertension, bacterial endocarditis of the bicuspid aortic valve, and aortic rupture. Because hypertension may worsen in pregnancy, antihypertensive therapy using 3-blocking drugs is usually required. Aortic rupture is more likely late in pregnancy or early puerperium.

Cerebral hemorrhage from circle of Wiis aneurysms may also occur.

Of outcomes from 188 pregnancies, a third of women had hypertension that was related to significant coarctation gradients, and one woman died from dissection at 36 weeks' gestation (Beauchesne, 2001). Of nearly 700 deliveries in women with coarctation from the Nationwide Inpatient Sample, hypertensive complications of pregnancy were increased threeto fourfold (rieger, 2011). Importantly, almost 5 percent of women with coarctation had an adverse cardiovascular outcome-maternal death, heart failure, arrhythmia, cerebrovascular or other embolic event-compared with only 0.3 percent of controls. Of women with coarctation, 41 percent underwent cesarean delivery compared with 26 percent of controls.

Congestive heart failure demands vigorous eforts to improve cardiac function and may warrant pregnancy interruption. Some authors recommend that resection of the coarctation be undertaken during pregnancy to protect against the possibility of a dissecting aneurysm and aortic rupture. This poses significant perfusion risk, especially for the fetus, because all the arterial collaterals must be clamped for variable periods.

Pregnant women with coronary artery disease commonly have the classic risk factors of diabetes, smoking, hypertension, hyperlipidemia, and obesity Games, 2006). Although relatively rare, the risk of acute myocardial infarction is approximately threefold higher in pregnant women compared with nonpregnant women of similar age (Elkayam, 2014b). From more than 50 million hospitalizations in the United States between 1998 and 2009, rates of acute myocardial infarction approximated 2 per 100,000 delivery hospitalizations and 4 per 100,000 postpartum hospitalizations (Callaghan, 2012). Ladner and colleagues (2005) reported a similar rate of 2.7 per 100,000 deliveries.

The mortality rate with myocardial infarction in pregnancy is higher compared with age-matched nonpregnant women. In a Nationwide Inpatient Sample study totaling 859 pregnancies complicated by acute infarction, the death rate was 5.1 percent Games, 2006). Women who sustain an infarction <2 weeks before delivery are at especially high risk of death due to the greater myocardial demand of labor and delivery (Esplin, 1999).

In a systematic review of 150 cases, most women developed an acute myocardial infarction (MI) during the third trimester or postpartum (Elkayam, 2014b). Approximately three fourths presented with ST segment-elevation MI (STEMI). he leading mechanisms of acute infarction included spontaneous coronary dissection (43 percent) and atherosclerotic disease (27 percent). Signiicant complications included heart failure/cardiogenic shock (38 percent), recurrent angina or infarction (19 percent), and ventricular arrhythmias (12 percent). he maternal and fetal mortality rates were 7 and 5 percent, respectively. Of other potential antecedents, coronary artery occlusion in two pregnant smokers with hypercholesterolemia has been described following ergometrine administration (Mousa, 2000; Ramzy, 2015; Sutaria, 2000). Schulte-Sasse (2000) reported myocardial ischemia associated with prostaglandin Ervaginal suppositories given for 1 labor induction.

Diagnosis of acute myocardial infarction during pregnancy does not difer from that in nonpregnant patients and is based on clinical presentation, characteristic ECG changes, and evidence of myocardial necrosis relected by elevated serum troponin levels (Pacheco, 2014). Of note, troponin I levels are undetectable near term in normal pregnancy and do not rise following either vaginal or cesarean delivery (Koscica, 2002; Shivvers, 1999). Importantly, however, troponin I levels are higher in preeclamptic women compared with normotensive controls (Atalay, 2005; Yang, 2006). With spontaneous coronary artery dissection, establishing the diagnosis requires a high index of suspicion in the gravida presenting with chest pain (Codsi, 2016). For this condition, coronary angiography is considered the diagnostic gold standard and should be expediently performed if acute coronary syndrome-deined as myocardial infarction or unstable angina-is present.

Treatment of acute myocardial infarction is similar to that for nonpregnant patients (Pacheco, 2014). An algorithm summarizing one approach to its management during pregnancy is shown in Figure 49-6. Several reports describe successful percutaneous transluminal coronary angioplasty and stent placement during pregnancy (Balmain, 2007; Duarte, 2011;

FIGURE 49-6 Initial management of acute myocardial infarction during pregnancy. Risk stratification refers to the risk ofdeveloping recurrent symptoms despite optimal medical management. (Adapted with permission from Pacheco LO, Saade GR, Hankins GO: Acute myocardial infarction during pregnancy, (lin Obstet Gynecol. 2014 Oec;S7(4):83S-843.)

Dwyer, 2005). Cardiopulmonary resuscitation may be required, as described in Chapter 47 (p. 931). If the infarct has healed suiciently, cesarean delivery is reserved for obstetrical indications, and epidural analgesia is ideal for labor (Esplin, 1999).

• Pregnancy with Prior Ischemic Heart Disease he advisability of pregnancy after a myocardial infarction is unclear. Ischemic heart disease is characteristically progressive, and because it is usually associated with hypertension or diabetes, pregnancy in most of these women seems inadvisable. In a review of 30 pregnancies in women who had sustained an inarction remoterompregnancy, none of the women died, four had congestive heart failure, and four had worsening angina during pregnancy (Vinatier, 1994). Pombar and coworkers (1995) evaluated outcomes of women with diabetes-associated ischemic heart disease and infarction. Three had undergone coronary artery bypass grafting before pregnancy. Of 17 women, eight died during pregnancy. Certainly, pregnancy raises cardiac workload, and these investigators concluded that ventricular performance should be assessed using ventriculography, radionuclide studies, echocardiography, or coronary angiography before conception. Without signiicant ventricular dysfunction, pregnancy will likely be tolerated. For the woman who becomes pregnant before these studies are performed, echocardiography is done. Exercise tolerance testing may be indicated, and radionuclide ventriculography exposes the fetus to minimal radiation.

Abdalla M, Mancini OM: Management of pregnancy in the post-cardiac transplant patient. Semin Perinatal 38(5):318, 2014

Agir A, Bozyel 5, Celikyurt U: Arrhythmogenic right ventricular cardiomyopathy in pregnancy. Int Heart J 55(4):372, 2014

Aliaga L, Santiago FM, Marti J, et al: Right-sided endocarditis complicating an atrial septal defect. Am J Med Sci 325:282, 2003

Altin FH, Yildiz 0, Karacalilar M: Complete atrioventricular septal defects and pulmonary stenosis diagnosed in a 49-year-old woman after 10 uneventful births. Tex Heart Inst J 42(2):166, 2015

Ambia M, Morgan JL, Wilson L, et al: Frequency and consequences ofconcentric hypertrophy in pregnant women with treated chronic hypertension. Abstract No. 808, mJ Obstet Gynecol 216:5463, 2017

American College of Obstetricians and Gynecologists: Thromboembolism in pregnancy. Practice Bulletin No. 123, September 2011, Reairmed 2017

American College ofObstetricians and Gynecologists: Use ofprophylactic antibiotics in labor and delivery. Practice Bulletin No. 120, June 2011, Reafirmed 2016

Ammash NM, Sundt TM, Connolly HM: Marfan syndrome-diagnosis and management. Curr Prabl Cardiol 33: ,t2008

Angeli F, Angeli E, Verdecchia P: Electrocardiographic changes in hypertensive disorders of pregnancy. Hypertens Res 3 (11):973,t2014 Arany Z, Elkayam U: Peripartum cardiomyopathy. Circulation 133(14): 1397, 2016

Armenti T, Radomski ]5, Moritz MJ, et al: Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl 121t:30,t2002

Atalay C, Erden G, Turhan T, et al: he efect ofmagnesium sulfate treatment on serum cardiac troponin I levels in preeclamptic women. Acta Obstet Gynecol Scand 84:617, 2005

Badalian 55, Silverman RK, Aubry RH, et al: Twin pregnancy in a woman on long-term epoprostenol therapy for primary pulmonary hypertension: a case report. J Reprod Med 45:149,t2000

Balci A, Orenthen W, Mulder BJ, et al: Pregnancy in women with corrected tetralogy of Fallot: occurrence and predictors of adverse events. m Heart J 161:307,t2011

Balmain S, McCullough CT, Love e, et al: Acute myocardial infarction during pregnancy successfully treated with primary percutaneous coronary intervention. Intl J Cardiol 116:e85, 2007

Banhidy F, Acs N, Puh6 EH, et al: Paroxysmal supraventricular tachycardia in pregnant women and birth outcomes of their children: a population-based study. Am J Med Genet Part A 167A(8):1779, 2015

Barbaro G, di Lorenzo G, Grisorio B, et al: Incidence of dilated cardiomyopathy and detection of HIV in myocardial cells of HIV-positive patients. N Engl J Med 339:1093, 1998

Barnes EJ, Eben F, Patterson 0: Direct current cardioversion during pregnancy should be performed with facilities available for fetal monitoring and emergency caesarean section. BJOG 109:1406,t2002

Bates SM, Greer A, Middleldorp S, et al: VTE, thrombophilia, anti thrombotic therapy, and pregnancy. Chest 141:e691S, 2012

Beauchesne LM, Connolly HM, Ammash NM, et al: Coarctation of the aorta: outcome of pregnancy. J Am Coll CardioIt38:1728, 2001

Bedard E, Dimopoulos K, Gatzoulis viA: Has there been any progress made on pulmonary outcomes among women with pulmonary arterial hypertension? Eur Heart J 30:256, 2009

Boggess A, Easterling TR, Raghu G: Management and outcome of pregnant women with interstitial and restrictive lung disease. Am J Obstet Gynecol 173:1007,t1995

Bonow RO, Carabello BA, Chatterjee K, et al: 2008 focused update incorporated into the ACA/ AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 guidelines for the management of patients with valvular heart disease). Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 118(l5):e523, 2008

Bouhout I, Poirier N, Mazine A, et al: Cardiac, obstetric, and fetal outcomes during pregnancy after biological or mechanical aortic valve replacement. Can J Cardiol 30(7):801, 2014

Boule S, Ovart L, Marquie e, et al: Pregnancy in women with and implantable cardioverter-defibrillator: is it safe? Europace 16(11):1587,t2014

Bradley A, Zaidi AN, Goldsmith P, et al: Major adverse maternal cardiovascular-related events in those with aortopathies. What should we expect? Int J Cardiol 177(1):229, 2014

Brickner ME: Cardiovascular management in pregnancy: congenital heart disease. Circulation 130(3):273,t2014

Brickner ME, Hillis LD, Lange A: Congenital heart disease in adults. First of two pans. N Engl J Med 342:256, 2000

Broberg CS: Challenges and management issues in adults with cyanotic congenital heart disease. Heart 102(9):720,t2016

Brodsky M, Doria R, Allen B, et al: New-onset ventricular tachycardia during pregnancy. Am Heart J 123:933, 1992

Bui AH, O'Gara PT, Economy E, et al: Clinical problem-solving. A tight predicament. N Engl J Med 371 (10):953,t2014

Biiltmann BD, Klingel K, Nibauer M, et al: High prevalence of viral genomes and inflammation in peripartum cardiomyopathy. Am J Obstet Gynecol 193:363, 2005

Callaghan WM, Creanga A, Kuklina EV: Severe maternal morbidity among delivery and postpartum hospitalizations in the United States. Obstet Gynecol 120(5):1029, 2012

Canobbio MM, Morris CD, Graham TP, et al: Pregnancy outcomes after atrial repair for transposition of the great arteries. Am J Cardiol 98:668, 2006

Capeless EL, Clapp JF: Cardiovascular changes in early phase of pregnancy.

Am J Obstet GynecoIt161:1449, 1989

Carruth JE, Mirvis SB, Brogan DR, et al: The electrocardiogram in normal pregnancy. Am Heart J 102:1075, 1981

Caul dwell M, Von Klemperer K, Uebing A, et al: A cohort study of women with a Fontan circulation undergoing preconception counseling. Heart 102(27):534, 2016

Caulin-Glaser T, Setaro JF: Pregnancy and cardiovascular disease. In Burrow GN, DuY TP (eds): Medical Complications During Pregnancy, 5th ed. Philadelphia, Saunders, 1999

Chan WS, Anand S, Ginsberg JS: Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature. Arch Intern Med 160:191,t2000

Chandrasekhar S, Cook CR, Collard CD: Cardiac surgery in the parturient.

Anesth Analg 108:777, 2009

Clark SL, Cotton DB, Lee W, et al: Central hemodynamic assessment of normal term pregnancy. Am J Obstet Gynecol 161:1439, 1989

Clark SL, Hankins GO: Preventing maternal death: 10 clinical diamonds.

Obstet Gynecol 119:360,2012

Clark SL, Phelan JP, Greenspoon J, et al: Labor and delivery in the presence of mitral stenosis: central hemodynamic observations. Am J Obstet Gynecol 152:984, 1985

Cleuziou J, Horer J, Kaemmerer H, et al: Pregnancy does not accelerate biological valve degeneration. Int J Cardiol 145:418, 2010

Codsi E, Tweet MS, Rose CH, et al: Spontaneous coronary artery dissection in pregnancy. Obstet GynecoIt128(4):731, 2016

Costanzo MR, Dipchand A, Starling R, et al: he International Society of Heart and Lung Transplantation guidelines for the heart transplant recipient. J Heart Lung Transplant 29(8):914,t2010

Cotrufo M, De Feo M, De Santo LS, et al: Risk of warfarin during pregnancy with mechanical valve prostheses. Obstet Gynecol 99:35, 2002

Cox SM, Hankins GO, Leveno KJ, et al: Bacterial endocarditis: a serious pregnancy complication. J Reprod Med 33:671, 1988

Creanga A, Syverson CJ, Seed K, et al: Pregnancy-related mortality in the United States, 2011-2013. Obstet GynecoIt130(2):366, 2017

Crossley GH, Poole JE, Rozner MA, et al: The Heart Rhythm Society (HRS)/ American Society of Anesthesiologists (ASA) Expert Consensus Statement on the perioperative management of patients with implantable deibrillators, pacemakers and arrhythmia monitors: facilities and patient management. Heart Rhythm 8(7):1t1t14, 2011

Cunningham FG: Peripartum cardiomyopathy: we've come a long way, but ....

Obstet Gynecol 120:992, 2012

Cunningham FG, Pritchard JA, Hankins GO, et al: Peripartum heart failure: idiopathic cardiomyopathy or compounding cardiovascular events? Obstet GynecoIt67:157, 1986

Curry A, Gelson E, Swan L, et al: Marfan syndrome and pregnancy: maternal and neonatal outcomes. BJOG 121(5):610,t2014

Curtis KM, Tepper NK, Jatlaoui TC, et al: U.S. medical eligibility criteria for contraceptive use, 2016. MMWR 65(3):1,t2016

Dashe JS, Ramin KD, Ramin SM: Pregnancy following cardiac transplantation. Prim Care Update Ob Gyns 5:257, 1998

Datt V, Tempe OK, Virmani S, et al: Anesthetic management for emergency cesarean section and aortic valve replacement in a parturient with severe bicuspid aortic valve stenosis and congestive heart failure. Ann Card Anaesth 13:64,t2010

Deger R, Ludmir J: Neisseria sicca endocarditis complicating pregnancy. J Reprod Med 37:473, 1992

Desai OK, Adanlawo M, Naidoo DP, et al: Mitral stenosis in pregnancy: a four-year experience at King Edward VIII Hospital, Durban, South Mrica. BJOG 107:953, 2000

DiCarlo-Meacham LT, Dahlke LC: Atrial ibrillation in pregnancy. Obstet Gynecol 117:389,2011

Drenthen W, Pieper PG, Ploeg M, et al: Risk of complications during pregnancy after Senning or Mustard (atrial) repair of complete transposition of the great arteries. Eur Heart J 26:2588, 2005a

Drenthen W, Pieper PG, Roos-HesselinktJW, et al: Non-cardiac complications during pregnancy in women with isolated congenital pulmonary valvar stenosis. Heart 92: 1838, 2006

Drenthen W, Pieper PG, van der Tuuk K, et al: Cardiac complications relating to pregnancy and recurrence of disease in the ofspring of women with atrioventricular septal defects. Eur Heart J 26:2581, 2005 b

Drenthen W, Pieper PG, van der Tuuk K, et al: Fertility, pregnancy and delivery in women after biventricular repair for double outlet right ventricle. Cardiology 109:105,t2008

Driver K, Chisholm CA, Darby E, et al: Catheter ablation of arrhythmia during pregnancy. J Cardiovasc ElectrophysioIt26(6):698, 2015

Duarte FP, O'Neill P, Centeno MJ, et al: Myocardial infarction in the 31st week of pregnancy-case report. Rev Bras Anesthesiol 61:225, 2011

Ducas A, Elliot JE, Melnyk SF, et al: Cardiovascular magnetic resonance in pregnancy: insights from the Cardiac Hemodynamic Imaging and Remodeling in Pregnancy (CHIRP) study. J Cardiovasc Magn Reson 16:1,t2014

Dunn JS J r, Brost BC: Fetal bradycardia after IV adenosine for maternal PSVT.

Am J Emerg Med 18:234,t2000

Dwyer BK, Taylor L, Fuller A, et al: Percutaneous transluminal coronary angioplasty and stent placement in pregnancy. Obstet Gynecol 106: 1162, 2005

Easterling TR, Benedetti TJ, Schmucker Be, et al: Maternal hemodynamics and aortic diameter in normal and hypertensive pregnancies. Obstet Gynecol 78:1073, 1991

Easterling TR, Chadwick HS, Otto CM, et al: Aortic stenosis in pregnancy.

Obstet Gynecol 72:113, 1988

Egbe A, Uppu S, Stroustrup A, et al: Incidences and sociodemographics of specific congenital heart diseases in the United States of America: an evaluation of hospital discharge diagnoses. Pediatr CardioI35(6):975, 2014

Elassy SMR, Elmidany A, Elbawab HY: Urgent cardiac surgery during pregnancy: a continuous challenge. Ann Thorac Surg 97(5): 1624,t2014

Elkayam U: Clinical characteristics of peripartum cardiomyopathy in the United States: diagnosis, prognosis, and management. J Am ColI Cardiol 58:659,t2011

Elkayam U: isk of subsequent pregnancy in women with a history of peripartum cardiomyopathy. J Am Coll Cardiol 64(15):1629, 2014a

Elkayam U, Jalnapurkar S, Barakkat MN, et al: Pregnancy-associated acute myocardial infarction: a review of contemporary experience in 150 cases between 2006 and 2011. Circulation 129(16):1695, 2014b

Elliott P, Andersson B, Arbustini E, et al: Classification of the cardiomyopathies: a position statement from the European Society of Cardiology working group on myocardial and pericardial diseases. Euro Heart J 29:270, 2008

Elliott PM, Anastasakis A, Borger A, et al: 2014 ESC Guidelines on diagnosis and managemem of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 35(39):2733, 2014

Enriquez AD, Economy E, Tedrow UB: Contemporary management of arrhythmias during pregnancy. CircArrhythm ElectrophysioIt7(5):961, 2014

Erkut B, Kocak H, Becit N, et al: Massive pulmonary embolism complicated by a patem foramen ovale with straddling thrombus: report of a case. Surg Today 36:528,t2006

Esplin S, Clark SL: Ischemic heart disease and myocardial infarction during pregnancy. Contemp Ob/Gyn 44:27, 1999

Estensen M, Gude E, Ekmehag B, et al: Pregnancy in heart-and heartllung recipients can be problematic. Scand Cardiovasc J 45:349, 2011

Esteves CA, Munoz JS, Braga S, et al: Immediate and long-term follow-up of percutaneous balloon mitral valvuloplasty in pregnant patients with rheumatic mitral stenosis. Am J Cardiol 98:812, 2006

European Society of Cardiology (ESG), Association for European Paediatric Cardiology (AEPC) , German Society for Gender Medicine (DGesGM), et al: ESC guidelines on the management of cardiovascular diseases during pregnancy: the Task Force on the Managemem of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC). Eur Heart J 32(24):3147, 2011

Feinstein JA, Benson W, Dubin M, et al: Hypoplastic left heart syndrome: current considerations and expectations. J Am Coll CardioIt59:S1, 2012

Felker GM, Thompson E, Hare JM, et al: Underlying causes and long-term survival in patiems with initially unexplained cardiomyopathy. N Engl J Med 342:1077, 2000

Fong A, Lovell S, Gabby L, et al: Peripartum cardiomyopathy: demographics, antenatal factors, and a strong association with hypertensive disorders. Am J Obstet Gynecol 21 0:S254, 2014

Friedman T, Mani A, Eleteriades JA: Bicuspid aortic valve: clinical approach and scientific review of a common clinical emity. Expert Rev Cardiovasc Ther 6:235, 2008

Fryar CD, Chen T, Li X: Prevalence of uncontrolled risk factors for cardiovascular disease: United States, 1999-2010. NCHS Data Brief 103: 1, 20t12

Galal MO, Jadoon S, Momenah TS: Pulmonary valvuloplasty in a pregnant woman using sole transthoracic echo guidance: technical considerations. Can J CardioIt31(1):103.e5, 2015

Galie N, Humbert M, Vachiery JL, et al: 2015 ESc/ERC guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), Imernational Society for Heart and Lung Transplamation (ISHLT). Eur Heart J 37(1):67, 2016

Garabedian MJ, Hansen WF, Gianferrari A, et al: Epoprostenol treatment for idiopathic pulmonary arterial hypertension in pregnancy. J Perinatol 30:628,t2010

Gardin J, Schumacher 0, Constantine G, et al: Valvular abnormalities and cardiovascular status following exposure to dexfenluramine or phenterminel fenluramine. JAMA 283: 1703, 2000

Gei A, MontUfar-Rueda C: Pulmonary hypertension and pregnancy: an overview. Clin Obstet Gynecol (4):806,t2014

Gei AF, Hankins GO: Cardiac disease and pregnancy. Obstet Gynecol Clin North Am 28:465, 2001 Geva T, Martins JD, Wald RM: Atrial septal defects. Lancet 383(9932):1921, 2014

Gleicher N, Midwall J, Hochberger 0, et al: Eisenmenger's syndrome and pregnancy. Obstet Gynecol Surv 34:721, 1979

Goland S, Tsai F, Habib M, et al: Favorable ourcome of pregnancy with an elective use of epoprostenol and sildenail in women with severe pulmonary hypertension. Cardiology 115(3):205, 2010

Goya M, Mesequer ML, Merced C, et al: Successful pregnancy in a patient with pulmonary hypertension associated with mixed collagen vascular disease. J Obstet Gynaecol 34(2): 191, 2014

Greutmann M, Tobler 0, Kovacs AH, et al: Increasing mortality burden among adults with complex congenital heart disease. Congenit Heart Dis 10(2):117,t2015

Grewal J, Silvers ides CK, Colman JM: Pregnancy in women with heart disease: risk assessmem and management of heart failure. Heart Fail Clin 10(1): 117, 20t14

Gunderson EP, Croen LA, Chiang V, et al: Epidemiology of peripartum cardiomyopathy: incidence, predictors, and outcomes. Obstet Gynecol 118:583,t2011

Guo C, Xu 0, Wang C: Successful treatment for acute aortic dissection in pregnancy-Bentall procedure concomitant with cesarean section. J Cardiothorac Surg 6:139,t2011

Guy TS, Hill AC: Mitral valve prolapse. Annu Rev Med 63:277,t2012

Haas S, Trepte C, Rybczynski M, et al: Type A aortic dissection during late pregnancy in a patient with Marfan syndrome. Can J Anesth 58: 1024, 20 II

Habib G, Lancellotti P, Antunes MJ, et al: 2015 ESC Guidelines of the management of infective endocarditis: the TASK Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-horacic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J 36(44):3075,2015

Haghikia A, Podewski E, Berliner 0, et al: Rationale and design of a randomized, controlled multicenter clinical trial to evaluate the efect ofbromocriptine on left ventricular function in women with peripartum cardiomyopathy. Clin Res Cardiolt104(1l):911, 2015

Hameed A, khter M, Bitar F, et al: Left atrial thrombosis in pregnant women with mitral stenosis and sinus rhythm. Am J Obstet Gyneco1t193:50 1,2005

Hameed A, Karaalp IS, Tummala PP, et al: The efect of valvular heart disease on maternal and fetal outcome of pregnancy. J m Coll Cardiol 37:893, 200t1

Harper MA, Meyer RE, Berg CJ: Peripartum cardiomyopathy: populationbased birth prevalence and 7-year mortality. Obstet Gynecol 120:1013, 2012

Hassan N, Patenaude V, Oddy L, et al: Pregnancy outcomes in Marfan Syndrome: a retrospective cohort study. Am J PerinatoI30(2):123, 2015

Head CEG, horne SA: Congenital heart disease in pregnancy. Postgrad Med J 81 :292, 2005

Herrey AS: Pregnancy in inherited and acquired cardiomyopathies. Best Pract Res Clin Obstet Gynaecol 28(4):563, 2014

Hibbard JU, Lindheimer M, Lang M:A modiied deinition for peripartum cardiomyopathy and prognosis based on echocardiography. Obstet Gynecol 94:311,t1999

Hidaka N, Chiba Y, Fukushima K, et al: Pregnant women with complete atrioventricular block: perinatal risks and review of management. Pacing Clin Electrophysiol 34: 1161, 2011

Hidaka N, Chiba Y, Kurita T, et al: Is intrapartum temporary pacing required for women with complete atrioventricular block? An analysis of seven cases. BJOG 113:605,t2006

Hiliker-Kleiner 0, Haghikia A, Masuko 0, et al: Outcome of subsequent pregnancies in patients with a history of peripartum cardiomyopathy. Eur J Heart Fail March 27, 2017 [Epub ahead of print]

Hiliker-Kleiner 0, Sliwa K: Pathophysiology and epidemiology of peripartum cardiomyopathy. Nat Rev Cardiol 11(6):364,t2014

Hiratzka LF, Bakris G L, Beckman JA, et al: 2010 ACCF I AHAI ATSI ACRAl ASA/SCA/SCAIISIRISTS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society ofInterventional Radiology, Society of horacic Surgeons, and Society of Vascular Medicine. J Am ColI CardioIt55(l4):e27, 20t10

Hoen B, Duval X: Infective endocarditis. N Engl J Med 369(8):785, 2013

Hoendermis ES, Drenthen W, Sollie M, et al: Severe pregnancy-induced deterioration of truncal valve regurgitation in an adolescent patient with repaired truncus arteriosus. Cardiology 109: 177, 2008

Hsu CH, Gomberg-Maitland M, Glassner C, et al: The management of pregnancy and pregnancy-related medical conditions in pulmonary arterial hypertension patients. Int J Clin Pract Suppl 172:6, 2011

Hytten FE, Chamberlain G: Clinical Physiology in Obstetrics. Oxford, Blackwell, 1991

Iturbe-Alessio I, Fonseca MD, Mutchinik 0, et al: Risks of anticoagulant therapy in pregnant women with artiicial heart valves. N Engl J Med 315: l390, 1986

Jafe R, Gruber A, Fejgin M, et al: Pregnancy with an artiicial pacemaker.

Obstet Gynecol Surv 42: , 1987

James AH, Jamison MG, Biswas MS, et al: Acute myocardial infarction in pregnancy: a United States population-base study. Circulation 113: 1564, 2006 ]eejeebhoy FM, Zelop CM, Windrim R, et al: Management of cardiac arrest in pregnancy: a systematic review. Resuscitation 82:801, 2011

Jimenez-Juan L, Krieger EV, Valente AM, et al: Cardiovascular magnetic resonance imaging predictors of pregnancy outcomes in women with coarctation of the aorta. Eur Heart] Cardiovasc Imaging 15(3):299, 2014 ]oglar ]A, Page RL: Management of arrhythmia syndromes during pregnancy.

Curr Opin Cardiol 29(1):36, 2014

John AS, Gurley F, Schaf HV, et al: Cardiopulmonary bypass during pregnancy. Ann Tho rae Surg 91:1191,t2011

Kametas NA, McAulife F, Krampl E, et al: Maternal cardiac function in twin pregnancy. Obstet Gynecol 102:806,t2003

Kamiya CA, Iwamiya T, Neki R, et al: Outcome of pregnancy and efects on the right heart in women with repaired tetralogy of Fallor. Circ] 76:957, 2012

Kangavari 5, Collins ], Cercek B, et al: Tricuspid valve group B streptococcal endocarditis after an elective termination of pregnancy. Clin Cardiol 23:301,t2000

Karchmer A W: Infective endocarditis. In Longo Kasper DL, Fauci AS, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill,t2015

Karthikesalingam A, Vidal-Diez A, Holt P], et al: Thresholds for abdominal aortic aneurysm repair in England and the United States. N Engl ] Med 375(21):2051,t2016

Kebed Y, Bishu K, I Adham I, et al: Pregnancy and postpartum infective endocarditis: a systematic review. Mayo Clin Proc 89(8):1143, 2014

Keepanasseril A, Maurya DK, Suriya Y, et al: Complete atrioventricular block in pregnancy: report of seven pregnancies in a patient without pacemaker. BM] Case Rep, 2015. pii:bcr2014208618

Keizer ]L, Zwart]], Meerman RH, et al: Obstetric intensive care admission: a 12-year review in a tertiary care centre. Eurt] Obstet Gynecol Reprod BioI 128:152,t2006

Kenchaiah 5, Evans ]C, Levy D, et al: Obesiry and the risk of heart failure. N Englt] Med 347:305, 2002

Key TC, Resnik R, Dittrich HC, et al: Successful pregnancy after cardiac transplantation. Amt] Obstet GynecoIt160:367, 1989

Khairy P, Ouyang DW, Fernandes SM, et al: Pregnancy outcomes in women with congenital heart disease. Circulation 113:517, 2006

Khan A, Kim Y: Pregnancy in complex CHD: focus on patients with Fontan circulation and patients with a systemic right ventricle. Cardiol Young 25(8):1608,t2015

Kim M, Suhani R, SlogofS, et al: Central hemodynamic changes associated with pregnancy in a long-term cardiac transplant recipient. Am ] Obstet GynecoIt174:1651,t1996

Kizer ]R, Devereux RB: Patent foramen ovale in young adults with unexplained stroke. N Engl] Med 353:2361,t2005

Klingberg 5, Brekke HK, Winkvist A, et al: Parity, weight change, and maternal risk of cardiovascular events. Am] Obstet Gynecol 216(2): 172.e 1, 2017 Knotts R], Garan H: Cardiac arrhythmias in pregnancy. Semin Perinatol 38(5):285,t2014

Kolte D, Khera 5, Aronow WS, et al: Temporal trends in incidence and outcomes of peripartum cardiomyopathy in the United States: a nationwide population-based study. ] Am Heart Assoc 3(3):e001056, 2014

Koscica L, Anyaogu C, Bebbingron M, et al: Maternal levels of troponin I in patients undergoing vaginal and cesarean delivery. Obstet Gynecol 99:835, 2002 Krat K, Graf M, Karch M, et al: T akotsubo syndrome ater cardioplmonary resuscitation during emergency cesarean delivery. Obstet Gynecolt129:521, 2017

Krexi D, Sheppard MN: Pulmonary hypertensive vascular changes in lungs of patients with sudden unexpected death. Emphasis on congenital heart disease, Eisenmenger syndrome, postoperative deaths, and death during pregnancy and postpartum.] Clin PathoIt68(1):18, 2015

Krieger EV, Landzberg M], Economy E, et al: Comparison of risk of hypertensive complications of pregnancy among women with versus without coarctation of the aorta. Am] Cardiolt107:1529, 2011

Krul SP, van der Smagt]], van den Berg MP, et al: Systematic review of pregnancy in women with inherited cardiomyopathies. Euro ] Heart Failure 13:584,t2011

Kulas T, Habek D: Infective puerperal endocarditis caused by Escherichia coli. ] Perinat Med 34:342, 2006

Kuleva M, Youssef A, Maroni E, et al: Maternal cardiac function in normal twin pregnancy: a longitudinal study. Ultrasound Obstet Gynecol 38:575, 201t1

Ladner HE, Danielser B, Gilbert WM: Acute myocardial infarction in pregnancy and the puerperium: a population-based study. Obstet Gynecol 105:480, 2005

Lane CR, Trow TK: Pregnancy and pulmonary hypertension. Clin Chest Med 32:165,t2011

LaRue 5, Shanks A, Wang IW, et al: Let ventricular assist device in pregnancy.

Obstet Gynecol 118:426,t2011

Lawley CM, Lain 5], lgert CS, et al: Prosthetic heart valves in pregnancy, outcomes for women and their babies: a systematic review and meta-analysis. B]OG 122(11):1446,t2015

Lee LC, Bathgate SL, Macri C]: Arrhythmogenic right ventricular dysplasia in pregnancy. A case report.] Reprod Med 51:725, 2006

Ldniak-Sobelga A, Tracz W, Kostkiewicz M, et al: Clinical and echocardiographic assessment of pregnant women with valvular heart disease-maternal and fetal outcome. Int] Cardiol 94: 15, 2004

Leyh RG, Fischer 5, Ruhpatwar A, et al: Anticoagulation for prosthetic heart valves during pregnancy: is low-molecular-weight heparin an alternative? Eur] Cardiothorac Surg 21:577,t2002 Leyh RG, Fischer 5, Ruhpatwar A, et al: Anticoagulation therapy in pregnant women with mechanical valves. Arch Gynecol Obstet 268: 1, 2003 Li W, Li H, Long Y: Clinical characteristics and long-term predictors of persistent left ventricular systolic dysfunction in peripartum cardiomyopathy. Can] CardioIt32:362, 2016 Lin LT, Tsui KH, Change R, et al: Management of recurrent and refractory ventricular tachycardia in pregnancy. Taiwan] Obstet Gynecol 54(3):319,t2015 Lindley K], Conner SN, Cahill AG: Adult congenital heart disease in pregnancy. Obstet Gynecol Surv 70(6):397,t2015 Link MS: Evaluation and initial treatment of supraventricular tachycardia. N Engl] Med 367:1438, 2012 Lu CW, Shih ]C, Chen SY, et al: Comparison of 3 risk estimation methods for predicting cardiac outcomes in pregnant women with congenital heart disease. Circt] 79(7):1609, 2015 Lupton M, Oteng-Ntim E, Ayida G, et al: Cardiac disease in pregnancy. Curr Opin Obstet GynecoIt14:137, 2002 Maron B]: Hypertrophic cardiomyopathy: an important global disease. Amt] Med 116:63, 2004 Maron B], Towbin ]A, Thiene G, et al: Contemporary deinitions and classification of the cardiomyopathies an merican Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research nd Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation 113:1807,2006

Martin RB, Nelson DB, Stewart R, et al: Impact of pregnancy on maternal cardiac atria. Abstract No. 508, Am] Obstet Gynecol 216:5632, 2017 McLintock C: Anticoagulant therapy in pregnant women with mechanical prosthetic heart valves: no easy option. hromb Res 127:556,t2011

McLintock C: Thromboembolism in pregnancy: challenges and controversies in the prevention of pregnancy-associated venous thromboembolism and management of anticoagulation in women with mechanical prosthetic heart valves. Best Pract Res Clin Obstet GynecoIt28(4):519, 2014

McNamara DM, Elkayam U, Alharethi R, et al: Clinical outcomes for peripartum cardiomyopathy in North America: results of the IPAC study (investigations of pregnancy-associated cardiomyopathy). ] Am Coll Cardiol 66(8):905, 2015

Meijboom L], Drenthen W, Pieper PG, et al: Obstetric complications in Marfan syndrome. Intit] Cardiol 110:53, 2006

Melchiorre K, Sharma R, Khalil A, et al: Maternal cardiovascular function in normal pregnancy: evidence of maladaptation to chronic volume overload. Hypertension 67(4):754, 2016

Meng ML, Landau R, Viktorsdottir 0, et al: Pulmonary hypertension in pregnancy: a report of 49 cases at four tertiary North American sites. Obstet GynecoIt129(3):511,t2017

Miller BR, Strubian D, Sundararajan 5: Stroke in the young: patent foramen ovale and pregnancy. Stroke 46(8):e181, 2015

Miniero R, Tardivo I, Centofanti P, et al: Pregnancy in heart transplant recipients. ] Heart Lung Transplant 23:898, 2004

Mohamed-Ahmed 0, Nelson-Piercy C, Bramham K, et al: Pregnancy outcomes in liver and cardiothoracic transplant recipients: a UK national cohort study. PLoS One 9(2):e89151, 2014

Moioli M, Mendada MV, Bentivoglio G, et al: Peripartum cardiomyopathy.

Arch Gynecol Obstet 281:183, 2010

Mousa A, McKinley CA, hongt]: Acute postpartum myocardial infarction after ergometrine administration in a woman with familial hypercholesterolaemia. B]OG 107:939,t2000

Mul TFM, van Herwerden A, Cohen-Overbeek TE, et al: Hypoxic-ischemic fetal insult resulting from maternal aortic root replacement, with normal fetal heart rate at term. Am ] Obstet Gynecol 179:825, 1998

Murray ML, Pepin M, Peterson 5, et al: Pregnancy-related deaths and complications in women with vascular Ehlers-Danlos syndrome. Genet Med 16(12):874,t2014

Nanna M, Stergiopoulos K: Pregnancy complicated by valvular heart disease: an update.t] Am Heart Assoc 3:e000712, 2014

Nappi F, Spadaccio C, Chello M, et al: Impact of structural valve deterioration on outcomes in the cryopreserved mitral homograft valve. ] Card Surg 29(5):616,t2014

Nelson DB, Martin R, Stewart D, et al: The forgotten ventricle. Right ventricular remodeling across pregnancy and postpartum. Abstract No. 641. Am] Obstet GynecoIt216;S376, 2017

Newman T, Cafardi ]M, Warshak CR: Human immunodeiciency virusassociated pulmonary arterial hypertension diagnosed postpartum. Obstet Gynecol 125(1):193,t2015

Nishimura A, Otto CM, Bonow RO, et al: 2014 AHNACC guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiologyl American Heart Association Task Force on Practice Guidelines.] Thorac Cardiovasc 148(1):e1, 2014

Nishimura A, Otto CM, Bonow RO, et al: 2017 AHIACC focused update of the 2014 AHAIACC Guideline for the Management of Patients with Valvular Heart Disease: A Report of the American College of Cardiologyl American Heart Association Task Force on Clinical Practice Guidelines. Circulation 135(25):el159, 2017

Ntusi NB, Badri M, Gumedze F, et al: Pregnancy-associated heart failure: a comparison of clinical presentation and outcome berween hypertensive heart failure of pregnancy and idiopathic peripartum cardiomyopathy. PLoS One 10(8):e0133466, 2015

Obican SG, Cleary KL: Pulmonary arterial hypertension in pregnancy. Semin Perinatol 35(5):289, 2014

O'Gara PT, Greenfield A], Afridi NA, et al: Case 12-2004: a 38-yearold woman with acute onset of pain in the chest. N Engl ] Med 350:16, 2004

OosterhofT, Meijboom F], Vliegen HW, et al: Long-term follow-up of homograft function after pulmonary valve replacement in patients with tetralogy of Fallor. Eur Heart] 27: 1478, 2006

Opotowsky AR, Siddiqi OK, D'Souza B, et al: Maternal cardiovascular events during childbirth among women with congenital heart disease. Heart 98:145,t2012

Pacheco LD, Saade GR, Hankins GD: Acute myocardial infarction during pregnancy. Clin Obstet Gynecol 57(4):835, 2014

Page RL, ]oglar ]A, Caldwell MA, et al: 2015 ACCIAHAlHRS guideline for the management of adult patients with supraventricular tachycardia: executive summary. Circulation 133:e471, 2015

Papatsonis DNM, Heetkamp A, van den Hombergh C, et al: Acute type A aortic dissection complicating pregnancy at 32 weeks: surgical repair after cesarean section. Am] Perinatol 26: 153, 2009

Pappone C, Santinelli V, Manguso F, et al: A randomized study of prophylactic catheter ablation in asymptomatic patients with the Wolf-Parkinson-Whi te syndrome. N Englt] Med 349: 1803, 2003

Patten IS, Rana S, Shahul S, et al: Cardiac angiogenic imbalance leads to peripartum cardiomyopathy. Nature 485:333,t2012

Pearson GD, Veille Jc, Rahimtoola S, et al: Peripartum cardiomyopathy.

National Heart, Lung, and Blood Institute and Oice of Rare Diseases (National Institutes of Health) workshop recommendations and review. ]AMA 283: 1183, 2000

Penning S, Robinson KD, Major CA, er al: A comparison of echocardiography and pulmonary artery catheterization for evaluation of pulmonary artery pressures in pregnant patients with suspected pulmonary hypertension. Am ] Obstet Gynecol 184:1568,t2001

Pepin M, Schwarze U, Superti-Furga A, et al: Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med 342:6 3, 2000

Pessel C, Bonanno C: Valve disease in pregnancy. Semin Perinatal 38(5):273, 20t14

Pierce D, Calkins BC, hornton K: Infectious endocarditis: diagnosis and treatment. Am Fam Physician 85:981, 2012

Pijuan-Domenech A, Galian L, Goya M, et al: Cardiac complications during pregnancy are better predicted with the modiied WHO risk score. Int ] Cardiol 195:149,t2015

Pinski SL, Trohman RG: Interference in implanted cardiac devices, part II.

Pacing Clin Electrophysiol 25(10):1496, 2002

Pitton A, Petolillo M, Munegato E, et al: Hypertrophic obstructive cardiomyopathy and pregnancy: anesthesiological observations and clinical series. Minerva Anesthesiol 73:313,t2007

Pombar X, Strassner HT, Fenner PC: Pregnancy in a woman with class H diabetes mellitus and previous coronary artery bypass graft: a case report and review of the literature. Obstet Gynecol 85:825, 1995

Pyatt ]R, Dubey G: Peripartum cardiomyopathy: current understanding, comprehensive management review and new developments. Postgrad Med ] 87:34,t2011

Raman AS, Sharma S, Hariharan: Minimal use of luoroscopy to reduce fetal radiation exposure. Tex Heart Inst] 42(2):152,t2015

Ramzyt], New G, Cheong A, et al: Iatrogenic anterior myocardial infarction secondary to ergometrine-induced coronary artery spasm during dilation and curettage for an incomplete miscarriage. Int J Cardiol 198: 154, 2015

Rashba E], Zareba W, Moss A], et al: Inluence of pregnancy on the risk for cardiac events in patients with hereditary

QT syndrome. Circulation 97:451, 1998

Ray WA, Murray KT, Hall K, et al: Azithromycin and the risk of cardiovascular death. N Engl ] Med 366: 1881, 2012

Redield MM: Heart failure with preserved ejection fraction. N Englt] Med 375(19):1868,t2016

Reich 0, Tax P, Marek ], et al: Long term results of percutaneous balloon valvoplasty of congenital aortic stenosis: independent predictors of outcome. Heart 90:70, 2004

Rich S, McLaughlin W: Pulmonary hypertension. In Zipes DP (ed):

Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 7th ed. Philadelphia, Saunders, 2005

Robins K, Lyons G: Supraventricular tachycardia in pregnancy. Br ] Anaesth 92: 140, 2004

Roden DM: Drug-induced prolongation of the QT interval. N Engl ] Med 350:1013,t2004

Roden DM: Long-QT syndrome. N Engl] Med 358:169, 2008

Roeder HA, Kuller ]A, Barker PC, et al: Maternal valvular heart disease in pregnancy. Obstet Gynecol Surv 66:561,t2011

Rowan ]A, McCowan LM, Raudkivi P], et al: Enoxaparin treatment in women with mechanical heart valves during pregnancy. m ] Obstet Gynecol 185:633,t2001

Russo ML, Gandhi M, Morris SA: Aortic dissection in pregnancy-a Texas population-based study. Abstract No. 769. Am] Obstet GynecoI216:S445, 2017

Ruys TP, Roos-Hesselinkt]W, Hall R, et al: Heart failure in pregnant women with cardiac disease: data from the ROPAC. Heart 100(3):231,t2014

Ruys TP, Roos-Hesselink ]W, Pijuan-Domenech A, et l: Is a planned caesarean section in women with cardiac disease beneicial? Heart 101(7):530, 2015

Savu 0, ]urcuf R, Giu§ca S, et al: Morphological and functional adaptation of the maternal heart during pregnancy. Circ Cardiovasc Imaging 5:289,t2012 Sawhney H, Aggarwal N, Suri V, et al: Maternal and perinatal outcome in rheumatic heart disease. Intt] Gynaecol Obstet 80:9, 2003

Schade R, Andersohn F, Suissa S, et al: Dopamine agonists and the risk of cardiac-valve regurgitation. N Engl] Med 356:29, 2007

Schinkel AF: Pregnancy in women with hypertrophic cardiomyopathy. Cardio Rev 22(5):217,t2014

Schulte-Sasse U: Life threatening myocardial ischaemia associated with the use of prostaglandin EI to induce abortion. B]OG 107:700,t2000

Seaworth B], Durack DT: Infective endocarditis in obstetric and gynecologic practice. Am] Obstet Gynecol 154: 180, 1986

Seeburger ], Wilhelm-Mohr F, Falk V: Acute type A dissection at 17 weeks of gestation in a Marfan patient. Ann Thorac Surg 83:674, 2007

Seshadri S, Oakeshott P, Nelson-Piercy C, et al: Prepregnancy care. BM] 344:34,t2012

Seth R, Moss A], McNitt S, et al: Long QT syndrome and pregnancy. ] Am ColI Cardiol 49: 1 092, 2007

Sheield ]S, Cunningham FG: Diagnosing and managing peripartum cardiomyopathy. Contemp Ob/Gyn 44:74, 1999 Sheield ]S, Cunningham FG: Thyrotoxicosis and heart failure that complicate pregnancy. Am] Obstet GynecoIt190:211, 2004

Sherer DM: Coarctation of the descending thoracic aorta diagnosed during pregnancy. Obstet Gynecol 100: 1 094, 2002

Shivvers SA, Wians FH ]r, Kefer ]H, et al: Maternal cardiac troponin I levels during normal labor and delivery. Am] Obstet Gynecol 180: 122, 1999

Shrof H, Benenstein R, Freedberg R, et al: Mitral valve Libman-Sacks endocarditis visualized by real time three-dimensional transesophageal echocardiography. Echocardiography 29:E 100, 2012

Silversides CK, Harris L, Haberer K, et al: Recurrence rates of arrhythmias during pregnancy in women with previous tachyarrhythmia and impact on fetal and neonatal outcomes. n1 ] Cardiol 97: 1206, 2006

Simpson LL: Matenal cardiac disease: update for the clinician. Obstet Gynecol 119:345,t2012

Sims DB, Vinkt], Uriel N, et al: A successful pregnancy during mechanical circulatory device support.] Heart Lung Transplant 30:1065,t2011

Siu SC, Colman ]M: Congenital heart disease: heart disease and pregnancy.

Heart 85:710, 2001a

Siu Sc, Sermer M, Colman ]M, et al: Prospective multicenter study of pregnancy outcomes in women with heart disease. Circulation 104:515, 200t1b

Siva A, Shah AM: Moderate mitral stenosis in pregnancy: the haemodynamic impact of diuresis. Heart 91t:e3, 2005

Sliwa K, Blauwet L, Tibazarwa K, et al: Evaluation of bromocriptine in the treatment of acute severe peripartum cardiomyopathy: a proof-of-concept pilot study. Circulation 121:1465,t2010

Small M), James AH, Kershaw T, et al: Near-miss maternal mortality: cardiac dysfunction as the principal cause of obstetric intensive care unit admissions. Obstet Gynecol 119:250, 2012

Smith I), Gillham MJ: Fulminant peripartum cardiomyopathy rescue with extracorporeal membranous oxygenation. Int) Obstet Anesth 18: 186, 2009

Smok DA: Aortopathy in pregnancy. Semin PerinatoIt38(5):295, 2014

Stergiopoulos K, Shiang E, Bench T: Pregnancy in patients with pre-existing cardiomyopathies.t) m Coli Cardiol 58:337, 2011

Stewart RD, Nelson DB, Matulevicious SA, et al: Cardiac magnetic resonance imaging to assess the impact of maternal habitus on cardiac remodeling during pregnancy. m) Obstet Gynecol 214(5):640.e1, 2016

Sutaria N, O'Toole L, Northridge 0: Postpartum acute MI following routine ergometrine administration treated successfully by primary PTCA. Heart 83:97,t2000

Thaman R, Varnava A, Hamid MS, et al: Pregnancy related complications in women with hypertrophic cardiomyopathy. Heart 89:752, 2003 hompson )L, Kuklina EV, Bateman BT, et al: Medical and obstetric outcomes among pregnant women with congenital heart disease. Obstet Gynecol 126(2):346,t20t15

Thorne S, MacGregor A, Nelson-Piercy C: Risks of contraception and pregnancy in heart disease. Heart 92(10):152, 2006

Thurman R, Zafar N, Sayyer P, et al: Labour profile and outcomes in pregnant women with heart disease. Abstract No. 799. Amt) Obstet Gynecol 216:S459,t2017

Trigas V, Nagdyman N, Pildner von Steinburg S, et al: Pregnancy-related obstetric and cardiologic problems in women after atrial switch operation for transposition of the great arteries. Circ) 78(2):443, 2014

Tuzcu V, Gul EE, Erdem A, et al: Cardiac interventions in pregnant patients without luoroscopy. Pediatr Cardiol 36(6): 1304,t2015 Van Hagen 1M, Roose-Hesselink)W, Ruys TP, et al: Pregnancy in women with a mechanical heart valve: data of the European Society of Cardiology Registry of Pregnancy and Cardiac Disease (ROPAC). Circulation 132(2):132,t2015 Vashisht A, Katakam N, Kausar S, et al: Postnatal diagnosis of maternal congenital heart disease: missed opportunities. BM) Case Rep, 2015. pii: bcr2015209938

Vinatier 0, Virelizier S, Depret-Mosser S, et al: Pregnancy after myocardial infarction. Eur) Obstet Gynecol Reprod Bioi 56:89, 1994

Vitarelli A, Capotosto L: Role of echocardiography in the assessment and management of adult congenital heart disease in pregnancy. Int ) Cardiovasc Imaging 27:843,t201t1

Vos R, Ruttens 0, Verleden SE, et al: Pregnancy ater heart and lung transplantation. Best Pract Res Clin Obstet Gynecol 28(8): 1146, 2014

Wang H, Zhang W, Liu T: Experience of managing pregnant women with Eisenmenger's syndrome: maternal and fetal outcome in 13 cases. ) Obstet Gynaecol Res 37:64,t2011

Ware )S, Seidman )G, Arany Z: Shared genetic predisposition in peripartum and dilated cardiomyopathies. N Engl) Med 374(26):2601,t2016

Warnes CA: Pregnancy and delivery in women with congenital heart disease.

Circ) 79(7):1416, 2015

Watkins H, Ashrafian H, Redwood C: Inherited cardiomyopathies. N Englt) Med 364:1643, 2011

Weiss BM, Zemp L, Seifert B, et al: Outcome of pulmonary vascular disease in pregnancy: a systematic overview from 1978 through 1996. ) m Coll CardioIt31:1650, 1998

Wilson W, Taubert A, Gewitz M, et al: Prevention of infective endocarditis.

Guidelines from the American Heart Association. Circulation 116: 1736, 2007

World Health Organization: Medical eligibility for contraceptive use, 4th ed. 2009. Geneva, World Health Organization, 2010

Wylie B), Epps KC, Gaddipati S, et al: Correlation of transthoracic echocardiography and right heart catheterization in pregnancy. ) Perinat Med 35(6):497, 2007

Xia W, Messerlian AK, Mackleyt), et al: Successful epidural anesthesia for cesarean section in a parturient with severe aortic stenosis and a recent history of pulmonary edema-a case report. ) Clin Anesth 18: 142, 2006

YangX, Wang H, Wang Z, et al: Alteration and signiicance of serum cardiac troponin I and cystatin C in preeclampsia. Clin Chim Acta 374: 168, 2006

Yu M, Yi K, Zhou L, et al: Pregnancy increases heart rates during paroxysmal supraventricular tachycardia. Can) Cardiol 31(6):820.e5, 2015

Zanettini R, Antonini A, Gatto G, et al: Valvular heart disease and the use of dopamine agonists for Parkinson's disease. N Englt) Med 356:39, 2007

Zeeman GG: Obstetric critical care: a blueprint for improved outcomes. Crit Care Med 34:S208, 2006

Zwiers WJ, Blodgett TM, Vallejo MC, et al: Successful vaginal delivery for a parturient with complete aortic coarctation.) Clin Anesth 18:300,t2006

GENERAL CONSIDERATIONS ..................... 975 DIAGNOSIS AND EVALUATION IN PREGNANCY ...... 977

ADVERSE PREGNANCY EFFECTS ...................978

ANTIHYPERTENSIVE DRUGS ....i....i....i....i.......... 980

ANTIHYPERTENSIVE TREATMENT IN PREGNANCY ... 981

SUPERIMPOSED PREECLAMPSIA .................. 983

FETAL ASSESSMENT ....i.........i............... 983

DELIVERY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 983

POSTPARTUM CARE ............................ 984

A smal proportion of women suiringrom chronic nephritis had eclampsia. For the most part, autopsy wil reveal the presence of renal changes usualy of acute nephritis, though occasionaly it may be engrafied upon a chronic process.

-J. Whitridge Williams (1903)

At the time of Wiliams Obstetrics' first edition, little attention was paid to blood pressure changes, even with "toxemia." At that time, chronic hypertension was designated "senile" and thought to develop only in older individuals (Lindheimer, 2015). Indeed, chronic hypertension is not mentioned, per se, in Williams' 1903 textbook, except for some deference given to chronic anatomical renal changes occasionally associated with eclampsia.

It is now apparent that chronic hypertension is one of the most common serious complications encountered during pregnancy. his is not surprising because, according to the National the Centers for Disease Control and Prevention (2011), the prevalence of hypertension in women aged 18 to 39 years approximates 7 percent.

he incidence of chronic hypertension complicating pregnancy varies depending on population vicissitudes. In a study of more than 56 million births from the Nationwide Patient Sample, the incidence was 1.8 percent (Bateman, 2012). And, in more than 878,000 pregnancies from the Medicaid Analytic Extract, 2.3 percent were complicated by chronic hypertension (Bateman, 2015). Despite this substantive prevalence, optimal management has not been well studied. It is known that chronic hypertension usually improves during early pregnancy. his is followed by variable behavior later in pregnancy and, importantly, by the unpredictable development of superimposed preeclampsia. The latter carries increased risks for maternal and perinatal morbidity and mortality.

To define chronic hypertension, the range of normal blood pressure must irst be established. This is not a simple task because, like all polygenically determined biological variants, blood pressure norms difer between populations. And, within these norms, wide variations are found between individuals. Moreover, numerous epigenetic factors inluence presentation. For example, not only do blood pressures vary between races and genders, but pressures-especially systolic-rise directly with increasing age and weight. Thus, pragmatically, normal adults have a broad range of blood pressures, but so do those with chronic hypertension. And finally, resting blood pressure measurements do not reflect daily activities.

After these variables are acknowledged, important considerations for any population are the attendant risks of chronic hypertension. It is a leading cause of death and accounts for nearly 15 percent of mortality worldwide. Approximately 65 million Americans have hypertension, and this number is growing concurrently with epidemic obesity (Kotchen, 2015). Hypertension increases substantively the risk of cardiovascular disease, coronary heart disease, congestive heart failure, stroke, renal failure, and peripheral arterial disease (Forouzanfar, 2017).

For the foregoing reasons, chronic hypertension would logically be deined as some level of sustained resting blood pressure that is associated with acute or long-term adverse efects. In this regard, most consider 140/90 mm Hg as the upper limit of normal for blood pressure values. But, in the United States, these values are based primarily on actuarial tables constructed using data derived from white adult males and compiled by life insurance companies. These "norms" disregard interrelated factors such as ethnicity, gender, and other important covariants. he importance of race, for example, was emphasized by Kotchen (2015), who cites the incidence of hypertensiondeined as blood pressurea> 140/90 mm Hg-to be 34 percent in blacks, 29 percent in whites, and 21 percent in Mexican Americans.

For many years, the Joint National Committee has promulgated guidelines for diagnosis, classification, and management of chronic hypertension. In 2008, the National Heart, Lung, and Blood Institute discontinued these guidelines, and the Joint National Committee 8 GNC 8) was instead asked to provide an evidence-based review Games, 2014). Findings pertinent to caring for young women with chronic hypertension are summarized in Table

Proven benefits accrue with treatment of otherwise normal adults who have sustained hypertension. Numerous studies evaluating many combinations of antihypertensive therapy have been conducted. Importantly, these trials evaluated monotherapy versus combination therapeutic regimens and their ethnospecific beneits. Most evaluated cardiovascular outcomes, but many also confirmed risk reductions in rates of cerebrovascular accident, renal insuficiency, and mortality. Because of these incontrovertible beneits, the JNC 8 recommends the management outlined in Table 50-1.

Thus, even for mildly elevated blood pressure, interventions to reduce these sequelae are beneficial (SPRINT Research Group, 2015). Moreover, antihypertensive therapy in nonpregnant reproductive-aged women with sustained diastolic pressures ::90 mm Hg is considered standard. Not clear from these observations, however, is what constitutes the best management for women being treated who contemplate pregnancy, for those undergoing treatment who become pregnant, or for those first identified to have chronic hypertension during pregnancy (August, 2015). In these women, the benefits and safety of instituting antihypertensive therapy are less clear, as subsequently discussed on page 981.

Women with chronic hypertension are ideally counseled before pregnancy. The duration of hypertension, degree of blood pressure control, and current therapy are ascertained. hose women who require multiple medications for control or those who are poorly controlled carry greater risk for adverse pregnancy outcomes. Home measurement devices are checked for accuracy. General health, daily activities, and dietary habits are also assessed (Table 50-2).

For hypertensive women with disease lasting longer than 5 years or with comorbid diabetes, cardiovascular and renal function is assessed (August, 2015; Gainer, 2005). Women with evidence for organ dysfunction or those with prior adverse events such as a stroke, myocardial infarction (MI), arrhythmias, or ventricular failure are at markedly higher risk for a recurrence or worsening dysfunction during pregnancy. Renal function is evaluated by serum creatinine measurement. Also, if

TABLE 50-1. Eighth Joint National Committee (JNC 8}-2014 Chronic Hypertension Guidelines and Recommendations

Lifestyle modifications endorsed from the Lifestyle Work Group (Eckel, 2013)

Recommend selection among four specific medication classes: angiotensin-converting enzyme inhibitors (ACE-I), angiotensin-receptor blockers (ARB), calcium-channel blockers, or diuretics:

General population: <60 years old-initiate pharmacological therapy to lower diastolic pressure :;90 mm Hg and systolic pressuren:;140 mm Hg Diabetics: lower pressure to < 140/90 mm Hg

Chronic kidney disease: lower pressure to < 140/90 mm Hg. Also add ACE-lnor ARB to improve outcomes

General non black population: initial therapy should include thiazide-type diuretic, calcium-channel blocker, ACE-I, or ARB General black population: primary antihypertensive therapy should include thiazide-type diuretic or calcium-channel blocker Assess monthly, and after 1 month, if goals not met, then increase primary drug dose or add second drug. If no response, increase either or add third drug; then if no response, refer to hypertension specialist

Summarized from James, 201a4.

TABLE 50-2. Lifestyle Modifications for Hypertensive Patients

Consume a dietary pattern that emphasizes intake of vegetables, fruits, and whole grains; includes low-fat dairy products, poultry, fish, legumes, nontropical vegetable oils, and nuts; limits sweets and red meats. Examples are DASH, USDA Food Pattern, or the AHA Diet

Engage in aerobic physical activity three to four sessions per week, lasting on average 40 minutes per session, and involving moderate-to-vigorous intensity physical activity

Moderation of alcohol consumption

AHA = American Heart Association; DASH = Dietary Approaches to Stop Hypertension; USDA = United States Department of Agriculture.

Summarized from Eckel, 2013; Kotchen, 2015.

a urine spot protein/creatinine ratio is abnormally high (>0.3), proteinuria is further quantified with a 24-hour urine collection (Hladunewich, 2011; Kuper, 2016; Morgan, 2016a). The Working Group Report on High Blood Pressure in Pregnancy (2000) of the National Heart, Lung, and Blood Institute concluded that the risks of fetal loss and accelerated renal disease deterioration are increased if the serum creatinine level is above 1.4 mg/dL (Chap. 53, p. 1034).

Although pregnancy is considered by many to be contraindicated in women with severe, poorly controlled hypertension, there is no consensus. Certainly, women who maintain persistent diastolic pressures ::110 mm Hg despite therapy; require multiple antihypertensives; have a serum creatinine level > 2 mg/ dL; or have a history of prior stroke, MI, or cardiac failure must be counseled as to the marked risks to themselves and to their pregnancy outcome.

he hypertensive disorders that uniquely complicate pregnancy are discussed in Chapter 40 (p. 710). Women are diagnosed with chronic hypertension if it is documented to precede pregnancy or ifhypertension is identified before 20 weeks' gestation. Evidence also supports that prehypertension may herald adverse outcomes similar to those in women with chronic hypertension (Rosner, 2017). In some women without overt chronic hypertension, a history of repeated pregnancies complicated by gestational hypertension, with or without the preeclampsia syndrome, may be elicited. Each is a risk marker for latent chronic hypertension, and this is especially so for preeclampsia, and in particular early-onset preeclampsia. In many ways, gestational hypertension is analogous to gestational diabetes in that such women have a chronic hypertensive diathesis, in which heredity and environment playaa major role.

Although uncommon, secondary causes of hypertension are always a possibility in afected women. Thus, consideration is given to underlying chronic renal disease, connective-tissue disease, primary aldosteronism, Cushing syndrome, pheochromocytoma, and myriad other causes. That said, most pregnant women with antecedent hypertension will have otherwise uncomplicated disease.

Several factors increase the likelihood that pregnant women will have chronic hypertension. hree of those most frequently cited are ethnicity, obesity, and diabetes. As previously dis cussed, chronic hypertension has a population incidence that women (Kotchen, 2015). Related to this, hundreds of blood identified, including candidate genes for preeclampsia and chronic hypertension (Cowley, 2006; Ward, 2015).

The metabolic syndrome is a clinical cluster that includes hypertension, high blood sugar, excess fat at the waist, and abnormal cholesterol or triglyceride levels. This constellation is a risk marker for superimposed preeclampsia and for persistent postpartum hypertension Qeyabalan, 2015; Spaan, 2012). This is not surprising because obesity may increase the prevalence of chronic hypertension tenfold (Chap. 48, p. 938). In addition, obese women are more likely to develop superimposed preeclampsia. Diabetes is also prevalent in chronically hypertensive women, and its interplay with obesity and preeclampsia is overwhelming (Leon, 2016). In aforementioned study from the Nationwide Patient Sample, the most frequent comorbidities associated with chronic hypertension were pregestational diabetes-6.6 percent, thyroid disorders-4.1 percent, and collagen-vascular disease-0.6 percent (Bateman, 2012). Similar comorbidities were described by Cruz and associates (201a1).

• Efects of Pregnancy on

Blood pressure drops in early pregnancy in most women with chronic hypertension, and it rises again during the third trimester (Fig.

According to studies by Tihtonen and coworkers (2007), women with chronic hypertension have persistently elevated vascular resistance and possibly reduced intravascular volume expansion. Adverse outcomes in these women are dependent largely on whether superimposed preeclampsia develops. This may be related to observations reported by Hibbard and colleagues (2005, 2015) that arterial mechanical properties are most marked in women with superimposed preeclampsia.

.120 Chronic hypertension )..:ln 100 n (yellow) compared with blood pressures across pregnancy in 4589 healthy nulliparas (blue). (Data from August, 2015; Levine, 1997;

Sibai, 1990a.)

Chronic hypertension is associated with several adverse maternal and perinatal outcomes listed in Table 50-3. In sum, these adversities are directly related to severity and duration of hypertension before pregnancy and whether superimposed preeclampsia develops, especially early in gestation. Importantly, in women with mild chronic hypertension, outcomes are also related to blood pressure levels during pregnancy. At this time, however, there are no proven benefits of "tight" versus "lesstight" control of chronic hypertension during pregnancy, as discussed later (p. 982) (Magee, 2015).

Most women whose chronic hypertension is well controlled with therapy before pregnancy will do well. Even these women, however, are at increased risk for adverse outcomes. Complications are more likely with severe baseline hypertension and

TABLE 50-3. Some Adverse Efects of Chronic Hypertension on Maternal and Perinatal Outcomes

HELLP = hemolYSiS, elevated liver enzyme levels, low platelet cou nt.

especially with documented end-organ damage (Czeizel, 2011; Odibo, 2013). In a study of pregnancy outcomes in nearly 30,000 chronically hypertensive women, Gilbert and associates (2007) reported markedly increased rates of maternal morbidity that included stroke, pulmonary edema, and renal failure. hese observations were verified in the report from the Nationwide Patient Sample by Bateman and colleagues (2012). In this latter study, hypertension complications included stroke-2.7 per 1000, acute renal failure-5.9 per 1000, pulmonary edema-1.5 per 1000, mechanical ventilation-3.8 per 1000, and in-house maternal mortality-O.4 per 1000. he contribution of hypertension to pregnancy-related strokes is discussed in Chapter 60 (p. 1160) and to hypertensive and idiopathic peripartum cardiomyopathy in Chapter 49 (p. 963).

Pregnancy-aggravated hypertension may be due to gestational hypertension or to superimposed preeclampsia. In either instance, blood pressures can be dangerously elevated. As emphasized by Clark and Hankins (2012), systolic pressure :::160 mm Hg or diastolic pressure :::110 mm Hg will rapidly cause renal or cardiopulmonary dysfunction or cerebral hemorrhage. With superimposed severe preeclampsia or eclampsia, the maternal prognosis is poor unless the pregnancy is ended. Placental abruption is a common and serious complication (Chap. 41, p. 767). In addition to hypertensive heart failure mentioned above, aortic dissection was described by Weissman-Brenner and coworkers (2004) and is discussed in Chapter 49 (p. 967).

In aggregate, chronic hypertension is associated with a fivefold risk for maternal death (Gilbert, 2007). his is emphasized by the report by Creanga and colleagues (2015) describing 3358 pregnancy-related deaths in the United States from 2006 through 2010. Hypertensive disorders, including chronic hypertension and preeclampsia syndrome, accounted for 9.4 percent of these deaths. Undoubtedly related were other causes of death such as cardiovascular conditions-14.6 percent, cerebrovascular conditions-6.2 percent, and cardiomyopathy-11.8 percent. Moodley (2007) reported similar indings with 3406 maternal deaths from South Africa.

Because superimposed preeclampsia is not precisely defined in women with chronic hypertension, the reported incidence varies from 13 to 40 percent (American College of Obstetricians and Gynecologists, 2013; Bramham, 2016; Kim, 2016b; Moussa, 2017). August and colleagues (2015) posit that this predilection may stem from similar genetic, biochemical, and metabolic abnormalities. For example, the risk for superimposed preeclampsia is directly related to the severity of baseline hypertension (Ankumah, 2014; Morgan, 2016b). In a Maternal-Fetal Medicine Units (MFMU) Network trial, Caritis and coworkers (1998) identiied superimposed preeclampsia in 25 percent of hypertensive gravidas. he rate was 29 percent in a California database study (Yanit, 2012). And, women whose hypertension becomes severe enough to warrant chronic antihypertensive therapy during pregnancy are at inordinately high risk for superimposed preeclampsia (Morgan, 2016a). And, this risk is even higher if there is baseline proteinuria. Finally, and women at high risk for preeclampsia (Henderson, 2014). The recommendation to initiate 81 mg between 12 and 28 weeks' gestation and continue therapy until delivery was adopted by the American College of Obstetricians and Gynecologists (2016b). In addition to chronic hypertension, indications for aspirin prophylaxis for those at high-risk of preeclampsia include a history ofpreeclampsia, multifetal gestation, diabetes, renal disease, and autoimmune disease.

Antioxidants to prevent preeclampsia have been studied.

with chronic hypertension to treatment with vitamins C and E or with a placebo. A similar number in both groups developed preeclampsia-17 versus 20 percent, respectively.

FIGURE 50-2 Blood pressure trends in treated, chronically hypertensive women with and without superimposed preeclampsia. Mean maternal pressures (MAPs) at entry (p = 0.002) and throughout gestation (p <0.001) are significantly diferent for each group. MAP nadir at 23.3 weeks (95% CI, 22.5-24.1) for superimposed preeclampsia versus 26.4 weeks (95% CI, 22.5-27.6) for those without preeclampsia is significant (3.1 weeks, 95% (I, 2.3-4.3). (Data from Morgan, 2016a.) shown in Figure 50-2, chronically hypertensive women destined to develop severe superimposed preeclampsia have higher initial blood pressures that nadir earlier than those of women who do not develop severe disease.

Thus far, clinical prognostic and predictive tests for superimposed preeclampsia have been disappointing (CondeAgudelo, 2015). Di Lorenzo and colleagues (2012) studied serum markers for Down syndrome to predict preeclampsia and calculated a sensitivity of 60 percent, with a 20-percent false-positive rate. Similar results were found using antiangiogenic factors to discriminate among chronic hypertension, gestational hypertension, and preeclampsia (Costa, 2016; Sibai, 2008). According to Anton and coworkers (2013), microRNA assays may prove valuable as predictors of pregnancy-associated hypertension.

Trials ofvarious medications to prevent preeclampsia in women with chronic hypertension have generally been disappointing and

Chronic hypertension augments the risk two-to threefold for premature placental separation. he general obstetrical population risk is 1 in 200 to 300 pregnancies, and this rises to 1 in 60 to 120 pregnancies in women with chronic hypertension (Ankumah, 2014; Cruz, 2011; Magee, 2015). he abruption risk is elevated further if the woman smokes. Most abruptions are in women with worsening gestational hypertension or superimposed preeclampsia. The abruption risk is highest with severe hypertension, and Vigil-De Gracia and colleagues (2004) reported it to be 8.4 percent. From medical record data from the Norwegian Birth Registry, folic acid and/or multivitamin supplements slightly lowered the abruption incidence in women with chronic hypertension (Nilsen, 2008).

Rates of almost all adverse perinatal outcomes are greater in women with chronic hypertension than in nonafected controls. As expected, for the entire group of hypertensive women, those who developed preeclampsia have substantially higher adverse outcome rates compared with those without preeclampsia. As shown in Figure 50-3, adverse outcome rates rise incrementally with rising blood pressures. Evidence also supports that chronic hypertension-treated or untreated-is associated with show little or no benefit. Low-dose aspirin has been evaluated 55

FIGURE 50-3 Frequency of selected adverse maternal and perinaLa! uuLcomes by blood stratification in women with mild chronic hypertension. SGA = small for gestational age. (Data Ankumah,o2014.) most frequently (Mol, 2016; Sta, 2015). In the MFMU Network study by Caritis (1998) cited above, the incidence ofsuperimposed preeclampsia, fetal-growth restriction, or both is similar in women given low-dose aspirin or placebo. Using the same database, Moore and associates (2015) found that early administration of low-dose aspirin « 17 weeks' gestation) resulted in a significant 41-percent lower frequency of superimposed preeclampsia in chronically hypertensive women-18 versus 31 percent. Duley (2007) and Meads (2008) and their colleagues performed systematic reviews and noted that low-dose aspirin was beneicial in some high-risk women. Moderate beneits were also found from a metaanalysis by Askie and coworkers (2007). In a secondary analysis, Poon and associates (2017) noted that aspirin was inefective to reduce the incidence ofpreterm preeclampsia.

he U.S. Preventive Services Task Force recommends treatment with low-dose aspirin for chronically hypertensive congenital anomalies. Bateman and coworkers (2015) from the Medicaid Analytic Extract cited earlier found an elevated risk for severe congenital malformations-especially cardiac defects. Moreover, severe hypertension and fetal esophageal atresia or stenosis have been associated (Binhidy, 2011; Van Gelder, 2015).

The stillbirth frequency with chronic hypertension is substantively greater in most reports (Chap. 35, p. 646). In the Nationwide Patient Sample study, the stillbirth rate was 15.1 per 1000 births (Bateman, 2012). This is similar to that of 18 per 1000 from a Norwegian study by Ahmad and coworkers (2012) and of 24 per 1000 births from a Network study reported by Ankumah and colleagues (2014) and described on page 982. Low-birthweight neonates are also common. hey are due to fetal-growth restriction, preterm delivery that is largely clinically indic�ted, or both (see Fig. 50-3). In the California database study noted earlier, a fourth of fetuses were delivered preterm (Yanit, 2012).

These and other studies attest to the elevated risk for fetalgrowth restriction, and the incidence averages 20 percent. Zetterstrom and coworkers (2006) reported a 2.4-fold risk for fetal-growth restriction in 2754 chronically hypertensive Swedish women compared with the risk in normotensive women. Broekhuijsen and associates (2012) found a 1.3-fold increased risk for 1609 Dutch nulliparas with chronic hypertension compared with that in normotensive controls. As with other complications, fetal-growth dysfunction is more likely in chronically hypertensive women who develop superimposed preeclampsia. In one study, the incidence of growth-restricted fetuses born to women with superimposed preeclampsia was almost 50 percent compared with only 21 percent in chronically hypertensive women without preeclampsia (Chappell, 2008). Finally, women with chronic hypertension severe enough to warrant treatment had an II-percent incidence of fetal-growth restriction to a degree yielding birthweights ;3rd percentile (Morgan, 2016a). For all of these reasons, neonates born to these women have a correspondingly high rate of intensive-care nursery admission.

All of these adverse perinatal efects of chronic hypertension contribute to the greater perinatal mortality rate, which is threeto fourfold higher than the rate in nonafected gravidas (American College of Obstetricians and Gynecologists, 2013). In the Network study by Ankumah (2014) referenced in Figure 50-3, the perinatl death rate was 31 per 1000 births with mild hypertension, 72 per 1000 births with moderate disease, and 100 per 1000 births in women with severe chronic hypertension. And, in the study from Parkland Hospital by Morgan (20 16a), the perinatal mortality rate was 32 per 1000 births in women who were treated for their chronic hypertension. Again, as expected, the highest rates are in women who develop superimposed preeclampsia, for whom the risk doubled from 4 to 8 percent. Finally, if diabetes coexists with chronic hypertension, then preterm delivery, fetalgrowth restriction, and perinatal mortality rates are increased even more (Gonzalez-Gonzalez, 2008; Yanit, 2012).

he diagnosis of chronic hypertension in pregnancy should be confirmed. The American College of Obstetricians and Gynecologists (2013) recommends use of ambulatory monitoring to exclude suspected white-coat hypertension before initiating antihypertensive therapy. Goals for chronic hypertension management include rate reductions of adverse maternal or perinatal outcomes just discussed. Treatment is targeted to prevent moderate or severe hypertension and to delay or dampen the severity of pregnancy-aggravated hypertension. To some extent, these goals can be achieved pharmacologically. Blood pressure self-monitoring is encouraged, but for accuracy, automated devices must be properly calibrated (Brown, 2004; Staessen, 2004). Personal health modification includes dietary counseling and reduction of behaviors such as tobacco, alcohol, cocaine, or other substance use (see Table 50-2). A low-sodium diet is not required (American College of Obstetricians and Gynecologists, 2013).

Some women-especially those with long-term or untreated hypertension-have complications that increase the risk of adverse pregnancy events. For example, in one study, a fourth of gravidas with chronic hypertension also had concentric ventricular hypertrophy (Ambia, 2017; Kim, 20 16a). Thus, if not already accomplished, assessment during pregnancy is done for the cardiovascular and renal systems (Morgan, 2016a,b).

As concluded by the American College of Obstetricians and Gynecologists (2013, 2016a), treatment of hypertension during pregnancy has included every drug class, but information is still limited regarding safety and eicacy (Czeizel, 2011; Podymow, 2011). lthough many studies indicate greater perinatal adverse efects in gravidas requiring treatment, it is still not known whether this is due to cause or efect (Orbach, 2013). The following summary of antihypertensive drugs is abstracted from several sources, including the 2016 Physicians' Desk Rf erence. Many of these drugs are also discussed throughout Chapter 12 (p. 241) and have been reviewed by Umans and associates (2015).

PeripheraLy acting 3-adrenergic-receptor blockers cause a generalized decline in sympathetic tone and decreased cardiac output. Examples are propranolol, metoprolol, and atenolol. Labetalol is a popular and commonly used QJ3-adrenergic blocker that is considered safe. Some adrenergic-blocking drugs act centraLy by reducing sympathetic outflow to efect a generalized decreased vascular tone. These include clonidine and a-methyldopa. Drugs in this class most frequently used in pregnancy to treat hypertension are methyldopa or an a-or 3-receptor blocking agent such as labetalol.

hese drugs are divided into three subclasses based on their modiication of calcium entry into cells and interference with binding sites on voltage-dependent calcium channels. Common agents include nifedipine-a dihydropyridine, and verapamil-a phenylalkyl amine derivative. These agents have negative inotropic efects and thus can worsen ventricular dysfunction and congestive heart failure. Theoretically, they may potentiate the vasoactive actions of magnesium sulfate that is given for eclampsia neuroprophylaxis. Although data are limited regarding their use during pregnancy, they appear to be safe therapy for chronic hypertension (Briggs, 2015; U mans, 2015).

hiazide diuretics are sulfonamides, and these were the first drug group used to successfully treat chronic hypertension (Beyer, 1982). hese agents and loop-acting diuretics such as furosemide are commonly used in nonpregnant hypertensive patients. In the short term, they provide sodium and water diuresis with volume depletion. But with time, there is sodium escape, and volume depletion is partially corrected. Some aspect of lowered peripheral vascular resistance likely contributes to their efectiveness in reducing long-term morbidity (Umans, 2015).

Thiazide drugs may be mildly diabetogenic, and expected volume expansion may be curtailed in pregnant women. Sibai and colleagues (1984) showed that plasma volume expanded only about 20 percent over time in hypertensive pregnant women who continued diuretic therapy compared with a 50-percent expansion in women who discontinued treatment. lthough perinatal outcomes were similar in these women, such concerns have led to practices of withholding diuretics as irst-line therapy for chronic hypertension, particularly after 20 weeks' gestation (Working Group Report, 2000). Even so, in a Cochrane review, Churchill and associates (2007) reported no diferences in perinatal outcomes in 1836 nonhypertensive women randomly assigned to a thiazide diuretic or placebo for primary preeclampsia prevention. Overall, thiazide diuretics are considered safe in pregnancy (Briggs, 2015). But for preeclampsia treatment, they are considered to be inefective (Umans, 2015).

Hydralazine relaxes arterial smooth muscle and has been used parenterally for decades to safely treat severe peripartum hypertension (Chap. 40, p. 739). Oral hydralazine mono therapy for chronic hypertension is not generally used because of its weak antihypertensive efects and resultant tachycardia. It may be an efective adjunct for long-term use with other antihypertensives, especially if there is chronic renal insuiciency. In one study, vasodilator treatment of chronically hypertensive women was associated with a twofold rise in rates of low-birthweight and growth-restricted neonates (S u, 2013).

These drugs inhibit the conversion of angiotensin-I to the potent vasoconstrictor angiotensin-II. They can cause severe fetal malformations when given in the second and third trimesters. These include oligohydramnios, hypocalvaria, and renal dysfunction (Chap. 12, p. 241). Some preliminary studies also suggest teratogenic efects, and because of this, they are not recommended at any time during pregnancy (Briggs, 2015; Podymow, 2011).

Angiotensin-receptor blockers act in a similar manner. But, instead of blocking the production of angiotensin-II, they inhibit binding to its receptor. They are presumed to have the same fetal efects as angiotensin-converting enzyme inhibitors and thus are also contraindicated.

The prognosis for pregnancy outcome with chronic hyperten sion is somewhat dependent on the severity of disease ante dating pregnancy. This may be related to indings that many women with severe hypertension have renal disease-as either cause or efect (Cunningham, 1990; Morgan, 2016a). It fol lows that women whose hypertension is severe enough to require antihypertensive therapy are at inordinately high risk for superimposed preeclampsia.

pregnancies in women whose blood pressure at 6 to 11 weeks' gestation was 2170/110 mm Hg. All were given oral treat ment with a-methyldopa and hydralazine to maintain pres sures < 160/1a10 mm Hg. Of the 44 pregnancies, superimposed preeclampsia developed in half, and all adverse perinatal out comes were in this group. Moreover, all neonates of women in the superimposed group were delivered preterm, nearly 80 percent were also growth restricted, and 48 percent sufered perinatal death. Conversely, those women with severe chronic had reasonably good outcomes. There were no perinatal deaths, and only 5 percent of fetuses were growth restricted. Webster and colleagues (2017) found labetalol and nifedipine to be equally efective for chronic hypertension in pregnant women.

Morgan and coworkers (2016a) reported 447 women whose chronic hypertension required treatment beginning prior to 20 weeks. More than half of these women developed superimposed severe preeclampsia. he rate of preeclampsia was 53 percent for those whose 24-hour protein excretion was <300 mg. But for those with antecedent baseline proteinuriaa> 300 mg/day, 79 percent developed severe preeclampsia.

Continuing prepregnancy antihypertensive treatment during pregnancy is debatable for those with mild or moderate hypertension. Although blood pressure reduction certainly beneits the mother long term, it at least theoretically can reduce uteroplacental perfusion. In older observational reports, most pregnancy outcomes in women with mild to moderate hypertension generally were good without treatment and unless superimposed preeclampsia developed (Chesley, 1978; Umans, 2015).

N ewer data are accruing that address potential salutary efects on pregnancy outcomes by simply lowering blood pressure. Earlier studies were relatively small and had widely varying inclusion and outcome criteria. In a Cochrane review of 49 of these studies that included a total of 4723 women with mild to moderate hypertension, Abalos and coworkers (2014) conirmed that the risk for subsequent severe hypertension was lowered with therapy. Compared with untreated women, the frequencies of superimposed preeclampsia, eclampsia, abruption, preterm birth, fetal-growth restriction, and perinatal or maternal mortality did not difer. This latter Cochrane review raised concerns for fetal-growth restriction with 3-blocking

TABLE 50-4. Selected Pregnancy Outcomes in Women with Chronic Hypertension Treated During Pregnancy with and without Baseline Proteinuriaa

Superimposed preeclampsia 79% 49% <0.001 Abruption 0 1% 0.45 EGA at delivery (mean)b 35.1 ± 4.3 wks 37.2 ± 3.3 wks <0.001 ;30 weeks 18% 6% 0.001 ;34 weeks 34% 17% 0.005 ;37 weeks 48% 26% 0.002

Birthweight (mean)b 2379 ± 1028 g 2814 ± 807 g <0.001 ;3rd percentile 20% 9% 0.01 ; 10th percentile 41 % 22% <0.001

Perinatal mortality 36/1000 31/1000 0.47 aDefined as ::300 mgld protein excretion before 20 weeks' gestation. bMean ± standard deviations.

EGA = estimated gestational age.

Data from Morgan, 2016b.

drugs, ,notably atenolol. It is not resolved, however, because diminished placental perfusion secondary to lowered maternal blood pressure is confounded by the fact that worsening blood pressure itself is associated with abnormal fetal growth. Some also posit that the drugs have a direct fetal action (Umans, 2015). In two of the larger randomized trials, however, the incidence of growth restriction was not altered in women randomly assigned to treatment (Gruppo di Studio Ipertensione in Gravidanza, 1998; Sibai, 1990a).

he observations of Morgan and colleagues (20 16a) support the findings of the Cochrane review by Abalos. Specifically, they reported that despite therapy for chronic h) pertension, there was frequent superimposed preeclampsia, fetal-growth restriction, preterm delivery, and perinatal mortality. Moreover, and as shown in Table 50-4, women with baseline proteinuria >300 mg/ d had even worse obstetrical outcomes.

During the past decade, the concept of tight control of blood pressure has been espoused as a means of optimizing maternal and perinatal outcomes. Such control is analogous to that of glycemic control for management of the pregnant diabetic patient. he observational study by Ankumah (2014) noted earlier lends credence to tighter control of blood pressure. hese investigators showed that the risk of adverse pregnancy outcomes in 759 women with chronic hypertension was lower when blood pressures before 20 weeks were < 140 mm Hg compared with higher pressure categories and increasing blood pressures. Unfortunately, this did not hold up when less-tight was compared with tight control. Speciically, Magee and coworkers (2015) randomized 987 women with chronic hypertension or gestational hypertension to either one of these two management schemes. Except for a lower rate of severe hypertension in the tightly controlled group, they found no signiicant diferences between these two groups' other adverse pregnancy outcomes (Table 50-5). Tight control was also not more costly (Ahmed, 2016). These and similar findings prompted an ongoing randomized controlled trial-Project CHAP (ClinicaITrials.gov, 2016)-to answer this question.

Until there are data to conirm any salutary efects of treatment of uncomplicated mild to moderate chronic hypertension in pregnancy, it seems reasonable to follow the guidelines of the American College of Obstetricians and Gynecologists (2013) and the Society for Maternal-Fetal Medicine (2015). Pregnant women with severe hypertension must be treated for maternal neuro-, cardio-, and renoprotection. Treatment is ap <0.001, all other comparisons p >0.05.

HELLP = hemolysis, elevated liver enzyme levels, low platelet count.

Data from Magee, 201n5.

also mandatory for women with prior adverse outcomes such as strokes, MIs, and evidence for cardiac or renal dysfunction.

With end-organ dysfunction, treatment to diastolic pressure level ;90 mm Hg is reasonable to mitigate further organ damage.

For most women with mild to moderate hypertension, the

College recommends that treatment be withheld as long as systolic blood pressure is < 160 mm Hg and diastolic blood pressure is < 105 mm Hg. Some find it reasonable to begin women with persistent systolic pressuresa> 150 mm Hg or dia stolic pressures of95 to 100 mm Hg or greater (August, 2015;

Working Group Report, 2000). At Parkland Hospital we initi ate treatment with antihypertensive agents for blood pressures of 150/100 mm Hg or higher. Our preferred regimens include mono therapy with a 3-blocking drug such as labetalol or a calcium-channel blocking agent such as amlodipine. For women in the first half of pregnancy, therapy with a thiazide diuretic seems reasonable. This is especially true in black women, in whom there is a high prevalence of salt-sensitive chronic hypertension.

It is controversial whether or not women who present early in pregnancy and who are already taking antihypertensive drugs should continue to take these (Rezk, 2016). According to the American College of Obstetricians and Gynecologists (2013) and the Society for Maternal-Fetal Medicine (2015), for women with mild to moderate hypertension, it is reasonable to discontinue medications during the irst trimester and to restart them if blood pressures approach the severe range. Our practice at Parkland Hospital is to continue treatment if the woman is already taking drugs when she presents for prenatal care. Exceptions are discontinuation of angiotensin-converting enzyme inhibitors and receptor blockers.

Some women will have persistently worrisome hypertension despite usual therapy (Samuel, 2011; Sibai, 1990a). In these women, primary attention is given to the likelihood of pregnancy-aggravated hypertension, with or without superimposed preeclampsia. Other possibilities include inaccurate blood-pressure measurements, suboptimal treatment, and antagonizing substances such as chronic ingestion of nonsteroidal antiinlammatory drugs (NSAIDs) (Moser, 2006; Sowers, 2005).

As discussed, the frequency of superimposed preeclampsia for women with chronic hypertension varies depending on the study population and hypertension severity (Ankumah, 2014). Importantly, in 40 to 50 percent of chronically hypertensive women, superimposed preeclampsia develops before 37 weeks (Chappell, 2008; Harper, 2016). This proportion is even higher in women who required hypertension treatment during pregnancy (Morgan, 20 16a).

The diagnosis may be diicult to make, especially in women with hypertension who have underlying renal disease with chronic proteinuria (Cunningham, 1990; Morgan, 2016b). As discussed in Chapter 40 (p. 712), conditions that support the diagnosis of superimposed preeclampsia include worsening hypertension, new-onset proteinuria, neurological symptoms such as severe headaches and visual disturbances, generalized edema, oliguria, and certainly, convulsions or pulmonary edema. Making the diagnosis based on worsening proteinuria in women with baseline proteinuria is problematic. Supporting laboratory abnormalities are rising serum creatinine or hepatic transaminase levels, thrombocytopenia, or any of the facets of

HELLP (hemolysis, �levated liver enzyme levels, low 2latelet count) syndrome. For women with chronic hypertension and superimposed preeclampsia with severe features, magnesium sulfate for maternal neuroprophylaxis is recommended (Ameri can College of Obstetricians and Gynecologists, 2013). Severe hypertension is treated as described in Chapter 40 (p. 738).

Some pregnant women with chronic hypertension have worsening hypertension with no other findings of superim posed preeclampsia. This is most commonly encountered near the end of the second trimester. In the absence of other supporting criteria for superimposed preeclampsia, this likely represents the higher end of the normal blood-pressure curve shown in Figure 50-1. In such women, if preeclampsia can be confidently excluded, it is reasonable to begin or to increase the dose of antihypertensive therapy.

Women with well-controlled chronic hypertension who have no complicating factors can generally be expected to have a good pregnancy outcome. Because even those with mild hypertension have a greater risk of superimposed preeclampsia and fetal-growth restriction, serial antepartum assessment of fetal well-being is recommended by many. That said, according to the American College of Obstetricians and Gynecologists (2013), with the exception of sonographic fetal-growth monitoring, described in Chapter 44 (p. 852), no conclusive data address either benefit or harm associated with various antepartum surveillance strategies.

• Expectant Management of Early-Onset

Given that many women with chronic hypertension develop superimposed preeclampsia before term, considerations for expectant management may be reasonable in some cases. In a study from Magee-Women's Hospital, 41 careully selected women with a median gestational age of 31.6 weeks were expectantly managed (Samuel, 2011). Despite liberal criteria to mandate delivery, 17 percent developed either placental abruption or pulmonary edema. The latency period was extended by a mean of 9.7 days. There were no perinatal deaths, however, salutary outcomes were similar. These investigators recommend randomized trials to study expectant management before this becomes usual care.

For chronically hypertensive women who have complications such as fetal-growth restriction or superimposed preeclampsia, the decision to deliver is made by clinical judgment. The route of delivery is dictated by obstetrical factors. Certainly, most women with superimposed severe preeclampsia are better delivered even when the fetus is markedly preterm. Increased risk for placental abruption, cerebral hemorrhage, and peripartum heart failure attend delivery delays (Cunningham, 1986, 2005; Martin, 2005).

For women with chronic hypertension without preeclampsia, expectant management at later gestational ages was reported recently by Harper and colleagues (2016). They concluded that expectant management beyond 39 weeks' gestation was associated with an increasing incidence of severe preeclampsia and that planned delivery before 37 weeks was associated with a rise in rates of adverse neonatal outcomes.

For women with mild to moderate chronic hypertension who continue to have an uncomplicated pregnancy, the merican College of Obstetricians and Gynecologists (2013) recommends delivery not be pursued until 38°17 weeks. The consensus committee indings by Spong and associates (2011) recommend consideration for delivery at 38 to 39 weeks, that is, :::37 completed weeks. A trial of labor induction is preferable, and many of these women respond favorably and will be delivered vaginally (Alexander, 1999; Atkinson, 1995).

For women with severe preeclampsia, peripartum management is the same as described in Chapter 40 (p. 729). Epidural analgesia for labor and delivery is optimal with the caveat that it is not given to treat hypertension (Lucas, 2001). hat said, women with severe superimposed preeclampsia are more sensitive to the acute hypotensive efects of epidural analgesia (Vricella, 2012). Also in this group, magnesium sulfate neuroprophylaxis is initiated for prevention of eclampsia. Severe hypertension-diastolic blood pressure :::110 mm Hg or systolic pressurea:::160 mm Hg-is treated with either intravenous hydralazine or labetalol. Some prefer to treat women when the diastolic pressure reaches 100 to 105 mm Hg. Vigil-De Gracia and colleagues (2006) randomly assigned 200 women to intravenous hydralazine or labetalol to acutely lower severe high blood pressure in pregnancy. Outcomes were similar except for significantly more maternal palpitations and tachycardia with hydralazine and signiicantly more neonatal hypotension and bradycardia with labetalol.

In most respects, postpartum observation, prevention, and management of adverse complications are similar in women with severe chronic hypertension and in those with severe preeclampsia-eclampsia. For persistent severe hypertension, consideration is given for a cause such as pheochromocytoma or Cushing disease (Sibai, 2012). And, in women with chronic end-organ damage, certain complications are more common. These include cerebral or pulmonary edema, heart failure, renal dysfunction, or cerebral hemorrhage, especially within the irst 48 hours after delivery (Martin, 2005; Sibai, 1990b, 2012). hese frequently are preceded by sudden elevations"spikes"-of mean arterial blood pressure and of the systolic component (Cunningham, 2000, 2005).

Following delivery, as maternal peripheral resistance rises, left ventricular workload also grows. This elevation is further aggravated by appreciable and pathological amounts of interstitial luid that are mobilized to be excreted as endothelial disruption from preeclampsia resolves. In these women, sudden hypertension-either moderate or severe-may exacerbate diastolic dysfunction, cause systolic dysfunction, and lead to pulmonary edema (Cunningham, 1986; Gandhi, 2001). Prompt hypertension control, along with furosemide-evoked diuresis, usually quickly resolves pulmonary edema.

he antihypertensive regimen given antepartum can be restarted in the puerperium. It is also possible in many women to forestall postpartum hypertension by administering intravenous or oral furosemide to augment the normal postpartum diuresis. In one study, 20-mg oral furosemide given daily for 5 days to postpartum women with severe preeclampsia aided blood pressure control (Ascarelli, 2005). Daily weights are helpful in this regard. On average, a woman should weigh 15 pounds less immediately after delivery. Excessive extracellular fluid can then be estimated. Other studies are in progress to determine aspects of postpartum blood pressure management (Cursino, 2015).

Some evidence supports that chronic ingestion ofNSAIDs in the puerperium elevates blood pressure in women with severe preeclampsia (Vigil-De Gracia, 2017). his may not be problematic if these drugs are given only as needed (Wasden, 2014).

Women with chronic hypertension have special considerations for contraceptive and sterilization choices. These are discussed in detail throughout Chapters 38 and 39.

Ultimately, women with chronic hypertension are at high risk for lifetime cardiovascular complications, especially when accompanied by diabetes, obesity, and the metabolic syndrome. Recent evidence also suggests that these women are at greater risk to develop cardiomyopathy remote from pregnancy (Behrens, 2016).

Abalos E, Duley L, Steyn OW, et al: Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev 2:CD002252,t2014

Ahmad AS, Samuelsen SO: Hypertensive disorders in pregnancy and fetal death at diferent gestational lengths: a population study of2 121 371 pregnancies. BJOG 119(12):1521,t2012

Ahmed RJ, Gafni A, Hutton EK, et al: The cost implications ofless tight versus tight control of hypertension in pregnancy (CHIPS Trial). Hypertension 68(4):1049,t2016

Alexander JM, Bloom SL, Mcintire DO, et al: Severe preeclampsia and the very low birth weight infant: is induction of labor harmful? Obstet Gynecol 93:485, 1999

Ambia M, Morgan JL, Wilson L, et al: Frequency and consequences of ventricular hypertrophy in pregnant women with treated chronic hypertension. Am J Obstet GynecoIt217:467.e1, 2017

American College of Obstetricians and Gynecologists: Chronic hypertension in pregnancy and superimposed preeclampsia. In: Hypertension in Pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. 2013

American College of Obstetricians and Gynecologists: Hypertension. In Clinical Updates in Women's Health Care, Volume V, No. I, January 2016a American College of Obstetricians and Gynecologists: Practice advisory on lowdose aspirin and prevention of preeclampsia: updated recommendations.

2016b. Available at: http://ww.acog.org/About-ACOG/News-Room/ Practice-Advisories/Practice-Advisory-Low-Dose-Aspirin-and-Preventionof-Preeclampsia-U pdated-Recommendations. Accessed January 5, 2017

Ankumah NA, Cantu J, Jauk V, et al: Risk of adverse pregnancy outcomes in women with mild chronic hypertension before 20 weeks of gestation. Obstet Gynecol 123(5):966,t2014

Anton L, Olarerin-George AO, Schwartz N, et al: miR-210 inhibits trophoblast invasion and is a serum biomarker for preeclampsia. Am J Pathol 183(5):1437,t2013

Ascarelli MH, Johnson V, McCreary H, et al: Postpartum preeclampsia management with furosemide: a randomized clinical trial. Obstet Gynecol 105(1):29,t2005

Askie LM, Duley L, Henderson-Smart OJ, et al: Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet 369(9575):1791,t2007

Atkinson MW, Guinn 0, Owen J, et al: Does magnesium sulfate afect the length of labor induction in women with pregnancy-associated hypertension? Am J Obstet GynecoIt173(4):1219, 1995

August P, Jeyabalan A, RobertS JM: Chronic hypertension and pregnancy. In:

Taylor N, RobertS JM, Cunningham FG, et al (eds): Chesley's Hypertensive Disorders in Pregnancy. Amsterdam, Academic Press, 2015

Banhidy F, Acs N, Puh6 EH, et al: Chronic hypertension with related drug treatment of pregnant women and congenital abnormalities in their ofspring: a population-based study. Hypertens Res 34(2):257, 2011

Bateman BT, Bansil P, Hernandez-Diaz S, et al: Prevalence, trends, and outcomes of chronic hypertension: a nationwide sample of delivery admissions. Am J Obstet Gynecol 206(2):134.e1, 2012

Bateman BT, Huybrechts KF, Fischer MA, et al: Chronic hypertension in pregnancy and the risk of congenital malformations: a cohort study. Am J Obstet Gynecol 212:337.e1, 2015

Behrens 1, Basit S, Lykke JA, et al: Association between hypertensive disorders of pregnancy and later risk of cardiomyopathy. JAMA 315(10): 1026, 2016 Beyer KH: Chlorothiazide. J Clin Pharmacol 13:15, 1982

Bramham K, Hladunewich A, Jim B, et al: Pregnancy and kidney disease.

NephSAP Nephrology Assessment Program 15(1):1, 2016

Briggs GG, Freeman RK: Drugs in Pregnancy and Lactation, 10th ed. Philadelphia, Lippincott Williams & Wilkins, 2015

Broekhuijsen K, Langeveld J, van den Berg P, et al: Maternal and neonatal outcomes in pregnancy in women with chronic hypertension. Am J Obstet GynecoIt206:S344,t20t12

Brown M, McHugh L, Mangos G, et al: Automated self-initiated blood pressure or 24-hour ambulatory blood pressure monitoring in pregnancy? BJOG 111 :38, 2004

Caritis S, Sibai B, Hauth J, et al: Low-dose aspirin to prevent preeclampsia in women at high risk. N EnglJ Med 338(11):701,t1998

Centers for Disease Control and Prevention: Vital signs: prevalence, treatment, and control of hypertension-United States, 1999-2002 and 2005-2008. MMWR 60(4):1,t2011

Chappell LC, Enye S, Seed P, et al: Adverse perinatal outcomes and risk factors for preeclampsia in women with chronic hypertension: a prospective study. Hypertension 51(4):1002, 2008

Chesley LC: Superimposed preeclampsia or eclampsia. In Chesley LC (ed): Hypertensive Disorders in Pregnancy. New York, Appleton-Century-Crots, 1978 Churchill 0, Beevers GO, Meher S, et al: Diuretics for preventing pre-eclamp sia. Cochrane Database Syst Rev 1 :CD004451, 200

Clark SL, Hankins GO: Preventing maternal death. 10 clinical diamonds.

Obstet Gynecol 119(2):360,t2012

ClinicalTrials.gov: Chronic Hypertension and Pregnancy (CHAP) Project. 2016. Available at: https:llclinicaltrials.gov/ct2/show/NCT02299414. Accessed JanualY 5,t2017

Conde-Agudelo A, Romero R, RobertS ltvl: Tests to predict preeclampsia. In Taylor N, RobertS JM, Cunningham FG, et al (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 20t15

Costa A, Hoshida MS, Alves A, et al: Preeclampsia and superimposed preeclampsia: the same disease? he role of angiogenic biomarkers. Hypertens Pregnancy 35(2): 139,t2016

Cowley AW Jr: he genetic dissection of essential hypertension. Nat Rev Genet 7:829,t2006

Creanga A, Berg CJ, Syverson C, et al: Pregnancy-related mortality in the United States, 2006-2010. Obstet Gynecol 125(1):5,t2015

Cruz MO, Gao W, Hibbard JU: Obstetrical and perinatal outcomes among women with gestational hypertension, mild preeclampsia, and mild chronic hypertension. Am J Obstet GynecoIt205:260.el, 2011

Cunningham FG: Severe preeclampsia and eclampsia: systolic hypertension is also important. Obstet Gynecol 105:237,t2005

Cunningham FG, Cox SM, Harstad W, et al: Chronic renal disease and pregnancy outcome. Am J Obstet Gynecol 163:453, 1990

Cunningham FG, Pritchard JA, Hankins GO, et al: Idiopathic cardiomyopathy or compounding cardiovascular events? Obstet GynecoI67:157, 1986 Cunningham FG, Twickler 0: Cerebral edema complicating eclampsia. Am J

Obstet Gynecol 182(1):94,t2000

Cursino T, Katz L, Coutinho I, et al: Diuretics vs. placebo for postpartum blood pressure control in preeclampsia (DIUPRE): a randomized clinical trial. Reprod Health 12:66,t2015

Czeizel AE, Banhidy F: Chronic hypertension in pregnancy. Curr Opin Obstet Gynecol 23(2):76, 2011

Di Lorenzo G, Ceccarello M, Cecotti V, et al: First trimester maternal serum PIGF, free b-hCG, PAPP-A, PP-13, uterine artery Doppler and maternal history for the prediction of preeclampsia. Placenta 33(6):495, 2012

Duley L, Henderson-Smarr OJ, Meher S, et al: Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev 2:CD004659, 2007

Eckel RH, Jakicic JM, Ard JD, et al: 2013 AHAIACC guidelines on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiologyl American Heart Association Task Force on Practice Guidelines. Circulation 129(25 Suppl 2):S76, 2013

Forouzanfar MH, Liu P, Roth GA, et al: Global burden of hypertension and sysrolic blood pressure of at least 110 to 115 mm Hg, 1990-2015. JM1A 317:165,t2017

Gainer J, Alexander J, Mclntire 0, et al: Maternal echocardiogram findings in pregnant patients with chronic hypertension. Presented at the 25th Annual Meeting of the Society for Maternal-Fetal Medicine, Reno, February 7-12, 2005

Gandhi SK, Powers JC, Nomeir A, et al: The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 344(1): 17, 2001 Gilbert M, YoungAL, Danielsen B: Pregnancy-outcomes in women with chronic hypertension: a population-based study. J Reprod Med 52(11): 1 046, 2007

Gonzalez-Gonzalez NL, Ramirez 0, Mozas J, et al: Factors inluencing pregnancy outcomes in women with type 2 versus type 1 diabetes mellitus. Acta Obstet Gynecol Scand 87(1):43, 2008

Gruppo di Studio Iperrensione in Gravidanza: Nifedipine versus expectant management in mild to moderate hypertension in pregnancy. BJOG 105(7): 718, 1998

Harper LM, Biggio JR, Anderson S, et al: Gestational age of delivery in pregnancies complicated by chronic hypertension. Obstet Gynecol 127(6):1101,t2016

Henderson JT, Whitlock EP, O'Connor E, et al: Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med 160(10): 695,t2014

Hibbard JU, Korcarz CE, Nendaz GG, et al: The arterial system in pre-eclampsia and chronic hypertension with superimposed pre-eclampsia. BJOG 112(7):897,t2005

Hibbard JU, Shrof SG, Cunningham FG: Cardiovascular alterations in pregnancy and preeclamptic pregnancy. In Taylor RN, Roberts JM, Cunningham FG, et al (eds): Chesley's Hypertensive Disorders in Pregnancy. Amsterdam, Academic Press, 2015

Hladunewich MA, Schaefer F: Proteinuria in special populations: pregnant women and children. Adv Chronic Kidney Dis 18(4):267,t2011

James PA, Oparil S, Carter BL, et al: 2014 evidence-based guidelines for the management of high blood pressure in adults. Report from the panel members appointed to the Eighth Joint National Committee ONC 8). JAMA 311(5):507,t2014

Jeyabalan A, Hubel CA, Roberts JM: Metabolic syndrome and preeclampsia.

In Taylor RN, RobertS JM, Cunningham FG, et al (eds): Chesley's Hyper tensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 2015

Kim MJ, Seo J, Cho Kl, et al: Echocardiographic assessment of structural and hemodynamic changes in hypertension-related pregnancy. J Cardiovasc Ultrasound 24:28, 2016a

Kim SA, Park JB: OS 23-03 Midtrimester risk prediction of superimposed pre-eclampsia in pregnant women with chronic hypertension. J Hypertens 34 Suppl 1:e241, 2016b

Kotchen TA: Hypertensive vascular disease: In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill Education, 20t15

Kuper SG, Tita AT, Youngstrom ML, et al: Baseline renal function tests and adverse outcomes in pregnant patients with chronic hypertension. Obstet Gynecol 128:93,t2016

Leon MG, Moussa HN, Longo M, et al: Rate of gestational diabetes mellitus and pregnancy outcomes in patients with chronic hypertension. Am J PerinatoIt33(8):745,t2016

Levine RJ, Hauth JC, Curet LB, et al: Trial of calcium to prevent preeclampsia.

N Engl J Med (2):69, 199

Lindheimer MD, Taylor RN, Roberts JM et al: Introduction, history, controversies, and deinitions. In Taylor RN, Roberts JM, Cunningham FG, et al (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 2015

Lucas M), Sharma SK, McIntire DD, et al: A randomized trial of labor analgesia in women with pregnancy-induced hypertension. Amt) Obstet Gynecol 185(4):970,t2001

Magee A, von Dadelszen P, Rey E, et al: Less-tight versus tight control of hypertension in pregnancy. N Engl) Med 2(5):407,t2015

Martin )N )r, Thigpen BD, Moore RC, et al: Stroke and severe preeclampsia and eclampsia: a paradigm shift focusing on systolic blood pressure. Obstet Gynecol 105(2):246, 2005

Meads CA, Cnossen )S, Meher S, et al: Methods of prediction and prevention of pre-eclampsia: systematic reviews of accuracy and efectiveness literature with economic modelling. Health Technol Assess 12(6):1,t2008

Mol BW, Roberts CT, Thangaratinam S, et al: Pre-eclampsia. Lancet 387(10022):999,t2016

Moodley): Maternal deaths due to hypertensive disorders in pregnancy: Saving Mothers report 2002-2004. Cardiovasc) Afr 18:358,t2007

Moore GS, Allshouse A, Post AL. et al: Early initiation of/ow-dose aspirin for reduction in preeclampsia risk in high-risk women: a secondary analysis of the MFMU high-risk aspirin study.) Perinatol 35(5):328,t2015

Morgan )L, Nelson DB, RobertS SW, et al: Blood pressure profiles across pregnancy in women with chronic hypertension. Am) PerinatoI33(12): 1128, 2016a

Morgan )L, Nelson DB, Roberts SW, et al: The association of baseline proteinuria and adverse pregnancy outcomes in pregnant women with treated chronic hypertension. Obstet Gynecol 128:270, 2016b

Moser M, Setaro )F: Resistant or diicult-to-control hypertension. N Engl ) Med 355:385, 2006

Moussa HN, Leon MG, Marti A, et al: Pregnancy outcomes in women with preeclampsia superimposed on chronic hypertension with and without severe features. Am) PerinatoIt34(4):403, 2017

Nilsen RM, Vollset SE, Rasmussen SA, et al: Folic acid and multivitamin supplement use and risk of placental abruption: a population-based registry study. Am) Epidemiol 167(7):867,t2008

Odibo I, Zilberman D, Apuzzio ), et al: Utiliry of posterior and septal wall thickness in predicting adverse pregnancy outcomes in patients with chronic hypertension. Abstract No. 624, Am) Obstet Gynecol 208:S265, 2013

Orbach H, Matok I, Gorodischer R, et al: Hypertension and antihypertensive drugs in pregnancy and perinatal outcomes. Am ) Obstet Gynecol 208(4):301.e1,t2013

Physicians' Desk Reference, 70th ed. Chestertown, PDR Network, 2016 Podymow T, August P: Antihypertensive drugs in pregnancy. Semin Nephrol 31(1):70,t2011

Poon LC, Wright D, Rolnik DL, et al: Aspirin for evidence-based preeclampsia prevention trial: efect of aspirin in prevention of preterm preeclampsia in subgroups of women according to their characteristics and medical and obstetrical history. Am ) Obstet Gynecol August 4, 2017 [Epub ahead of print]

Rezk M, Eliakwa H, Gamal A, Emara M: Maternal and fetal morbidiry following discontinuation of antihypertensive drugs in mild to moderate chronic hypertension: a 4-year observational study. Pregnancy Hypertens 6:291, 2016

Rosner )Y, Gutierrez M, Dziadosz M, et al: Prehypertension in early pregnancy: what is the signiicance? Am) PerinatoIt34(2):1l7, 2017

Samuel A, Lin C, Parviainen K, et al: Expectant management of preeclmpsia superimposed on chronic hypertension. ) Matern Fetal Neonatal Med 24(7) :907, 2011 Sibai BM: Etiology and management of postpartum hypertension-preeclampsia. Amt) Obstet Gynecol 206(6):470, 2012

Sibai BM, Anderson GD: Pregnancy outcome of intensive therapy in severe hypertension in irst trimester. Obstet Gynecol 67(4):517, 1986

Sibai BM, Grossman A, Grossman HG: Efects of diuretics on plasma volume in pregnancies with long-term hypertension. Am ) Obstet Gynecol 150(7):831, 1984

Sibai BM, Koch vA, Freire S, et al: Serum inhibin A and angiogenic factor levels in pregnancies with previous preeclampsia andlor chronic hypertension: are they useful markers for prediction of subsequent preeclampsia? Am ) Obstet Gynecol 199(3):268.e 1, 2008

Sibai BM, Mabie We, Shamsa F, et al: A comparison of no medication versus methyldopa or labetalol in chronic hypertension during pregnancy. Am ) Obstet Gynecol 162(4):960, 1990a

Sibai BM, Villar A, Mabie BC: Acute renal failure in hypertensive disorders of pregnancy. Pregnancy outcome and remote prognosis in thirry-one consecutive cases. Am) Obstet GynecoIt162(3): 7, 1990b

Sociery for Maternal-Fetal Medicine: SMFM statement: beneit of antihypertensive therapy for mild-to-moderate chronic hypertension during pregnancy remains uncertain. Am) Obstet GynecoIt213(1):3, 2015

Sowers )R, White WB, Pitt B, et al: he efects of cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory therapy on 24-hour blood pressure in patients with hypertension, osteoarthritis, and rype 2 diabetes mellitus. Arch Intern Med 165(2):161,t2005

Spaan JJ, Sep S), van Balen VL, et al: Metabolic syndrome as a risk factor for hypertension after preeclampsia. Obstet Gynecol 120(2 Pt 1):311, 2012

Spinnato)A 2nd, Freire S, Pinto ESilva)L, et al: Antioxidant therapy to prevent preeclampsia: a randomized controlled trial. Obstet Gynecol 11 O(6): 131t1, 2007

Spong CY, Mercer BM, D'lton M, et al: Timing of indicated late-preterm and early-term birth. Obstet Gynecolt118(2 Pt 1):323,t2011

SPRINT Research Group, Wright )T )r, Williamson )D, et al: A randomized trial of intensive versus standard blood-pressure control. N Engl ) Med 373(22):2103,t2015

Staessen )A, Den Hond E, Celis H, et al: Antihypertensive treatment based on blood pressure measurement at home or in the physician's oice: a randomized controlled trial. JAMA 291(8):955,t2004

Staf CA, Sibai BM, Cunningham FG: Prevention of preeclampsia and eclampsia. In Taylor RN, Roberts )M, Cunningham FG, et al (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 2015

Su CY, Lin HC, Cheng HC, et al: Pregnancy outcomes of anti-hypertensives for women with chronic hypertension: a population-based study. PLoS One 8(2):e53844,t2013

Tihtonen K, Koobi T, Huhtala H, et al: Hemodynamic adaptation during pregnancy in chronic hypertension. Hypertens Pregnancy 26(3):315, 2007 Umans )G, Abalos E, Cunningham FG: Antihypertensive treatment. In Taylor RN, Roberts )M, Cunningham FG, et al (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 2015

Van Gelder MM, Van Bennekom CM, Louik C, et al: Maternal hypertensive disorders, antihypertensive medication use, and the risk of birth defects: a case control-study. B)OG 122(7):1002,t2015

Vigil-De Gracia P, Lasso M, Montufar-Rueda C: Perinatal outcome in women with severe chronic hypertension during the second half of pregnancy. Intt) Gynaecol Obstet 85(2): 139,t2004

Vigil-De Gracia P, Lasso M, Ruiz E, et al: Severe hypertension in pregnancy: hydralazine or labetalol a randomized clinical trial. Eur ) Obstet Gynecol Reprod BioI 128(1-2):157, 2006

Vigil-De Gracia P, Solis V, Ortega N: Ibuprofen versus acetaminophen as a post-partum analgesic for women with severe pre-eclampsia: randomized clinical study.t) Matern Fetal Neonatal Med 30(11):1279,t2017

V ricella LK, Louis )M, Mercer BM, et al: Epidural-associated hypotension is more common among severely preeclamptic patients in labor. Amt) Obstet GynecoIt207(4):335.e1,t2012

Ward K, Taylor RN: Genetic factors in the etiology of preeclampsia/eclampsia. In Taylor RN, Roberts )M, Cunningham FG, et al (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 2015

Wasden SW, Ragsdale ES, Chasen ST, et al: Impact of non-steroidal antiinflammatory drugs on hypertensive disorders of pregnancy. Pregnancy Hypertens 4:259,t2014

Webster LM, Myers )E, Nelson-Piercy C, et al: Labetalol versus nifedipine as antihypertensive treatment for chronic hypertension in pregnancy: a randomized controlled trial. Hypertension 70:915, 2017

Weissman-Brenner A, Schoen R, Divon MY: Aortic dissection in pregnancy.

Obstet Gynecol 103: 1110, 2004

Working Group Report on High Blood Pressure in Pregnancy: Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am) Obstet Gynecol 183:S1, 2000

Yanit E, Snowden )M, Cheng W, et al: he impact of chronic hypertension and pregestational diabetes on pregnancy outcomes. Am ) Obstet Gynecol 207(4):333.e1,t2012

Zetterstrom K, Lindeberg SN, Haglund B, et al: Chronic hypertension as a risk factor for ofspring to be born small for gestational age. Acta Obstet Gynecol Scand 85(9):1046,t2006

ASTHMA................i.............i.....i.....988

ACUTE BRONCHITIS ...i.....i......i...............991

PNEUMONIA.i...............i.......i.......i..... 992

TUBERCULOSIS.. . .................i............ 995

SARCOIDOSIS.....................i............997

CYSTIC FIBROSIS.. . ................i............ 997

CARBON MONOXIDE POISONING.. . ..i............ 999

A lung which is partialy destroyed or thrown out of function may suice or the respiration of a normal individual, but be unable to respond to the added demands of pregnancy, particulary in the latter months, when the enlarged restricts the mobiliy of the diaphragm.

-J. Whitridge Williams (1903)

As indicated by the above, it has long been appreciated that women in advanced pregnancy tolerate lung disease poorly. Nevertheless, pulmonary disorders are frequently encountered during pregnancy. Chronic asthma or an acute exacerbation is the most common and afects up to 8 percent of pregnant women. Moreover, asthma along with community-acquired pneumonia accounted for almost 10 percent of nonobstetrical antepartum hospitalizations in one managed care plan (Gazmararian, 2002). Pneumonia is also a frequent postpartum complication requiring readmission (Belfort, 2010). These and other pulmonary disorders are superimposed on several important pregnancy-induced changes of ventilatory physiology. For example, pregnant women, especially those in the last trimester, are susceptible to complications of severe acute pneumonitis as evidenced by the disparate number of maternal deaths during influenza pandemics.

The important and sometimes marked changes in the respira tory system induced by pregnancy are reviewed in Chapter 4 (p.

64), and values for associated tests can be found in the Appendix (p. 1260). Lung volumes and capacities that are measured directly to assess pulmonary pathophysiology may be signiicantly altered. In turn, these change gas concentrations and acid-base values in blood. Some of the physiological alterations induced by pregnancy were summarized by Wise and associates (2006): 1.

ital capaciy and inspiratory capaciy increase by approximately 20 percent by late pregnancy.

2.

Expiratory reserve volume decreases from 1300 mL to approximately 1100 mL.

3.

idal volume increases approximately 40 percent as a result of respiratory stimulation by progesterone.

4.

Minute ventilation increases 30 to 40 percent due to increased tidal volume. As a result, arterial P02 increases from 100 to 105 mm Hg.

5.

Increasing metabolic demands cause a 30-percent rise in carbon dioxide (C02) production. But, because of its concomitantly increased difusion capacity and hyperventilation, the arterial Peo2 decreases from 40 to 32 mm Hg.

6.

Residual volume decreases approximately 20 percent from 1500 mL to approximately 1200 mL.

7.

Chest wal compliance is reduced by a third by the expanding uterus and increased intraabdominal pressure. This causes a 10-to 25-percent decrease in functional residual capacithe sum of expiratory reserve and residual volumes.

In a longitudinal cohort study, Grindheim and colleagues (2012) also showed that forced vital capacity and peak expiratory flow rose progressively across pregnancy after 14 to 16 weeks' gestation. The end result of these pregnancy-induced changes is substantively increased ventilation due to deeper but not more frequent breathing. hese are thought to be stimulated by basal oxygen consumption as it rises incrementally from 20 to 40 mLimin in the second half of pregnancy.

Reactive airway disease is seen frequently in young women and therefore oten complicates pregnancy. Asthma prevalence grew steadily in many countries beginning in the mid-1970s but may have plateaued in the United States with a prevalence in adults of approximately 10 percent (Barnes, 2015; Centers for Disease Control and Prevention, 201Oc, 2013). The estimated asthma prevalence during pregnancy ranges between 4 and 8 percent, and this appears to be rising (Kelly, 2015; Racusin, 2013). Finally, evidence is accruing that fetal and neonatal environmental exposures may contribute to the origins or mitigation of asthma (Grant, 2016; Litonjua, 2016; Spiegel, 2016).

Asthma is a chronic inlammatory airway syndrome with a major hereditary component. Increased airway responsiveness and persistent subacute inflammation are associated with polymorphism genes on chromosomes 5q that include cytokine gene clusters, 3-adrenergic and glucocorticoid receptor genes, and the T-cell antigen receptor gene (Barnes, 2015). Asthma is etiologically and clinically heterogeneous, and an environmental allergic stimulant such as influenza or cigarette smoke serves as a promoter for susceptible individuals (Bel, 2013).

he hallmarks of asthma are reversible airway obstruction from bronchial smooth muscle contraction, vascular congestion, tenacious mucus, and mucosal edema. Mucosal inlammation is characterized by infiltration with eosinophils, mast cells, and T lymphocytes. hese causes airway inflammation and increased responsiveness to numerous stimuli that include irritants, viral infections, aspirin, cold air, and exercise. Several inflammatory mediators produced by these and other cells include histamine, leukotrienes, prostaglandins, cytokines, IgE, and many others. Importantly, because F-series prostaglandins and ergonovine exacerbate asthma, these commonly used obstetrical drugs should be avoided if possible.

Pulmonary unction changes are more pronounced in asthmatics compared with healthy women (Zairina, 2015). Asthma manifestations range from mild wheezing to severe bronchoconstriction, which obstructs airways and decreases airflow. his lowers the forced expiratory volume in 1 second/forced vital capacity (FEVJFVC) ratio and the peak expiratory flow (PEF). The work ofbreathing progressively increases, and patients note chest tightness, wheezing, or breathlessness. Subsequent alterations in oxygenation primarily reflect ventilation-perfusion mismatching because the distribution of airway narrowing is uneven.

Varied manifestations of asthma have led to a simple classiication that considers severity, onset, and duration of symptoms (Table 51-1). With persistent or worsening bronchial obstruction, clinical stages progress as shown in Figure

Hypoxia initially is mitigated by hyperventilation, which maintains arterial P02 within a normal range but lowers Peo2' creating respiratory alkalosis. As airway narrowing worsens, ventilation-perusion defects increase, and arterial hypoxemia ensues. With severe obstruction, ventilation becomes impaired as fatigue causes early CO2 retention. Because ofhyperventilation, this may only be seen initially as an arterial Peo2 returning to the normal range. With continuing obstruction, respiratory failure follows from fatigue.

Although these changes are generally reversible and well tolerated by the healthy nonpregnant individual, even early asthma stages may be dangerous for the pregnant woman and her fetus. This is because smaller functional residual capacity and increased pulmonary shunting render the woman more susceptible to hypoxia and hypoxemia.

Effects of Pregnancy on Asthma

Pregnancy has an unpredictable efect on underlying asthma. In their review of six prospective studies of more than 2000 gravidas, Gluck and Gluck (2006) reported that approximatelyaa third each improved, remained unchanged, or clearly

TABLE 51-1. Classification of Asthma Severity

FIGURE 51-1 Clinical stages of asthma. FEV1 = forced expiratory volume in 1 second.

worsened. Exacerbations are more common with severe disease (Ali, 2013). In a study by Schatz and associates (2003), baseline severity correlated with asthma morbidity during pregnancy. With mild disease, 13 percent of women had an exacerbation and 2.3 percent required admission; with moderate disease, these numbers were 26 and 7 percent; and for severe asthma, 52 and 27 percent. Others have reported similar observations (Charlton, 2013; Hendler, 2006). Finally, morbidity rates are disproportionately increased in black compared with white women.

Up to 20 percent of women with mild or moderate asthma have been reported to have an intrapartum exacerbation (Schatz, 2003). Conversely, Wendel and associates (1996) reported exacerbations at the time of delivery in only 1 percent of women.

Mabie and coworkers (1992) reported an 18-fold increased exacerbation risk following cesarean versus vaginal delivery.

Women with asthma have had improved pregnancy outcomes during the past 20 years. he incidence of spontaneous abortion in women with asthma may be slightly increased (Blais, 2013).

Maternal and perinatal outcomes for nearly 30,000 pregnan cies in asthmatic women are shown in Table 51-2. Findings are not consistent among these studies. For example, in some, but not all, the incidences of preeclampsia, preterm labor, growth restricted infants, and perinatal mortality are slightly increased (Murphy, 2011). Other reports cited a small rise in the incidence of placental abruption and previa, preterm rupture of mem branes, and gestational diabetes (Getahun, 2006; Wang, 2014).

But, in a European report of 37,585 pregnancies of women with asthma, the risks for most obstetrical complications were not increased (Tata, 2007). Finally, Cossette and coworkers (2013) and increasing inhaled-corticosteroid dosage.

Increased morbidity appears to be signiicantly linked to severe disease, poor control, or both. In the study by the Maternal-Fetal Medicine Units (MFMU) Network, delivery before 37 weeks' gestation was not increased among the 1687 pregnancies of asthmatic women compared with those of 881 controls (Dombrowski, 2004a). But for women with severe asthma, the rate was increased approximately twofold. In a prospective evaluation of 656 asthmatic pregnant women and 1052 pregnant controls, Triche and coworkers (2004) found that women with moderate to severe asthma, regardless of treatment, are at increased risk of preeclampsia. Finally, the MFMU Network study suggests a direct relationship of baseline pregnancy FEV] with birthweight and an inverse relationship with rates of gestationl hypertension and preterm delivery (Schatz, 2006).

Maternal morbidity includes life-threatening complications from status asthmaticus. his causes muscle fatigue with respiratory arrest, pneumothorax, pneumomediastinum, acute cor pulmonale, and cardiac arrhythmias. Not surprisingly, maternal and perinatal mortality rates rise substantively when mechanical ventilation is required.

TABLE 51-2. Maternal and Perinatal Outcomes in Pregnancies Complicated by Asthma blncidence not significantly diferent compared with control group or generan l obstetrical population.

clncidence significantly greater than control group or general obstetrical population. NS = not stated.

As discussed, with reasonable asthma control, perinatal outcomes are generally good. In the Network study cited above, rates of adverse neonatal sequelae caused by asthma were not signiicantly increased (Dombrowski, 2004a). he caveat is that severe asthma was uncommon in this closely monitored group. When respiratory alkalosis develops, earlier animal and human studies suggest that fetal hypoxemia develops well before the alkalosis compromises maternal oxygenation (Rolston, 1974). It is hypothesized that the fetus is jeopardized by decreased uterine blood flow, decreased maternal venous return, and an alkaline-induced letward shit of the oxyhemoglobin dissociation curve (Chap. 47, p. 920).

The fetal response to maternal hypoxemia is decreased umbilical blood flow, increased systemic and pulmonary vascular resistance, and decreased cardiac output. Observations by Bracken and colleagues (2003) confirm that the incidence of fetal-growth restriction increases with asthma severity. Because the fetus may be seriously compromised as asthma severity increases, the need for aggressive management is underscored. Monitoring the fetal response is, in efect, an indicator of maternal status.

Possible teratogenic or adverse fetal efects of drugs given to control asthma have been a concern. Several reports show a slightly greater risk for varied abnormalities such as cleft lip and palate and autism spectrum disorders. However, not all studies have veriied this (Eltonsy, 2016; Gidaya, 2016; Murphy, 2013b; Wang, 2014). It is worrisome that up to half of these women discontinue essential treatment between 5 and 13 weeks' gestation (Enriquez, 2006).

he subjective severity of asthma frequently does not correlate with objective measures of airway function or ventilation. Although clinical examination can also be an inaccurate predictor, useful signs include labored breathing, tachycardia, pulsus paradoxus, prolonged expiration, and use of accessory muscles. Signs of a potentially fatal attack include central cyanosis and altered consciousness.

Arterial blood gas analysis provides objective assessment of maternal oxygenation, ventilation, and acid-base status. With this information, the severity of an acute attack can be assessed (see Fig. 51-1). That said, in a prospective evaluation, Wendel and associates (1996) found that routine arterial blood gas analysis did not help to manage most pregnant women who required admission for asthma control. If used, the results must be interpreted in relation to normal values for pregnancy. For example, a Pco2>35 mm Hg with a pH <7.35 is consistent with hyperventilation and CO2 retention in a pregnant woman.

Pulmonary function testing should be routine in the management of chronic and acute asthma. Sequential measurement of the FEV1 or of the peak expiratoy low rate-PEFR-is the best measure of severity. n FEV1 less than 1 L, or less than 20 percent of predicted value, correlates with severe disease defined by hypoxia, poor response to therapy, and a high relapse rate. The PEFR correlates well with the FEVl, and it can be measured reliably with inexpensive portable meters. It is advantageous for each woman to determine her own baseline when asymptomatic to compare with values when symptomatic.

• Management of Chronic Asthma

Asthma management by an experienced team produces the most salutary outcomes (Bonham, 2017; Lim, 2014; Wendel, 1996). Management guidelines include: 1.

Patient education-general asthma management and its efect on pregnancy.

2.

Environmental precipitating factors-avoidance or control.

Viral infections that include the common cold are frequent triggering events (Ali, 2013; Murphy, 2013a).

3.

Objective assessment of pulmonary function and fetal status-monitor with PEFR or FEVl.

4.

Pharmacological therapy-in appropriate combinations and doses to provide baseline control and treat exacerbations. Compliance may be a problem, and periodic medication reviews are helpful (Sawicki, 2012).

In general, women with moderate to severe asthma ideally measure and record either their FEV1 or PEFR twice daily. The FEVl ideally is >80 percent of predicted. For PEFR, predicted values range from 380 to 550 L/min. Each woman has her own baseline value, and therapeutic adjustments can be made using this (American College of Obstetricians and Gynecologists, 2016a; Rey, 2007).

Treatment depends on disease severity. No therapeutic regimen for management of pregnant asthmatics is universally accepted (Bain, 2014). 3-Agonists help abate bronchospasm, and corticosteroids treat inflammation. Regimens recommended for outpatient management are listed in Figure 51-2. For mild asthma, inhaled 3-agonists as needed are usually suicient. For persistent asthma, inhaled corticosteroids are administered every 3 to 4 hours. The goal is to reduce the use of 3-agonists for symptomatic relie. A case-control study from Canada with a cohort of more than 15,600 nonpregnant women with asthma showed that inhaled corticosteroids reduced hospitalizations by 80 percent (Blais, 1998). At Parkland Hospital, Wendel and

FIGURE 51-2 Stepwise approach to asthma treatment.oICS = inhaled corticosteroids; LABA = long-acting 3-agonists; OCS = oral coticosteroids. (Modified from Barnes PJ: Asthma. In Kasper D, Fauci A, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hili Education, 2015, p 1669.) sions for severe exacerbations with inhaled steroids.

corticosteroids became available. Minimal beneit is gained with use of these compounds and they have a high rate of side efects. However, some theophylline derivatives are considered useful for oral maintenance therapy if the initial response to inhaled corticosteroids and 3-agonists is not optimal (Dom browski, 2004b).

zileuto n, zairlukast, and montelukast. hese drugs are given orally or by inhalation for prevention, but they are not efec tive for acute disease (Barnes, 2015). For maintenance, they are used in conjunction with inhaled corticosteroids to allow minimal dosing. Approximately half of asthmatics will improve with these drugs. hese agents are not as efective as inhaled corticosteroids, and there is little experience with their use in pregnancy (Fanta, 2009).

mast cell degranulation. They are inefective for acute asthma and are used primarily to treat childhood asthma.

• Management of Acute Asthma

Treatment of acute asthma during pregnancy is similar to that for the nonpregnant asthmatic. Importantly, the threshold for hospitalization is signiicantly lower. Intravenous (IV) hydration may help clear pulmonary secretions, and supplemental oxygen is given by mask. The therapeutic aim is to maintain the P02 >60 mm Hg, and preferably normal, along with 90to 95-percent oxygen saturation. Baseline pulmonary function testing includes FEV) or PEFR. Continuous pulse oximetry and electronic fetal monitoring, depending on gestational age, may provide useful information. Antibiotics are not given unless there is concomitant pneumonitis, which is caused by the same organisms discussed on page 992 (T erraneo, 2014).

First-line therapy for acute asthma includes a short-acting 3-adrenergic agonist, such as terbutaline, albuterol, isoetharine, epinephrine, isoproterenol, or metaproterenol, which is given subcutaneously, taken orally, or inhaled. In severely ill women, these drugs can be given IV (Barnes, 2015). They bind to speciic cell-surface receptors and activate adenylyl cyclase to increase intracellular cyclic AMP and modulate bronchial smooth muscle relaxation. Long-acting preparations are used for outpatient therapy.

If not previously given for maintenance, inhaled corticosteroids are commenced. A nebulized anticholinergic drug may be added if the response at this point is unsatisfactory (Barnes, 2015). Also, for severe exacerbations, IV magnesium sulfate or theophylline may prove eicacious. Corticosteroids are given early to all patients with severe acute asthma. Unless the response to bronchodilator and inhaled corticosteroid therapy is prompt, oral or parenteral corticosteroids are given (Lazarus, 2010). One regimen is oral prednisone or prednisolone or IV methylprednisolone in a dose of 30 to 45 mg daily for 5 to 10 days without tapering (Barnes, 2015). Because their onset of action is several hours, corticosteroids are given initially along with 3-agonists for severe acute asthma.

At this juncture, further management depends on the severity and response to therapy. If initial therapy with 3-agonists is associated with improvement of FEV, or PEFR to above 70 percent of baseline, then discharge can be considered. Some women may beneit from longer observation. Alternatively, for the woman with obvious respiratory distress, or if the FEV) or PEFR is <70 percent of predicted after three doses of 3-agonist, admission is usually advisable (Lazarus, 2010). Intensive therapy is continued with inhaled 3-agonists, IV corticosteroids, and close observation for worsening respiratory distress or fatigue in breathing (Racusin, 2013). The woman is cared for in the delivery unit or an intermediate or intensive care unit (ICU) (Dombrowski, 2006; Zeeman, 2003).

Severe asthma of any type not responding after 30 to 60 minutes of intensive therapy is termed status asthmaticus. This has been termed by some as critical asthma symptoms (Kenyon, 2015). Generally, management of nonpregnant patients with status asthmaticus in an intensive care setting results in a good outcome. Consideration should be given to early intubation when maternal respiratory status worsens despite aggressive treatment (see Fig. 51-1). Fatigue, CO2 retention, and hypoxemia are indications for mechanical ventilation (Chan, 2015). Although Lo and colleagues (2013) described a woman with status asthmaticus in whom cesarean delivery was necessary to efect ventilation, Andrews (2013) cautioned that such clinical situations are uncommon.

For the laboring asthmatic, maintenance medications are continued through delivery. Stress-dose corticosteroids are administered to any woman given systemic corticosteroid therapy within the preceding 4 weeks. The usual dose is 100 mg of hydrocortisone given IV every 8 hours during labor and for 24 hours ater delivery. The PEFR or FEV) is determined on admission, and serial measurements are taken if symptoms develop.

Oxytocin or prostaglandins E) or E2 are used for cervical ripening and induction. A nonhistamine-releasing narcotic such as fentanyl may be preferable to meperidine for labor, and epidural analgesia is ideal. For surgical delivery, conduction analgesia is preferred because tracheal intubation can trigger severe bronchospasm. Postpartum hemorrhage is treated with oxytocin or prostaglandin E) or E2. Prostaglandin F2: or ergotamine derivatives are contraindicated because they may cause signiicant bronchospasm.

Infection of the large airways is manifest by cough without pneumonitis. It is common in adults, especially in winter months. Infections are usually caused by viruses, and of these, influenza A and B, parainluenza, respiratory syncytial, coronavirus, adenovirus, and rhinovirus are frequent isolates (Wenzel, 2006). Bacterial agents causing community-acquired pneumonia are rarely implicated. The cough of acute bronchitis persists for 10 to 20 days (mean 18 days) and occasionally lasts for a month or longer. According to the 2006 guidelines of the American College of Chest Physicians, routine antibiotic treatment is not indicated (Smith, 2014).

his is a leading cause of death in the United States (Heron, 2016). Current classiication includes communiy-acquired pneumonia (CAP), which is typically encountered in otherwise healthy young women, including during pregnancy. Healthcare-associated pneumonia (HAP) develops in patients in outpatient care facilities and more closely resembles hospitalacquired pneumonia (HAP).

In most cases of community-acquired pneumonia, the ofending pathogen is not identified. In a recent study from the Centers for Disease Control and Prevention (CDC), pathogens were identified in only 38 percent of nearly 2S00 adults with pneumonia Gain, 201S). hese included viruses in 23 percent, bacteria in 11 percent, both in 3 percent, and ungi or protozoa in 1 percent. Half of bacterial isolates were Sreptococcus pneumoniae.

Pneumonia in pregnant women is relatively common (Brito, 2011; Sheield, 2009). Gazmararian and coworkers (2002) reported that pneumonia accounts for 4.2 percent of antepartum admissions for nonobstetrical complications. Pneumonia is also a frequent indication for postpartum readmission (Belfort, 2010). During inluenza season, admission rates for respiratory illnesses double compared with rates in the remaining months (Cox, 2006). Regardless of etiology, mortality from pneumonia is infrequent in young women, but during pregnancy severe pneumonitis with appreciable loss of ventilatory capacity is not as well tolerated (Callaghan, 201S; Rogers, 2010). Hypoxemia and acidosis are also poorly accommodated by the fetus and frequently stimulate preterm labor after midpregnancy. Because many cases of pneumonia follow viral upper respiratory illnesses, worsening or persistence of symptoms may represent developing pneumonia. Any gravida suspected of having pneumonia should undergo chest radiography.

Many bacteria that cause community-acquired pneumonia, such as Streptococcus pneumoniae, are part of the normal resident lora. Some factors that perturb the symbiotic relationship between colonizing bacteria and mucosal phagocytic defenses include acquisition of a virulent strain or bacterial infections following a viral infection. Cigarette smoking and chronic bronchitis favor colonization with S pneumoniae, HaemophiIus inluenzae, and Legionella species. Other risk factors include asthma, binge drinking, and human immunodeficiency virus (HIV) infection (Sheield, 2009).

Pregnancy itself does not appear to predispose to pneumonia. Jin and colleagues (2003) reported the antepartum hospitalization rate for pneumonia in Alberta, Canada, to be 1.S per 1000 deliveries-almost identical to the rate of 1.47 per 1000 for nonpregnant women. Likewise, Yost and associates (2000) reported an incidence of 1.S per 1000 for pneumonia complicating 7S,000 pregnancies cared for at Parkland Hospital. s discussed, at least hlf are caused by viruses. A fourth are bacterial, and S pneumoniae causes half of the latter. Over the past few years community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as a common pathogen that may cause necrotizing pneumonia (Mandell, 201S; Moran, 2013). Occasionally, Legionnaires disease is encountered (Close, 2016).

FIGURE 51-3 Chest radiograph in a pregnant woman with right lower lobe and left upper lobe pneumonia. Rounded right basilar and let apical infiltrates are consistent with the diagnosis.

Typical symptoms of pneumonia include cough, dyspnea, sputum production, and pleuritic chest pain. Mild upper respiratory symptoms and malaise usually precede these symptoms, and mild leukocytosis is usually present. Chest radiography is essential for diagnosis (Fig. SI-3). Radiographical findings do not accurately predict the etiology, and as discussed, the responsible pathogen is identiied in fewer than half of cases. According to the Infectious Diseases Society of America (IDSA) and the American horacic Society (A TS), tests to identiy a specific agent are optional (Mandell, 2007). hus, sputum cultures, serological testing, cold agglutinin identiication, and tests for bacterial antigens are not routinely recommended. The one exception to this may be rapid serological testing for inluenza A and B (Sheield, 2009).

Although many otherwise healthy young adults can be safely treated as outpatients, at Parkland Hospital we hospitalize all pregnant women with radiographically proven pneumonia. Another option is outpatient therapy or 23-hour observation, which is reasonable with optimal follow-up. At least for nonpregnant patients, the pneumonia severity index (PSI) and the CURB-6S scoring system are used as a guide to admission (Mandell, 201S). Neither has been studied in pregnancy. Given that, risk factors shown in Table 5a1-3 should prompt consideration for hospitalization.

With severe disease, admission to an intensive or intermediate care unit is advisable. Approximately 20 percent of pregnant women admitted to Parkland Hospital for pneumonia require this level of care (Zeeman, 2003). Severe pneumo

TABLE 51-3. Criteria for Severe Community-Acquired Pneumoniaa

Leukopenia: WBC <4000/-LL

Thrombocytopenia-platelets < 1 OO,OOO/-LL aCriteria of the Infectious Diseases Society of America/

American Thoracic Society.

Pao/Fio2 = partial pressure oxygen in arterial blood/ fraction of inspired oxygen; WBC = white blood cell. Adapted from Mandell, 2007.

nia is a relatively common cause of acute respiratory distress syndrome (ARDS) during pregnancy, and mechanical ventilation may become necessary (Chap. 47, p. 919). Indeed, of the 51 gravidas who required mechanical ventilation in the review by Jenkins and coworkers (2003), 12 percent had pneumonia.

Initial antimicrobial and antiviral treatment is empirical (Mandell, 2015). Because most adult bacterial pneumonias are caused by pneumococci, mycoplasma, or chlamydophila, monotherapy initially is with a macrolide-azithromycin, clarithromycin, or erythromycin (Table 51-4). Yost and colleagues (2000) reported that erythromycin mono therapy, given IV and then orally, was efective in all but one of 99 pregnant women with uncomplicated pneumonia. During inluenza season, we routinely administer oseltamivir treatment along with empirical therapy for bacterial pneumonia.

For women with severe disease according to criteria in Table 51-3, Mandell and associates (2007) summarized IDSAI ATS guidelines, which call for either: (1) a respiratory luoroquinolone-Ievofloxacin, moxifloxacin, or gemiloxacin; or (2) a macrolide plus a preferred �-lactam-either high-dose amoxicillin or amoxicillin-clavulanate. �-Lactam alternatives include ceftriaxone, cefpodoxime, or cefuroxime (see Table 51-4). In areas in which the resistance of pneumococcal isolates to macrolides is great, these latter regimens are preferred. he teratogenicity risk of luoroquinolones is low, and these should be given if indicated (Briggs, 2015). IfCA-MRSA is suspected, then vancomycin or linezolid is added (Mandell, 2015; Moran, 2013; Wunderink, 2013).

Clinical improvement is usually evident in 48 to 72 hours with resolution of fever in 2 to 4 days. Radiographic abnormalities may take up to 6 weeks to completely resolve (Torres, 2008). Worsening disease is a poor prognostic feature, and subsequent radiography is recommended if fever persists. Even with improvement, however, approximately 20 percent of women develop a pleural eusion. Treatment of uncomplicated pneumonia is recommended for 5 to 7 days (Musher, 2014). Treatment failure may occur in up to 15 percent of cases, and a wider antimicrobial regimen and more extensive diagnostic testing is warranted.

During the preantimicrobial era, as many as a third of pregnant women with pneumonia died (Finland, 1939). Although much improved, maternl and perinatl morbidity and mortality remain formidable. In ive studies with a total of 632 women published ater 1990, almost 7 percent required intubation and mechanical ventilation, and the maternal mortality rate was 0.8 percent.

Prematurely ruptured membranes and preterm delivery are frequent complications and have been reported in up to a third of cases of acute lung infection (Getahun, 2007; Shariatzadeh, 2006). Likely related are older studies reporting a twofold increase in low-birthweight neonates (Sheield, 2009). In one populationbased study from Taiwan of nearly 219,000 births, incidences of preterm and growth-restricted newborns and of preeclampsia and cesarean delivery were significantly increased (Chen, 2012).

Two pneumococcal vaccines, a 23-serotype older preparation and a newer 13-serotype vaccine, are used in children (Swamy, 2015). he 23-serotype vaccine is 60-to 70-percent protective, and its use lowers emergence of drug-resistant pneumococci (Kyaw, 2006). he 13-serotype vaccine is not recommended for

TABLE 51-4. Empirical Antimicrobial Treatment for Community-Acquired Pneumonia

Uncomplicated, otherwise health'

Macrolidesb: clarithromycin or azithromycin

Respiratory fluoroquinolones: moxifloxacin, gemifloxacin, or levofloxacin 3-lactams: amoxicillin/clavulanate, ceftriaxone, cefotaxime, or cefuroxime plus a macrolide aUse as inpatient or outpatient regimen. bDoxycyciine may be given instead if postpartum. (See Table 51-3 for criteria.

otherwise healthy pregnant women. It is, however, recommended for women who are immunocompromised, including those with HIV infection; significant smoking history; diabetes; cardiac, pulmonary, or renal disease; and asplenia, such as with sicklecell disease (Table 9-7, p. 173). Protection against pneumococcal infection in women with chronic diseases may be less eicacious than in healthy patients (Moberley, 2013).

Each year, 10 percent of pregnant women develop influenza (Cantu, 2013). Influenza A and B are RNA viruses that cause respiratory infection, including pneumonitis, that is epidemic in the winter months. The virus is spread by aerosolized droplets and quickly infects ciliated columnar epithelium, alveolar cells, mucus gland cells, and macrophages. Disease onset is 1 to 4 days following exposure. Common symptoms include fever, cough, myalgia, and chills (Sokolow, 2015). In most healthy adults, infection is self-limited.

Pneumonia is the most frequent complication of inluenza and mimics bacterial pneumonia. According to the CDC (201 Oa), infected pregnant women are more likely to be hospitalized and admitted to an ICU. Others have corroborated these observations (Mertz, 2017). At Parkland Hospital during the 2003 to 2004 inluenza season, pneumonia developed in 12 percent of gravidas with influenza (Rogers, 2010).

he 2009 to 2010 pandemic with the influenza (NHINI) pdm09 strain was particularly severe (Rasmussen, 2014). In an MFMU Network study, 10 percent of pregnant or postpartum women admitted with HINI inluenza were cared for in an ICU, and 11 percent of these patients died (Varner, 201I). Risk factors included late pregnancy, smoking, and chronic hypertension. Overall, inluenza accounted for 12 percent of pregnancy-related deaths during the 2009 to 2010 pandemic (Callaghan, 2015). During the 2013 to 2014 inluenza season, a fourth of pregnant women admitted to California ICUs died (Louie, 2015). Of865 pregnant women with influenza, Oboho and coworkers (2016) noted that 7 percent of their cohort had severe disease, and four women died. If inluenza causes ARDS, extracorporeal membrane oxygenation (ECMO) may be lifesaving (Anselmi, 2015; Saad, 2016).

Primary influenza pneumonitis is characterized by sparse sputum production and radiographic interstitial infiltrates (Cohen, 2015). More commonly, either secondary or mixed pneumonia develop from bacterial superinfection by streptococci or staphylococci after 2 to 3 days of initial clinical improvement. he CDC (2007) reported several cases in which CA-MRSA caused influenza-associated pneumonitis with a case-fatality rate of 25 percent. Other possible adverse efects of inluenza A and B on pregnancy outcome are discussed in Chapter 64 (p. 1213).

Supportive treatment is recommended for uncomplicated influenza, and early antiviral treatment is efective Gamieson, 2011; Oboho, 2016). Hospitalization is considered for severely ill women, and for those with pneumonia. As discussed, inluenza hospitalization rates for those with advanced pregnancy are increased compared with nonpregnant women (Dodds, 2007; Schanzer, 2007). he CDC (2016b) recommends neuraminidase inhibitors given within 2 days of symptom onset for chemoprophylaxis and treatment of influenza A and B (Chap. 64, p. 1214). he drugs interfere with release of progeny virus from infected host cells and thus prevent infection of new host cells (Cohen, 2015). Oseltamivir is given orally, 75 mg twice daily, or zanamivir is given by inhalation, 10 mg twice daily. Recommended treatment duration with either is 5 days. The drugs shorten the course of illness by 1 to 2 days, and they probably reduce the risk for pneumonitis (Belgi, 2014; Muthuri, 2014). Our practice is to treat all pregnant women with influenza whether or not pneumonitis is identiied (Rasmussen, 2014). Few data guide use of these agents in pregnant women, but the drugs are not teratogenic in animal studies and are considered low risk (Briggs, 2015).

A major potential concern for viral resistance comes from avian inluenza isolates. "Bird lu" with HPAI, H5N8, H5N2, and H5Nl isolates has been reported in the United States by the CDC Ohung, 2015). In Asia, human infection has been documented with some of these, and mortality rates are high.

Preventively, vaccination for inluenza A is recommended by the American College of Obstetricians and Gynecologists (2016b) and the CDC (2016b). Vaccination is discussed in detail in Chapter 64 (p. 1214). Prenatal vaccination also afords some temporary protection for infants (Madhi, 2014; Tita, 2016). During the 2014 to 2015 lu season, the CDC reported that only half of pregnant women received influenza vaccine (Ding,a2015).

Infection with varicella-zoster virus, the same agent responsible for chicken pox, results in pneumonitis in 5 percent of gravidas (Harger, 2002). Diagnosis and management are considered in Chapter 64 (p. 1212).

Fungal and parasitic pulmonary infections are usually of greatest consequence in immunocompromised hosts, especially in women with acquired immunodeficiency syndrome (AIDS). Of these, lung infection with Pneumoystis jiroveci, formerly called Pneumoystis carinii, is a common complication. The opportunistic fungus causes interstitial pneumonia characterized by dry cough, tachypnea, dyspnea, and difuse radiographic infiltrates. Although this organism can be identiied by sputum culture, bronchoscopy with lavage or biopsy may be necessary.

In an earlier report from the AIDS Clinical Trials Centers, Stratton and colleagues (1992) described pneumocystis pneumonia as the most frequent HIV-related disorder in pregnant women. In some cases, tracheal intubation and mechanical ventilation may be required. Ahmad and coworkers (200 I) reviewed 22 cases during pregnancy and cited a 50-percent mortality rate. Treatment is with trimethoprim-sulfamethoxazole for 14 to 21 days (Masur, 2015). Alternative agents include the more toxic pentamidine (Walzer, 2005).

For prophylaxis, several international health agencies recommend one double-strength trimethoprim-sulfamethoxazole tablet orally daily for certain groups of HIV-infected pregnant women. These include women with CD4+ T-lymphocyte counts <2001LL, those whose CD4+ T lymphocytes constitute < 14 percent, or if there is an AIDS-defining illness, particularly oropharyngeal candidiasis (Centers for Disease Control and Prevention, 2016a).

Any of several fungi can cause pneumonia. In pregnancy, this is usually seen in women with HIV infection or who are oth erwise immunocompromised. Infection is usually mild and self-limited. It is characterized initially by cough and fever, and dissemination is infrequent (Mansour, 2015).

Histoplasmosis and blastomycosis do not appear to be more frequent or more severe during pregnancy (Youssef, 2013). Data concerning coccidioidomycosis are conlicting (Bercovitch, 2011; Patel, 2013). In a case-control study from an endemic area, Rosenstein and associates (2001) reported that pregnancy was a signiicant risk factor for disseminated disease. In another study, however, Caldwell and coworkers (2000) identified 32 serologically confirmed cases during pregnancy and documented dissemination in only three cases. Women with associated erythema nodosum have a better prognosis, whereas mediastinal lymphadenopathy may more likely relect disseminated disease (Caldwell, 2000; Mayer, 2013). Finally, Crum and Ballon-Landa (2006) reviewed 80 cases of antepartum coccidioidomycosis and found that almost all women diagnosed in the third trimester had disseminated disease. Although the overall maternal mortality rate was 40 percent, it was only 20 percent for 29 cases reported since 1973. Spinello (2007) and Bercovitch (201a1) with their colleagues have provided reviews of coccidioidomycosis in pregnancy.

Most cases of cryptococcosis reported during pregnancy manifest as meningitis. Otherwise healthy pregnant women occasionally have cryptococcal pneumonia (Asadi Gharabaghi, 2014; Ely, 1998). Diagnosis is diicult because clinical presentation is similar to that of other community-acquired pneumonias.

Treatment. The 2007 IDSNATS guidelines recommend itraconazole as preferred therapy for disseminated fungal infections (Mandell, 2007). Pregnant women have also been given IV amphotericin B or ketoconazole (Paranyuk, 2006; Pilmis, 2015). Amphotericin B has been used extensively in pregnancy with no embryofetal efects. Because of evidence that fluconazole, itraconazole, and ketoconazole may be embryo toxic in large doses in early pregnancy, Briggs and coworkers (2015) recommend that irst-trimester use should be avoided if possible.

hree echinocandin derivatives-caspofongin, micaongin, and anidulafungin-are efective for invasive candidiasis (Pilmis, 2015; Reboli, 2007). They are embryotoxic and teratogenic in laboratory animals, and use in human pregnancies has not been reported (Briggs, 2015).

his coronaviral respiratory infection was first identiied in China in 2002, but no new cases have been reported since 2005. It caused atypical pneumonitis with a case-fatality rate of approximately 10 percent (Dolin, 2012). SARS in pregnancy had a case-fatality rate of up to 25 percent (Lam, 2004; Wong, 2004). Ng and coworkers (2006) reported that the placentas from 7 of 19 cases showed abnormal intervillous or subchorionic ibrin deposition in three, and extensive fetal thrombotic vasculopathy in two.

Tuberculosis is still a major worldwide concern. Indeed, it is estimated that a third of the world population is infected (Getahun, 2015). However, it is uncommon in the United

States. The incidence of active tuberculosis in this country has plateaued since 2000 (Scott, 2015). More than half of active cases are in immigrants (Centers for Disease Control and Pre vention, 2009b). Persons born in the United States have newly acquired infection, whereas foreign-born persons usually have reactivation of latent infection. In this country, tuberculosis is a disease of the elderly, the urban poor, minority groups especially black Americans, and patients with HIV infection (Khan, 2013; Raviglione, 2015).

Infection is via inhalation of Mycobacterium tuberculosis, which incites a granulomatous pulmonary reaction. In more than 90 percent of patients, infection is contained and is dor mant for long periods (Getahun, 2015; Zumla, 2013). In some, especially those who are immunocompromised or who have other diseases, tuberculosis becomes reactivated to cause clini cal disease. Manifestations usually include cough with minimal sputum production, low-grade fever, hemoptysis, and weight loss. Various iniltrative patterns are seen on chest radiograph, ated. Acid-fast bacilli are seen on stained smears of sputum in approximately two thirds of culture-positive individuals. Forms of extrapulmonary tuberculosis include lymphadenitis, pleural, genitourinary, skeletal, meningeal, gastrointestinal, and miliary or disseminated (Raviglione, 2015).

Resistance to antituberculosis drugs in the United States in the early 1990s was associated with emergence of strains of multidrug-resistant tuberculosis (MDR-TB). Because of this, the CDC (2009a) now recommends a multidrug regimen for initial empirical treatment of patients with symptomatic tuberculosis. Isoniazid, rifampin, pyrazinamide, and ethambutol are given until susceptibility studies are performed (Horsburgh, 2015). Cure rates with 6-month short-course directy observed therapy-DOT -approach 90 percent for new infections (Raviglione, 2015). Other second-line drugs may need to be added. Drug susceptibility is performed on all irst isolates.

The considerable influx of women into the United States from Asia, Africa, Mexico, and Central America has been accompanied by an increased frequency of tuberculosis in pregnancy. Sackof and coworkers (2006) reported positive tuberculin test results in half of 678 foreign-born women attending prenatal clinics in New York City. Almost 60 percent were newly diagnosed. Pillay and colleagues (2004) stress the prevalence of tuberculosis in HIV-positive pregnant women. At Jackson Memorial Hospital in Miami, Schulte and associates (2002) reported that 21 percent of 207 HIV-infected pregnant women had a positive skin test result. Recall also that silent endometrial tuberculosis can cause tubal infertility (Levison, 2010; Raviglione, 2015).

Without therapy, active tuberculosis appears to have adverse efects on pregnancy (Mnyani, 2011). Several studies indicate that outcomes are dependent on the site of infection and gestational age at diagnosis. J ana and colleagues (1994) from India and Figueroa-Damian and Arrendondo-Garcia (1998) from Mexico City noted that active pulmonary tuberculosis was associated with increased incidences of preterm delivery, low-birthweight and growth-restricted newborns, and perinatal mortality. Others have found similar efects (EI-Messidi, 2016; Lin, 2010; Sobhy, 2017). From her review, Eferen (2007) cited twofold greater rates of low birthweight, preterm delivery, and preeclampsia. The perinatal mortality rate was increased almost tenfold. Adverse outcomes correlate with late diagnosis, incomplete or irregular treatment, and advanced pulmonary lesions. Conversely, treated tuberculosis is associated with good pregnancy outcomes (Nguyen, 2014; Taylor, 2013).

Extrapulmonary tuberculosis is less common. Jana and coworkers (1999) reported outcomes in 33 pregnant women with renal, intestinal, and skeletal tuberculosis, and a third had low-birthweight newborns. Llewelyn and associates (2000) reported that nine of 13 pregnant women with extrapulmonary disease had delayed diagnoses. Prevost and Fung Kee Fung (I999) reviewed 56 cases of tuberculous meningitis in which a third of mothers died. Spinal tuberculosis may cause paraplegia, but vertebral fusion may prevent it from becoming permanent (Badve, 2011; Nanda, 2002). Psoas abscess develops in 5 percent of those with spinal infections (Nigam, 2013). Other presentations include widespread intraperitoneal tuberculosis simulating ovarian carcinomatosis and degenerating leiomyoma, and hyperemesis gravidarum from tubercular meningitis (Kutiu, 2007; Moore, 2008; Sherer, 2005).

Two types of tests are used to detect latent or active tuberculosis. One is the time-honored tuberculin skin test (TSj) and the others are inteeron-gamma release assays IGRAs)} which are becoming preferred (Getahun, 2015; Horsburgh, 2011). IGRAs are blood tests that measure interferon-gamma release in response to antigens present in M tuberculosis, but not bacille Calmette-Guerin (BCG) vaccine (Levison, 2010). he CDC (2005b, 2010b) recommends either skin testing or IGRA testing of gravidas who are in any of the high-risk groups. For those who have received BCG vaccination, IGRA testing is used (Mazurek, 2010).

For skin testing, the preferred antigen is purified protein derivative (PPD) of intermediate strength of 5 tuberculin units. If the intracutaneously applied test result is negative, no further evaluation is needed. A positive skin test result measures �5 mm in diameter and requires evaluation for active disease, including a chest radiograph.

Two IGRAs are available: QuantiFERON-TB Gold and T-SPOT TB tests are recommended by the CDC (2005a,b) for the same indications as skin testing. Although these tests have not been evaluated as extensively as tuberculin skin testing, Kowada (2014) concluded that the tests are cost efective.

Other essential laboratory methods for detection or verification of infection-both active and latent-include microscopy, culture, nucleic acid amplification assay, and drug-susceptibility testing (Horsburgh, 2015; Raviglione, 2015).

Latent Infection. In nonpregnant tuberculin-positive patients with latent infection who are younger than 35 years and who have no evidence of active disease, isoniazid, 300 mg orally daily, is given for 9 months. Isoniazid has been used for decades, and it is considered safe in pregnancy (Briggs, 2015; Taylor, 2013). Compliance is a major problem, and Sackof (2006) and Cruz (2005) and their associates reported a disappointing 10-percent treatment completion. One obvious disconnect is that care for tuberculosis is given in diferent health systems than prenatal care (Zenner, 2012). hese observations are important because most recommend that isoniazid therapy be delayed until ater delivery. Because of possibly increased isoniazid-induced hepatitis risk in postpartum women, some even recommend withholding treatment until 3 to 6 months ater delivery. hat said, neither method is as efective as antepartum treatment to prevent active infection. Boggess and colleagues (2000) reported that only 42 percent of 167 tuberculin-positive asymptomatic women delivered at San Francisco General Hospital completed 6-month therapy that was not begun until the irst postpartum visit.

There are exceptions to delayed treatment for latent infection in pregnancy. Known recent skin-test convertors are treated antepartum because the incidence of active infection is 5 percent in the first year (Zumla, 2013). Skin-test-positive women exposed to active infection are also treated because the incidence of infection is 0.5 percent per year. Finally, HIVpositive women are treated because they have an approximate 10-percent annual risk of active disease.

Active Infection. Recommended initial treatment for active tuberculosis in pregnant women is a four-drug regimen with isoniazid, rifampin, ethambutol, and pyrazinamide, along with pyridoxine. For meningitis, levoBoxacin may be added (Kalita, 2014). In the irst 2-month phase, all four drugs are givenbactericidal phase. his is followed by a 4-month phase of isoniazid and rifampin-continuation phase (Raviglione, 2015; Zumla, 2013). A few reports describe MDR-TB during pregnancy, and treatment options have been reviewed (Horsburgh, 2015; Lessnau, 2003). Breastfeeding is not prohibited during antituberculous therapy.

Treatment of active disease is of special concern if there is antiretroviral naivete. In these circumstances, beginning concomitant therapy with antituberculosis and antiretroviral therapy can cause the immune reconstitution inlammatory syndrome IRIS) with toxic drug efects (Lai, 2016; Torok, 2011). hat said, recent studies support earlier administration of highly active antiretroviral therapy (HAART)-within 2 to 4 weeksafter beginning antituberculosis therapy (Blanc, 2011; Havlir, 2011; Karim, 2011). lso, for HIV-infected women, rifampin or rifabutin use may be contraindicated if certain protease inhibitors or nonnucleoside reverse transcriptase inhibitors are being administered. If there is resistance to rifabutin or rifampin, then pyrazinamide therapy is given. Of the secondline regimens, the aminoglycosides-streptomycin, kanamycin, amikacin, and capreomycin-are ototoxic to the fetus and are contraindicated (Briggs, 2015).

Neonatal Tuberculosis. Tubercular bacillemia can infect the placenta, but the fetus infrequently becomes infected-con genital tuberculosis. The term also applies to newborns who are infected by aspiration of infected secretions at delivery. Each route of infection constitutes approximately half of the cases.

manifests with hepatosplenomegaly, respiratory distress, fever, and lymphadenopathy (Dewan, 2014; Osowicki, 2016).

Cantwell and associates (1994) reviewed 29 cases of congenital tuberculosis reported since 1980. Only 12 of the mothers had active infection, and tuberculosis was frequently demonstrated by postpartum endometrial biopsy. Adhikari and colleagues (1997) described 11 South African postpartum women whose endometrial biopsy was culture-positive. Six of their neonates had congenital tuberculosis.

Neonatal infection is unlikely if the mother with active disease has been treated before delivery or if her sputum culture is negative. Because the newborn is susceptible to tuberculosis, most experts recommend isolation from the mother suspected of having active disease. If untreated, the risk of disease in the infant born to a woman with active infection is 50 percent in the irst year Qacobs, 1988).

his is a chronic, multisystem inflammatory disease of unknown etiology characterized by an accumulation of T-helper lymphocytes and phagocytes within noncaseating granulomas (Baughman, 2015; Celada, 2015). Predisposition to the disease is genetically determined and characterized by an exaggerated response of helper T lymphocytes to environmental triggers. Pulmonary involvement is most common, followed by skin, eyes, lymph nodes, and then all other organ systems. The prevalence of sarcoid in the United States is 20 to 60 per 100,000, with equal sex distribution. It is more than 10 times more common for blacks than for whites (Baughman, 2015). Most patients are between 20 and 40 years. Clinical presentation varies, but more than half of patients have dyspnea and a dry cough without constitutional symptoms that develop insidiously over months. Disease onset is abrupt in approximately 25 percent of patients, and 10 to 20 percent are asymptomatic at discovery.

Pulmonary symptoms are dominant, and more than 90 percent of patients have an abnormal chest radiograph at some point. Interstitial pneumonitis is the hallmark of pulmonary involvement, and half of afected patients develop permanent radiological changes. Lymphadenopathy, especially of the mediastinum, is present in 75 to 90 percent of cases. A fourth each have uveitis and skin involvement, the latter usually manifest as eythema nodosum. In women, sarcoid causes approximately 10 percent of cases of erythema nodosum (Mert, 2007). Impor tantly, any other organ system may be involved (Kandolin, 2015; Powe, 2015; Wallmiiller, 2012). Conirmation of the diagnosis is with biopsy-preferably a lymph node. However, because the lung may be the only obviously involved organ, tissue acquisition is often diicult.

The overall prognosis for sarcoidosis is good, and it resolves without treatment in 50 percent of patients. Still, quality of life is diminished (de Vries, 2007). In the other 50 percent, permanent organ dysfunction, albeit mild and nonprogressive, persists. Approximately 10 percent die because of their disease.

Glucocorticoids are the most widely used treatment for symptomatic disease. Permanent organ derangement is seldom reversed by their use (Paramothayan, 2002). Thus, the deci sion to treat is based on symptoms, physical indings, chest radiograph, and pulmonary function tests. Unless respiratory symptoms are prominent, therapy is usually withheld for a several-month observation period. If inlammation does not subside, then prednisone, 1 mg/kg, is given daily and tapered to < 10 mg by 6 months (Baughman, 2015). For those with an inadequate response, immunosuppressive or cytotoxic agents and cytokine modulators can be used.

Because it is uncommon and frequently benign, sarcoidosis is not often seen in pregnancy. Although it seldom afects pregnancy adversely, meningitis, heart failure, and neurosarcoidosis have been described (Cardonick, 2000; Maisel, 1996; Wallmiiller, 2012). In a study of the Nationwide Inpatient Sample of 678 cases of sarcoidosis in pregnancy, incidences of preeclampsia, preterm delivery, and thromboembolism were increased (Hadid, 2015). Selroos (1990) studied 252 women with sarcoidosis in Finland, and 15 percent had sarcoidosis during pregnancy. Disease did not progress in the 26 pregnancies in women with active disease. Three aborted spontaneously, and the other 23 women were delivered at term. Agha and coworkers (1982) reported similar experiences with 35 pregnancies at the University of Michigan.

Active sarcoidosis is treated using the same guidelines as for the woman who is not pregnant. Severe disease warrants serial determination of pulmonary function. Symptomatic uveitis, constitutional symptoms, and pulmonary symptoms are treated with prednisone, 1 mg/kg orally per day.

This autosomal recessive exocrinopathy is one of the most common fatal genetic disorders in whites. Cystic ibrosis is caused by one of more than 2000 mutations in a 230-kb gene on the long arm of chromosome 7 that encodes an amino acid polypeptide (Patel, 2015; Sorscher, 2015). his peptide functions as a chloride channel and is termed the cystic ibrosis transmembrane conductance regulator (CFTR). As discussed in Chapter 14 (p. 289), phenotypes vary widely, even among homozygotes for the common 6F508 mutation (Rowntree, 2003). Approximately 10 to 20 percent of afected newborns are diagnosed shortly after birth because of meconium peritonitis (Boczar, 2015; Sorscher, 2015). Currently, the median predicted survival is 37 years, and nearly 80 percent of females with cystic ibrosis now survive to adulthood (Gillet, 2002; Patel, 2015).

Mutations in the chloride channel cause altered epithelial cell membrane transport of electrolytes. his afects all sites in which epithelium expresses CFTR-secretory cells. These include the sinuses, lung, pancreas, liver, and reproductive tract. Disease severity depends on which two alleles are inherited, and approximately 10 percent are disease-causing mutations (Sorscher, 2015). Homozygosity for Phe508del (�F508) is one of the most severe, and 90 percent of individuals with clinical disease carry at least one F508 allele.

Exocrine gland ductal obstruction develops from thick, viscid secretions (Rowe, 2005). In the lung, submucosal glandular ducts are afected. Eccrine sweat gland abnormalities are the basis for the diagnostic sweat test, characterized by elevated sodium, potassium, and chloride levels in sweat.

Lung involvement is commonplace and is usually the cause of death. Bronchial gland hypertrophy with mucous plugging and small-airway obstruction leads to subsequent infection that ultimately causes chronic bronchitis and bronchiectasis. For complex and not completely explicable reasons, chronic inflammation from Pseudomonas aeruginosa occurs in more than 90 percent of patients. In a minority,aS aureus, H inluenzae, and Burkholderia cepacia are recovered (Rowe, 2005). Colonization with the last has been reported to signiy a worse prognosis, especially in pregnancy (Gillet, 2002). Acute and chronic parenchymal inlammation ultimately causes extensive fibrosis, and along with airway obstruction, ventilation-perfusion mismatch develops. Pulmonary insuiciency is the end result. Lung or heart-lung transplantation has a 5-year survival rate of only 50 to 60 percent (Sorscher, 2015). A few women have successfully undergone pregnancy following lung transplantation (Kruszka, 2002; Shaner, 2012).

This CFTR2 resource delineates gene variants with a clear etiological role-http://ww.cftr2.org. Women with clinical cystic fibrosis are sub fertile because of tenacious cervical mucus. Males have oligospermia or aspermia from vas deferens obstruction, and 98 percent are infertile (hmad, 2013). Despite this, the North American Cystic Fibrosis Foundation estimated that 4 percent of afected women become pregnant every year (Edenborough, 1995). he endometrium and tubes express some CFTR but are functionally normal, and the ovaries do not express the CFTR gene (Eden borough, 2001). Both intrauterine insemination and in vitro fertilization can be successful for afected women (Rodgers, 2000). Several ethical considerations regarding plans for pregnancy by these women were reviewed by Wexler and colleagues (2007). One important factor is the long-term prognosis for the mother. For male infertility, Sobczynska-Tomaszewska and associates (2006) have emphasized the importance of molecular diagnosis.

he American College of Obstetricians and Gynecologists (20a17) recommends that carrier screening be ofered to all women currently pregnant or considering conception (Chap. 14, p. 289). The CDC also added cystic ibrosis to newborn screening programs (Southern, 2009) (Chap. 32, p. 614).

Pregnancy outcome is inversely related to severity of lung dysfunction. Advanced chronic lung disease, hypoxia, and frequent infections may prove deleterious. At least in the past, cor pulmonale was common, but even that does not preclude successful pregnancy (Cameron, 2005). In some women, pancreatic dyunction may cause poor maternal nutrition. Otherwise normal pregnancy-induced insulin resistance frequently results in gestational diabetes after midpregnancy (Hardin, 2005). In one study of 48 pregnancies, half had pancreatic insuiciency and a third required insulin (horpe-Beeston, 2013). Up to 25 percent of patients develop diabetes by age 20, and diabetes is most frequent with the Phe508del homozygous mutation (Giacobbe, 2012; Patel, 2015).

Cystic fibrosis per se is not afected by pregnancy (Schechter, 2013). Early reports of a deleterious efect on the course of cystic fibrosis were related to severe disease (Olson, 1997). When matched with nonpregnant women by disease severity, recent reports indicate no deleterious efects on long-term survival (Schechter, 2013).

Prep regnancy counseling is imperative. Women who choose to become pregnant require close surveillance for development of superimposed infection, diabetes, and heart failure. Serial pulmonary function testing assists management and estimating prognosis. When the FEV] is at least 70 percent, women usually tolerate pregnancy well. Emphasis is placed on postural drainage, bronchodilator therapy, and infection control.

�-Adrenergic bronchodilators help control airway constriction. Inhaled recombinant human deoxyribonuclease I improves lung function by reducing sputum viscosity (Sorscher, 2015). Inhaled 7 -percent saline produces short-and long-term benefits (Elkins, 2006). Nutritional status is assessed and appropriate dietary counseling given. Pancreatic insuiciency requires replacement of oral pancreatic enzymes. Promising new therapy to correct CFTR protein dysfunction was recently described by Wainwright and colleagues (2015). Using a combination of lumacaftor and ivacaftor, these investigators showed that patients homozygous for the Phe508del mutation were significantly benefitted. No reports of either drug are available regarding pregnant women.

Infection is heralded by increasing cough and mucus production. Oral semisynthetic penicillins or cephalosporins usually suice to treat staphylococcal infections. Pseudomonas infection is problematic, and inhaled tobramycin and colistin have been used successfully to control this organism. Immediate hospitalization and aggressive therapy are warranted for serious pulmonary infections. he threshold for hospitalization with other complications is low. For labor and delivery, epidural analgesia is recommended (Deighan, 2014).

Earlier reports chronicled the poor maternal and perinatal outcomes of women with cystic ibrosis (Cohen, 1980; Kent, 1993). vlore recent reports describe better outcomes, but there still are serious complications. Disease severity is now quantified by pulmonary function studies, which are the best predictor of pregnancy and long-term maternal outcome. Edenborough and colleagues (2000) reported 69 pregnancies and found that if prep regnancy FEV! was <60 percent of predicted, the risk for preterm delivery, respiratory complications, and death of the mother within a few years of childbirth was substantive. Thorpe-Beeston (2013) and Fitzsimmons (1996) and their associates reported similar indings. Gillet and colleagues (2002) reported 75 pregnancies from the French Cystic Fibrosis Registry. Almost 20 percent of newborns were delivered preterm, and 30 percent had growth restriction. he one maternal death was due to Pseudomonas sepsis in a woman whose prepregnancy FEV! was 60 percent. Long-term, however, 17 percent of women died, and four infants had conirmed cystic fibrosis.

Maternal complications are daunting. Patel and coworkers (2015) recently queried the National Inpatient Sample database and reported that the prevalence of cystic ibrosis in pregnancy had a signiicant linear increase from 2000 to 2010. They analyzed 1119 afected women in more than 12 million births and reported a litany of risks (Table 51-5). In contrast, perinatal outcomes were surprisingly good.

Cystic fibrosis is a common antecedent disease leading to lung transplantation. Gyi and coworkers (2006) reviewed 10 pregnancies in such women and reported nine liveborn neonates. Maternal outcomes were less favorable. Of the three gravidas who developed rejection during pregnancy, all had progressively declining pulmonary function and died of chronic rejection by 38 months after delivery.

TABLE 51-5. Odds Ratios for Maternal Complications in 11e19 Pregnant Women with Cystic Fibrosis Compared with Controls

Carbon monoxide is a ubiquitous gas, and most nonsmoking adults have a carbon monoxyhemoglobin saturation of 1 to 3 per cent. In cigarette smokers, levels may be as high as 5 to 10 per cent. Carbon monoxide is the most frequent cause of poisoning worldwide (Stoller, 2007). Toxic levels are oten encountered in inadequately ventilated areas warmed by space heaters.

Carbon monoxide is particularly toxic because it is odorless and tasteless and has a high ainity for hemoglobin binding. hus, it displaces oxygen and impedes its transfer with resultant hypoxia. Besides acute sequelae including death and anoxic encephalopathy, cognitive defects develop in as many as half of patients following loss of consciousness or in those with carbon monoxide levels >25 percent (Weaver, 2002). Hypoxic brain damage has a predilection for the cerebral cortex and white matter and for the basal ganglia (Lo, 2007; Prockop, 2007). A Parkinson syndrome sometimes follows after recovery (Hemphill,a2015).

Through several physiological alterations, the rate of endogenous carbon monoxide production almost doubles in normal pregnancy (Longo, 1977). Although the pregnant woman is not more susceptible to carbon monoxide poisoning, the fetus does not tolerate excessive exposure (Friedman, 2015). With chronic exposure, maternal symptoms usually appear when the carboxyhemoglobin concentration is 5 to 20 percent. Symptoms include headache, weakness, dizziness, physical and visual impairment, palpitations, and nausea and vomiting. With acute exposure, concentrations of 30 to 50 percent produce symptoms of impending cardiovascular collapse. Levels > 50 percent may be fatal for the mother.

Because hemoglobin F has an even higher ainity for carbon monoxide, fetal carboxyhemoglobin levels are 10 to 15 percent higher than those in the mother. This may be due to facilitated difusion (Longo, 1977). Importantly, the half-life of carboxyhemoglobin is 2 hours in the mother but 7 hours in the fetus. Because carbon monoxide is bound so tightly to hemoglobin F, the fetus may be hypoxic even before maternal carbon monoxide levels are appreciably elevated. Several anomalies are associated with embryonic exposure, and anoxic encephalopathy is the primary sequela of later fetal exposure (Alehan, 2007; Aubard,a2000).

For all victims, treatment of carbon monoxide poisoning is supportive along with immediate administration of 100-percent inspired oxygen. Indications for hyperbaric oxygen treatment in nonpregnant individuals are unclear (Kao, 2005). Weaver and associates (2002) reported that hyperbaric oxygen treatment minimized the incidence of cognitive defects in adults at both 6 weeks and 1 year compared with that with normobaric oxygen. Hyperbaric oxygen is generally recommended in pregnancy if carbon monoxide exposure has been "significant" (Aubard, 2000; Ernst, 1998). The problem is how to deine signiicant exposure (Friedman, 2015). Although maternal carbon monoxide levels are not accurately predictive of those in the fetus, some clinicians recommend hyperbaric therapy if maternal levels exceed 15 to 20 percent. With fetal heart rate pattern evaluation, Towers and Corcoran (2009) described afected fetuses to have an elevated baseline, diminished variability, and absent accelerations and decelerations. Treatment of the afected newborn with hyperbaric oxygen is also controversial (Bar, 2007).

Elkharrat and colleagues (1991) reported successful hyperbaric treatments in 44 pregnant women. Silverman and Montano (1997) reported successful management of a woman whose abnormal neurological and cardiopulmonary indings abated in a parallel fashion with resolution of associated variable decelerations in fetal heart rate. Greingor and coworkers (2001) used 2.5-atm hyperbaric 100-percent oxygen for 90 minutes in a 21-week pregnant woman who was delivered of a healthy infant at term. According to the Divers Alert Network-DAN (201a6)-at Duke University, 700 chambers are located in North and Central America. Emergency consultation from the Network is available at 91a9-684-91a11a.

Adhikari M, Pillay T, Pillay DG: Tuberculosis in the newborn: an emerging disease. Pediatr Infect Dis J 16: 1108, 1997

Agha FP, Vade A, Amendola A, et al: Efects of pregnancy on sarcoidosis.

Surg Gynecol Obstet 155:817,t1982

Ahmad A, Ahmed A, Patrizio P: Cystic fibrosis and fertility. Curr Opin Obstet GynecoIt25(3):167,t2013

Ahmad H, Mehta NJ, Manikal VM, et al: Pneumoystis carinii pneumonia in pregnancy. Chest 120:666, 2001

Alehan F, Erol I, Onay OS: Cerebral palsy due to nonlethal maternal carbon monoxide intoxication. Birth Defects Res A Clin Mol Teratol 79(8):614, 2007 Ali Z, Ulrik CS: Incidence and risk factors for exacerbations of asthma during pregnancy. J Asthma Allergy 6:53, 2013

American College of Obstetricians and Gynecologists: Asthma in pregnancy.

Practice Bulletin No. 90, February 2008, Reairmed 2016a

American College of Obstetricians and Gynecologists: Inluenza vaccination during pregnancy. Committee Opinion No. 608, September 2014, Reaffirmed 2016b

American College of Obstetricians and Gynecologists: Carrier screening for genetic conditions. Committee Opinion No. 691, March 2017

Andrews W: Cesarean delivety for refractory status asthmaticus. Obstet Gynecol 121:417,t2013

Anselmi A, Ruggieri VG, Letheulle J, et al: Extracorporeal membrane oxygenation in pregnancy. J Card Surg 30(10):781,t2015

Asadi Gharabaghi M, llameh SF: Primary pulmonary cryptococcosis. BMJ Case Rep 2014:pii: bcr2014203821, 2014

Aubard Y, Magne I: Carbon monoxide poisoning in pregnancy. BJOG 107:833, 2000

Badve SA, Ghate SO, Badve MS, et al: Tuberculosis of spine with neurological deicit in advanced pregnancy: a report of three cases. Spine J 11 (1):e9, 2011

Bain E, Pierides KL, Clifton VL, et al: Interventions for managing asthma in pregnancy. Cochrane Database Syst Rev 10:CD010660, 2014

Bar R, Cohen M, Bentur Y, et al: Pre-labor exposure to carbon monoxide: should the neonate be treated with hyperbaric oxygenation? Clin Toxicol 45(5): 579, 200

Barnes PJ: Asthma. In Kasper 0, Fauci A, Hauser SL, et al (eds): Harrison's Principles ofInternal Medicine, 19th ed. New York, McGraw-Hili Education, 2015, p 1669

Baughman RP, Lower EE: Sarcoidosis. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles ofInternal Medicine, 19th ed. New York, 1cGraw-Hill Education, 2015, p 2205

Bel EH: Mild asthma. N Engl J Med 369(6):549,t2013

Belfort A, Clark SL, Saade GR, et al: Hospital readmission after delivety: evidence for an increased incidence of non urogenital infection in the immediate postpartum period. Am J Obstet Gynecol 202:35.e1, 2010

Belgi RH, Venkataramanan R, Caritis SN, et al: Oseltamivir for inluenza in pregnancy. Semin PerinatoIt38(8):503, 2014

Bercovitch RS, Catanzaro A, Schwartz BS, et al: Coccidioidomycosis during pregnancy: a review and recommendations for management. Clin Infect Dis 53(4):363,t2011

Blais L, Kettani FZ, Forget A: Relationship between maternal asthma, its severity and control and abortion. Hum Reprod 28(4):908,t2013

Blais L, Suissa S, Boivin JF, et al: First treatment with inhaled corticosteroids and the prevention of admissions to hospital for asthma. Thorax 53:1025,t1998

Blanc FX, Sok T, Laureillard 0, et al: Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med 365(16):14 1,2011

Boczar M, Sawicka E, Zybert K: Meconium ileus in newborns with cystic fibrosis-results of treatment in the group of patients operated on in the years 2000-2014. Dev Period Med 19(1):32, 2015

Boggess A, Myers ER, Hamilton CD: Antepartum or postpartum isoniazid treatment of latent tuberculosis infection. Obstet Gynecol 96:747, 2000 Bonham CA, Patterson KC, Strek ME: Asthma outcomes and management during pregnancy. Chest September 1, 2017 [Epub ahead of print]

Bracken MB, Triche EW, Belanger K, et al: Asthma symptoms, severity, and drug therapy: a prospective study of efects on 2205 pregnancies. Obstet Gynecol 102:739,t2003

Briggs GG, Freeman RK (eds): Drugs in Pregnancy and Lactation, 10th ed. Philadelphia, Wolters Kiuwer, 2015

Brito V, Niederman MS: Pneumonia complicating pregnancy. Clin Chest Med 32:121,t2011

Caldwell JW, Asura EL, Kilgore B, et al: Coccidioidomycosis in pregnancy during an epidemic in California. Obstet Gynecol 95:236, 2000

Callaghan WM, Creanga A, Jamieson OJ: Pregnancy-related mortality resulting from inluenza in the United States during the 2009-2010 pandemic. Obstet Gynecol 126:486,t2015

Cameron AJ, Skinner T A: Management of a parturient with respiratory failure secondary to cystic fibrosis. Anaesthesia 60:77, 2005

Cantu J, Tita AT: vlanagement of influenza in pregnancy. Am J Perinatol 30:99,t2013

Cantwell MF, Shehab ZM, Costello M, et al: Congenital tuberculosis. N Engl J Med 330:1051,t1994

Cardonick EH, Naktin J, Berghella V: Neurosarcoidosis diagnosed during pregnancy by thoracoscopic lymph node biopsy. J Reprod Med 45:585, 2000

Celada LJ, Drake P: Targeting CD4( +) T cells for the treatment· of sarcoidosis: a promising strategy? Immunotherapy 7(1):57,t2015

Centers for Disease Control and Prevention: Controlling tuberculosis in the United States. Recommendations from the American Thoracic Society, CDC, and the Infectious Disease Society of America. MMWR 54(12):1, 2005a

Centers for Disease Control and Prevention: Guidelines for using the QuantiFERON-TB gold test for detecting Mycobacterium tuberculosis infection, United States. MMWR 54(15):29, 2005b

Centers for Disease Control and Prevention: Severe methicillin-resistant Staphylococcus aureus community-acquired pneumonia associated with inluenza-Louisiana and Georgia-December 2006-January 2007. MMWR 56(14):325,t2007

Centers for Disease Control and Prevention: Plan to combat extensively drugresistant tuberculosis. MMWR 58(3): 1, 2009a

Centers for Disease Control and Prevention: Trends in tuberculosis-United States, 2008. MMWR 58(10):1, 2009b

Centers for Disease Control and Prevention: 2009 pandemic influenza A (H1N1) in pregnant women requiring intensive care-New York City, 2009. MMWR 59(11):321, 2010a

Centers for Disease Control and Prevention: Decrease in reported tuberculosis cases-United States, 2009. MMWR 59(10):289, 2010b

Centers for Disease Control and Prevention: National Center for Health E-Stat: asthma prevalence, health care use and morbidity: United States, 2003-05. 2010c. Available at: http://www.cdc.gov/nchs/data/hestat/asthma03-05/ asthma03-05.htm. Accessed May 5, 2016

Centers for Disease Control and Prevention: Asthma attacks among persons with current asthma-United States, 2001-2010. MvlWR 62:93,t2013

Centers for Disease Control and Prevention: Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents, May 3,t2016. Available at: http://aidsinfo.nih.gov/contentfiles/Adulc OI.pd. Accessed May 5, 2016a

Centers for Disease Control and Prevention: Influenza (flu). 2016b. Available at: http://www.cdc.gov/flu.l Accessed May 5,t2016

Chan L, Juarez MM, Gidwani N, et al: Management of critical asthma syndrome during pregnancy. Clin Rev Allergy ImmunoI45(l)45, 2015 Charlton A, Hutchison A, Davis KJ, et al: Asthma management in pregnancy. PLoS One 8(4):e60247, 2013

Chen H, Keller J, Wang IT, et al: Pneumonia and pregnancy outcomes: a nationwide population-base study. Am J Obstet :288.e1,2012

Close A, Gimovsky A, Macri C: Adult respiratory distress due to Legionnaires disease in pregnancy: a case report.] Reprod Med 610-2):83,t2016 Cohen LF, di Sant Agnese PA, Friedlander ]: Cystic fibrosis and pregnancy: a national survey. Lancet 2:842, 1980

Cohen YZ, Dolin R: Inluenza. In Kasper DL, Fauci AS, Hauser DL, et al: (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill Education, 2015, p 1209

Cossette B, Forget A, Beauchesne MF: Impact of maternal use of asthma-controller therapy on perinatal outcomes. Thorax 68:724, 2013

Cox S, Posner SF, McPheeters M, et al: Hospitalizations with respiratory illness among pregnant women during inluenza season. Obstet Gynecol 107:1315,t2006

Crum NF, Bailon-Landa G: Coccidioidomycosis in pregnancy: case report and review of the literature. Am] Med 119:993, 2006

Cruz CA, Caughey AB, Jasmer R: Postpartum follow-up of a positive puriied protein derivative (PPD) among an indigent population. Am ] Obstet GynecoIt192:1455,t2005

Deighan M, Ash S, McMorrow R: Anaesthesia for parturients with severe cystic ibrosis: a case series. Intt] Obstet Anesth 23(1):75, 2014 de Vries], Drent M: Qualiry of life and health status in sarcoidosis: a review.

Semin Respir Crit Care Med 28:121,t2007

Dewan P, Gomber S, Das S: Congenital tuberculosis: a rare manifestation of a common disease. Paediatr Int Child Health 34(1):60,t2014

Ding H, Black CL, Ball S, et al: Inluenza vaccination coverage among pregnant women-United States, 2014-15 inluenza season. MMWR 64(36):1000, 2015

Divers Alert Network: Chamber location and availabiliry. Available at: http:// ww.diversalertnetwork.org/medical. Accessed May 5,t2016

Dodds L, McNeil SA, Fell DB, et al: Impact of inluenza exposure on rates of hospital admissions and physician visits because of respirarory illness among pregnant women. CMA] 17:463, 2007

Dolin R: Common viral respiratory infections. In Longo 0, Fauci A, Kasper 0, et al (eds): Harrison's Principles of Internal Medicine, 18th ed. New York, McGraw-Hill Education, 2012, p 1485

Dombrowski MP: Asthma and pregnancy. Obstet Gynecol 108:667, 2006 Dombrowski MP, Schatz M, Wise R, et al: Asthma during pregnancy. Obstet Gynecol 103:5, 2004a

Dombrowski MP, Schatz M, Wise R, et al: Randomized trial of inhaled beclomethasone dipropionate versus theophylline for moderate asthma during pregnancy. Am] Obstet GynecoIt190:737, 2004b

Edenborough FP: Women with cystic ibrosis and their potential for reproduction. Thorx 56:648, 2001

Edenborough FP, Mackenzie WE, Stableforth DE: The outcome of 72 pregnancies in 55 women with cystic ibrosis in the United Kingdom 19771996. B]OG 107:254,t2000

Edenborough FP, Stableforth DE, Webb AK, et al: The outcome of pregnancy in cystic ibrosis. Thorax 50: 170, 1995

Eferen LS: Tuberculosis and pregnancy. Curr Opin Pulm Med 13:205,t2007 Elkharrat 0, Raphael ]c, Korach ]M, et al: Acute carbon monoxide intoxication and hyperbaric oxygen in pregnancy. Intensive Care Med 17:289, 1991

Elkins MR, Robinson M, Rose BR, et al: A controlled trial of long-term inhaled hypertonic saline in patients with cystic ibrosis. N Engl ] Med 354:229, 2006

El-Messidi A, Czuzoj-Shulman N, Spence AR, et al: Medical and obstetric outcomes among pregnant women with tuberculosis: a population-based study of .8 million births. Am] Obstet GynecoI215:797.e6, 2016

Eltonsy S, Blais L: Asthma during pregnancy and congenital malformations: the challenging task of separating the medication efect from asthma itself. ] Allergy Clin ImmunoIt137(5):1623, 2016

Ely EW, Peacock ]E, Haponik EF, et al: Cryptococcal pneumonia complicating pregnancy. Medicine : 153, 1998

Enriquez R, Pingsheng W, Griin MR, et al: Cessation of asthma medication in early pregnancy. Am] Obstet Gynecol 195: 149, 2006 Ernst A, Zibrak ]0: Carbon monoxide poisoning. N Engl ] Med 339: 1603, 1998

Fanta CH: Asthma. N Engl ] Med 360: 1002, 2009

Figueroa-Damian R, Arrendondo-Garcia ]L: Pregnancy and tuberculosis: inluence of treatment on perinatal outcome. Am] Perinatol 15:303, 1998 Finland M, Dublin TO: Pneumococcic pneumonias complicating pregnancy and the puerperium.]AMA 112:1027,t1939

Fitzsimmons Sc, Fitzpatrick S, hompson 0, et al: A longitudinal study of the efects of pregnancy on 325 women with cystic ibrosis. Pediatr Pulmonol 113:99, 1996

Friedman P, Guo M, Stiller R], et al: Carbon monoxide exposure during pregnancy. Obstet Gynecol Surv 70(11):705, 2015

Gazmararian ]A, Petersen R, Jamieson OJ, et al: Hospitalizations during pregnancy among managed care enrollees. Obstet Gynecol 100:94, 2002

Getahun 0, Ananth CV, Oyelese Y, et al: Acute and chronic respiratory diseases in pregnancy: associations with spontaneous premature rupture of membranes.t] Matern Fetal Neonatal Med 20:669, 2007

Getahun 0, Ananth CV, Peltier MR: Acute and chronic respiratory disease in pregnancy: association with placental abruption. Am ] Obstet Gynecol 195:1180,t2006

Getahun H, Matteelli A, Chaisson R. et al: Latent Mycobacterium tuberculosis infection. N Engl] Med 3 2:2127,t2015

Giacobbe LE, Nguyen RH, Aguilera MN, et al: Efect of maternal cystic ibrosis genotype on diabetes in pregnancy. Obstet Gynecol 120(6): 1394, 2012

Gidaya NB, Lee BK, Burstyn 1, et al: In utero exposure to 3-2-adrenergic receptor agonist drugs and risk for autism spectrum disorders. Pediatrics 137 (2): 1, 2016

Gillet 0,de Brackeleer M, Bellis G, et al: Cystic ibrosis and pregnancy. Report from French data 0980-1999). B]OG 109:912,t2002

Gluck Jc, Gluck PA: he efect of pregnancy on the course of asthma. Immunol Allergy Clin North Am 26:63, 2006

Grant CC, Crane ], Mitchell EA, et al: Vitamin 0 supplementation during pregnancy and infancy reduces aero allergen sensitisation: a randomised controlled trial. Allergy 71(9):1325,t2016

Greingor ]L, Tosi JM, Ruhlmann S, et al: Acute carbon monoxide intoxication during pregnancy. One case report and review of the literature. Emerg Med J 18:399,t2001

Grindheim G, T oska K, Estensen ME, et al: Changes in pulmonary function during pregnancy: a longitudinal cohort study. B]OG 119:94,t2012

Gyi KM, Hodson ME, Yacoub MY: Pregnancy in cystic ibrosis lung transplant recipients: case series and review. J Cyst Fibros 5(3):171, 2006

Hadid V, Patenaude V, Oddy L, et al: Sarcoidosis and pregnancy: obstetrical and neonatal outcomes in a population-based cohort of 7 million births. J Perinat Med 43(2):201, 2015

Hardin OS, Rice ], Cohen RC, et al: he metabolic efects of pregnancy in cystic ibrosis. Obstet Gynecol 106(2):367, 2005

Harger ]H, Ernest ]M, hurnau GR, et al: Risk factors and outcome of varicella-zoster virus pneumonia in pregnant women. ] Infect Dis 185:422, 2002

Havlir DV, Kendall MA, Ive P, et al: Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl] Med 365(16):1482, 2011

Hemphill JC, Smith WS, Gress DR: Neurologic critical care, including hypoxic-ischemic encephalopathy and subarachnoid hemorrhage. In Kasper DL, Fauci AS, Hauser DL, et al: Harrison's Principles ofInternal Medicine, 19th ed. New York, McGraw-Hill Education, 2015, p 1782

Hendler I, Schatz M, Momirova V, et al: Association of obesity with pulmonaty and nonpulmonary complications of pregnancy in asthmatic women. Obstet Gynecolt108(1):77, 2006

Heron M: Deaths: leading causes for 2013. Nat! Vital Stat Rep 65(2):1,t2016 Horsburgh CR ]r, Barry CE, Lange C: Treatment of tuberculosis. N Englt] Med 373:2149,t2015

Horsburgh CR]r, Rubin E]: Latent tuberculosis infection in the United States.

N Engl] Med 364:15:1441,t2011

Jacobs RF, Abernathy RS: Management of tuberculosis in pregnancy and the newborn. Clin Perinatol 15:305, 1988

Jain S, Self H, Wunderink RG, et al: Community-acquired pneumonia requiring hospitalization among U.S. adults. N Engl] Med 373:415,t2015

Jamieson 0], Rasmussen SA, Uyeki TM, et al: Pandemic inluenza and pregnancy revisited: lessons learned from 2009 pandemic inluenza A (H 1 N 1). Am] Obstet Gynecol204(6 Suppl 1):Sl, 2011 lana N, Vasishta K, Jindal SK, et al: Perinatal outcome in pregnancies complicated by pulmonary tuberculosis. Int J Gynecol Obstet 44: 119, 1994 lana N, Vasishta K, Saha SC, et al: Obstetrical outcomes among women with extrapulmonary tuberculosis. N Engl] Med 341 :645, 1999

Jenkins TM, Troiano NH, Grave CR, et al: Mechanical ventilation in an obstetric population: characteristics and delivery rates. Am ] Obstet Gynecol 188:549,t2003 ]hung A, Nelson 01, Centers for Disease Control and Prevention (CDC): Outbreaks of avian inluenza A (H5N2), and (H5N8), and (H5N1) among birdsUnited States, December 20 14-]anuary 2015. MMWR 64(4):111,t2015 lin Y, Carriere KC, Marrie T], et al: he efects of community-acquired pneumonia during pregnancy ending with a live birth. Am] Obstet Gynecol 188: 800,t2003

Kalita ], Misra UK, Prasad S, et al: Safety and eicacy of levoloxacin versus rifampicin in tuberculous meningitis: an open-label randomized controlled trial. J Antimicrob Chemother 69(8):2246,t2014

Kandolin R, Lehtonen J, Airaksinen], et al: Cardiac sarcoidosis: epidemiology, characteristics, and outcome over 25 years in a nationwide study. Circulation 131(7):624,t2015

Kao L W, Naiagas A: Carbon monoxide poisoning. Med Clin North Am 89(6):1161,t2005

Karim SSA, Naidoo K, Grobler A, et al: Integration of antiretroviral therapy with tuberculosis treatment. N Engl] Med 365(16):1492, 2011

Kelly W, Massoumi A, Lazarus A: Asthma in pregnancy: physiology, diagnosis, and management. Postgrad Med 127(4):349, 2015 Kent NE, Farquharson DF: Cystic fibrosis in pregnancy. Can Med Assoc ] 149:809, 1993 Kenyon N, Zeki AA, lbertSon TE, et al: Definition of critical asthma syndromes. Clin Rev Allergy ImmunoI48(1):1, 2015

Khan AD, Magee E, Grant G, et al: Tuberculosis-United States, 1993-2010.

MMWR 3:149,t2013

Kowada A: Cost efectiveness of interferon-gamma release assay for TB screening of HI V positive pregnant women in low TB incidence countries.] Infect 688:32,t2014

Kruszka S], Gherman RB: Successful pregnancy outcome in a lung transplant recipient with tacrolimus immunosuppression. A case report. ] Reprod Med 47:60,t2002

Kutlu T, Tugrul S, Aydin A, et al: Tuberculosis meningitis in pregnancy presenting as hyperemesis gravidarum. ] Matern Fetal Neonatal vIed 20:357, 2007

Kyaw MH, Lynield R, Schafner W, et al: Efect of introduction of the pneumococcal conjugate vaccine on drug-resistant Streptococcus pneumoniae. N Engl] Med 354:1455, 2006

Lai RP, Meintjes G, Wilkinson R]: HIV-1 tuberculosis-associated immune reconstitution inflammatory syndrome. Semin Immunopathol 38(2):185, 2016

Lam CM, Wong SF, Leung TN, et al: A case-controlled study comparing clinical course and outcomes of pregnant and non-pregnant women with severe acute respiratory syndrome. B]OG 1,t2004

Lazarus SC: Emergency treatment of asthma. N Engl] Med 363(8):755, 2010 Lessnau KD, Qarah S: Multidrug-resistant tuberculosis in pregnancy: case report and review of the literature. Chest 123:953, 2003

Levison ]H, Barbieri RL, Katx ]T, et al: Hard to conceive. N Engl ] Med 363(10):965,t2010

Lim AS, Stewart K, Abramson M], et al: Multidisciplinary approach to management of maternal asthma (MAMMA): a randomized controlled trial. Chest 145(5):1046, 2014

Lin HC, Lin HC, Chen SF: Increased risk of low birthweight and small for gestational age infants among women with tuberculosis. B]OG 117(5):585, 2010

Litonjua AA, Carey VJ, Laranjo N, et al: Efect of prenatal supplementation with vitamin D on asthma or recurrent wheezing in ofspring by age 3 years: the VDAART randomized clinical trial. ]M1A 315(4):362,t2016

Liu S, Wen SW, Demissie K, et al: Maternal asthma and pregnancy outcomes: a retrospective cohort study. Am ] Obstet Gynecol 184:90, 200t1

Llewelyn M, Cropley I, Wilkinson R], et al: Tuberculosis diagnosed during pregnancy: a prospective study from London. horax 55:129, 2000

Lo CP, Chen SY, Lee W, et al: Brain injury after acute carbon monoxide poisoning: early and late complications. AJR Am] Roentgenol 189(4):W205, 2007

Longo L: The biologic efects of carbon monoxide on the pregnant woman, fetus and newborn infant. Am] Obstet GynecoIt129:69, 1977

Louie ]K, Sailbay C], Kang M, et al: Pregnancy and severe inluenza infection in the 2013-2014 influenza season. Obstet Gynecol 125(1):184,t2015 Mabie WC, Barton ]R, Wasserstrum N, et al: Clinical observations on asthma in pregnancy. ] Matern Fetal Med 1 :45, 1992

Madhi SA, Cutland CL, Kuwanda L, et al: Inluenza vaccination of pregnant women and protection of their infants. N Engl] Med 371(10):918,t2014 Maisel ]A, Lynam T: Unexpected sudden death in a young pregnant woman: unusual presentation of neurosarcoidosis. Ann Emerg Med 28:94, 1996

Mandell A, Wunderink RG: Pneumonia. In Kasper DL, Fauci A, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill Education, 2015, p 803

Mandell A, Wunderink RG, Anzueto A, et al: Infectious Diseases Society of America/American horacic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 44:S27, 2007

Mansour MK, Ackman ]B, Branda]A, et al: Case 32-2015: a 57-year-old man with severe pneumonia and hypoxemic respiratory failure. New Engl ] Med 373:1554,t2015

Masur H, Morris A: Pneumocystis infections. In Kasper DL, Fauci AS, Hauser SL, et al: Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill Education, 2015, p 1358

Mayer AP, Morris MF, Panse PM, et al: Does the presence of mediastinal adenopathy confer a risk for disseminated infection in immunocompetent persons with pulmonary coccidioidomycosis? Mycoses 56(2):145, 2013

Mazurek GH, Vernon A, LoBue P, et al: Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection, United States, 2010. MMWR 59(5):2,t2010

Mendola P, Laughon SK, Mannisto TI, et al: Obstetric complications among US women with asthma. Am] Obstet GynecoIt208(2):127.e1, 2013

Mert A, Kumbasar H, Ozaras R, et al: Erythema nodosum: an evaluation of 100 cases. Clin Exp Rheumatol 25:563, 2007

Mertz D, Geracit], Winkupt], et al: Pregnancy as a risk factor for severe outcomes from inluenza virus infection: a systematic review and meta-analysis of observational studies. Vaccine 35:521,t2017

Mnyani CN, McIntyre]A: Tuberculosis in pregnancy. B]OG 118(2):226,2011 Moberley S, Holden], Tatham DP, et al: Vaccines for preventing pneumococcal infection in adults. Cochrane Database Syst Rev 1 :CD000422, 2013

Moore AR, Rogers FM, Dietrick D, et al: Extrapulmonary tuberculosis in pregnancy masquerading as a degenerating leiomyoma. Obstet Gynecol III (2): 551,t2008

Moran G], Rothman E, Volturo GA: Emergency management of community-acquired bacterial pneumonia: what is new since the 2007 Infectious Diseases Society of America/American Thoracic Society guidelines. Am ] Obstet Gynecol 31 :602, 20t13

Murphy VE, Namazy]A, Powell H, et al: A meta-analysis of adverse perinatal outcomes in women with asthma. B]OG 118:1314,t2011

Murphy VE, Powell H, Wark PA: A prospective study of respiratory viral infection in pregnant women with and without asthma. Chest 144(2):420, 2013a

Murphy VE, Wang G, Namazyt]A, et al: The risk of congenital malformations, perinatal mortality and neonatal hospitalization among pregnant women with asthma: a systematic review and meta-analysis. B]OG 120(7):812, 2013b

Musher DM, Thorner AR: Community-acquired pneumonia. N Engl ] Med 371:1619-28,t2014

Muthuri SG, Venkatesan S, Myles PR, et al: Efectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with inluenza A HI N 1 pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med 2:395,t2014

Nanda S, Agarwal U, Sangwan K: Complete resolution of cervical spinal tuberculosis with paraplegia in pregnancy. Acta Obstet Gynecol Scand 81:569, 2002

National Heart, Lung, and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma, 2007. Available at: http:// www.nhlbi.nih.gov/health-pro/guidelines/current/ asth na-guidelines. Accessed May 5, 2016

NgF, Wong SF, Lam A, et al: The placentas of patients with severe acute respiratory syndrome: a pathophysiological evaluation. Pathology 38:210,t2006 Nguyen HT, Pandolfini C, Chiodini P, et al: Tuberculosis care for pregnant women: a systematic review. BMC Infect Dis 14:617,t2014

Nigam A, Prakash A, Pathak P, et al: Bilateral psoas abscess during pregnancy presenting as an acute abdomen: atypical presentation. BM] Case Rep 2013:pii: bcr2013200860, 2013

Oboho IK, Reed C, Gargiullo P, et al: Beneit of early initiation of inluenza antiviral treatment to pregnant women hospitalized with laboratory-conirmed inluenza.] Infect Dis 214(4):507,t2016

Olson GL: Cystic ibrosis in pregnancy. Semin Perinatol 21:307, 1997

Osowicki], Wang S, McKenzie C, et al: Congenital tuberculosis complicated by hemophagocytic lymphohistiocytosis. Pediatr Infect Dist] 35(1):108, 2016 Paramothayan S, Jones PW: Corticosteroid therapy in pulmonary sarcoidosis.

A systematic review.]AMA 287:1301,t2002

Paranyuk Y, Levine G, Figueroa R: Candida septicemia in a pregnant woman with hyperemesis receiving parenteral nutrition. Obstet Gynecol 107:535,t2006

Patel EM, Swamy GK, Heine RP, et al: Medical and obstetric complications among pregnant women with cystic ibrosis. Am] Obstet Gynecol 212:98. e1,t201t5

Patel S, Lee RH: The case of the sinister spores: the patient was hospitalized for a menacing infection in the second trimester of pregnancy. Am ] Obstet Gynecol 208(5):417.e1, 2013

Pillay T, Khan M, Moodley], et al: Perinatal tuberculosis and HIV-l: considerations for resource-limited settings. Lancet Infect Dis 4: 155,t2004

Pilmis B, ] ullien V, Sobel ], et al: Antifungal drugs during pregnancy: an updated review. ] Antimicrob Chemother 70(1): 14, 2015

Powe NR, Peterson PG, Mark E]: Case 27-2015: a 78-year-old man with hypercalcemia and renal failure. N Engl Med 373:864, 2015

Prevost MR, Fung Kee Fung M: Tuberculous meningitis in pregnancyimplications for mother and fetus: case report and literature review. ] Matern Fetal Med 8:289, 1999

Prockop LD, Chichkova I: Carbon monoxide intoxication: an updated review. ] Neurol Sci 262(1-2): 122, 2007

Racusin DA, Fox A, Ramin SM: Severe acute asthma. Semin Perinatal 37(4):234,t2013

Rasmussen SA, Jamieson D]: 2009 H1N1 Inluenza and pregnancy-5 years later. N Engl] Med 371:1373,t2014

Raviglione MC: Tuberculosis. In Kasper DL, Fauci A, Hauser SL, et al (eds):

Harrison's Principles of Internal Medicine, 19th ed. New York, McGrawHill Education, 2015, p 1102

Reboli AC, Rotstein e, Pappas PG, et al: Anidulafungin versus fluconazole for invasive candidiasis. N Engl ] Med 356:2472, 2007

Rey E, Boulet LP: Asthma in pregnancy. BM] 334:582, 200

Rodgers He, Knox A] , Toplis PH, et al: Successful pregnancy and birth after IVF in a woman with cystic ibrosis. Human Reprod 15:2152, 2000

Rogers L, Sheield ]5, Roberts SW, et al: Presentation of seasonal inluenza A in pregnancy: 2003-2004 inluenza season. Obstet GynecoItI15(5):924, 2010

Rolston DH, Shnider SM, de Lorimer A: Uterine blood low and fetal acidbase changes after bicarbonate administration to the pregnant ewe. Anesthesiology 40:348, 1974

Rosenstein NE, Emery W, Werner SB, et al: Risk factors for severe pulmonary and disseminated coccidioidomycosis: Kern Counry, California, 1995-1996. Clin Infect Dis 32:708, 2001

Rowe SM, Miller 5, Sorscher E]: Cystic ibrosis. N Engl] Med 353: 1992, 2005 Rowntree RK, Harris A: The phenotypic consequences of CFTR mutations.

(5):471,t2003

Saad AF, Rahman M, Maybauer OM, et al: Extracorporeal membrane oxygenation in pregnant and postpartum women with HI N I-related acute respiratory distress syndrome. Obstet Gynecol 127:241, 2016

Sackof ]E, Pfiefer MR, Driver CR, et al: Tuberculosis prevention for nonU.S.-born pregnant women. Am] Obstet Gynecol 194:451, 2006

Sawicki E, Stewart K, Wong 5: Management of asthma by pregnant women attending an Australian matenity hospital. Aust N Z ] Obstet Gynecol 52(2): 183, 2012

Schanzer DL, Langley ]M, Tam TW: Inluenza-attributed hospitalization rates among pregnant women in Canada 1994-2000. ] Obstet Gynaecol Can 29:622, 2007

Schatz M, Dombrowski MP, Wise R, et al: Asthma morbidity during pregnancy can be predicted by severity classification. ] Allergy Clin Immunol 11t2:283,t2003

Schatz M, Dombrowski MP, Wise R, et l: Spirometty is related to perinatal outcomes in pregnant women with asthma. Am] Obstet Gynecolt194: 120,2006

Schechter MS, Quittner AL, Konstan MW, et al: Long-term efects of pregnancy and motherhood on disease outcomes of women with cystic fibrosis. Ann Am horac Soc 10(3):213,t2013

Schulte ]M, Bryan P, Dodds 5, et al: Tuberculosis skin testing among HIVinfected pregnant women in Miami, 1995 to 1996.] Perinatol 22: 159,2002 Scott e, Kirking HL, Jefries C, et al: Tuberculosis trends-United States, 2014. MMWR 64(10):265,t2015

Selroos 0: Sarcoidosis and pregnancy: a review with results of a retrospective survey.t] Intern Med 227:22t1, 1990

Shaner ], Coscia LA, Constantinescu 5, et al: Pregnancy after lung transplant.

Prog Transplant 22(2):134, 2012

Shariatzadeh MR, Marrie T]: Pneumonia during pregnancy. Am ] Med 119:872, 2006

Sheield ]5, Cunningham FG: Management of community-acquired pneumonia in pregnancy. Obstet Gynecol 114(4):915,t2009

Sherer OM, Osho JA, Zinn H, et al: Peripartum disseminated extrapulmonary tuberculosis simulating ovarian carcinoma. Amt] Perinatol 22:383, 2005 Silverman RK, Montano ]: Hyperbaric oxygen treatment during pregnancy in acute carbon monoxide poisoning. A case report.] Reprod Med 42:309, 1997 Smith SM, Smucny ], Fahey T: Antibiotics for acute bronchitis. ]AMA 312(24):2678,t2014

Sobczynska-Tomaszewska A, Bak 0, Wolski JK, et al: Molecular analysis of defects in the CFTR gene and ZF locus of the Y chromosome in male infertility.] Reprod Med 51(2):120, 2006

Sobhy 5, Babiker Z, Zamora ], et al: Maternal and perinatal mortality and morbidity associated with tuberculosis during pregnancy and the postpartum period: a systematic review and meta-analysis. B]OG 124:727,2017

Sokolow LZ, Naleway AL, LI OK, et al: Severity of inluenza and noninluenza acute respiratory illness among pregnant women, 2010-2012. Am] Obstet Gynecol 212:202.e 1, 2015

Sorscher EJ: Cystic ibrosis. In Kasper DL, Fauci AS, Hauser SL, et al (eds):

Harrison's Principles of Internal Medicine, 19th ed. New York, McGrawHill Education, 2015, 1697

Southern W, Merelle MM, Dankert-Roelse ]E, et al: Newborn screening for cystic fibrosis. Cochrane Database Syst Rev I:CDOOI402, 2009

Spiegel E, Shoham-Vardi I, Sergienko R, et al: Maternal bronchial asthma is an independent risk factor for long-term respiratory morbidiry of the ofspring. Abstract No. 817. Am] Obstet GynecoIt214:S425, 2016

Spinello 1M, Johnson RH, Baqi 5: Coccidioidomycosis and pregnancy: a review. Ann N Y Acad Sci 1111 :358, 2007

Stoller KP: Hyperbaric oxygen and carbon monoxide poisoning: a critical review. Neurol Res 29(2): 146, 2007

Stratton P, Mofenson LM, Willoughby AD: Human immunodeiciency virus infection in pregnant women under care at AIDS Clinical Trials Centers in the United States. Obstet Gynecol 79:364, 1992

Swamy GK, Heine RP: Vaccinations for pregnant women. Obstet Gynecol 125:212,t2015

Tata L], Lewis SA, McKeever TM, et al: A comprehensive analysis of adverse obstetric and pediatric complications in women with asthma. Am J Respir Crit Care Med 1 5:991,t2007

Taylor A W, Mosimaneotsile B, Mathebula U, et al: Pregnancy outcomes in HIV-infected women receiving long-term isoniazid prophylaxis for tuberculosis and antiretroviral therapy. Infect Dis Obstet Gynecol 2013:195637, 2013

Terraneo 5, Polverino E, Cilloniz e, et al: Severity and outcomes of community acquired pneumonia in asthmatic patients. Respir Med 1 08( 11): 13, 2014

Thorpe-Beeston ]G, Madge 5, Gyi K, et al: The outcome of pregnancies in women with cystic ibrosis-single centre experience 1998-2011t. B]OG 120(3):354,t2013

Tita AT, Andrews W: Inluenza vaccination and antiviral therapy in pregnant women. ] Infect Dis 214(4):505,t2016

Torok ME, Farrar J], et al: When to start antiretroviral therapy in HIV-associated tuberculosis. N Engl] Med 365(16): 1538,t2011

Torres A, Menendez R: Hospital admission in community-acquired pneumonia. [Spanish]. Med Clin (Barc) 131(6):216,t2008

Towers CV, Corcoran VA: Inluence of carbon monoxide poisoning on the fetal heart monitor tracing: a report of 3 cases. ] Reprod Med 54(3):184, 2009

Triche EW, Saftlas AF, Belanger K, et al: Association of asthma diagnosis, severity, symptoms, and treatment with risk of preeclampsia. Obstet Gynecol 104:585,t2004

Varner MW, rice MM, Anderson B, et al: Inluenza-like illness in hospitalized pregnant and postpartum women during the 2009-20120 HI N 1 pandemic. Obstet Gynecol 118(3),t2011

Wainwright CE, Elborn ]5, Ramsey BW, et al: Lumacaftor-ivacaftor in patients with cystic ibrosis homozygous for Phe508del CFTR. N Engl ] Med 3:220,t2015

Wallmiiller e, Domanovits H, Mayr FB, et al: Cardiac arrest in a 35-year-old pregnant woman with sarcoidosis. Resuscitation 83(6)eI51, 2012

Walzer PO: Pneumocystis infection. In Kasper DL, Fauci AS, Longo DL, et al (eds): Harrison's Principles of Internal Medicine, 16th ed. New York, McGraw-Hill, 2005, p 1194

Wang G, Murphy VE, Namazy ], et al: he risk of maternal and placental complications in pregnant women with asthma: a systematic review and meta-analysis. J Matern Fetal Neonatal Med 27(9):934-42,t2014

Weaver LK, Hopkins RO, Chan K], et al: Hyperbaric oxygen for acute carbon monoxide poisoning. N Englt] Med 347: ,t2002

Wendel P], Ramin SM, Hamm CB, et al: Asthma treatment in pregnancy: a randomized controlled study. Am] Obstet Gynecol 175: 150, 1996

Wenzel RP, Fowler A 3rd: Acute bronchitis. N Engl ] Med 355:2125, 2006

Wexler 10, ]ohnnesson M, Edenborough FP, et al: Pregnancy and chronic progressive pulmonary disease. Amt] Respir Crit Care Med 175:330, 2007 Wise A, Polito A], Krishnan V: Respiratory physiologic changes in preg nancy. Immunol Allergy Clin North Am 26:1, 2006

Wong SF, Chow M, Leung TN, et al: Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome. Am ] Obstet Gynecol 191: 292,t2004

Wunderink RG: How important is methicillin-resistant Staphylococcus aureus as a cause of community-acquired pneumonia and what is best antimicrobial therapy? Infect Dis Clin North Am 27(1):17 ,2013

Yost NP, Bloom SL, Richey SO, et al: An appraisal of treatment guidelines for antepartum community-acquired pneumonia. Am ] Obstet Gynecol 183: 131,t2000

Youssef 0, Raval B, El-Abbassi A, et al: Pulmonary blastomycosis during pregnancy: case report and review of the literature. Tenn Med 106(3):37, 2013

Zairina E, Abramson M], McDonald CF, et al: A prospective cohort study of pulmonary function during pregnancy in women with and without asthma. ] Asthma 12:1,t2015

Zeeman GG, Wendel GO, Cunningham FG: A blueprint for obstetrical critical care. Am] Obstet Gynecol 188:532,2003

Zenner 0, Kruijshaar ME, Andrews N, et al: Risk of tuberculosis in pregnancy: a national, primary care-based cohort and self-controlled case series study. Amt] Respir Crit Care Med 9,t2012

Zumla A, Raviglione M, Hafner R, et al: Tuberculosis. N Engl] Med 368:745, 2013

PATHOPHYSIOLOGY .........................i. 1004

THROMBOPHILIAS ............i..i........i..... 1005

THROMBOPHILIA SCREENING . . . . . . . . . . . . . . . .... 1009

DEEP-VEIN THROMBOSIS ..................i..... 1010 LABOR AND DELIVERY . . . . . . . . . . . . . . . . . . . . . .... 1014

SUPERFICIAL VENOUS THROMBOPHLEBITIS ...i..... 1016

PULMONARY EMBOLISM ..................i..... 1016

THROMBOPROPHYLAXIS ..................i.i... 1019 he patient complains of intense and sudden precordial pain, becomes livid in appearance, and presents symptoms of proound dyspnea and eventualy of air hunger. hese embolisms, however, are not always atal, a smal proportion of the patients recovering. The treatment is purey palliative.

-J. Whitridge Williams (1903)

During the past century, the frequency of venous thromboembolism (VTE) during the puerperium decreased remarkably as early ambulation became more widely practiced. Despite this and other advances in prevention and treatment, however, thromboembolism remains a leading cause of maternal morbidity and mortality. Indeed, thrombotic pulmonary embolism accounted for 9.2 percent of pregnancy-related deaths in the United States between 2011 and 2013 (Creanga, 2017).

he absolute incidence ofVTE during pregnancy is low-1 or 2 cases per 1000 pregnancies. However, the risk is approximately ive times higher than that among women who are not pregnant (Greer, 2015). Approximately equal numbers of cases are identiied antepartum and in the puerperium. Deep-vein thrombosis alone is more frequent antepartum, and pulmonary embolism is more common in the first 6 weeks postpartum (Jacobsen, 2008). During the puerperium, the estimated incidence of a thromboembolic complication is 22 events per 100,000 deliveries. Although still elevated, the risk falls to approximately 3 cases per 100,000 deliveries during the second 6-week postpartum period (Kamel, 2014).

Rudolf Virchow (1856) postulated that stasis, local trauma to the vessel wall, and hypercoagulability predisposed to venous thrombosis. During normal pregnancy, the risk for each of these rises. Compression of the pelvic veins and inferior vena cava by the enlarging uterus renders the lower extremity venous system particularly vulnerable to stasis. From their review, Marik and Plante (2008) cite a 50-percent reduction in venous Row velocity in the legs that lasts from the early third trimester until 6 weeks postpartum. This stasis is the most constant predisposing risk factor for venous thrombosis. Venous stasis and delivery may also contribute to endothelial cell injury. Last, as listed in the Appendix (p. 1256), the synthesis of most clotting factors is markedly enhanced during pregnancy and favors coagulation.

Characteristics for developing thromboembolism during pregnancy are shown in Table 52-1. he most important of these is a personal history of thrombosis. Speciically, 15 to 25 percent of all VTE cases during pregnancy are recurrent events (American College of Obstetricians and Gynecologists, 20 17b). In one study, the magnitude of other risks was estimated from 7177 VTE cases during pregnancy and 7158 events during the postpartum period (James, 2006). Calculated risks for thromboembolism were approximately doubled in women with multifetal gestation, anemia, hyperemesis, hemorrhage, and cesarean

TABLE 52-1. Some Risk Factors Associated with an Increased Risk for Thromboembolism delivery. he risk was even greater in pregnancies complicated by postpartum infection. Waldman and associates (2013) found that the risk of VTE was slightly higher in women with advanced maternal age and approximately doubled in women with great parity, a hypertensive disorder, cesarean delivery, or obesity. Risks were signiicantly higher among women who had a stillbirth or who underwent peripartum hysterectomy.

he next most important individual risk factor is a genetically determined thrombophilia. An estimated 20 to 50 percent ofwomen who develop a venous thrombosis during pregnancy or postpartum have an identiiable underlying genetic disorder (American College ofObstetricians and Gynecologists, 2017b).

Several important regulatory proteins act as inhibitors in the coagulation cascade (Fig. 52-1). Normal values for many of these proteins during pregnancy are found in the Appendix (p. 1256). Inherited or acquired deficiencies of these inhibitory proteins are collectively referred to as thrombophilias. These can lead to hypercoagulability and recurrent TE (Connors, 2017). lthough these disorders are collectively present in approximately 15 percent ofwhite European populations, they are responsible for approximately 50 percent of all thromboembolic events during pregnancy (Lockwood, 2002; Pierangeli, alncludes May-Thurner syndrome (iliac vein compression syndrome).

Prothrombin------....Thrombin---....Coagulation Factor V Leiden mutation Factor V resistant to degradation by protein C\\\,, "0''� Inactivates factor Va PROTEINS . /" IIIII Inactivates factor Villa Thrombin binds to thrombomodulin on endothelial cells Protein C deficiencyIIIIII tProtein S deficiency -; ActivatedproteinC ProteinCII Hyperhomocysteinemia (inhibits activation of protein C)

FIGURE 52-1 Inherited thrombophilias and their efect(s) on the coagulation cascade.

aOdds ratio for pregnancy-associated TE compared with gravid noncarriers.

Data from the American College of Obstetricians and Gynecologists, 2017c; Croles, 2017.

2011). Some aspects of the more common inherited thrombophilias are summarized in Table 52-2.

Patients with inherited thrombophilic disorders often have a family history of thrombosis. Inherited thrombophilias are also found in up to half of all patients who present with VTE before the age of 45 years, particularly in those whose event occurred in the absence of well-recognized risk factors. Of greatest significance is a family history of sudden death due to pulmonary embolism or a history of multiple family members requiring long-term anticoagulation therapy because of recurrent thrombosis (Anderson, 2011).

Synthesized in the liver, antithrombin is one of the most important inhibitors of thrombin and inactivates thrombin and factor Xa (heaume, 2016). Notably, the rate of antithrombin interaction with its target is accelerated by heparin (Anderson, 2011). Antithrombin deiciency may result from hundreds of diferent mutations that are almost always autosomal dominant. Type I deficiency results from reduced synthesis of biologically normal antithrombin, and type II deficiency is characterized by normal levels of antithrombin with reduced functional activity (Anderson, 2011). Homozygous antithrombin deficiency is lethal.

Antithrombin deiciency is rare-it afects approximately 1 in 500 to 5000 individuals (Ilonczai, 2015; Rheaume, 2016). It is the most thrombogenic of the heritable coagulopathies. Indeed, antithrombin deiciency is associated with a 25-to 50-fold higher relative risk of VTE in the general population and a sixfold increased risk of thromboembolic complications during pregnancy (Ilonczai, 2015). Those afected have approximatelyaa 50-percent lifetime risk ofVTE (Duhl, 2007).

Sabadell and associates (2010) studied the outcomes of 18 pregnancies complicated by antithrombin deiciency. Twelve of these women were treated with therapeutic doses of lowmolecular-weight heparin (LMWH), and six were not treated because antithrombin deiciency had not yet been diagnosed. Three of the untreated patients sufered a thromboembolic episode compared with none in the treated group. Untreated women also had a 50-percent risk of stillbirth and fetal-growth restriction. By comparison, none of the treated women had a stillbirth, but a fourth developed fetal-growth restriction. Similar results were reported by Ilonczai and colleagues (2015). Garda-Botella and associates (2016) described a mesenteric vein thrombosis in a pregnant woman with antithrombin deiciency. In one review of outcomes in 23 newborns with antithrombin deficiency, there were 11 cases of thrombosis and 10 infant deaths (Seguin, 1994).

Given such risk, afected women are treated during pregnancy with heparin regardless of whether they have had a prior thrombosis. When anticoagulation is necessarily withheld, such as during surgery or delivery, Paidas and colleagues (2016) found that treatment with recombinant human antithrombin protected against VTE development. Sharpe and associates (201a1) described successful use of antithrombin concentrate infusions plus therapeutic anticoagulation in a pregnant woman with antithrombin deficiency who developed a thrombosis during the third trimester despite therapeutic LMWH.

When thrombin is bound to thrombomodulin on endothelial cells of small vessels, its procoagulant activities are neutralized. his binding also activates protein C, a natural anticoagulant that in the presence of protein S controls thrombin generation, in part, by inactivating factors Va and VIlla (see Fig. 52-1). Protein C activity increases modestly but significantly throughout the first half of pregnancy, and some have speculated that this augmentation may play a role in maintaining early pregnancy through both anticoagulant and inflammatory regulatory pathways (Said, 2010b).

More than 160 diferent autosomal dominant mutations for the protein C gene have been described (Louis-Jacques, 2016). he prevalence of protein C deiciency is 2 to 3 per 1000, but many of these individuals do not have a thrombosis history because the phenotypic expression is highly variable (Anderson, 2011). hese prevalence estimates correspond with functional activity threshold values of 50 to 60 percent, which are used by most laboratories and which are associated with a six-to 12-fold higher risk for VTE (Lockwood, 2012).

his circulating aticoagulant is activated by protein C, which enhances the capacity of protein S to inactivate factors Va and VIlla (see Fig. 52-1). Protein S deiciency may be caused by more than 130 diferent mutations, with an aggregate prevalence of approximately 0.3 to 1.3 per 1000 individuals (LouisJacques, 2016). Protein S deiciency may be measured by antigenically determined free, functional, and total S levels. ll three decline substantively during normal gestation (Appendix, p. 1256). Thus, the diagnosis in pregnant women-as well as in those taking certain oral contraceptives-is diicult (Archer, 1999). If screening during pregnancy is necessary, threshold values for free protein S antigen levels in the second and third trimesters have been identiied at <30 percent and <24 percent, respectively. Among those with a positive family history, the VTE risk in pregnancy is 6 to 7 percent (American College of Obstetricians and Gynecologists, 2017c).

Conard and coworkers (1990) described thrombosis in five of 29 pregnant women with protein S deiciency. hey, as well as Burneo and colleagues (2002), reported maternal cerebral vein thrombosis. Neonatal homozygous protein C or S deiciency is usually associated with a fatal clinical phenotype known as purpurafulminans (Shanbhag, 2015).

his is the most prevalent of the known thrombophilia syndromes and is characterized by resistance of plasma to the anticoagulant efects of activated protein C. here are several mutations that create this resistance, but the most common is the factor V Leiden mutation, which was named after the city in which it was described. his missense mutation in the factor V gene results from a substitution of glutamine for arginine at position 506 in the factor V polypeptide. As a result of this mutation, activated factor V is neutralized approximately tenfold more slowly by activated protein C (see Fig. 52-1). his leads to enhanced thrombin generation (MacCallum, 2014).

Heterozygous inheritance of factor V Leiden is the most common heritable thrombophilia. Found in 3 to 15 percent of select European populations and 3 percent of African Americans, it is virtually absent in African blacks and Asians (Lockwood, 2012). One theory for its relatively high prevalence suggests that the heterozygous state may confer a survival advantage, possibly because of reduced bleeding with childbirth or trauma (MacCallum, 2014).

Women who are heterozygous for factor V Leiden account for approximately 40 percent of VTE cases during pregnancy. However, the actual risk among pregnant women who are heterozygous and who do not have a personal history or a irstdegree relative with a thrombotic episode before age 50 years is 5 to 12 events per 1000 gravidas (see Table 52-2). In contrast, this risk rises to at least 10 percent among pregnant women with a personal or family history. Pregnant women who are homozygous without a personal or family history have a 1-to 4-percent risk for VTE, whereas those with such a history have an approximately 17 -percent risk (American College of Obste tricians and Gynecologists, 2017c).

Diagnosis during pregnancy is performed by DNA analy sis for the mutant factor V gene. Bioassay is not used because of the normal resistance that develops after early pregnancy (Walker, 1997). Of note, activated protein C resistance can also be caused by anti phospholipid syndrome, which is described on page 1008 and also detailed in Chapter 59 (p. 1143).

To assess the prognostic signiicance of maternal factor V

Leiden mutation during pregnancy, Kjellberg and colleagues (2010) compared the outcomes of 491 carriers with those of 1055 controls. All three of the thromboembolic events occurred among the carriers. But, preterm birth rates, birthweights, or hypertensive complication rates did not difer between the two groups. In a prospective observational study of approximately 5000 women conducted by the Maternal-Fetal Medicine Units

Network, the heterozygous mutant gene incidence was 2.7 percent (Dizon-Townson, 2005). Of three pulmonary emboli and one deep-vein thrombosis cases-a rate of 0.8 per 1000 pregnancies-none were among these carriers. Moreover, in the heterozygous women, the risks of preeclampsia, placental abruption, fetal-growth restriction, or pregnancy loss were not elevated. he investigators concluded that universal prenatal screening for the Leiden mutation and prophylaxis for carriers without a prior VTE is not indicated.

his missense mutation in the prothrombin gene leads to excessive accumulation of prothrombin, which then may be converted to thrombin. Prothrombin levels are increased approximately 30 percent in heterozygotes and 70 percent in homozygotes (MacCallum, 2014). As with factor V Leiden, a personal or family history of VTE in a irst-degree relative before age 50 years raises the risk of VTE during pregnancy (see Table 52-2). For a heterozygous carrier with such a history, the risk exceeds 10 percent. Without such a history, heterozygous carriers of the mutation have less than a I-percent risk of VTE during pregnancy (American College of Obstetricians and Gynecologists, 2017 c).

Silver and coworkers (2010) tested nearly 4200 women for the prothrombin G20210A mutation. A total of 157-or 3.8 percent-of the women carried the mutation, and only one of these was homozygous. Carriers had similar rates of pregnancy loss, preeclampsia, fetal-growth restriction, and placental abruption compared with noncarriers. hree thromboembolic events occurred in women who tested negative for the mutation.

Homozygous patients, or those who coinherit a G20210A mutation with a factor V Leiden mutation, have a greater thromboembolism risk than heterozygous carriers (Connors, 2017). Lim and associates (2016) have provided detailed information on pregnancy outcomes in women with such rare compound thrombophilias.

he most common cause of elevated homocysteine is the C667T thermolabile mutation of the 5,1 O-methylene-tetrahydrofolate reductase (MTHFR) enzyme. Inheritance is autosomal recessive. Elevated homocysteine levels may also result from deiciency of one of several enzymes involved in methionine metabolism and from correctible nutritional deficiencies of folic acid, vitamin B6, or vitamin Bl2 (Hague, 2003). During normal pregnancy, mean homocysteine plasma concentrations decline (Lopez-Quesada, 2003). hus, to make a diagnosis during pregnancy, Lockwood (2002) recommends a fasting threshold > 12 �mol/L to deine hyperhomocysteinemia.

In an interesting metaanalysis, Den Heijer and associates (2005) found that international studies of MTHFR polymorphisms were collectively associated with slightly greater risks for thrombosis. In contrast, studies conducted in North America collectively demonstrated no such association. The authors speculated that folic acid supplementation could explain the diference. Recall that folic acid serves as a cofactor in the remethylation reaction of homocysteine to methionine. Similarly, the American College of Chest Physicians concluded that the lack of an association with thromboembolism could relect the physiological reductions in homocysteine levels associated with pregnancy and the efects of widespread prenatal folic acid supplementation (Bates, 2012). he American College of Obstetricians and Gynecologists (2017 c) has concluded that there is insuicient evidence to support assessment of MTHFR polymorphisms or measurement of fasting homocysteine levels in the evaluation for VTE.

Potentially thrombophilic polymorphisms are being discovered at an ever-increasing rate. Unfortunately, information regarding the prognostic signiicance of such newly discovered mutations is limited. For example, protein Z is a vitamin K-dependent protein that serves as a cofactor in factor Xa inactivation. Studies have found that low protein Z levels are associated with an elevated thromboembolism risk in nonpregnant patients and may be implicated in the pathogenesis of poor pregnancy outcomes (lmawi, 2013). Similarly, plasminogen activator inhibitor ype I (PAl-I) is an important regulator of ibrinolysis. Certain polymorphisms in the gene promoter have been associated with slightly greater VTE risks. Although these thrombophilias may exacerbate risk among patients when coinherited with other thrombophilias, the American College of Obstetricians and Gynecologists (2017 c) has concluded that evidence to recommend screening is insuicient.

As an interesting aside, Galanaud and coworkers (2010) hypothesized that a paternal thrombophilia could increase the risk of maternal thromboembolism. Specifically, these investigators found that a paternal thrombophilia-the PROCR 6936G allele-afects the endothelial protein C receptor. his receptor is expressed by villous trophoblast and thus is exposed to maternal blood. Although this research is preliminary, it could help explain the pathogenesis of recurrent idiopathic thromboses in pregnant women.

Some examples of acquired hypercoagulable states include anti phospholipid syndrome (APS), heparin-induced thrombocytopenia (p. 1015), and cancer.

his prothrombotic disorder can afect both the venous and arterial circulations. The deeper veins of the lower limbs and the cerebral arterial circulation are the most frequent sites of venous and arterial thrombosis, respectively (Connors, 2017; Giannakopoulos, 2013). Besides thrombosis, the other major clinical manifestations of the APS are obstetrical (Table 18-5, p. 353). Criteria include: (1) at least one otherwise unexplained fetal death at or beyond 10 weeks; (2) at least one preterm birth before 34 weeks' gestation because of eclampsia, severe preeclampsia, or placental insuiciency; or (3) at least three unexplained consecutive spontaneous abortions before 10 weeks.

Once one of the above clinical criteria-thrombosis or obstetrical-is met, anti phospholipid antibody testing should be performed to diagnose APS. hese patients should be tested for the presence of three factors: (1) lupus anticoagulant, (2) anticardiolipin immunoglobulin G and M (IgG and IgM) antibodies, and (3) anti-�2-glycoprotein I IgG and IgM antibodies. If any of these laboratory test results are positive, a conirmatory test is performed 12 weeks later (Connors, 2017).

Based on their study of 750 singleton pregnancies complicated by APS, Saccone and associates (2017) found that anticardiolipin antibody is the most common sole antiphospholipid antibody present; but anti-�rglycoprotein I is associated with the lowest live birth rate and highest incidences of preeclampsia, fetal-growth restriction, and stillbirth compared with anticardiolipin antibodies or lupus anticoagulant alone. hese investigators also observed that despite therapy with lowdose aspirin and prophylactic LMWH heparin, the chance of a liveborn neonate was only 30 percent for women with positive test results for all three antibodies.

The thrombosis risk rises signiicantly during pregnancy in women with APS. Indeed, up to 25 percent of thrombotic events in women with APS occur during pregnancy or in the puerperium. Looking at this a diferent way, women with APS have a 5-to 12-percent risk of thrombosis during pregnancy or the puerperium (American College of Obstetricians and Gynecologists, 2017 a). This syndrome is discussed in more detail in Chapter 59 (p. 1143).

Attention has been directed toward possible relationships between inherited thrombophilias and pregnancy complications other than thromboses. Summarized in Table 52-3 are the findings of 25 studies systematically reviewed by Robertson and associates (2005) and incorporated into the recommendations of the American College of Chest Physicians (Bates, 2012). Importantly, the considerable heterogeneity and wide conidence intervals illustrate the uncertainty of these associations.

Other investigations underscore the heterogeneity of results.

For example, Kahn and coworkers (2009) found no higher risk for early-onset or severe preeclampsia in women with factor V Leiden mutation, prothrombin G20210A mutation, MTHFR C677T polymorphism, or hyperhomocysteinemia. Said and associates (201 Oa) prospectively screened more than 2000 healthy nulliparous women for factor V Leiden, prothrombin

Protein C deficiency 2.29 NA NA 3.05 5.15 NA (0.20-26.43) (0.24-38.51) (0.26-102.22) (0.23-151.58)

Protein 5 deficiency 3.55 NA NA 20.09 2.83 2.1o1 NA (0.35-35.72) (3.70-109.1•5) (0.76-10.57) (0.47-9.34)

Anticardiolipin 3.40 5.05 NA 3.30 2.73 1.42 6.91 antibodies (1.33-8.68) (1.82-14.01 ) (1.62-6.70) (1.65-4.51 ) (0.42-4.77) (2.70-1•7.68)

Lupus anticoagulants 2.97 NA 14.28 2.38 1.45 NA NA (nonspecific (1.03-9.76) (4.72-43.20) (0.81-6.98) (0.70-4.61)

Hyper-6.25 4.21 NA 0.98 3.49 2.40 NA homocysteinemia (1.37-28.42) (1.28-13.87) (0.1o7-5.55) (1.21-10.1•1) (0.36-15.89)

Homozygous and heterozygous carriers were grouped together; it is not possible to extract data for each state.

Data are presented as odds ratio (OR [95% CI]) and are derived from Robertson, 2005. Bolded numbers are statistically significant.

MTHFR = methylene tetrahydrofolate reductase variant; NA = not available.

Reproduced with permission from Bates 5M, Greer iA, Middledorp 5, et al: TE, thrombophilia, antithrombotic therapy, and pregnancy.

Chest 141 :e691 5,201o2.

gene mutation, MTHFR C677T, MTHFR A1298C, and thrombomodulin polymorphism. Women who carried the prothrombin gene mutation had a 3.6-fold greater risk of adverse pregnancy outcome, including severe preeclampsia, fetal-growth restriction, placental abruption, or stillbirth. But, none of the other polymorphisms conferred an elevated risk of these adverse outcomes. From the Stillbirth Collaborative Research Network, Silver and associates (2016) found a weak association between maternal factor V Leiden and stillbirth. here was no association between stillbirth and the other inherited thrombophilias. Based on their prospective study of 750 pregnancies complicated by stillbirth, Korteweg and colleagues (2010) concluded that routine thrombophilia testing after fetal death is inadvisable.

he American College of Obstetricians and Gynecologists (2017 c) notes that a deinitive causal link cannot be made between inherited thrombophilias and adverse pregnancy outcomes. Moreover, in one randomized trial, Rodger and associates (2014) found that antepartum prophylactic LMWH did not reduce a composite outcome of pregnancy loss, severe or early-onset preeclampsia, small-for-gestational age neonates, and TE in thrombophilic women.

Thus, because of uncertainties in the magnitude of risk and in the beneits of prophylaxis given to prevent pregnancy complications in women with heritable thrombophilias, it remains unproven that universal screening is indicated (Louis-Jacques, 2016). In contrast, the association between APS and adverse pregnancy outcomes-including fetal loss, recurrent pregnancy loss, and preeclampsia-is much stronger.

Given the relatively high incidence of thrombophilia in the population and the low incidence of TE, universal screening during pregnancy is not cost efective (Carbone, 2010). hus, a selective screening strategy is required. he American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017) recommend that thrombophilia screening be considered in the following clinical circumstances: (1) a personal history ofTE that was associated with a nonrecurrent risk factor such as fractures, surgery, and/or prolonged immobilization; and (2) a irst-degree relative (parent or sibling) with a history of high-risk thrombophilia or VTE before age 50 years in the absence of other risk factors.

The American College of Obstetricians and Gynecologists (2017 c) notes that testing for inherited thrombophilias in women who have experienced recurrent fetal loss or placental abruption is not recommended because clinical evidence that antepartum heparin prophylaxis prevents recurrence is insuicient. Similarly, testing is not recommended for women with a history of fetal-growth restriction or preeclampsia. The American College of Chest Physicians also recommends against screening women with prior pregnancy complications (Bates,

TABLE 52-4. How to Test for Thrombophilias

Is Testing Is Testing Reliable Reliable Is Testing During During Acute Reliable with Testing Method Pregnancy? Thrombosis? Anticoagulation?

alf screening in pregnancy is necessary, cutoff values for free protein S antigen levels in the second and third trimesters been identified at less than 30% and less than 24%, respectively.

Reproduced with permission from American College of and Gynecologists Women's Health Care Physicians:

ACOG Practice Bulletin No. 138: Inherited thrombophilias in pregnancy, Obstet Gynecol. 20103 Sep;122(3):706-717.

2012). However, screening for antiphospholipid antibodies may be appropriate in women who have experienced a fetal loss or early-onset preeclampsia (Berks, 2015).

Methods of screening for the more common inherited thrombophilias are shown in Table 52-4. Whenever possible, laboratory testing is performed at least 6 weeks after the thrombotic event, while the patient is not pregnant, and when she is not receiving anticoagulation or hormonal therapy. Screening for hyperhomocysteinemia is not recommended (American College of Obstetricians and Gynecologists, 2017 c).

During pregnancy, most venous thromboses are confined to the deep veins of the lower extremity. Approximately 70 percent of cases are located in the iliofemoral veins without involvement of the calf veins. Isolated iliac vein and calf vein thromboses occur in approximately 17 and 6 percent of cases, respectively (Chan, 2010). In contrast, in the general population, more than 80 percent of deep-vein thromboses involve calf veins, and iliofemoral or isolated iliac vein thromboses are uncommon (Huisman, 2015).

he signs and symptoms vary greatly and depend on the degree of occlusion and the intensity of the inlammatory response. Ginsberg and coworkers (1992) reported that 58 of 60 antepartum women-97 percent-had left leg thromboses. Blanco-Molina and coworkers (2007) reported left-leg involvement in 78 percent. Greer (2003) hypothesizes that this results from compression of the left iliac vein by the right iliac and ovarian artery, both of which cross the vein only on the left side. Yet, as described in Chapter 53 (p. 1026), the ureter is compressed more on the right side.

Classically, thrombosis involving the lower extremity is abrupt in onset, and there is pain and edema of the leg and thigh. The thrombus typically involves much of the deepvenous system to the iliofemoral region. Occasionally, relex arterial spasm causes a pale, cool extremity with diminished pulsations. Alternatively, there may be appreciable clot, yet little pain, heat, or swelling. Importantly, calf pain, either spontaneous or in response to squeezing or to Achilles tendon stretching-Homans sign-may be caused by a strained muscle or contusion. Between 30 and 60 percent of women with a confirmed lower-extremity acute deep-vein thrombosis have an asymptomatic pulmonary embolism (p. 1016).

Clinical diagnosis of deep-vein thrombosis is diicult, and in an earlier study of pregnant women, the clinical diagnosis was conirmed in only 10 percent (Hull, 1990). Another challenge is that many of the common diagnostic tests that have been investigated extensively in nonpregnant patients have not been validated appropriately in pregnancy (Huisman, 2015). Shown in Figure 52-2 is one diagnostic algorithm recommended by the American College of Chest Physicians that can be used for evaluation of pregnant women (Guyate, 2012). With a few modifications, we follow a similar evaluation at Parkland Hospital.

In pregnant women with suspected deep-vein thrombosis, the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017) recommend compression ultrasonography of the proximal veins as the initial diagnostic test. According to the American College of Chest Physicians, this noninvasive technique is currently the most-used irst-line test to detect deep-vein thrombosis (Guyatt, 2012). The diagnosis is based on the noncompressibility and typical echoarchitecture of a thrombosed vein.

For nonpregnant patients with suspected thrombosis, the safety of withholding anticoagulation for 1 week has been established for those who have a compression ultrasound examination that is initially normal (Birdwell, 1998; Heijboer, 1993). Serial compression examinations are then performed because isolated undetected calf thromboses that ultimately extend into the proximal veins will do so within 1 to 2 weeks of presentation in approximately a fourth of patients.

Pregnant women with suspected

Negative, but isolated iliac vein thrombosis is suspecteda

Doppler ultrasound of iliac vein, or CT-or MR-imaging or venography

FIGURE 52-2 Algorithm for evaluation of suspected deep-vein thrombosis in pregnancy. CT = computed tomography; MR = magnetic resonance. aSigns and symptoms include swelling of the entire leg, with or without flank, buttock, or back pain. (Data from Guyatt GH,

Akl EA, Crowther M, et al: Executive summary: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College ofChest Physicians evidence-based clinical practice guidelines, Chest. 2012 Feb;141(2 Suppl):7S-47S.)

In pregnant women, the important caveat is that normal findings with venous ultrasonography do not always exclude a pulmonary embolism. his is because the thrombosis may have already embolized or because it arose from iliac or other deeppelvic veins, which are less accessible to ultrasound evaluation (Goldhaber, 2004). As discussed, thrombosis associated with pulmonary embolism during pregnancy commonly originates in the iliac veins.

he results of two studies are helpful for evaluating the need for serial examinations in pregnant women suspected of having a deep-vein thrombosis but who have a negative initial compression ultrasound examination. The combined results are depicted in Figure 52-3. Chan and coworkers (20l3) studied 221 pregnant and postpartum women presenting with a suspected deep-vein thrombosis. The 205 women with a negative initial study result underwent serial testing, which was negative in all cases. Of these, one woman with normal serial testing had a pulmonary embolism 7 weeks later. Le Gal and colleagues (2012) studied 210 pregnant and postpartum women with a suspected deep-vein thrombosis. Of these, 177 women without a deep-vein thrombosis were not anticoagulated and did not undergo serial testing. Two had an objectively conirmed thrombosis diagnosed within 3 months. In sum, these preliminary data suggest that a negative single complete compression ultrasonography study may safely exclude the diagnosis of deep-vein thrombosis in most pregnant women.

This imaging technique allows excellent delineation ofanatomical detail above the inguinal ligament. Thus, in many cases, magnetic resonance (MR) imaging is immensely useful for diagnosis of iliofemoral and pelvic vein thrombosis. The venous system can also be reconstructed using MR venography (Chap. 46, p. 911). Erdman and associates (1990) reported that MR imaging was 100-percent sensitive and 90-percent speciic for detection of venographically proven deep-vein thrombosis in nonpregnant patients. Importantly, almost half of those without deep-vein thrombosis were found to have nonthrombotic conditions that included cellulitis, myositis, edema, hematomas, and supericial phlebitis.

halil and coworkers (2012) used MR venography to study the natural history ofpelvic vein thrombosis after vaginal delivery. Among the 30 asymptomatic patients who were all within four days of delivery, 30 percent had a deinitive thrombosis in either the iliac or ovarian veins, and another 37 percent had a suspected thrombosis. Our experiences with hundreds of postpartum MR scans do not support these findings. Thus, although the clinical significance of their findings is uncertain, it seems clear that some degree of pelvic vein intraluminal illing defect may be a normal inding.

These speciic ibrin degradation products are generated when fibrinolysin degrades ibrin, as occurs in thromboembolism (Chap. 41, p. 783). heir measurement is frequently incorporated into diagnostic algorithms for VTE in nonpregnant patients (Wells, 2003). Screening with the D-dimer test in pregnancy, however, is problematic for several reasons. As shown in the Appendix (p. 1256), depending on assay sensitivity, D-dimer serum levels rise with gestational age along n= 205Lost to follow-up Untreated during ortreated despite..follow-up Treat noDVT n = 177

Diagnosed with

VTE within 3 mas n= 3 (0.8%)

FIGURE 52-3 Findings from two studies of serial and nonserial compression ultrasound examinations in pregnant and postpartum women. CUS = compression ultrasonography. Df = deep vein thrombosis. VfE = venous thromboembolism. (Data from Chan, 2013;

Le Gal, 201o2.) with substantively elevated plasma fibrinogen concentrations (Murphy, 2015). Levels are also afected by multifetal gestation and cesarean delivery (Morikawa, 2011). D-Dimer concentrations can also be elevated in certain pregnancy complications such as placental abruption, preeclampsia, and sepsis syndrome. Moreover, higher levels have been observed in sickle-cell carriers and in women of Mrican and South Asian racial origin (Grossman, 2016). For all these reasons, their use during pregnancy remains uncertain, but a negative D-dimer test should be considered reassuring (Lockwood, 2012; Marik, 2008).

Optimal management ofVTE during pregnancy has not undergone major clinical study to provide evidence-based practices. here is, however, consensus for treatment with anticoagulation and limited activity. If thrombophilia testing is performed, it is done before anticoagulation. Heparin induces a decline in antithrombin levels, and warfarin lowers protein C and S concentrations. The results of these tests do not change treatment (Connors, 2017).

Anticoagulation is initiated with either unfractionated heparin (UFH) or LMWH. lthough either type is acceptable, most recommend one of the LMWHs (Bates, 2016; Kearon, 2016). For example, the American College of Chest Physicians suggests preferential use of LMWH during pregnancy because of better bioavailability, longer plasma half-life, more predictable dose response, reduced risks of osteoporosis and thrombocytopenia, and less frequent dosing (Bates, 2012). Dosages are shown in Table 52-5.

During pregnancy, heparin therapy is continued, and for postpartum women, anticoagulation is begun simultaneously with warfarin. Recall that pulmonary embolism develops in s many s 60 percent of patients with untreated venous thrombosis, and anticoagulation decreases this risk to less than 5 percent. In nonpregnant patients, the mortality rate with a pulmonary embolism approximates 1 percent (Douketis, 1998; Pollack, 2011).

Over several days, leg pain dissipates. Mter symptoms have abated, graded ambulation is begun. Elastic stockings are itted, and anticoagulation is continued. Recovery to this stage usually takes 7 to 10 days. Graduated compression stockings are continued for 2 years after the diagnosis to reduce the incidence of postthrombotic syndrome (Brandjes, 1997). This syndrome can include chronic leg paresthesias or pain, intractable edema, skin changes, and leg ulcers.

his agent should be considered for the initial treatment of thromboembolism and in situations in which delivery, surgery, or thrombolysis may be necessary (American College of Obstetricians and Gynecologists, 20 17b). U nfractionated heparin can be administered by one of two alternatives: (I) initial intravenous therapy followed by adjusted-dose subcutaneous UFH given every 12 hours; or (2) twice-daily, adjusted-dose subcutaneous UFH with doses adjusted to prolong the activated partial thromboplastin time (aPTT) into the therapeutic range 6 hours postinjection (Bates, 2012). As shown in Table 52-5, the therapeutic dose for subcutaneous UFH is usually 10,000 units or more every 12 hours.

For intravenous therapy, several protocols are acceptable. In general, if UFH is used, it is initiated with a bolus intravenous dose of70 to 100 U/kg, which is 5000 to 10,000 U. This is followed by continuous intravenous infusions beginning at

TABLE 52-5. Anticoagulation Regimen Definitions

Prophylactic LMWHa Enoxaparin,n40 mg SC once daily Dalteparin, 5,000 units SC once daily Tinzaparin, 4,500 units SC once daily

Therapeutic LMWHb Enoxaparin, 1 mg/kg every 12 hours Dalteparin, 200 units/kg once daily Tinzaparin, 175 units/kg once daily Dalteparin, 100 units/kg every 12 hours

May target an anti-Xa level in the therapeutic range of 0.6-1.0 units/mL for twice daily regimen; slightly higher doses may be needed for a once-daily regimen.

Minidose prophylactic UFH UFH, 5,000 units SC every 12 hours Prophylactic UFH UFH, 5,000-10,000 units SC every 12 hours

UFH, 5,000-7,500 units SC every 12 hours in first trimester

UFH 7,500-10,000 units SC every 12 hours in the second trimester

UFH, 10,000 units SC every 12 hours in the third trimester, unless the aPTI is elevated

Therapeutic UFHb UFH, 10,000 units or more SC every 12 hours in doses adjusted to target aPTI in the therapeutic range (1n.5-2.5) 6 hours after injection

Postpartum anticoagulation Prophylactic LMWH/UFH for 4-6 weeks or vitamin K antagonists for 4-6 weeks with a target INR of 2.0-3.0, with initial UFH or LMWH therapy overlap until the INR is 2.0 or more for

Surveillance Clinical vigilance and appropriate objective investigation of women symptoms suspicious of deep-vein thrombosis or pulmonary embolism

Abbreviations: aPTI, activated partial thromboplastin time; INR, international normalized ratio; LMWH, low-molecular-weight heparin; SC, subcutaneously; UFH, unfractionated heparin.

aAlthough at extremes of body weight, modification of dose may be required. bAlso referred to as weight adjusted, full treatment dose.

Reproduced with permission from American College of Obstetricians and Gynecologists Women's Health Care Physicians:

Bulletin No. 138: Inherited thrombophilias in pregnancy, Obstet Gynecol. 2013 Sep;122(3):706-717.

1000 U Ihr or 15 to 20 U Ikg/hr. his infusion rate is titrated to achieve an aPTT 1.5 to 2.5 times control values (Brown, 2010; Linnemann, 2016). Intravenous anticoagulation is maintained for at least 5 to 7 days, after which treatment is converted to subcutaneous heparin to maintain the aPTT to at least 1.5 to 2.5 times control throughout the dosing interval. For women with lupus anticoagulant, aPTT does not accurately assess heparin anticoagulation, and thus anti-factor Xa levels are preferred.

The duration of full anticoagulation varies, and no studies have defined the optimal duration for pregnancy-related thromboembolism. In nonpregnant patients with TE, evidence supports a minimum treatment duration of 3 months (Kearon, 2012). For pregnant patients, the American College of Chest Physicians recommends anticoagulation throughout pregnancy and postpartum for a minimum total duration of 3 months (Bates, 2012). Lockwood (2012) recommends that full anticoagulation be continued for at least 20 weeks followed by prophylactic doses if the woman is still pregnant. Prophylactic doses of subcutaneous UFH can range from 5000 to 10,000 U every 12 hours titrated to maintain an anti-factor Xa level of 0.1 to 0.2 U/mL, measured 6 hours after the last injection. If the TE occurs during the postpartum period, Lockwood (2012) recommends a minimum of 6 months of anticoagulation treatment.

This is a family of derivatives of unfractionated heparin, and their molecular weights average 4000 to 5000 daltons compared with 12,000 to 16,000 daltons for conventional heparin. None of these heparins cross the placenta, and all exert their anticoagulant activity by activating antithrombin. The primary diference is their relative inhibitory activity against factor a and thrombin. Specifically, UFH has equivalent activity against factor a and thrombin, but LMWHs have greater activity against factor a than against thrombin. They lso have a more predictable anticoagulant response and fewer bleeding complications than UFH because of their better bioavailability, longer half-life, dose-independent clearance, and decreased interference with platelets (Tapson, 2008). hese LMWH compounds are cleared by the kidneys and must be used cautiously when there is renal dysunction.

Several studies have shown that TE is treated efectively with LMWH (Quinlan, 2004; Tapson, 2008). Using serial venograms, Breddin and associates (2001) observed that these compounds were more efective than UFH in reducing thrombus size without increasing mortality rates or major bleeding complications. Several diferent treatment regimens using adjusted-dose LMWH for treatment of acute TE are recommended by the American College of Obstetricians and Gynecologists (2017b,c) and are listed in Table 52-5.

LMWHs available for use in pregnancy include enoxaparin, tinzaparin, and dalteparin. Enoxaparin (Lovenox) pharmacokinetics were studied in 36 women with TE during pregnancy or immediately postpartum (Rodie, 2002). he dose was approximately 1 mg/kg given twice daily based on early pregnancy weight. Treatment was monitored by peak anti-factor Xa activity at 3 hours postinjection, with a target therapeutic range of 0.4 to 1.0 U/mL. In 33 women, enoxaparin provided satisfactory anticoagulation. In the other three women, dose reduction was necessary. None developed recurrent thromboembolism or bleeding complications. In postcesarean women with a body mass index (BMI) �35, Stephenson and associates (2016) found that weight-based dosing of enoxaparin 0.5 mg/kg twice daily more efectively achieved prophylactic peak anti-Xa levels between 0.2 to 0.6 U/mL than a ixed dose of 40 mg daily. Similar indings were reported by Overcash and colleagues (2015).

For tinzaparin (Innohep), a dosage of 75 to 175 U/kg/d was necessary to achieve peak anti-factor Xa levels of 0.1 to 1.0 U/mL (Smith, 2004). In studies of dalteparin (Fragmin) pharmacokinetics, conventional starting doses of dalteparin-100 U/kg every 12 hours-were likely insuicient to maintain ull anticoagulation (Barbour, 2004; Jacobsen, 2003). Thus, slightly higher doses than that shown in Table 52-5 may be required.

Standard prophylactic and therapeutic dosages recommended by the American College of Obstetricians and Gynecologists (2017b) for various L\1WHs are listed in Table 52-5. Whether such dosages require adjustments during the course of pregnancy is controversial (Berresheim, 2014; Cutts, 2013). Some suggest periodic measurement of anti-factor Xa levels 4 to 6 hours after an injection with dose adjustment to maintain a therapeutic level. Large studies using clinical end points that demonstrate an optimal therapeutic range or show that dose adjustments increase therapy safety or eicacy are lacking. Accordingly, the American College of Chest Physicians and others note that routine monitoring with anti-Xa levels is difficult to justiy (Bates, 2012; McDonnell, 2017).

Early reviews concluded that LMWHs were safe and efective (Lepercq, 2001; Sanson, 1999). Despite this, in 2002, the manufacturer of Lovenox warned that its use in pregnancy had been associated with congenital anomalies and a higher risk of hemorrhage. Ater its own extensive review, the American College of Obstetricians and Gynecologists (20 17b) concluded that these risks were rare, that their incidence was not higher than expected, and that no cause-and-efect relationship had been established. It further concluded that enoxaparin and dalteparin could be given safely during pregnancy. Other reports confirm their safety (Andersen, 2010; Bates, 2012; Galambosi, 2012).

N elson-Piercy and coworkers (201a1) assessed the safety of tinzaparin through a comprehensive study of 1267 treated pregnant women. There were no maternal deaths or complications from regional analgesia. Although thrombocytopenia developed in 1.8 percent, there were no cases of heparin-induced thrombocytopenia (p. 1015). he allergy incidence was 1.3 percent. Osteoporotic fractures in three women (0.2 percent) were judged to be related to tinzaparin (p. 1015). A total of 43 women (3.4 percent) required medical intervention for bleeding. Of 15 stillbirths, four were judged as possibly being related to tinzaparin use. But, none of the neonatal deaths or congenital abnormalities was attributed to tinzaparin. The authors concluded that tinzaparin during pregnancy was safe for mother and fetus. LMWHs are also safe during breastfeeding (Lim, 2010).

However, LMWHs should be avoided in women with renal failure. Moreover, when given within 2 hours of cesarean delivery, these agents raise the risk of wound hematoma (van Wijk, 2002).

Women receiving either therapeutic or prophylactic anticoagulation should be converted from LMWH to the shorter halflife UFH in the last month of pregnancy or sooner if delivery appears imminent. he purpose of conversion to UFH has less to do with any risk of maternal bleeding at the time of delivery, but rather with neuraxial blockade complicated by an epidural or spinal hematoma (Chap. 25, p. 496). The American College of Chest Physicians recommends that women scheduled for a planned delivery who are receiving twice-daily adjusteddose subcutaneous UFH or fWH discontinue their heparin 24 hours before labor induction or cesarean delivery (Bates, 2012). Patients receiving once-daily LMWH should take only 50 percent of their normal dose on the morning of the day before delivery. he American College of Obstetricians and Gynecologists (2017 c) advises that adjusted-dose subcutaneous LlvfWH or UFH can be discontinued 24 to 36 hours before an induction of labor or scheduled cesarean delivery. he American Society of Regional Anesthesia and Pain Medicine advises withholding neuraxial blockade for 10 to 12 hours after the last prophylactic dose of LMWH or 24 hours after the last therapeutic dose (Horlocker, 2010).

If a woman begins labor while taking UFH, clearance can be veriied by an aPTT. Reversal of heparin with protamine sulfate is rarely required and is not indicated with a prophylactic dose of heparin. For women in whom anticoagulation therapy has temporarily been discontinued, pneumatic compression devices are recommended.

• Anticoagulation with Warfarin Compounds

Vitamin K antagonists are generally contraindicated because they readily cross the placenta and may cause fetal death and malformations from hemorrhages (Chap. 12, p. 247). They do not accumulate in breast milk and are thus safe during breastfeeding.

Postpartum venous thrombosis is usually treated with intravenous heparin and oral warfarin initiated simultaneously. The initial dose of warfarin is usually 5 to 10 mg for the first 2 days. Subsequent doses are titrated to achieve an international normalized ratio (INR) of 2 to 3. To avoid paradoxical thrombosis and skin necrosis from the early anti-protein C efect of warfarin, these women are maintained on therapeutic doses of

UFH or LMWH for 5 days and until the INR is in a therapeu tic range for 2 consecutive days (American College of Obstetri cians and Gynecologists, 2017 c; Stewart, 2010).

Treatment in the puerperium may require larger doses of anticoagulant. Brooks and colleagues (2002) compared antico agulation in postpartum women with that of age-matched non pregnant controls. The former required a significantly larger median total dose of warfarin-45 versus 24 mg-and a longer time-7 versus 4 days-to achieve the target INR.

Of newer oral anticoagulants, dabigatran (Pradaxal) inhibits thrombin. Rivaroxaban (Xarelto) and apixaban (Eliquis) inhibit factor Xa. Currently, very few reports address these newer agents during pregnancy, and thus the human reproductive risks are essentially unknown (Bates, 2012). Dabigatran crosses the human placenta (Bapat, 2014). However, it is unknown whether any of these agents are excreted in breast milk. Because of the potential for infant harm, a decision should be made to either avoid breastfeeding or use an alternative anticoagulant, such as warfarin, in postpartum women (Burnett, 2016).

• Complications of Anticoagulation hree significant complications associated with anticoagulation are hemorrhage, thrombocytopenia, and osteoporosis. he latter two are unique to heparin, and their risk may be reduced with LMWHs. The most serious complication is hemorrhage, which is more likely if there has been recent surgery or lacerations. Troublesome bleeding also is more likely if the heparin dosage is excessive. Unfortunately, management schemes using laboratory testing to identiY when a heparin dosage is suicient to inhibit further thrombosis, yet not cause serious hemorrhage, have been discouraging.

There are two types-the most common is a nonimmune, benign, reversible thrombocytopenia that develops within the first few days of therapy and resolves in approximately 5 days without therapy cessation. The second is the severe form of heparin-induced thrombocytopenia (HIT), which results from an immune reaction involving IgG antibodies directed against complexes of platelet factor 4 and heparin. The diagnosis of HIT is based on a drop in the platelet count of more than 50 percent or thrombosis beginning 5 to 10 days after the start of heparin in association with the appearance of platelet-activating HIT antibodies. The fall in platelet count in HIT occurs rapidly-over a period of 1 to 3 days-and is assessed relative to the highest platelet count after the start of heparin. he typical nadir is 40,000 to 80,000 platelets per microliter (Greinacher, 2015).

Although the incidence of HIT is approximately 3 to 5 percent in nonpregnant individuals, it is <0.a1 percent in obstetrical patients (Linkins, 2012). Fausett and coworkers (2001) reported no cases among 244 heparin-treated gravidas compared with 10 among 244 nonpregnant patients. Accordingly, the American College of Chest Physicians recommends against platelet count monitoring when the risk of HIT is considered to be less than 1 percent. In others, they sug (Linkins, 2012).

When HIT is diagnosed, heparin therapy is stopped and alternative anticoagulation initiated. Platelet transfusions are avoided (Greinacher, 2015). LMWH may not be entirely safe because it has some cross reactivity with UFH. The Ameri can College of Chest Physicians recommends danaparoid (Orgaran)-a sulfated glycosaminoglycan heparinoid (Bates, 2012; Linkins, 2012). In a review of nearly 50 pregnant women with either HIT or a skin rash, Lindhof-Last and associates tive. However, they reported two fatal maternal hemorrhages and three fetal deaths. Magnani (2010) reviewed case reports of 83 pregnant women treated with danaparoid. Although it was generally efective, two patients died related to bleeding, three patients sufered nonfatal major bleeds, and three women developed thromboembolic events unresponsive to danaparoid.

The drug has been removed from the u.S. market.

bin inhibitor (Kelton, 2013; Linkins, 2012). Successful use in pregnancy has been reported (Elsaigh, 2015; Knol, 2010).

Tanimura and coworkers (2012) successfully used argatroban, and later fondaparinux, to manage HIT in a pregnant woman with hereditary antithrombin deficiency.

Bone loss may develop with long-term heparin administration-usually 6 months or longer-and is more prevalent in cigarette smokers. UFH can cause osteopenia, and this is less likely with LMWHs (Deruelle, 2007). Women treated with any heparin should be encouraged to take an oral daily 1500-mg calcium supplement (Cunningham, 2005; Lockwood, 2012). In one study, Rodger and colleagues (2007) found that long-term use of dalteparin for a mean of212 days was not associated with a signiicant decline in bone mineral density.

he treatment of deep-vein thrombosis with heparin does not preclude pregnancy termination by careful curettage. After the products are removed without trauma to the reproductive tract, full-dose heparin can be restarted in several hours.

The efects of heparin on blood loss at delivery depend on several variables: (1) dose, route, and timing of administration; (2) number and depth of incisions and lacerations; (3) intensity of postpartum myometrial contractions; and (4) presence of other coagulation defects. Blood loss should not be greatly increased with vaginal delivery if the episiotomy is modest in depth, there are no lacerations, and the uterus promptly contracts. Unfortunately, such ideal circumstances do not always prevail. For example, Mueller and Lebherz (1969) described 10 women with antepartum thrombophlebitis treated with heparin. hree women who continued to receive heparin during labor and delivery bled remarkably and developed large hematomas. Thus, heparin therapy generally is stopped during labor and delivery. The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (20a17) recommend restarting UFH or LMWH no sooner than 4 to 6 hours after vaginal delivery or 6 to 12 hours after cesarean delivery. We wait at least 24 hours to restart therapy after cesarean delivery or after vaginal delivery with significant lacerations.

Slow intravenous administration of protamine sulfate generally reverses the efect of heparin promptly and efectively. It should not be given in excess of the amount needed to neutralize the heparin, because it also has an anticoagulant efect.

hrombosis limited strictly to the superficial veins of the saphenous system is treated with analgesia, elastic support, heat, and rest. If it does not soon subside or if deep-vein involvement is suspected, appropriate diagnostic measures are performed. Supericial vein thrombosis raises the risk of deep-vein thrombosis four-to sixfold. Heparin is given if deep-vein involvement is conirmed (Roach, 2013). Superficial thrombophlebitis is typically seen in association with varicosities or as a sequela of an indwelling intravenous catheter.

lthough it causes approximately 10 percent of maternal deaths, pulmonary embolism is relatively uncommon during pregnancy and the puerperium. he incidence averages 1 in 7000 pregnancies. According to Marik and Plante (200S), 70 percent of gravidas presenting with a pulmonary embolism have associated clinical evidence of deep-vein thrombosis. And recall that between 30 and 60 percent of women with a deep-vein thrombosis will have a coexisting silent pulmonary embolism.

In almost 2500 nonpregnant patients with a proven pulmonary embolism, symptoms included dyspnea in S2 percent, chest pain in 49 percent, cough in 20 percent, syncope in 14 percent, and hemoptysis in 7 percent (Goldhaber, 1999). Pollack and coworkers (2011) found similar symptoms. Other predominant clinical indings typically include tachypnea, apprehension, and tachycardia. In some cases, an accentuated pulmonic closure sound, rales, and/or friction rub is heard.

ight axis deviation and T -wave inversion in the anterior chest leads may be evident on the electrocardiogram. In at least 40 percent, chest radiography results are normal. In others, nonspecific indings may include atelectasis, an iniltrate, cardiomegaly, or an efusion (Pollack, 2011). Vascular markings in the lung region supplied by the obstructed artery can be lost. Although most women are hypoxemic, a normal arterial blood gas analysis does not exclude pulmonary embolism. Approximatelyaa third of young patients have P02 values >SO mm Hg. hus, the alveolar-arterial oxygen tension diference is a more useful indicator of disease. More than S6 percent of patients with acute pulmonary embolism will have an alveolar-arterial diference >20 mm Hg (Lockwood, 2012). Even with massive pulmonary embolism, signs, symptoms, and laboratory data to support the diagnosis may be deceptively nonspecific.

his is defined as embolism causing hemodynamic instability (Tapson, 200S). Acute mechanical obstruction of the pulmonary vasculature causes increased vascular resistance and pulmonary hypertension followed by acute right ventricular dilation. In otherwise healthy patients, significant pulmonary hypertension does not develop until 60 to 75 percent of the pulmonary vascular tree is occluded (Guyton, 1954). Moreover, circulatory collapse requires 75-to SO-percent obstruction. This is depicted schematically in Figure 52-4 and emphasizes that most acutely symptomatic emboli are large and likely a saddle embolism. hese are suspected when the pulmonary artery pressure is substantively increased as estimated by echocardiography.

If there is evidence of right ventricular dysfunction, the mortality rate approaches 25 percent. This compares with a I-percent rate without such dysfunction (Kinane, 200S). It is important in these cases to infuse crystalloids carefully and to support blood pressure with vasopressors. As discussed on page lOIS, oxygen treatment, endotracheal intubation, and mechanical ventilation are completed preparatory to thrombolysis, filter placement, or embolectomy (T apson, 200S).

In most cases, recognition of a pulmonary embolism requires a high index of suspicion that prompts objective evaluation. Exposure of the mother and fetus to ionizing radiation is a concern when investigating a suspected pulmonary embolism during pregnancy. However, this concern is largely overruled by the hazards of missing a potentially fatal diagnosis. Moveover, erroneously assigning a diagnosis of pulmonary embolism to a pregnant woman is also fraught with problems. It unnecessarily exposes the mother and fetus to the risks of anticoagulation treatment and will impact delivery plans, future contraception, and thromboprophylaxis during subsequent pregnancies. herefore, investigations should aim at diagnostic certainty (Konstantinides, 2014).

In 2011a, the American horacic Society and the Society of Thoracic Radiology developed an algorithm-shown in Figure 52-5 for the diagnosis of pulmonary embolism during pregnancy (Leung, 201l). In addition to compression ultrasonography, which was previously discussed (p. 1010), the algorithm includes computed-tomographic pulmonary angiography (CTPA) and ventilation-perfusion scintigraphy.

Multidetector computed tomography with pulmonary angiography is currently the most commonly employed technique used for pulmonary embolism diagnosis in nonpregnant patients (Bourjeily, 2012; Pollack, 2011). he technique is described further in Chapter 46 (p. 907), and an imaging example is

Dia. 1.5 cm each; total area 9 cm2

Dia. 8 mm each; total area 1 3 cm2 arteries Dia. 6 mm each; = arteries Dia. 4 mm each;

FIGURE 52-4 Schematic of pulmonary arterial circulation. Note that the cross-sectional area of the pulmonary trunk and the combined 2 pulmonary arteries is 9 cmo. A large saddle embolism could occlude 50 to 90 percent of the pulmonary tree, causing hemodynamic instability. As the arteries give of distal branches, the total surface area rapidly increases, that is, 13 cm2 for the combined five lobar arteries, 36 cm2 for the combined 19 segmental arteries, and more than 800 cm2 for the total 65 subsegmental arterial branches. Thus, hemodynamic instability is less likely with emboli past the lobar arteries. (Data from Singhal S, Henderson R, Horsfield K, et al: Morphometry of the human pulmonary arterial tree, Circ Res. 1973 Aug;33(2):190-197.)

Stop CUS, CTPA Treat Stop

FIGURE 52-5 The American Thoracic Society and Society of Thoracic Radiology diagnostic algorithm for suspected pulmonary embolism during pregnancy. CTPA = computed tomographic pulmonary angiography; CUS = compression ultrasonography; CXR = chest x-ray; PE = pulmonary embolism; V/O = ventilation/perfusion scintigraphy. (Modified with permission from Leung AN, Bull TM, jaeschke R, et al: An oficial American Thoracic Society/Society of Thoracic Radiology Clinical Practice Guideline: Evaluation of suspected pulmonary embolism in pregnancy, Am j Respir Crit Care Med. 2011 Nov 15;184(10):1200-1208.)

FIGURE 52-6 Axial image of the chest from a four-channel multidetector spiral computed tomographic scan performed ater administration of intravenous contrast. There is enhancement of the pulmonary artery with a large thrombus on the right (arrow) consistent with pulmonary embolism. (Reproduced with permission from Dr. Michael Landay.) shown in Figure 52-6. The estimated fetal radiation exposure averages 0.45 to 0.6 mGy. he estimated maternal breast dose is 10 to 70 mGy (Waksmonski, 2014).

Bourjeily and colleagues (2012) performed a follow-up study of 318 pregnant women who had a negative CTP A performed for a suspected pulmonary embolism. All were seen 3 months following their initial presentation or at 6 weeks postpartum. None of these women were subsequently diagnosed with a thromboembolism.

CTP A has many advantages, but we find that the higher resolution allows detection of previously inaccessible smaller distal emboli that have uncertain clinical significance. Similar observations have been reported by others (Anderson, 2007; Hall, 2009). Also, the hyperdynamic circulation and augmented plasma volume associated with pregnancy leads to a higher number of nondiagnostic studies compared with nonpregnant patients (Ridge, 2011; Scarsbrook, 2006).

his technique involves a small dose of radiotracer such as intravenously administered technetium-99m-macroaggregated albumin. There is negligible fetal and maternal breast radiation exposure-0.1 to 0.4 mGy. The scan may not provide a deinite diagnosis because many other conditions can cause perfusion defects. Examples are pneumonia or local bronchospasm. Chan and coworkers (2002) found that a fourth of ventilationperfusion scans in pregnant women were nondiagnostic. In these instances, CTPA is preferred (T romeur, 2017).

To compare the performance of lung scintigraphy and CTPA, Revel and colleagues (201a1) evaluated 137 pregnant women with suspected pulmonary embolism. he two modalities performed comparably and had no signiicant diferences between the proportions of positive, negative, or indeterminate results. Speciically, the proportion of indeterminate results for both approximated 20 percent. By way of comparison, about a fourth of the nonpregnant population had indeterminate studies. The investigators attributed this diference to the younger age of the pregnant patients. Similarly, one systematic review concluded that both CTP A and lung scintigraphy seem appropriate for exclusion of pulmonary embolism during pregnancy (van Mens, 2017).

his requires catheterization of the right side of the heart and is considered the reference test for pulmonary embolism. With newer generation multidetector CT scanners, however, the role of invasive pulmonary angiography has been questioned. his is especially true given the higher radiation exposure for the fetus (Konstantinides, 2014; Kuriakose, 2010). Other detractions are that it can be time consuming, uncomfortable, and associated with dye-induced allergy and renal failure. Indeed, the procedure-related mortality rate approximates 1 in 200 (Stein, 1992). It is reserved for confirmation when less invasive tests are equivocal.

Immediate treatment for pulmonary embolism is full anticoagulation similar to that for deep-vein thrombosis as discussed on page 1012. Several complementary procedures may be indicated.

The woman who has very recently sufered a pulmonary embolism and who must undergo cesarean delivery presents a particularly serious problem. Reversal of anticoagulation may be followed by another embolus, and surgery while ully anticoagulated frequently results in life-threatening hemorrhage or troublesome hematomas. In these cases, placement of a vena caval ilter should be considered before surgery (Marik, 2008). Moreover, in the very infrequent circumstances in which heparin therapy fails to prevent recurrent pulmonary embolism from the pelvis or legs, or when embolism develops from these sites despite heparin treatment, a vena caval ilter may also be indicated. Such filters can also be used following massive emboli in patients who are not candidates for thrombolysis (Deshpande, 2002).

he device is inserted through either the jugular or femoral vein and can be inserted during labor Jamjute, 2006). Routine filter placement has no added advantage to heparin given alone (Decousus, 1998). Retrievable ilters may be used as short-term protection and then removed 1 to 2 weeks later (Liu, 2012). From their systematic review, Harris and associates (2016) found that complication rates in pregnant women with vena caval filters are comparable to those in nonpregnant patients.

Compared with heparin, thrombolytic agents provide more rapid lysis of pulmonary clots and improvement of pulmonary hypertension (Tapson, 2008). Konstantinides and coworkers (2002) studied 256 nonpregnant patients receiving heparin for an acute submassive pulmonary embolism. hey also were randomly assigned to a placebo or the recombinant tissue plasminogen activator alteplase. hose given the placebo had a threefold greater risk of death or treatment escalation compared with those given alteplase. Agnelli and associates (2002) per formed a metaanalysis of trials involving 461 nonpregnant patients. They reported that the risk of recurrence or death and heparin compared with those given heparin alone-1 0 versus 17 percent. Importantly, however, there were ive-2 percent-fatal bleeding episodes in the thrombolysis group and none in the heparin-only group.

In their review, Leonhardt and colleagues (2006) identiied 28 reports of tissue plasminogen activator use during pregnancy. T en cases were for thromboembolism. Complication rates were similar to those in nonpregnant patients, and the authors concluded that such therapy should not be withheld during pregnancy if indicated. However, Akazawa and Nishida (2017) reviewed 13 cases of systemic thrombolytic therapy administered during the irst 48 hours after delivery. Blood transfusion was required in five of the eight cesarean deliveries, including three cases of hysterectomy and two cases of hematoma removal.

Given the eicacy of thrombolysis and filters, surgical embolectomy is uncommonly indicated. Published experience with emergency embolectomy during pregnancy is limited to case reports (Colombier, 2015; Saeed, 2014). From their review, Ahearn and associates (2002) found that although the operative risk to the mother is reasonable, the stillbirth rate is 20 to 40 percent.

Most recommendations regarding thromboprophylaxis during pregnancy stem from consensus guidelines. In one review of guidelines for thromboprophylaxis in pregnancy, the authors concluded that there is a lack of overall agreement about which women should be ofered thromboprophylaxis or ofered testing for thrombophilias (Okoroh, 2012). Bates and associates (2016) also conducted a review of guidelines for obstetrically associated VTE. hey summarized that evidence-based recommendations are based largely on observational studies and extrapolated from data in nonpregnant patients. Similarly, a Cochrane review concluded that evidence is insuicient for firm recommendations regarding thromboprophylaxis during pregnancy (Bain, 2014).

he confusion that has ensued has provided fertile ground for litigators. Cleary-Goldman and associates (2007) surveyed 151 fellows of the American College of Obstetricians and Gynecologists and reported that intervention without a clear indication is common. Table 52-6 lists several consensus recommendations for thromboprophylaxis. In some cases, more than one option is listed, thus illustrating the confusion that currently reigns.

In general, either antepartum surveillance or heparin prophylaxis is recommended for women with prior TE but without a recurrent risk factor, including no known thrombophilia. The study by Tengborn and coworkers (1989), however, suggested that such management may not be efective. hey reported out boembolic disease and were not tested for thrombophilias.

Despite unfractionated heparin prophylaxis, which was usually 5000 U twice daily, three of 20 women (15 percent) developed antepartum recurrence. his compared with eight of 67 women (12 percent) not given heparin.

125 pregnant women with a single prior VTE. Antepartum hep arin was not given, but anticoagulant therapy was given for 4 to 6 weeks postpartum. Six women had a recurrent venous throm bosis-three antepartum and three postpartum. here were no recurrences in the 44 women without a known thrombophilia or whose prior thrombosis was associated with a temporary risk factor. These findings imply that prophylactic heparin may not be required for these two groups of women. In contrast, and as shown in Table 52-6, women with a prior thrombosis in association with a thrombophilia or in the absence of a tempo postpartum prophylaxis (Connors, 2017).

De Stefano and coworkers (2006) studied 1104 nonpregnant women who had a irst-episode VTE before the age of 40 years. After excluding those with antiphospholipid antibodies, 88 women were identiied who subsequently had a total of 155 pregnancies and who were not given anti thrombotic prophylaxis. There were 19 women (22 percent) who had a subsequent pregnancy-or puerperium-related VTE. Of 20 women whose original thrombosis was associated with a transient risk factornot including pregnancy or oral contraceptive use-there were no recurrences during pregnancy, but two during the puerperium. hese data also suggest that for women with a prior VTE, anti thrombotic prophylaxis during pregnancy could be tailored according to the circumstances of the original event.

It is important to emphasize that VTE may recur despite antithrombotic prophylaxis. Galambosi and associates (2014) studied 270 women during 369 pregnancies who had at least one previous VTE. A total of 28 women (l0.4 percent) sufered a recurrent VTE. Twelve of these recurrences occurred early in pregnancy before the initiation of antithrombotic prophylaxis, and 16 occurred despite prophylactic use of LMWH.

Our practice at Parkland Hospital for many years for women with a history of prior VTE was to administer subcutaneous UFH, 5000 to 7500 units two to three times daily. With this regimen, the recurrence of documented deep-vein thrombosis embolization was rare. Beginning approximately 10 years ago, we have successfully used 40 mg enoxaparin given subcutaneously daily for thromboprophylaxis.

The risk for deep-vein thrombosis and especially for fatal thromboembolism rises manyfold in women following cesarean compared with that ater vaginal delivery. When considering that a third of women giving birth in the United States yearly undergo cesarean delivery, pulmonary embolism is understandably a major cause of maternal mortality (Creanga, 2017). hat said, the "lack

TABLE 52-6. Some Recommendations for Thromboprophylaxis during Pregnancy some experts." INR 2.0-3.0 x long-term therapy some experts" INR 2.0-3.0 x warfarin LMWH or 75% of anticoagulation

Associated with a high-Prophylactic, NSS Postpartum Prophylactic or risk thrombophiliad intermediate-, r anticoagulationC intermediate- anticoagulation or an LMWH or UFH x INR 2.0-3.0 x affected fi rst -d eg ree 6 weeksc 6 weeks relative Associated with a low-Prophylactic or NSS Postpartum Prophylactic or risk thrombophiliae intermed iate-dose anticoagulationc or intermediate-

INR 2.0-3.0 x

Two or more prior VTEs with or without thrombophilia 6 weeks INR 2.0-3.0 x 6 weeks Receiving long-term Therapeutic-dose Adjusted-dose Resumption of long-Resumption of anticoagulation LMWH or UFH LMWH or 75% of term anticoagulation long-term a therapeutic dose anticoagulation

No prior.VTE prophylactic or intermed iate-dose a nticoag u lation. dose LMWH or intermediate-dose LMWH warfarin target

LMWH or UFH INR 2.0-3.0 x mutation INR 2.0-3.0 x

TABLE 52-6. Continued mutation INR 2.0-3.0 x or S deficient,

INR 2.0-3.0

History of fE Prophylactic NSS Prophylactic NSS anticoagulation with a nticoag u lationC;

UFH or LMWH (?plus referral to specialist9

LMWH or UFH plus low-LMWH, both given pregnancy loss r dose aspirin if prior with 75-100 mg/ stillbirth9 aAmerican College of Obstetricians and Gynecologists, 2017a, c.

bAmerican College of Chest PhYSicians (Bates, 201n2).

(Postpartum treatment levels should be � antepartum treatment.

dAntithrombin deficiency; doubly heterozygous or homozygous for prothrombin 2021 OA and factor V Leiden.

eHeterozygous factor V Leiden or prothrombin 2021 OA; protein S or C deficiency.

fFirst-degree relative with fE at <50 years; other major thrombotic risk factors, e.g., obesity, prolonged immobility.

9Women with antiphospholipid syndrome should not use estrogen-containing contraceptives.

hTreatment is recommended if the diagnosis of antiphospholipid syndrome is based on three or more prior pregnancy losses.

LMWH = low-molecular-weight heparin; NSS = not specifically stated; UFH = unfractionated heparin; fE = venous thromboembolism.

Prophylactic, intermediate-, and adjusted-dose regimens are listed in Table 52-5 (p. 1013).

of high quality data" described earlier by Bates and colleagues compression devices before cesarean delivery for all women (2016) creates considerable variation in the current recommennot already receiving thromboprophylaxis. his recommendations promulgated by the American College of Obstetricians dation was based primarily on consensus and expert opinion. and Gynecologists, the Royal College of Obstetricians, and the For patients undergoing cesarean delivery with additional risk American College of Chest Physicians (Palmero la, 2016). factors for thromboembolism, both pneumatic compression

In 2011, the American College of Obstetricians and Gynedevices and UFH or LMH may be recommended. he Colcologists (20 17b) recommended placement of pneumatic lege stipulated that cesarean delivery in an emergency setting should not be delayed because of the time necessary to implement thromboprophylaxis. Implementation of this strategy by the Hospital Corporation of America, the largest for-profit obstetrical health care delivery system in the United States, was associated with a reduction in deaths from pulmonary embolism from 7 of 458,097 cesarean births to 1 of 465,880 cesarean births (Clark, 2011, 2014).

In 2016, the National Partnership for Maternal Safety published several consensus recommendations for the prevention of maternal TE (D'lton, 2016). These recommendations included expanded use of antenatal prophylaxis for women hospitalized 3 days or longer, expanded use of prophylaxis during and after vaginal delivery, and expanded use of pharmacological prophylaxis to most women after cesarean delivery. In response, Sibai and Rouse (2016) expressed concern that these new recommendations derive from sparse data of questionable applicability to obstetrical patients. They called for better quality evidence to measure the benefits, harms, and costs of increased pharmacological thromboprophylaxis. As aptly expressed by Macones (2017), "an intervention, such as increased postcesarean pharmacologic thromboprophylaxis, where there are legitimate concerns about eicacy and safety, requires a much higher degree of evidence before a national guideline is implemented." We agree with these sentiments.

Agnelli G, Becattini C, Kirschstein T: Thrombolysis vs heparin in the treatment of pulmonary embolism. Arch Intern Med 162: 2537, 2002

Ahearn GS, Hadjiliadis 0, Govert JA, et al: Massive pulmonary embolism during pregnancy successfully treated with recombinant tissue plasminogen activator. Arch Intern Med 162: 1221, 2002

Akazawa M, Nishida M: Thrombolysis with intravenous recombinant tissue plasminogen activator during early postpartum period: a review of the literature. Acta Obstet Gynecol Scand 96(5):529, 2017

Almawi Y, AI-Shaikh FS, Melemedjian OK, et al: Protein Z, an anticoagulant protein with expanding role in reproductive biology. Reproduction 3,t2013

American Academy of Pediatrics, American College of Obstetricians and Gynecologists: Guidelines for Perinatal Care, 8th ed. Elk Grove Village, P, 2017 American College of Obstetricians and Gynecologists: Antiphospholipid syn drome. Practice Bulletin No. 132, December 2012, Reairmed 2017 a American College of Obstetricians and Gynecologists: hromboembolism in pregnancy. Practice Bulletin No. 123, September 2011, Reairmed 2017b American College of Obstetricians and Gynecologists: Inherited thrombophilias in pregnancy. Practice Bulletin No. 138, September 2013, Reairmed 20l7c

Andersen AS, Berthelsen JG, Bergholt T: Venous thromboembolism in pregnancy: prophylaxis and treatment with low molecular weight heparin. Acta Obstet Gynecol Scand 89(1):15,t2010

Anderson DR, Kahn SR, Rodger MA, et al: Computed tomographic pulmonary angiography vs ventilation-perfusion lung scanning in patients with suspected pulmonary embolism: a randomized controlled trial. JAvlA 298:2743, 2007

Anderson JA, Weitz JI: Hypercoagulable states. Crit Care C1in 27:933, 2011

Archer OF, Mammen EF, Grubb GS: he efects of a low-dose monophasic preparation of levonorgestrel and ethinyl estradiol on coagulation and other hemostatic factors. Am J Obstet Gynecol 181 :S63, 1999

Bain E, Wilson A, T ooher R, et al: Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period. Cochrane Database Syst Rev 2:CD001689, 2014

Bapat P, Kedar R, Lubetsky A, et al: Transfer of dabigatran and dabigatran etexilate mesylate across the dually perfused human placenta. Obstet Gynecol 123(6):1256, 2014

Barbour A, Oja ]L, Schultz LK: A prospective trial that demonstrates that dalteparin requirements increase in pregnancy to maintain therapeutic levels of anticoagulation. Am J Obstet Gynecol 191:1024,t2004

Bates SM, Greer lA, Middledorp S, et al: VTE, thrombophilia, anti thrombotic therapy, and pregnancy. Chest 141:e691S, 2012

Bates SM, Middeldorp S, Rodger M, et al: Guidance for the treatment and prevention of obstetric-associated venous thromboembolism. ] hromb Thrombolysis 41(1):92,t2016

Berks 0, Duvekot n, Basalan H, et a1: Associations between phenotypes of preeclampsia and thrombophilia. Eur] Obstet Reprod Bioi 194: 199, 2015

Berresheim M, Wilkie J, Nerenberg A, et al: A case series of LMWH use in pregnancy: should trough anti-Xa levels guide dosing? hromb Res 134(6):1234,t2014

Birdwell BG, Raskob GE, Whitsett TL, et al: he clinical validity of normal compression ultrasonography in outpatients suspected of having deep venous thrombosis. Ann Intern Med 128: 1, 1998

Blanco-Molina A, Trujillo-Santos J, Criado ], et al: Venous thromboembolism during pregnancy or postpartum: indings from the RIETE Registry. Thromb Haemost 97:t1t86,t2007

Bourjeily G, Khalil H, Raker C, et al: Outcomes of negative multi detector computed tomography with pulmonary angiography in pregnant women suspected of pulmonary embolism. Lung 190:105, 2012

Brandjes DP, Buller HR, Heijboer H, et a1: Randomised trial of efect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 349:759, 1997

Breddin HK, Hach-Wunderle V, Nakov R, et al: Efects of a low-molecularweight heparin on thrombus regression and recurrent thromboembolism in patients with DVT. N Engl J Med 344:626,t2001 Brill-Edwards P, Ginsberg ]S, Gent M, et 1: Safety of withholding heparin in pregnant women with a history of venous thromboembolism. N Engl J Med 343:1439, 2000

Brooks C, Rutherford JM, Gould J, et al: Warfarin dosage in postpartum women: a case-control study. Br J Obstet Gynaecol 109: 187, 2002 Brown HL, Hiett AK: Deep vein thrombosis and pulmonary embolism in pregnancy: diagnosis, complications, and management. C1in Obstet Gynecol 53:345, 2010 Burneo JG, Elias SB, Barkley GL: Cerebral venous thrombosis due to protein S deficiency in pregnancy. Lancet 359:892, 2002 Burnett E, Mahan CE, Vazquez SR, et a1: Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb hrombolysis 41(1):206,t2016 Carbone JF, Rampersad R: Prenatal screening for thrombophilias: indications and controversies. Clin Lab Med 30:747, 2010 Chan WS, Ray ]G, Murray S, et al: Suspected pulmonary embolism in pregnancy. Arch Intern Med 162: 1170, 2002

Chan WS, Spencer FA, Ginsberg JS: Anatomic distribution of deep vein thrombosis in pregnancy. CMAJ 182:657,t2010 Chan WS, Spencer FA, Lee AY, et al: Safety of withholding anticoagulation in pregnant women with suspected deep vein thrombosis following negative serial compression ultrasound and iliac vein imaging. CNlAJ 185(4):E194, 2013 Clark SL, Christmas JT, Frye DR, et a1: Maternal mortality in the United States: predictability and the impact of protocols on fatal postcesarean pulmonary embolism and hypertension-related intracranial hemorrhage. Am J Obstet GynecoIt211:32, 2014 Clark SL, Meyers JA, Frye OK, et al: Patient safety in obstetrics-the Hospital Corporation of America experience. Am J Obstet Gynecol204( 4):283, 2011 Cleary-Goldman ], Bettes B, Robinson IN, et al: Thrombophilia and the obstetric patient. Obstet Gynecol 110:669,t2007

Colombier S, Niclauss L: Successful surgical pulmonary embolectomy for massive perinatal embolism after emergency cesarean section. Ann Vase Sutg 29(7): 1452.el, 2015 Conard ], Horellou MH, Van Dreden P, et a1: hrombosis and pregnancy in congenital deiciencies in AT III, protein C or protein S: study of 78 women. Thromb Haemost 63:319, 1990 Connors JM: Thrombophilia testing and venous thrombosis. N Engl J Med 377(12):1177,t2017 Creanga A, Syverson C, Seed K, et a1: Pregnancy-related mortality in the United States, 2011-2013. Obstet GynecoIt130(2):366, 2017 Croles FN, Nasserinejad K, Duvekot n, et al: Pregnancy, thrombophilia, and the risk of a irst venous thrombosis: systematic review and bayesian metaanalysis. BMJ 359:j4452, 2017 Cunningham FG: Screening for osteoporosis. N Engl J Med 353:1975, 2005 Cutts BA, Dasgupta 0, Hunt BJ: New directions in the diagnosis and treatment of pulmonary embolism in pregnancy. Am J Obstet Gynecol 208(2):102,t2013 D'Alton ME, Friedman :, Smiley M, et al: National partnership for maternal safety: consensus bundle on venous thromboembolism. Obstet Gynecol 128(4):688,t2016 Decousus H, Leizorovicz A, Parent F, et al: A clinical trial of vena caval ilters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. N Engl J Med 338:409, 1998

Den Heijer M, Lewington S, Clarke R: Homocysteine, MTHRF and risk of venous thrombosis: a meta-analysis of published epidemiological studies. hromb Haemost 3:292, 2005

Deruelle P, Coulon C: The use of low-molecular-weight heparins in pregnancy-how safe are they? Curr Opin Obstet Gynecol 19:573,t2007

Deshpande KS, Hatem C, Karwa M, et al: he use of inferior vena cava ilter as a treatment modality for massive pulmonaty embolism. A case series and review of pathophysiology. Respir Med 96:984, 2002

De Stefano V, Martinelli I, Rossi E, et al: he risk of recurrent venous thromboembolism in pregnancy and puerperium without anti thrombotic prophylaxis. Br J Haematol 135:386,t2006

Dizon-Townson D, Miller C, Sibai B, et al: The relationship of the Factor V Leiden mutation and pregnancy ourcomes for mother and fetus. Obstet Gynecoltl06:517,t2005

Douketis ]D, Kearon C, Bates S, et al: Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. ]AMA 279:458, 1998

Duhl A], Paid as M], Ural SH, et al: Antithrombotic therapy and pregnancy: consensus report and recommendations for prevention and treatment of venous thromboembolism and adverse pregnancy outcomes. Amt] Obstet Gynecol 197(5):45 .e1,t2007

Elsaigh E, Thachilt], Nash MJ, et al: he use offondaparinux in pregnancy. Br ] HaematoIt168(5):762, 2015

Erdman WA, Jayson HT, Redman HC, et al: Deep venous thrombosis of extremities: role of MR imaging in the diagnosis. Radiology 174:425, 1990 Fausett MB, Vogtlander M, Lee RM, et al: Heparin-induced thrombocytope nia is rare in pregnancy. Am] Obstet Gynecol 185: 148, 2001

Galambosi PJ, Kaaja R], Stefanovic V, et al: Safety of low-molecular-weight heparin duting pregnancy: a retrospective controlled cohort study. Eur ] Obstet Gynecol Reprod Bio 163:154,t2012

Galambosi P], Ulander VM, Kaaja R]: The incidence and risk factors of recurrent venous thromboembolism during pregnancy. Thromb Res 134(2):240,t2014

Galanaud JP, Cochety-Nouvellon E, Alonso S, et al: Paternal endothelial protein C receptor 219Gly variant as a mild and limited risk factor for deep vein thrombosis during pregnancy. J Thromb Haemost 8:707, 2010

Garcia-Botella A, Asenjo S, De la Morena-Barrio ME, et al: First case with antithrombin deficiency, mesenteric vein thrombosis and pregnancy: multidisciplinary diagnosis and successful management. hromb Res 144:72,2016

Giannakopoulos B, Krilis SA: he pathogenesis of the anti phospholipid syn drome. N Engl] Med 368(11):1033,t2013

Ginsberg ]S, Brill-Edwards P, Burrows RF, et al: Venous thrombosis during pregnancy: leg and trimester of presentation. Thromb Haemost 67:519, 1992

Goldhaber SZ, Tapson VF, DVT FREE Steering Committee: A prospective registry of 5,451 patients with ultrasound-conirmed deep vein thrombosis. m J Cardiol 93:259, 2004

Goldhaber SZ, Visani L, De Rosa M: Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 353:1386,t1999

Greer IA: Clinical practice. Pregnancy complicated by venous thrombosis. N Engl] Med 373(6):540,t2015

Greer IA: Prevention and management of venous thromboembolism in pregnancy. Clin Chest Med 24: 123, 2003

Greinacher A: Heparin induced thrombocytopenia. N Engl J Med 373(3):252, 2015

Grossman KB, Arya R, Peixoto AB, et al: Maternal and pregnancy characteristics afect plasma ibrin monomer complexes and D-dimer reference ranges for venous thromboembolism in pregnancy. Am ] Obstet Gynecol 215(4):466.e1,t2016

Guyatt GH, Akl EA, Crowther M, et al: Executive summary: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 141:7S, 2012

Guyton AC, Lindsey A W, Gilluly J]: The limits of right ventricular compensation following acute increase in pulmonary circulatory resistance. Circ Res 2:326, 1954

Hague WM: Homocysteine and pregnancy. Best Pract Res Clin Obstet Gynaecol 1 :459, 2003

Hall B, Truitt SG, Scheunemann LP, et al: The prevalence of clinically relevant incidental findings on chest computed tomographic angiograms ordered to diagnose pulmonary embolism. Arch Intern Med 169: 1961, 2009

Harris SA, Velineni R, Davies AH: Inferior vena cava ilters in pregnancy: a systematic review. J Vasc Interv Radiol 27(3):354, 2016

Heijboer H, Buller HR, Lensing A W, et al: A comparison of real-time compression ultrasonography with impedance plethysmography for the diagnosis of deepvein thrombosis in symptomatic outpatients. N Engl] Med 329: 1365, 1993

Horlocker TT, Wedel D], Rowlingson JC, et al: Executive summary: Regional anesthesia in the patient receiving anti thrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine evidence-based guideline, 3rd ed. Reg Anesth Pain Med 35:102,t2010

HuismanY, Klok FA: Current challenges in diagnostic imaging of venous thromboembolism. Hematology m Soc Hematol Educ Program 2015:202,t2015

Hull RD, Raskob GF, Carter CJ: Serial IPG in pregnancy patients with clinically suspected DVT: clinical validity of negative findings. Ann Intern Med 112:663, 1990

Ilonczai P, Olah Z, Selmeczi A, et al: Management and outcomes of pregnancies in women with antirhrombin deficiency: a single-center experience and review of literature. Blood Coagul Fibrinolysis 26(7):798, 2015

Jacobsen AF, Qvigstad E, Sandset PM: Low molecular weight heparin (dalteparin) for the treatment of venous thromboembolism in pregnancy. BJOG 110:139,t2003

Jacobsen AF, Skjeldstad FE, Sandset PM: Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium-a register-based casecontrol study. Am] Obstet Gynecol 198:233.e1, 2008

James AH, Jamison MG, Brancazio LR, et al: Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am] Obstet Gynecol 194: 1311, 2006

Jamjute P, Reed N, Hinwood D: Use of inferior vena cava ilters in thromboembolic disease during labor: case report with a literature review. J Matern Fetal Neonatal Med 19:741, 2006

Kahn SR, Platt R, McNamara H, et al: Inherited thrombophilia and preeclampsia within a multicenter cohort: the Montreal Preeclampsia Study. Am] Obstet Gynecol 200: 151.e1, 2009

Kamel H, Navi BB, Sriram N, et al: Risk of a thrombotic event after the 6-week postpartum period. N Engl J Med 3 0(14): 1307, 2014

Kearon C, l EA, Comerota AJ, et al: Antithrombotic therapy for VTE disease: anti thrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 141:e419S, 2012

Kearon C, l A, Ornelas J, et al: Antithrombotic therapy for VTE disease:

CHEST guidelines and expert panel report. Chest 149(2):315,t2016 Kelton JG, Arnold DM, Bates SM: Nonheparin anticoagulants for heparininduced thrombocytopenia. N Engl J Med 368:737, 2013

Khalil H, Avruck L, Olivier A, et al: he natural history of pelvic vein thrombosis on magnetic resonance venography after vaginal delivery. Am J Obstet Gynecol 206:356.e1, 2012

Kinane TB, Grabowski EF, Sharma A, et al: Case 7-2008: a 17-year-old girl with chest pain and hemoptysis. N Engl] Med 358:941,t2008

Kjellberg U, van Rooijen M, Bremme K, et al: Factor V Leiden mutation and pregnancy-related complications. Am J Obstet Gynecol 203:469.e1, 2010 Knol HM, Schultinge L, Erwich J], et al: Fondaparinux as an alternative anti coagulant therapy during pregnancy. J Thromb Haemost 8: 1876, 2010

Konstantinides S, Geibel A, Heusel G, et al: Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 347:1143, 2002

Konstantinides SV, Torbicki A, Agnelli G, et al: 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 35(43):3033,t2014

Korteweg F], Erwich J], Folkeringa N, et al: Prevalence of parental thrombophilic defects after fetal death and relation to cause. Obstet Gynecol 116:355,t2010

Kuriakose J, Patel S: Acute pulmonary embolism. Radiol Clin North Am 48:31,t2010

Le Gal G, Kercret G, Yahmed KB, et al: Diagnostic value of single complete compression ultrasonography in pregnant and postpartum women with suspected deep vein thrombosis: prospective study. BMJ 344:e2635, 2012

Leonhardt G, Gaul C, Nietsch HH, et al: Thrombolytic therapy in pregnancy.

J hromb Thrombolysis 21:271, 2006

Lepercq J, Conard J, Borel-Derlon A, et al: Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies. BJOG 108:1134,t2001

Leung AN, Bull TM, Jaeschke R, et al: An oicial American Thoracic Society/ Sociery of Thoracic Radiology Clinical Practice Guideline: evaluation of suspected pulmonary embolism in pregnancy. m J Respir Crit Care Med 184:1200,t2011

Lim MY, Deal M, Musty MD, et al: hrombophilic risk of individuals with rare compound factor V Leiden and prothrombin G20210A polymorph isms: an international case series of 100 individuals. Eur J Haematol 97(4):353,t2016

Lim W: Using low molecular weight heparin in special patient populations. J Thromb hrombolysis 29:233, 2010

Lindhof-Last E, Kreurzenbeck HJ, Magnani HN: Treatment of 51 pregnancies with danaparoid because of heparin intolerance. hromb Haemost 93:63,t2005

Linkins L-A, Dans AL, Moores LK, et al: Treatment and prevention of heparin-induced thrombocytopenia. Chest 141 :e495S, 2012

Linnemann B, Scholz U, Rott H, et al: Treatment of pregnancy-associated venous thromboembolism-position paper from the Working Group in

Women's Health of the Society of hrombosis and Haemostasis (GTH). Vasa 45(2):103,t2016

Uu Y, Sun Y, Zhang S, et al: Placement of a retrievable inferior vena cava ilter for deep venous thrombosis in term pregnancy. J Vasc Surg 55:1042, 2012

Lockwood C: hrombosis, thrombophilia, and thromboembolism: clinical updates in women's health care. American College of Obstetricians and Gynecologists Vol. VI, No.t4, October 2007, Reairmed 2012

Lockwood CJ: Inherited thrombophilias in pregnant patients: detection and treatment paradigm. Obstet Gynecol 99:333,t2002

Lopez-Quesada E, Vilaseca A, Lailla JM: Plasma total homocysteine in uncomplicated pregnancy and in preeclampsia. Eur J Obstet Gynecol Reprod Bioi 108:45, 2003

Louis-Jacques AF, Maggio L, Romero ST: Prenatal screening for thrombophilias. Clin Lab Med 36(2):421,t2016

Macones GA: Patient safety in obstetrics. More evidence, less emotion. Obstet Gynecol 103(2):25 ,2017

MacCallum P, Bowles L, Keeling 0: Diagnosis and management of heritable thrombophilias. BMJ ,t2014

Magnani HN: n analysis of clinical outcomes of91 pregnancies in 83 women treated with danaparoid (Orgaran). hromb Res 125:297,2010

Marik PE, Plante A: Venous thromboembolic disease and pregnancy. N Engl J Med 359:2025, 2008

McDonnell BP, Glennon K, McTiernan A, et al: Adjustment of therapeutic LMWH to achieve specific target anti-FXa activity does not afect outcomes in pregnant patients with venous thromboembolism. J Thromb Thrombolysis 43(1):105,t2017

Morikawa M, Yamada T, Yamada T, et al: Changes in D-dimer levels after cesarean section in women with singleton and twin pregnancies. hromb Res 128:e33, 2011

Mueller MJ, Lebherz TB: Antepartum thrombophlebitis. Obstet Gynecol 34:867, 1969

Murphy N, Broadhurst 01, Khashan AS, et al: Gestation-speciic n-dimer reference ranges: a cross-sectional study. BJOG 122(3):395,2015

Nelson-Piercy C, Powrie R, Borg J-Y, et al: Tinzaparin use in pregnancy: an international, retrospective study of the safety and eicacy proile. Eur J Obstet Gynecol Reprod Bioi 159:293, 2011

Okoroh E, Azonobi I, Grosse S, et al: Prevention of venous thromboembolism in pregnancy. J Women Health 21:611, 2012

Overcash RT, Somers AT, LaCoursiere DY: Enoxaparin dosing after cesarean delivery in morbidly obese women. Obstet GynecoI125(6):1371, 2015

Paidas MJ, Triche EW, James AH, et al: Recombinant human antithrombin in pregnant patients with hereditaty antithrombin deficiency: integrated analysis of clinical data. Am J Perinatol 33(4):343, 2016

Palmerola KL.D'Alton ME, Brock CO, et al: A comparison of recommendations for pharmacologic thromboembolism prophylaxis ater caesarean delivety from three major guidelines. BJOG 123:2157,2016

Pierangeli SS, Leader B, Barilaro G, et al: Acquired and inherited thrombophilia disorders in pregnancy. Obstet Gynecol Clin North Am 38:271, 2011

Pollack CV, Schreiber 0, Goldhaber SZ, et al: Clinical characteristics, management, and outcomes of patients diagnosed with acute pulmonary embolism in the emergency department. JACC 57:700, 2011

Quinlan OJ, McQuillan A, Eikelboom JW: Low-molecular-weight heparin compared with intravenous unfractionated heparin for treatment of pulmonaty embolism: a meta-analysis of randomized, controlled trials. Ann Intern Med 140:143, 2004

Revel MP, Cohen S, Sanchez 0, et al: Pulmonary embolism during pregnancy: diagnosis with lung scintigraphy or CT angiography? Radiology 258:590, 2011

Rheaume M, Weber F, Durand M, et al: Pregnancy-related venous thromboembolism risk in asymptomatic women with antithrombin deficiency: a systematic review. Obstet GynecoIt127(4):649, 2016

Ridge CA, Mhuircheartaigh IN, Dodd JD, et al: Pulmonary CT angiography protocol adapted to the hemodynamic efects of pregnancy. AJR Am J RoentgenoIt197:1058,t2011

Roach RE, Ufering WM, van Hylckama Vlieg A, et al: he risk of venous thrombosis in individuals with a history of superficial vein thrombosis and acquired venous thrombotic risk factors. Blood 122(26):4264,t2013

Robertson L, Wu 0, Langhorne P, et al: hrombophilia in pregnancy: a systematic review. Br J HaematoIt132:171, 2005

Rodger MA, Hague WM, Kingdom J, et al: Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): a multinational open-label randomized trial. Lancet 84(9955):1673, 2014

Rodger MA, Kahn SR, Cranney A, et al: Long-term dalteparin in pregnancy not associated with a decrease in bone mineral density: substudy of a randomized controlled trial. J hromb Haemost 5:1600, 2007

Rodie VA, Thomson AJ, Stewart FM, et al: Low molecular weight heparin for the treatment of venous thromboembolism in pregnancy: a case series. BJOG 109:1020,t2002

Sabadell J, Casellas M, Alijotas-Reig J, et al: Inherited antithrombin deficiency and pregnancy: maternal and fetal outcomes. Eur J Obstet Gynecol Reprod Bioi 149:47, 2010

Saccone G, Berghella V, Maruotti GM, et al: Antiphospholipid antibody profile based obstetric outcomes of primary anti phospholipid syndrome: the PREGNANTS study. Am J Obstet GynecoIt216(5):525.e1, 2017

Saeed G, Moller M, Neuzner J, et al: Emergent surgical pulmonary embolectomy in a pregnant woman: case report and literature review. Tex Heart InstJ 41(2):188,t2014

Said JM, Higgins JR, Moses EK, et al: Inherited thrombophilia polymorphisms and pregnancy outcomes in nulliparous women. Obstet Gynecol 115:5, 2010a Said JM, Ignjatovic V, Monagle PT, et al: Altered reference ranges for protein C and protein S during early pregnancy: implications for the diagnosis of protein C and protein S deficiency during pregnancy. Thromb Haemost 103:984,t2010b

Sanson BJ, Lensing A W, Prins MH, et al: Safety oflow-molecular-weight heparin in pregnancy: a systematic review. hromb Haemost 81 :668, 1999 Scarsbrook AF, Evans AL, Owen AR, et al: Diagnosis of suspected venous thromboembolic disease in pregnancy. Clin RadioIt61:1, 2006 Seguin J, Weatherstone K, Nankervis C: Inherited antithrombin III deficiency in the neonate. Arch Pediatr Adolesc Med 148:389, 1994

Seligsohn U, Lubetsky A: Genetic susceptibility to venous thrombosis. N Engl J Med 344:1222,t2001

Shanbhag S, Pai N, Ghosh K, et al: Letters to the editor. Prenatal diagnosis in a family with purpura fulminans. Blood Coagul Fibrinolysis 26:350,t2015

Sharpe CJ, Crowther A, Webert E, et al: Cerebral venous thrombosis during pregnancy in the setting of type I antithrombin deficiency: case report and literature review. TransfMed Rev 25:61,t2011

Sibai BM, Rouse OJ: Pharmacologic thromboprophylaxis in obstetrics: broader use demands better data. Obstet GynecoIt128(4):681, 2016

Silver vI, Saade GR, Thorsten V, et al: Factor V Leiden, prothrombin G20210A, and methylene tetrahydrofolate reductase mutations and stillbirth: the Stillbirth Collaborative Research Network. Am J Obstet Gynecol 215(4):468.e1,2016

Silver M, Zhao Y, Spong CY, et al: Prothrombin gene G20210A mutation and obstetric complications. Obstet Gynecol 115: 14, 2010

Singhal S, Henderson R, Horsield K, et al: Morphometry of the human pulmonary arterial tree. Circ Res 33: 190, 1973

Smith MP, Norris A, Steer PJ, et al: Tinzaparin sodium for thrombosis treatment and prevention during pregnancy. Am J Obstet GynecoIt190:495, 2004 Stein PO, Athanasoulis C, Alavi A, et al: Complications and validity of pulmonary angiography in acute pulmonary embolism. Circulation 85:462, 1992

Stephenson ML, Serra E, Neeper JM, et al: A randomized controlled trial of difering doses of postcesarean enoxaparin thromboprophylaxis in obese women. J Perinatol 36(2):95, 2016

Stewart A: Warfarin-induced skin necrosis treated with protein C concentrate (human). Am J Health-Syst Pharm 67:901, 2010

Tanimura K, Ebina Y, Sonoyama A, et al: Argatroban therapy for heparininduced thrombocytopenia during pregnancy in a woman with hereditary antithrombin deficiency. J Obstet Gynaecol Res 38:749, 2012

Tapson VF: Acute pulmonary embolism. N Engl J Med 358:1037,t2008 Tengborn L, Bergqvist 0, Matzsch T, et al: Recurrent thromboembolism in pregnancy and puerperium: is there a need for thromboprophylaxis? Am J Obstet Gynecol 160:90, 1989 Tromeur C, van der Pol LM, Klok FA, et al: Pitfalls in the diagnostic management of pulmonaty embolism in pregnancy. Thromb Res 151 Suppl 1 :S86, 2017 van Mens TE, Scheres LJ, de Jong PG, et al: Imaging for the exclusion of pulmonary embolism in pregnancy. Cochrane Database Syst Rev 1 :CDO 11 053, 2017 van Wijk FH, WolfH, Piek J11, et al: Administration of low molecular weight heparin within two hours before caesarean section increases the risk of wound haematoma. BJOG 109:955, 2002

Virchow R: Gesammelte Abhandlungen zur wissenschaftlichen Medizin.

Frankfurt, Medinger Sohn & Co., 1856

Waksmonski CA: Cardiac imaging and functional assessment I pregnancy.

Semin PerinatoIt38(5):240, 2014

Waldman M, Sheiner E, Vardi IS: Can we profile patients at risk for thromboembolic events after delivery: a decade of follow up. Am J Obstet Gynecol 208:S234,t2013

Walker MC, Garner PR, Keely EJ, et al: Changes in activated protein C resistance during normal pregnancy. Am J Obstet Gynecol 177: 162, 1997 Wells PS, Anderson DR, Rodger M, et al: Evaluation ofD-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med 349: 1227, 2003

PREGNANCY-INDUCED URINARY TRACT CHANGES.... 1025

URINARY TRACT INFECTIONS.. . . . . . . . . . . . . . . . . . .. 1026 NEPHROLITHIASIS.. . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1030 PREGNANCY AFTER RENAL TRANSPLANTATION .... 1030 POLYCYSTIC KIDNEY DISEASE . . . . . . . . . . . . . . . . . .. 1031

GLOMERULAR DISEASES ....i......i....i...0..o...i.0...... 1032

CHRONIC KIDNEY DISEASE.. . . . . . . . . . . . . . . . . . . . .. 1034 ACUTE KIDNEY INJURY.. . . . . . . . . . . . . . . . . . . . . . . .. 1036

LOWER GENITAL TRACT LESIONS .0...0.i.......i......i.. 1037

In rare instances in patients suiringfrom pyelitis, the preg nant uterus may so compress the ureter as to cause a dam ming back of the purulent discharge, and thus give rise to a pyelonephritis.

-]. Whitridge Williams (1903)

Renal and urinary tract disorders are frequently encountered in pregnancy. Some precede pregnancy-one example being nephrolithiasis. In some women, pregnancy-induced changes may predispose to development or worsening of urinary tract disorders-an example is the markedly increased risk for pyelonephritis, described above by Williams. Finally, some renal pathology is unique to pregnancy, such as preeclampsia. With good prenatal care, however, most women with these disorders will likely have no long-term sequelae.

Significant changes in both structure and function within the urinary tract during normal pregnancy are discussed in Chapter 4 (p. 65). he kidneys become larger, and dilatation of the right renal calyces and ureters can be striking Some dilatation develops before 14 weeks and likely

E .

FIGURE 53-1 The 50th, 75th, and 90th percentiles for maternal renal caliceal diameters measured using sonography in 1395 pregnant women from 4 to 42 weeks' gestation. (Redrawn from Faundes A, Bricola-Filho M, Pinto e Silva JC: Dilatation of the urinary tract during pregnancy: proposal of a curve of maximal caliceal diameter by gestational age. Am J Obstet Gynecol 178: 1082, 1998.) from progesterone-induced relaxation of the muscularis. More marked dilatation is apparent beginning in midpregnancy because of more distal ureteral compression, especially on the right side (Faundes, 1998). There is also some vesicoureteral relux during pregnancy. Because of these physiological changes, the risk of upper urinary infection rises. Also, imaging studies done to evaluate urinary tract obstruction may occasionally be erroneously interpreted.

Evidence of functional renal hypertrophy becomes apparent very soon ater conception. Glomeruli are larger, although cell numbers do not grow (Strevens, 2003). Pregnancy-induced intrarenal vasodilatation develops, and both aferent and eferent resistances decline. This leads to greater efective renal plasma flow and glomerular filtration (Helal, 2012; Hussein, 2014). By 12 weeks' gestation, the glomerular filtration rate (GFR) is already augmented 20 percent above nonpregnant values (Hladunewich, 2004). Ultimately, plasma low and GFR rise by 40 and 65 percent, respectively. Consequently, serum concentrations of creatinine and urea drop substantively across pregnancy, and values within a nonpregnant normal range may be abnormal for pregnancy (Appendix, p. 1257). Other alterations include those related to maintaining normal acid-base homeostasis, osmoregulation, and fluid and electrolyte retention.

• Assessment of Renal Function During

Urinalysis results are essentially unchanged during pregnancy, except for occasional glucosuria. Although protein excretion normally rises, it seldom reaches levels that are detected by usual screening methods. Higby and colleagues (1a994) reported 24-hour protein excretion in pregnancy to be 11a5 mg/d with a 95-percent confidence level of 260 mg/d. Values did not signiicantly difer by trimester (Fig. 4-14, p. 67). Albumin constitutes only a small part of total protein excretion and ranges from 5 to 30 mg/d. Airoldi and Weinstein (2007) concluded that proteinuria must exceed 300 mg/ d to be considered abnormal. Many consider 500 mg/d to be important with gestational hypertension. Investigators have correlated a urinary proteinto-creatinine ratio of :0.3 in a spot urine sample-ideally from a irst morning void-with a 24-hour protein excretion rate of :300 mg (Kuper, 2016).

In one study, 3 percent of 4589 nulliparas screened before 20 weeks had idiopathicihematuria, deined as 1 + or greater blood on urine dipstick (Stehman-Breen, 2002). These women had a twofold risk of developing preeclampsia. In another study of 1000 women screened during pregnancy, the incidence of dipstick hematuria was 15 percent (Brown, 2005). Most women had only trace levels of hematuria, and the falsepositive rate was 40 percent.

If the serum creatinine level in pregnancy persistently exceeds 0.9 mg/dL (75 LmollL), then intrinsic renal disease is suspected. In these cases, some determine the creatinine clearance as an estimate of the GFR. Of other assessment tools, sonography provides imaging of renal size, relative consistency, and elements of obstruction (see Fig. 53-1). Magnetic resonance (MR) imaging of renal masses provides excellent anatomic information (Putra, 2009). Full-sequence intravenous pyelography is not done routinely, but injection of contrast media with one or two abdominal radiographs may be indicated by the clinical situation. The usual clinical indications for cystoscopy are followed. Ureteroscopy is another available tool when indicated.

Although renal biopsy is relatively safely performed during pregnancy, it usually is postponed unless results may change therapy. From a review of 243 biopsies in pregnant women, the incidence of complications was 7 percent-this compares with 1 percent in postpartum women (Piccoli, 2013). Some consider biopsy for rapid deterioration of renal function with no obvious cause or for symptomatic nephrotic syndrome (Lindheimer, 2007 a). We and others have found biopsy helpful in selected cases to direct management (Chen, 2001; Piccoli, 2013). In one series, renal biopsy in 12 normal pregnant volunteers showed that five had slight to moderate glomerular endotheliosis (Strevens, 2003). Recall this is the histopathological lesion that is putatively typical of preeclampsia and is characterized by ibrin deposition within the glomerular endothelium leading to capillary occlusion. In contrast, all 27 women with protein uric hypertension had endotheliosis, and in all but one, it was moderate to severe.

In these cases, if the remaining kidney is normal, renal function becomes augmented. However, women who have donated a kidney have a higher frequency of gestational hypertension or preeclampsia in subsequent pregnancy-IaI versus 5 percent compared with non-donors (Garg, 2015). Otherwise, women with one normal kidney most often have no diiculty in pregnancy. Moreover, kidney donation does not lead to long-term adverse consequences. That said, thorough functional evaluation of the remaining kidney is essential (Ibrahim, 2009).

These infections are the most frequent bacterial infections complicating pregnancy. Although asymptomatic bacteriuria is the most common, symptomatic infection includes cystitis, or it may involve the renal calyces, pelvis, and parenchyma to cause pyelonephritis. Organisms that cause urinary infections are those from the normal perineal lora. Approximately 90 percent of Escherichia coli strains that cause nonobstructive pyelonephritis have adhesins such as P-and S-imbriae. These are cell-surface protein structures that enhance bacterial adherence and, thereby, virulence (Foxman, 2010; Hooton, 2012).

Data suggest that pregnant women have more severe sequelae from urosepsis. One possible underlying factor is the T -helper cell-Th1/h2 ratio-reversal of normal pregnancy, which is discussed in Chapter 4 (p. 59). Other perturbations of cytokine or of adhesin expression may be contributory (Chaemsaithong, 2013; Sledzinska, 2011). But even if pregnancy itself does not enhance these virulence factors, urinary stasis, vesicoureteral relux, and diabetes predispose to symptomatic upper urinary infections (Czaja, 2009).

In the puerperium, several risk factors predispose to urinary infections. Bladder sensitivity to intravesical fluid tension is often diminished due to labor trauma or epidural analgesia.

Bladder sensations can also be obscured by discomfort from vaginal or perineal injury. Normal postpartum diuresis may worsen bladder overdistention, and catheterization to relieve retention often leads to urinary infection. Postpartum pyelonephritis is treated in the same manner as antepartum renal infections (McDonnold, 2012).

This refers to persistent, actively multiplying bacteria within the urinary tract in asymptomatic women. he incidence during pregnancy is similar to that in nonpregnant women. It var ies from 2 to 7 percent, and it is characteristically population dependent. he highest incidence is in African-American mul tiparas with sickle-cell trait, and the lowest is in aluent white women of low parity. Asymptomatic infection is also more common in diabetics (Schneeberger, 2014).

Bacteriuria is typically present at the first antepartum visit.

An initial positive urine culture result done as a part of prenatal care should prompt treatment. After this, fewer than 1 percent of women develop a urinary tract infection (Whalley, 1967). A clean-voided specimen containing more than 100,000 organ isms/mL is diagnostic. It may be prudent to treat when lower concentrations are identified, because pyelonephritis devel ops in some women despite colony counts of only 20,000 to 50,000 organisms/mL (Lucas, 1993).

Most studies indicate that if asymptomatic bacteriuria is not treated, approximately 25 percent of infected women will develop symptomatic infection during pregnancy (Smaill, 2015). In a more recent study, only 2.4 percent of treated women developed pyelonephritis (Kazemier, 2015). Eradication of bacteriuria with antimicrobial agents prevents most of these serious infections. The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017), as well as the U.S. Preventive Services Task Force (2008), recommend screening for bacteriuria at the first prenatal visit. Standard urine cultures may not be cost efective when the prevalence is low. Less expensive screening tests such as the leukocyte esterase/nitrite dipstick are cost efective when the prevalence is ;2 percent (Rogozinska, 2016; Rouse, 1995). Also, a dipstick culture technique has excellent positive-and negative-predictive values (Mignini, 2009). With this, a special agar-coated dipstick is first placed into urine and then also serves as the culture plate. Because of a high prevalence-5 to 8 percent-at Parkland Hospital, most women are screened by traditional urine culture. Susceptibility determination is not necessary because initial treatment is empirical (Hooton, 2012).

In some but not all studies, covert bacteriuria has been associated with preterm or low-birthweight infants. It is even more controversial whether eradication of bacteriuria decreases these complications. Evaluating a cohort of 25,746 mother-infant pairs, Schieve and coworkers (1994) reported urinary tract infection to be associated with greater risks for low-birthweight infants, preterm delivery, pregnancy-associated hypertension, and anemia. hese findings vary from those of others (Gilstrap, 1981b; Whalley, 1967). Notably, in most studies, cohorts with asymptomatic infection are not evaluated separately from those with acute renal infection (Banhidy, 2007). One Cochrane database review noted insuicient data to answer this question (Smaill, 2015).

Bacteriuria responds to empirical treatment with any of several antimicrobial regimens listed in Table

Although selection can be based on in vitro susceptibilities, in our extensive experience, empirical oral treatment for 10 days with nitrofurantoin macrocrystals, 100 mg at bedtime, is usually efective. Satisfactory results are also achieved with a 7-day oral course of nitrofurantoin, 100 mg given twice daily (Lumbiganon, 2009). Single-dose antimicrobial therapy is less successful (Widmer, 2015). The important caveat is that, regardless of regimen given, the recurrence rate is approximatey 30 percent.

This may indicate covert upper tract infection and the need for longer therapy. hus, after initial therapy, periodic surveillance is necessary to prevent recurrent urinary infections (Schneeberger, 2015).

For recurrent bacteriuria, we have had success with nitrofurantoin, 100 mg orally at bedtime for 21 days (Lucas, 1994). For women with persistent or frequent bacteriuria recurrences, suppressive therapy for the remainder of pregnancy can be given. We routinely use nitrofurantoin, 100 mg orally at bedtime. This drug may rarely cause an acute pulmonary reaction that dissipates on its withdrawal (Boggess, 1996).

TABLE 53-1. Oral Antimicrobial Agents Used for Treatment of Pregnant Women with Asymptomatic Bacteriuria

Amoxicillin,n3 9

Ampicillin,n2 9

Cephalosporin, 2 9

Nitrofurantoin, 200 mg Trimethoprim-sulfamethoxazole, 320/1600 mg

Amoxicillin, 500 mg three times daily Ampicillin, 250 mg four times daily Cephalosporin, 250 mg four times daily Ciprofloxacin, 250 mg twice daily

Levofloxacin, 250 or 500 mg daily Nitrofurantoin, 50 to 100 mg four times daily or 100 mg twice daily Trimethoprim-sulfamethoxazole, 160/800 mg twice daily

Nitrofurantoin, 100 mg four times daily for 10 days Nitrofurantoin, 100 mg twice daily for 5 to 7 days Nitrofurantoin, 100 mg at bedtime for 10 days

Nitrofurantoin, 100 mg four times daily for 21 days

Nitrofurantoin, 100 mg at bedtime for pregnancy remainder

Lower urinary infection during pregnancy may develop without antecedent covert bacteriuria (Harris, 1981). Cystitis produces dysuria, urgency, and frequency, but with few associated systemic indings. Pyuria and bacteriuria are usually found. Microscopic hematuria is common, and occasionally there is gross hematuria from hemorrhagic cystitis. Although cystitis is usually uncomplicated, the upper urinary tract may become involved by ascending infection. Almost 40 percent of pregnant women with acute pyelonephritis have preceding symptoms of lower tract infection (Gilstrap, 1981a).

Women with cystitis respond readily to any of several regimens. Most of the 3-day regimens listed in Table 53-1 are usually 90-percent efective (Fihn, 2003). Single-dose therapy is less efective, and if it is used, concomitant pyelonephritis must be confidently excluded.

Lower urinary tract symptoms with pyuria accompanied by a sterile urine culture may stem from urethritis caused by Chlamydia trachomatis. Mucopurulent cervicitis usually coexists, and azithromycin therapy is efective (Chap. 65, p. 1240).

Renal infection is one of the most frequent serious medical complications of pregnancy. Data from the 2006 Nationwide Inpatient Sample showed that nearly 29,000 pregnancy-associated hospitalizations were for acute pyelonephritis Qolley, 2012). In one hospital-system database of nearly 550,000 births, its incidence was 0.5 percent (Wing, 2014). Importantly, pyelonephritis is a leading cause of septic shock during pregnancy (Snyder, 2013). In one Parkland Hospital Obstetrical Intensive Care Unit review, 12 percent of antepartum admissions were for sepsis syndrome caused by renal infections (Zeeman, 2003). Urosepsis may be related to an increased incidence of cerebral palsy in preterm infants Qacobsson, 2002). Fortunately, afected mothers sufer no serious long-term sequelae (Raz, 2003).

Renal infection develops more frequently in the second trimester, and nulliparity and young age are risks (Hill, 2005).

Pyelonephritis is unilateral and right-sided in more than half of cases, and it is bilateral in a fourth. Fever and shaking chills usually develop rather abruptly, and patients have aching pain in one or both lumbar regions. Anorexia, nausea, and vomiting may worsen dehydration. Tenderness usually can be elicited by percussion in one or both costovertebral angles. he differential diagnosis includes, among others, labor, chorioamnionitis, adnexal torsion, appendicitis, placental abruption, or infarcted leiomyoma. Evidence of the sepsis syndrome is common (Chap. 47, p. 921).

If this infection is suspected, a urine sample obtained by catheterization may be preferred to avoid obscuring contamination from the lower genital tract. he urinary sediment contains many leukocytes, frequently in clumps, and numerous bacteria. Bacteremia is demonstrated in 15 to 20 percent of these women. E coli is isolated from urine or blood in 70 to 80 percent of infections, Klebsiela pneumoniae in 3 to 5 percent, Enterobacter or Proteus species in 3 to 5 percent, and gram-positive organisms, including group B Streptococcus and Staphylococcus aureus, in up to 10 percent of cases (Hill, 2005; Wing, 2000).

Plasma creatinine is monitored because early studies reported that 20 percent of pregnant women developed acute kidney injury . More recent findings, however, show this to be only 5 percent if aggressive fluid resuscitation is provided (Hill, 2005). Follow-up studies have demonstrated that this endotoxin-induced damage is reversible long term. s shown in Figure 53-2, varying degrees of respiratory distress syndrome from endotoxin-induced alveolar injury are manifest in up to 2 percent of women (Cunningham, 1987; Snyder, 2013; Wing, 2014).

Uterine activity from endotoxin is common and is related to fever severity (Graham, 1993). In one study, women with pyelonephritis averaged five contractions per hour at admission, and this decreased to two per hour within 6 hours of intravenous luid and antimicrobial administration (Millar, 2003). Notably, 3-agonist therapy for tocolysis increases the likelihood of respiratory insuiciency from permeability edema (Lamont, 2000). The incidence of pulmonary edema in women with pyelonephritis who were given 3-agonists was reported to be 8 percent-a fourfold increase over that expected (Towers, 1991) .

a second-trimester pregnant woman with severe pyelonephritis. A.An extensive infiltrative process and complete obliteration of the diaphragm (white arrows) is seen. B. Improved aeration of lung fields bilaterally is noted as pleural disease resolves (arrows). c. Markedly improved visualization of the lung fields with residual platelike atelectasis and normal appearance of the diaphragm.

TABLE 53-2. Management of the Pregnant Woman with Acute Pyelonephritis

Evaluate hemogram, serum creatinine, and electrolytes

Monitor vital signs frequently, including urinary output-

Establish urinary output �50 mL/hr with intravenous

Obtain chest radiograph if there is dyspnea or tachypnea

Change to oral antimicrobials when afebrile

Discharge when afebrile 24 hours, consider antimicrobial therapy for 7 to 10 days

Repeat urine culture 1 to 2 weeks after antimicrobial

Modified from Lucas, 1994; Sheffield, 2005.

Endotoxin-induced hemoysis is common, and approximately a third of these women with pyelonephritis develop anemia (Cox, 1991). With recovery, hemoglobin regeneration is normal, and acute infection does not afect erythropoietin production (Cavenee, 1994).

One scheme for management of acute pyelonephritis is shown in Table 53-2. Urine cultures are taken, but prospective trials show that blood cultures are of limited clinical utility (Gomi, 2015; Wing, 2000). We obtain blood cultures if the temperature is >39°C. Intravenous hydration to ensure adequate urinay ouput is the cornerstone of treatment. Antimicrobials are also begun promptly with the caveat that they may initially worsen endotoxemia from bacterial lysis. Surveillance for worsening sepsis syndrome includes serial monitoring of urinary output, blood pressure, pulse, temperature, and oxygen saturation. High fevers are lowered with a cooling blanket and acetaminophen. his is especially important in early pregnancy because of possible teratogenic efects from hyperthermia.

Antimicrobial therapy usually is empirical, and ampicillin plus gentamicin; cefazolin or ceftriaxone; or an extended-spectrum antibiotic are all 95-percent efective in randomized trials (Sanchez-Ramos, 1995; Wing, 1998,a2000). Fewer than half of E coli strains are sensitive to ampicillin in vitro, but cephalosporins and gentamicin generally have excellent activity. Serum creatinine levels are monitored if nephrotoxic drugs are given. Initial treatment at Parkland Hospital is ampicillin plus gentamicin. Some recommend suitable substitutes if bacterial studies show in vitro resistance. With any of the regimens discussed, response is usually prompt, and 95 percent of women are afebrile by 72 hours (Hill, 2005; Sheield, 2005). ter discharge, most recommend oral therapy for a total of7 to 14 days (Hooton, 2012).

Persistent Infection. Generally, intravenous hydration and antimicrobial therapy are followed by stepwise defervescence of approximately 1°F per day. With persistent spiking fever or lack of clinical improvement by 48 to 72 hours, urinary tract obstruction, another complication, or both are considered. In these women, renal sonography is recommended to search for obstruction, which is manifest by abnormal ureteral or pyelo caliceal dilatation (Seidman, 1998). Although most women with continuing infection have no evidence of obstruction, some are found to have calculi. Although renal sonography will detect hydronephrosis, stones are not always seen in preg nancy (Butler, 2000; Maikranz, 1987). If stones are strongly suspected despite a nondiagnostic sonographic examination, a plain abdominal radiograph will identiy nearly 90 percent.

Another option is the modified one-shot intravenous pyelo injection-which usually provides adequate imaging (Butler, 2000).

In some women, MR imaging may disclose the cause of persistent infection (Spencer, 2004). Even without urinary obstruction, persistent infection can be due to an intrarenal or perinephric abscess or phlegmon (Cox, 1988; Rai, 2012).

Obstruction relief is important, and one method is cystoscopic placement of a double-J ureteral stent (Rodriguez, 1988).

Because these stents are usually left in place until after deliv ery, they frequently become encrusted and require replacement.

We have found that percutaneous nephrostomy is preferable because the stents are more easily replaced. Finally, surgical removal of stones may be required in some women (p. 1030).

Outpatient Management. This is sometimes done for non pregnant women with uncomplicated pyelonephritis (Hooton, 2012). Outpatient management was described in 92 pregnant axone, two 1-g doses 24 hours apart (Wing, 1999). After this, only a third of the group was considered suitable for outpatient therapy, and these women were randomly assigned either to discharge home and oral antimicrobials or to continued hospi talization with intravenous therapy. A third of the outpatient management group was unable to adhere to the treatment regi men and required readmission. his suggests that outpatient management is applicable to very few gravidas.

Recurrent urinary tract infection-either covert or symptomatic-develops in 30 to 40 percent of women following completion of pyelonephritis treatment (Cunningham, 1973). Unless other measures are taken to ensure urine sterility, nitrofurantoin, 100 mg orally at bedtime given for the remainder of the pregnancy, reduces bacteriuria recurrence (Van Dorsten, 1987).

Vesicoureteral reflux in early childhood can cause recurrent urinary tract infections, and subsequent chronic interstitial nephritis is attributed to chronic pyelonephritis. Moreover, high-pressure sterile reflux impairs normal renal growth. Combined, this leads to patchy interstitial scarring, tubular atrophy, and loss of nephron mass and is termed relux nephropathy. In some casesespecially those with staghorn calculi-xanthogranulomatous pyelonephritis causes suppurative destruction of renal tissue. In adults, long-term complications of chronic pyelonephritis include hypertension, which may be severe (Beck, 2015; Diamond,a2012).

Perhaps half of women with reflux nephropathy were treated during childhood for renal infections. Many also had surgical correction of reflux as children, and these women commonly have bacteriuria when pregnant (Mor, 2003). In the other half of women with relux nephropathy, a clear history of recurrent cystitis, acute pyelonephritis, or obstructive disease is lacking. Reports describing 939 pregnancies in 379 women with reflux nephropathy indicate that impaired renal function and bilateral renal scarring were associated with increased maternal complications (EI-Khatib, 1994; Jungers, 1996; Kohler, 2003). Chronic renal disease and pregnancy outcome are discussed on page 1034.

Kidney stones develop in up to 9 percent of women during their lifetime with an average age of onset in the third decade (Curhan, 2015). Calcium salts make up approximately 90 percent of stones, and hyperparathyroidism should be excluded. Although calcium oxalate stones in young nonpregnant women are most common, most stones in pregnancy-65 to 75 percent-are calcium phosphate or hydroxyapatite (Ross, 2008; Tan, 2013). Patients who have a stone typically form another one every 2 to 3 years. One study found pregnancy was a risk factor for stone formation (Reinstatler, 2017).

Contrary to past teachings, a low-calcium diet promotes stone formation. Thiazide diuretics diminish stone formation. In general, obstruction, infection, intractable pain, and heavy bleeding are indications for stone removal, discussed later.

he incidence of stone disease complicating pregnancy varies. At the low end, the incidence was 0.3 admissions per 1000 pregnancies at Parkland Hospital (Butler, 2000). In an Israeli study, the incidence in nearly 220,000 pregnancies was 0.8 per 1000 (Rosenberg, 2011). In Washington state, the incidence was 1.7 per 1000 pregnancies (Swartz, 2007). Bladder stones are rare, but recurrent infection and labor obstructed by stones have been reported (Ait Benkaddour, 2006; Ruan, 2011).

Data are conflicting whether women with kidney stones have an increased risk for low-birthweight and preterm newborns. In one study of 2239 women with nephrolithiasis compared with normal controls, stones were associated with a signiicantly elevated preterm delivery rate-l0.6 versus 6.4 percent (Swartz, 2007). The more recent nationwide study from Taiwan also found 20-to 40-percent increases in rates of low birthweight and pre term birth (Chung, 2013). In contrast, a study from Hungary reported that pregnancy outcomes, including preterm delivery, were similar in women with stones and normal controls (Banhidy, 2007). Comparable conclusions were drawn from the Israeli study discussed above (Rosenberg, 2011).

Pregnant women may have fewer symptoms with stone passage because of urinary tract dilatation (Hendricks, 1991; Tan, 2013). hat said, more than 90 percent of pregnant women with symptomatic nephrolithiasis present with pain.

Gross hematuria is less common than in afected nonpregnant women. It was a presenting symptom in 23 percent of women described by Butler and associates (2000). In another study, however, only 2 percent had gross hematuria (Lewis, 2003). Sonography is usually selected to visualize stones, but many are not detected because hydronephrosis may obscure indings (Iv1cAleer, 2004). Transabdominal color Doppler sonography to detect presence or absence of ureteral "jets" of urine into the bladder may exclude obstruction (As rat, 1998).

If the ureter is abnormally dilated but no stone is seen, then other imaging studies are indicated. While helical computed tomography (CT) scanning is the preferred imaging method for nonpregnant individuals, the associated x-ray exposure has led some to recommend MR imaging as a second-line test in pregnancy (Masselli, 2015). Thus CT scanning is usually avoided during pregnancy if possible (Curhan, 2015; Masselli, 2015). If it is used, the slices can be tailored as needed. White and colleagues (2007) recommend unenhanced helical CT and cite an average fetal radiation dose to be 7 mGy.

Treatment depends on symptoms and gestational age (Semins, 2014). Intravenous hydration and analgesics are given. In up to half of women with symptomatic stones, infection will be identiied, and this is treated vigorously as described earlier (p. 1029). Although stones infrequently cause symptomatic obstruction during pregnancy, persistent pyelonephritis should prompt a search for obstruction due to nephrolithiasis. Urinary obstruction with concomitant infection is an emergency-"pus under pressure" (Curhan, 2015).

Approximately 65 to 80 percent of symptomatic women will improve with conservative therapy, and the stone usually passes spontaneously (Tan, 2013). Others require an invasive procedure such as ureteral stenting, ureteroscopy, percutaneous nephrostomy, transurethral laser lithotripsy, or basket extraction (Butler, 2000; Johnson, 2012; Semins, 2014). Removal by a flexible basket via cystoscopy, although used less often than in the past, is still a reasonable consideration for pregnant women. In one study, 623 various procedures were performed in 2239 symptomatic pregnant women, but less than 2 percent required surgical exploration (Swartz, 200*). Of other treatments, the need for fluoroscopy limits the utility of percutaneous nephrolithotomy (Toth, 2005). Extracorporeal shock-wave lithotripsy is contraindicated in pregnancy.

Following transplantation, the I-year graft survival rate is 95 percent for grafts from living donors and 89 percent for those from deceased donors. Survival rates approximately doubled between 1988 and 1996, due in large part to the introduction of cyclosporine and muromonab-CD3 (OKT3 monoclonal antibody) to prevent and treat organ rejection. Since then, mycophenolate mofetil and tacrolimus have further reduced acute rejection episodes, however, the former is considered teratogenic (Briggs, 2014). he National Transplant Pregnancy Registry reports that 23 percent of fetuses exposed to mycophenolate had birth defects (Coscia, 2010). Importantly, resumption of renal function after transplantation promptly restores fertility in reproductive-aged women (Hladunewich, 2011; Rao, 2016). But, more than half of transplant recipients in one study reported that they were not counseled regarding contraception (French, 2013).

Women after transplantation do better with pregnancy than those with end-stage renal disease receiving dialysis (Saliem, 2016). In one review of 2000 pregnancies in transplant recipi ents, most were treated with cyclosporine and tacrolimus, and approximately 75 percent of pregnancies resulted in a live birth (Coscia, 2010). Studies from other countries describe similar outcomes (Bramham, 2013; Wyld, 20l3). In a study from

Uruguay, 62 percent of liveborns were preterm (Orihuela, 2016). Two other reports also cited a high prevalence of pre term delivery (Erman Akar, 2015; Stoumpos, 2016). Notably, the incidence of fetal malformations was not increased, except in those who took mycophenolate mofetil (Coscia, 2010).

The incidence of preeclampsia is increased in all transplant recipients (Brosens, 20l3). In the UK National Cohort Study, the incidence of preeclampsia was 22 percent (Bramham, 2013). From their review, Josephson and McKay (2011) cite an incidence of a third of pregnancies but question the validity of this frequency. Importantly, in some cases, rejection is difficult to distinguish from preeclampsia. hat said, the incidence of rejection episodes approximates 2 to 5 percent (Bramham, 2013; Orihuela, 2016). Viral infections-especially those by poyomavirus hominis 1, also called BK virus, are frequent. In kidney transplant recipients, this virus can cause nephropathy and graft loss, and afected patients generally have an asymptomatic decline in renal function (Wright, 2016). Gestational diabetes is also found in approximately 5 percent of transplant recipients. Both are likely related to immunosuppression therapy. Similar outcomes are reported by other investigators (Al Duraihimh, 2008; Cruz Lemini, 2007; Ghafari, 2008).

Several requisites should be satisfied by renal transplantation patients before attempting pregnancy G osephson, 2011; Lopez, 2014). First, women should be in good general health for at least 1 to 2 years after transplantation. Also, renal function should be stable and without severe renal insuiciency. Thus, serum creatinine is <2 mg/dL and preferably < 1.5 mg/ dL, and proteinuria is <500 mg/d. Evidence for graft rejection should be absent for 6 months, and pyelocalyceal distention by urography should not be seen. Moreover, hypertension should be absent or well controlled. And last, women should be taking no teratogenic drugs, and drug therapy should be reduced to maintenance levels.

Cyclosporine, tacrolimus, prednisone, and azathioprine are given routinely to renal transplantation recipients Gain, 2004; Lopez, 2014). Cyclosporine blood levels decline during pregnancy, although this was not reported to be associated with rejection episodes (Akturk, 2015; Kim, 2015). Unfortunately, these agents are nephrotoxic and also may cause renal hypertension. In fact, they likely contribute substantively to chronic renal disease that develops in 10 to 20 percent of patients with nonrenal solid-organ transplantation (Goes, 2007). Concern persists regarding the possible late efects in ofspring subjected to immunosuppressive therapy in utero. hese include malig nancy, germ cell dysfunction, and malformations in the chil dren of the ofspring. In addition, cyclosporine is secreted in breast milk (Moretti, 2003).

Finally, although pregnancy-induced renal hyperiltration theoretically may impair long-term graft survival, Sturgiss and study of 34 allograft recipients followed for a mean of 15 years.

Others have reported similar findings (Debska-Slizien, 2014;

Stoumpos, 2016).

Close surveillance is necessary. Covert bacteriuria is treated, and if it is recurrent, suppressive therapy is given for the remainder of the pregnancy. Serial hepatic enzyme concentrations and blood counts are monitored for toxic efects of azathioprine and cyclosporine. Some recommend measurement of serum cyclo sporine levels. Gestational diabetes is more common if corti costeroids are taken, and overt diabetes must be excluded with tation. Surveillance for opportunistic infections from herpesvi rus, cytomegalovirus, and toxoplasmosis is important because these infections are common. Some recommend surveillance for BK virus, however, treatment is problematic Gosephson, 2011).

Renal function is monitored, and the GFR usually increases 20 to 25 percent. If a signiicant rise in the serum creatinine level is detected, then its cause must be determined. Possibilities include acute rejection, cyclosporine toxicity, preeclampsia, infection, and urinary tract obstruction. Evidence of pyelonephritis or graft rejection should prompt aggressive management. Imaging studies and kidney biopsy may be indicated. The woman is carefully monitored for development or worsening of underlying hypertension, and especially superimposed preeclampsia. Management of hypertension during pregnancy is the same as for patients without a transplant.

Because of increased incidences of fetal-growth restriction and preterm delivery, vigilant fetal surveillance is indicated (Chaps. 42, p. 814 and 44, p. 852). Although cesarean delivery is reserved for obstetrical indications, occasionally the transplanted kidney obstructs labor. In all women with a renal transplant, the cesarean delivery rate exceeds 60 percent (Bramham, 2013; Rocha, 2013).

This usually autosomally dominant systemic disease primarily afects the kidneys. The disease is found in 1 in 800 live births and causes approximately 5 to 10 percent of end-stage renal disease in the United States. Although genetically heterogeneous, almost 85 percent of cases are due to PD1 gene mutations on chromosome 16, and the other 15 percent to PD2 mutations on chromosome 4 (Zhou, 2015). Prenatal diagnosis is available if the mutation has been identiied in a family member or if linkage is established in the family.

Renal complications are more common in men than in women, and symptoms usually appear in the third or fourth decade. Flank pain, hematuria, proteinuria, abdominal masses, and associated calculi and infection are common. Hypertension develops in 75 percent, and progression to renal failure is a major problem. Superimposed acute kidney injury may also develop from infection or obstruction from ureteral angulation by cyst displacement.

Other organs are frequently involved. Asymptomatic hepatic cysts coexist in a third of patients with polycystic kidneys. Hepatic involvement is more common and more aggressive in women, and massive polycystic liver disease is almost exclusively found in multiparous women (Zhou, 2015). Approximately 10 percent of patients with polycystic kidney disease die from rupture of an associated intracranial bery aneurysm. Up to a fourth of patients have cardiac valvular lesions that involve valve prolapse or incompetence.

Because of its generally late onset, adult polycystic kidney disease is uncommon in pregnancy (Banks, 2015). The prognosis for pregnancy in these women depends on the degree of associated hypertension and renal insuiciency. Urinary tract infections are common. One study compared pregnancy outcomes in 235 afected women who had 605 pregnancies with those of 108 unafected family members who had 244 pregnancies (Chapman, 1994). Composite perinatal complication rates were similar-33 versus 26 percent. However, hypertension, including preeclampsia, was significantly more frequent in women with polycystic kidneys. Pregnancy does not seem to accelerate the natural disease course (Lindheimer, 2007b).

he glomerulus and its capillaries are subject to various conditions and stimuli that can lead to acute and chronic diseases. Glomerular damage can be caused by toxins or infections or from systemic diseases that include hypertension, diabetes, or systemic

TABLE 53-3. Patterns of Clinical Glomerulonephritis lupus erythematosus (Lewis, 2015). It may also be idiopathic. When there is capillary inflammation, the process is termed glomerulonephritis, and oten, an autoimmune process is involved.

Persistent glomerulonephritis eventually leads to worsening renal function. Progression is variable and often does not manifest until chronic renal insuiciency is diagnosed. Lewis and Neilson (2015) group glomerular injuries into six syndromes based on clinical patterns (Table 53-3). Within each of these categories, there are disorders encountered in young women, and thus, these may antedate or irst appear during pregnancy.

Acute glomerulonephritis may result from any of several causes (see Table 53-3). The clinical presentation usually includes hypertension, hematuria, red-cell casts, pyuria, and proteinuria. Varying degrees of renal insuiciency and salt and water retention result in edema, hypertension, and circulatory congestion (Lewis, 2015). The prognosis and treatment of nephritic syndromes depends on their etiology. Some recede spontaneously or with treatment. However, in some patients, rapidy progressive glomerulonephritis leads to end-stage renal failure, whereas in others, chronic glomerulonephritis develops with slowly progressive renal disease.

Lupus nephritis identified before pregnancy has a 50percent chance of laring during pregnancy (Koh, 2015). IgA nephropathy, also known as Berger disease, is the most common form of acute glomerulonephritis worldwide (Wyatt, 2013). he isolated form occurs sporadically, and it may be related to Henoch-Schonlein purpura as the systemic form (Donadio, 2002). Isolated nephritis may be due to anti-glomerular basement membrane (anti-GBM) antibodies. hese may also involve the lungs to manifest as a pulmonary-renal syndrome with alveolar hemorrhage, which is termed Goodpasture syndrome (Friend, 2015; Huser, 2015).

Acute nephritic syndromes during pregnancy can be diicult to diferentiate from severe preeclampsia or eclampsia (Cabiddu,

Acute Nephritic Syndromes: poststreptococcal, infective endocarditis, SLE, antiglomerular basement membrane disease, IgA nephropathy (Berger disease), ANCA

Henoch-Schonlein purpura, cryoglobulinemia, membranoproliferative and mesangioproliferative glomerulonephritis

Pulmonary-Renal Syndromes: Goodpasture, ANCA vasculitis, Henoch-Schonlein purpura, cryoglobulinemia Nephrotic Syndromes: minimal change disease, focal segmental glomerulosclerosis, membranous glomerulonephritis, diabetes, amyloidosis, others

Basement Membrane Syndromes: anti-GBM disease, others

Glomerular Vascular Syndromes: atherosclerosis, chronic hypertension, sickle-cell disease, thrombotic microangiopathies, anti phospholipid antibody syndrome, ANCA vasculitis, others

Infectious Disease-Associated Syndromes: poststreptococcal, infective endocarditis, HIV, HBV, HCV, syphilis, others

ANCA = antineutrophilic cytoplasmic antibodies; anti-GBM = anti-glomerular basement membrane; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; IgA = immunoglobulin A; SLE = systemic lupus erythematosus.

Adapted from Lewis, 2015.

2016). One example is systemic lupus erythematosus with a flare during the second half of pregnancy (Bramham, 2012;

Zhao, 2013). In some of these cases, renal biopsy is sometimes needed to determine etiology and direct management (Lind heimer, 2007a; Ramin, 2006).

Whatever the underlying etiology, acute glomerulonephritis has profound efects on pregnancy outcome. One older study described 395 pregnancies in 238 women with primay glo merulonephritis diagnosed before pregnancy (Pacham, 1989).

merulonephritis, IgA glomerulonephritis, and difuse mesan gial glomerulonephritis. Although most of these women had normal renal function, half developed hypertension, a fourth were delivered preterm, and the perinatal mortality rate after 28 weeks' gestation was 80 per 1000. As expected, the worst peri natal outcomes were in women with impaired renal function, early or severe hypertension, and nephrotic-range proteinuria.

women with IgA nephropathy. From their review of more than 300 such pregnancies, Lindheimer and colleagues (2000) con cluded that pregnancy outcome was related to the degree of renal insuiciency and hypertension. Liu and coworkers (2014) reached similar conclusions.

Heavy proteinuria is the hallmark of the nephrotic syndromes.

ders that cause immunological or toxin-mediated injury with glomerular capillary wall breakdown to allow excessive filtra tion of plasma proteins. In addition to heavy urine protein excretion, the syndrome is characterized by hypoalbuminemia, hypercholesterolemia, and edema. There frequently is hyper tension, and along with albumin nephrotoxicity, renal insuf iciency eventually develops.

Some of the more frequent causes of the nephrotic syndrome are minimal change disease (10-15 percent), focal segmental glomerulosclerosis (35 percent), membranous glomerulonephritis (30 percent), and diabetic nephropathy. In most cases, renal biopsy will disclose microscopic abnormalities that may help direct treatment (Chen, 2015; Lo, 2014). Edema is problematic, especially during pregnancy. Normal amounts of dietary protein of high biological value are encouraged. The incidence of thromboembolism is increased and varies with the severity of hypertension, proteinuria, and renal insuiciency (Stratta, 2006). Although both arterial and venous thromboses may develop, renal vein thrombosis is particularly worrisome. he value, if any, of prophylactic anticoagulation is unclear. Some cases of nephrosis from primary glomerular disease respond to glucocorticosteroids and other immunosuppressants or cytotoxic drug therapy. In most of those cases caused by infection or drugs, proteinuria recedes when the underlying cause is corrected.

Maternal and perinatal outcomes in women with the nephrotic syndromes depend on its underlying cause and severity. Whenever possible, these should be ascertained, and renal biopsy may

FIGURE 53-3 Massive vulvar edema in a pregnant woman with the nephrotic syndrome due to secondary syphilis. (Used with permission from Dr. George Wendel, Jr.) be indicated to determine if the etiology will respond to treat ment. Half of women with nephrotic-range proteinuria will have a rise in daily protein excretion as pregnancy progresses (Packham, 1989). In women with nephrosis cared for at Park land Hospital, we reported that two thirds had protein excre tion that exceeded 3 g/d (Stettler, 1992). At the same time, however, if these women had only mild degrees of renal dys function, they had normally augmented CFR across pregnancy (Cunningham, 1990).

Management of edema during pregnancy can be particularly challenging as it is intensiied by normally increasing hydrostatic pressure in the lower extremities. In some women, massive vulvar edema may develop. An example of massive vulvar edema associated with the nephrotic syndrome caused by secondary syphilis is shown in Figure 53-3. Another major problem is that up to half of these women have chronic hypertension that may require treatment. In these, as well as in previously normotensive women, preeclampsia is common and often develops early in pregnancy.

Most women with nephrotic syndromes who do not have severe hypertension or renal insuiciency will have successful pregnancy outcomes. Conversely, if there is renal insuiciency, moderate to severe hypertension, or both, the prognosis is much worse. In a group of such women with 65 pregnancies cared for at Parkland Hospital, complications were frequent (Stettler, 1992). Protein excretion during pregnancy averaged 4 gl d, and a third of the women had classic nephrotic syndrome. here was some degree of renal insuiciency in 75 percent, chronic hypertension in 40 percent, and persistent anemia in 25 percent. Importantly, preeclampsia developed in 60 percent, and 45 percent had preterm deliveries. Even so, after excluding abortions, 53 of 57 neonates were born alive. In another series, fetal-growth restriction was noted in a third of pregnancies in afected women (Stratta, 2006).

Serious long-term adverse outcomes are a risk for women identiied to have nephrotic syndromes either before or during pregnancy (Su, 2017). In our series above, at least 20 percent of women followed for 10 years progressed to end-stage renal disease (Stettler, 1992). Similarly, in another group of 15 women, by 2 years postpartum, three had died, three had developed chronic renal failure, and two had progressed to end-stage renal disease (Chen, 2001). Of predictors, serum creatinine levela> 1.4 mg/ dL and 24-hour protein excretiona> 1 g/d are associated with the shortest renal survival times following pregnancy (Imbasciati, 2007).

his describes a pathophysiological process that can progress to end-stage renal disease. he National Kidney Foundation describes six stages of chronic kidney disease defined by decreasing GFR. It progresses from stage O-GFR >90 mLi min/1.73 mato stage 5-GFR < 15 mLimin/1.73 ma. Several diseases can worsen renal function, and many result from one of the glomerular diseases discussed earlier. hose that most frequently lead to end-stage disease requiring dialysis and kidney transplantation and their approximate percentages include: diabetes, 35 percent; hypertension, 25 percent; glomerulonephritis, 20 percent; and polycystic kidney disease, 15 percent (Abboud, 2010; Bargman, 2015).

reproductive-aged women with these diseases have varying degrees of renal insuiciency, proteinuria, or both. To counsel regarding fertility and pregnancy outcome, the degree of renal functional impairment and of associated hypertension are assessed. Successful pregnancy outcome in general may be more related to these two factors than to the speciic underlying renal disorder. A general prognosis can be estimated by considering women with chronic renal disease in arbitrary categories of renal function (Davison, 2011). hese include normal or mild impairment--deined as a serum creatinine < 1.5 mg/ dL; moderate impairment-deined as a serum creatinine 1.5 to 3.0 mg/dL; and severe renal insuiciencydeined as a serum creatinine >3.0 mg/dL. Although some have suggested adopting the classification of the National Kidney Foundation, others recommend using the older categories (Davison, 2011a; Piccoli, 201 Oa, 2011). Thus, the obstetrician is ideally familiar with both.

Most women have relatively mild renal insuiciency, and its severity along with any underlying hypertension is prognostic of pregnancy outcome. Renal disease with comorbidities secondary to a systemic disorder-for example, diabetes or systemic lupus erythematosus-portends a worse prognosis (Davison, 2011; Koh, 2015). For all women with chronic renal disease, the incidences of hypertension and preeclampsia, preterm and growthrestricted newborns, and other problems are high (Kendrick, 2015). Despite these, the National High Blood Pressure Education Program (2000) concluded that the prognosis has substantively improved since the 1980s. his has been verified by several reviews (Hladunewich, 2016a; Nevis, 2011; Ramin, 2006).

Loss of renal tissue is associated with compensatory intrarenal vasodilation and hypertrophy of the surviving nephrons. he resultant hyperperfusion and hyperiltration eventually damage surviving nephrons to cause nephrosclerosis and worsening renal function. With mild renal insuiciency, pregnancy causes 0.

..,c :J,�

FIGURE 53-4 Blood volume expansion in 44 normally pregnant women at term compared with 29 who had eclampsia; 10 with moderate chronic renal insufficiency (CRI)-serum creatinine 1.5 to 2.9 mg/dL; and four with severe CRI-serum creatinine �3.0 mg/dL . (Data from Cunningham, 1990; Zeeman, 2009.) greater augmentation of renal plasma low and GFR (Baylis, 2003; Helal, 2012). With progressively declining renal function, there is little, if any, augmented renal plasma low. In one study, only half of women with moderate renal insuiciency demonstrated a pregnancy-augmented GFR, and women with severe disease had no increase (Cunningham, 1990).

Importanty, severe chronic renal insuiciency curtails normal pregnancy-induced hypervolemia. Blood volume expansion during pregnancy is related to disease severity and correlates inversely with serum creatinine concentration. As shown in Figure 53-4, women with mild to moderate renal dysfunction have normal blood volume expansion that averages 55 percent. With severe renal insuiciency, however, volume expansion averages only 25 percent, which is similar to that seen with hemoconcentration from eclampsia. In addition, these women have variable degrees of chronic anemia due to intrinsic renal disease.

Renal Disease with Preserved Function

In some women, although glomerular disease has not yet caused renal dysfunction, incidences of pregnancy complications are still increased. As shown in Table 53-4, these problems are less frequent than in cohorts of women with moderate and severe renal insuiciency. Two earlier studies illustrate this. In one describing 123 pregnancies in women with biopsy-proven glomerular disease, only a few of the women had renal dysfunction, yet 40 percent developed obstetrical or renal complications (Surian, 1984). In another study of 395 pregnancies in women with preexisting glomerulonephritis and minimal renal insuiciency, impaired renal function developed in 15 percent during pregnancy, and 60 percent had worsening proteinuria (Packham, 1989). Only 12 percent had antecedent chronic hypertension, however, more than half of the 395 pregnancies were complicated by hypertension. he perinatal mortality rate was 140 per 1000, but even without early-onset or severe hypertension or nephrotic-range proteinuria, the perinatal

TABLE 53-4. Complications (Percent) Associated with 5000 Chronic Renal Disease During Pregnancy 4500 90th .�2500 apreeclampsia only.

NS = not stated.

Data from Alsuwaida, 2011; Cunningham, 1990; Farwell, 2013; Feng, 2015; Imbasciati, 2007; Maruotti, 2012; Nevis, 2011; Packham, 1989; Piccoli, 201 Oa, 2011; Stettler, 1992; Surian, 1984; Trevisan, 2004.

death rate was 50 per 1000. Importantly, in 5 percent of these women, worsening renal function was permanent.

In women with chronic kidney disease who also have renal insuiciency, adverse outcomes are generally directly related to the degree of renal impairment. Outcomes of women with moderate versus severe renal insuiciency are usually not separated (Table 53-5). hat said, Piccoli and associates (2010a) described 91 pregnancies complicated by stage 1 chronic kidney disease. Primarily because of hypertension, 33 percent were delivered preterm, and 13 percent had fetal-growth restriction. Alsuwaida and colleagues (2011) reported similar observations. Other investigators have described pregnancies complicated by moderate or severe renal insuiciency (Cunningham, 1990; Imbasciati, 2007; Zhang, 2015). Despite a high incidence of chronic hypertension, anemia, preeclampsia, preterm delivery, (red points). (Data from Cunningham, 1990; Stettler, 1992. Growth curves are those reported by Alexander, 1996.) and fetal-growth restriction, perinatal outcomes were generally acceptable. As shown in Figure 53-5, fetal growth is frequently impaired and related to renal dysfunction severity.

Prenatal care is tailored for women with chronic renal disease. Frequent monitoring of blood pressure is paramount, and serum creatinine levels, protein/creatinine ratio, and 24-hour protein excretion are quantiied as indicated. Bacteriuria is treated to decrease the risk of pyelonephritis and urther nephron loss. Protein-rich diets are recommended Gim, 2016; Lindheimer, 2000). In some women with anemia from chronic renal insuiciency, a response is seen with recombinant erythropoietin, however, hypertension is a common side efect. Serial sonography is performed to follow fetal growth. he diferentiation between worsening hypertension and superimposed preeclampsia is problematic. Preliminary data indicate that the angiogenic biomarkers placental growth factor (PIGF) and its soluble antiangiogenic receptor (sFlt-l) may be useful to separate chronic from gestational hypertension. This is described in Chapter 40 (p. 716).

In some women, pregnancy may accelerate chronic renal disease progression by increasing hyperfiltration and glomerular pressure to worsen nephrosclerosis (Baylis, 2003; Helal, 2012). his is more likely in women with severe chronic renal insuficiency (Abe, 1991 ; Jones, 1996). For example, Jungers and associates (1995) reported few long-term pregnancy-related adverse efects in 360 women with chronic glomerulonephritis and antecedent normal renal function. However, at 1 year after pregnancy, Jones and Hayslett (1996) reported that 10 percent of such women with moderate or severe renal insuiciency had developed end-stage renal failure-stage 5 chronic kidney disease. In a study from Parkland Hospital, we found that 20 percent of pregnant women with similar insuiciency had developed end-stage renal failure by a mean of 4 years (Cunningham, 1990). Similar indings in women with a median follow-up of 3 years were described by Imbasciati and coworkers (2007). By this time, end-stage disease was apparent in 30 percent of women whose serum creatinine was ::l.4 mg/dL and who had proteinuriaa> 1 g/d. Chronic proteinuria is also a marker for subsequent development of renal failure. In another report from Parkland Hospital, 20 percent of women with chronic proteinuria discovered during pregnancy progressed to end-stage renal failure within several years (Stettler, 1992).

Signiicantly impaired renal function is accompanied by subfertility that may be corrected with chronic renal replacement therapy-either hemodialysis or peritoneal dialysis (Hladunewich, 2016b; Shahir, 2013). Not unexpectedly, these pregnancies can be complicated. In one review of 131 cases, mean fetal birthweights were higher in women who conceived while undergoing dialysis-1530 g versus 1245 g-than in women who conceived before starting dialysis (Chou, 2008). his was also true for 77 pregnancies described by J esudason and coworkers (2014). Similar outcomes from several reports are shown in Table 53-5.

Outcomes are similar with either hemodialysis or peritoneal dialysis. hus, for the woman already undergoing either method, it seems reasonable to continue that method with consideration for its increasing frequency. In the woman who has never been dialyzed, the threshold for initiation during pregnancy is unclear. Lindheimer and colleagues (2007a) recommend dialysis when serum creatinine levels are between 5 and 7 mg/ dL. Because it is imperative to avoid abrupt volume changes that cause hypotension, dialysis frequency may be extended to five to six times weekly (Reddy, 2007).

Certain protocols emphasize attention to replacement of substances lost through dialysis Qim, 2016). Multivitamin doses are doubled, and calcium and iron salts are provided along with suicient dietary protein and calories. Chronic anemia is treated with erythropoietin. To meet pregnancy changes, extra calcium is added to the dialysate along with less bicarbonate.

Maternal complications are common and include severe hypertension, placental abruption, heart ailure, and sepsis. In a review of 90 pregnancies in 78 women, as well as those shown in Table 53-5, high incidences of maternal hypertension and anemia, preterm and growth-restricted infants, stillbirths, and hydramnios were reported (Piccoli, 2010b).

Previously termed acute renal ailure, acute kidney injury (AKI) is now used to describe suddenly impaired kidney function with retention of nitrogenous and other waste products normally excreted by the kidneys (W aikar, 2015). Severe AKI associated with pregnancy is less frequent today. For example, in a 6-year period, the overall incidence at the Mayo Clinic was 0.4 percent (Gurrieri, 2012). It is even less common for women who require dialysis-1 case per 10,000 births (Hildebrand, 2015). But, it still occasionally causes signiicant obstetrical morbidity, and women who require acute dialysis have increased maternal mortality rates (Kuklina, 2009; Van Hook, 2014). Outcomes are available from four older studies comprising a total of 266 women with renal failure (Drakeley, 2002; Nzerue, 1998; Sibai, 1990; Turney, 1989). Nearly 70 percent had preeclampsia, 50 percent had obstetrical hemorrhage, and 30 percent had a placental abruption. Almost 20 percent required dialysis, and the maternal mortality rate was 15 percent.

lthough obstetrical cases of AKI that require dialysis have become less prevalent, acute renal ischemia is still often associated with severe preeclampsia and hemorrhage (Gurrieri, 2012; Jim, 2017). Particularly contributory are HELLP (hemolysis, devated liver enzymes, low .latelet levels) syndrome and placental abruption (Audibert, 1996; Drakely, 2002). Septicemia is another frequent comorbidity, especially in resource-poor countries (Acharya, 2013; Srinil, 2011; Zeeman, 2003). AKI is also common in women with acute fatty liver of pregnancy (Sibai, 2007). Some degree of renal insuiciency was found in virtually all of 52 such women cared for at Parkland Hospital (Nelson, 2013). Another woman from Parkland Hospital developed AKI from dehydration caused by severe hyperemesis gravidarum at 15 weeks (Hill, 2002). Other causes include thrombotic micro angiopathies (Balofsky, 2016; Ganesan, 201a1) (Chap. 56, p. 1088).

In most women, AKI develops postpartum, thus management is usually not complicated by fetal considerations. An abrupt rise in serum creatinine level is most often due to renal ischemia. Oliguria is an important sign. In obstetrical cases, both prerenal and intrarenal factors are often contributory. For example, with total placental abruption, severe hypovolemia from massive hemorrhage is common, and preexistent renal ischemia from preeclampsia is often comorbid. In addition, disseminated intravascular coagulopathy may be contributory.

When azotemia is evident and severe oliguria persists, some form of renal replacement treatment is indicated. Hemofiltration or dialysis is initiated before marked deterioration occurs. Hemodynamic measurements are normalized. Importantly, medication doses are adjusted, and magnesium sulfate, iodinated contrast agents, aminoglycosides, and nonsteroidal antiinlammatory drugs (NSAIDs) are prominent examples (Waikar, 2015). Early dialysis appears to reduce the maternal mortality rate appreciably and may enhance the extent of renal function recovery. With time, renal function usually returns to normal or near normal.

AKI in obstetrics is most often due to acute blood loss, especially that associated with preeclampsia. hus, it may often be prevented by the following means: 1.

Prompt and vigorous volume replacement with crystalloid solutions and blood in instances of massive hemorrhage, such as in placental abruption, placenta previa, uterine rupture, and postpartum uterine atony (Chap. 41, p. 788).

2.

Delivery or termination of pregnancies complicated by severe preeclampsia or eclampsia, and careful blood transfusion ifloss is more than average (Chap. 40, p. 718).

3.

Close observation for early signs of sepsis syndrome and shock in women with pyelonephritis, septic abortion, chorioamnionitis, or sepsis from other pelvic infections (Chap. 47, p. 921).

4.

Avoidance of loop diuretics to treat oliguria before ensuring that blood volume and cardiac output are adequate for renal perfusion.

5.

Judicious use of vasoconstrictor drugs to treat hypotension, and only after it has been determined that pathological vasodilatation is the cause.

Irreversible ischemic renal failure caused by acute cortical necrosis is rare now in obstetrics (F rimat, 2016). Before widespread availability of dialysis, it complicated a fourth of obstetrical renal failure cases (Griinfeld, 1987; Turney, 1989). Most cases followed placental abruption, preeclampsia-eclampsia, and endotoxin-induced shock. Once common with septic abortion, this is a rare cause in this country today (Lim, 2011; Srinil, 2011). Histologically, the lesion appears to result from thrombosis of segments of the renal vascular system. he lesions may be focal, patchy, conluent, or gross. Clinically, renal cortical necrosis follows the course of AKI, and its diferentiation from acute tubular necrosis is not possible during the early phase. he prognosis depends on the extent of the necrosis. Recovery of function is variable, and stable renal insuiciency may result (Lindheimer, 2007a).

Rarely, bilateral ureteral compression by a very large pregnant uterus is greatly exaggerated. Resultant ureteral obstruction in turn may cause severe oliguria and azotemia. An extreme example is shown in Figure 53-6. In their series of 13 obstruction cases, Brandes and Fritsche (1991) described one woman with twins who developed anuria and a serum creatinine level of 12.2 mg/dL at 34 weeks' gestation. After amniotomy, urine flow resumed at 500 mL/hr, and her serum creatinine levels rapidly dropped to normal range. Eckford and Gingell (1991) described 10 women in whom ureteral obstruction was relieved by stenting. he stents were left in place for a mean of 15.5 weeks and removed 4 to 6 weeks postpartum. Others have reported similar experiences (Sadan, 1994; Satin, 1993).

FIGURE 53-6 A.Magnetic resonance image in a coronal plane of a pregnant woman with unilateral hydronephrosis caused by ureteral obstruction. The serum creatinine level was 8 mg/dL and decreased to 0.8 mg/dL ater a percutaneous nephrostomy tube was placed.

B. Let kidney (arrow) and associated hydronephrosis (asterisk) are again noted in this axial plane image from the same patient.

Partial ureteral obstruction may be accompanied by fluid retention and significant hypertension. When the obstructive uropathy is relieved, diuresis ensues and hypertension dissipates. In our experience, women with previous urinary tract surgery for reflux are more likely to have such obstructions.

Although infrequently complicating pregnancy, this type of diverticulum originates from an enlarging paraurethral gland abscess that ruptures into the urethral lumen. As infection clears, the remaining dilated diverticular sac and its ostium into the urethra persist. Urine collecting within and dribbling from the sac, pain, a palpable mass, and recurrent urinary infections may be associated findings. In general, a diverticulum is managed expectantly during pregnancy. Rarely, drainage may be necessary, or surgery required (Iyer, 2013). If additional antepartum evaluation is needed, MR imaging is preferred for its superior soft tissue resolution and ability to deine complex diverticula (Dwarkasing, 2011; Pathi, 2013) .

Fistulas found during pregnancy likely existed previously, but in rare cases, they form during pregnancy. In developed countries, vesicovaginal or cervicovaginal istula following a McDonald cerclage has been reported (Massengill, 2012; Zanconato, 2015). These fistulas may also form with prolonged obstructed labor that is more often seen in resource-poor countries (Cowgill, 2015). In these cases, the genital tract is compressed between the fetal head and bony pelvis. Brief pressure is not signiicant, but prolonged pressure leads to tissue necrosis with subsequent fistula formation (Wall, 2012). Vesicouterine istulas can develop after prior vaginal or cesarean delivery (DiMarco, 2006; Harfouche, 2014; Manjunatha, 2012). Rarely, vesicocervical istula can follow cesarean delivery or may form if the anterior cervical lip is compressed against the symphysis pubis (Dudderidge, 2005). Finally, an ileouterine istula from a degenerating posterior wall fibroid tumor has been described (Shehata, 2016).

Abboud H, Henrich L: Stage IV chronic kidney disease. N Engl J Med 362(1):56,t2010

Abe S: An overview of pregnancy in women with underlying renal disease. Am J Kidney Dis 17:1t12, 1991

Acharya A, Santos J, Linde B, et al: Acute kidney injury in pregnancy-current status. Adv Chronic Kidney Dis 20:215, 2013

Airoldi J, Weinstein L: Clinical signiicance of proteinuria in pregnancy.

Obstet Gynecol Surv 62(2):117,t2007

Ait Benkaddour Y, Aboulfalah A, Abbassi H: Bladder stone: uncommon cause of mechanical dystocia. Arch Gynecol Obstet 274(5):323, 2006

Akturk S, Celebi ZK, Erdogmus S, et al: Pregnancy after kidney transplant: outcomes, tacrolimus doses, and trough levels. Transplant Proc 47(5):1442, 2015

Al Duraihimh H, Ghamdi G, Moussa D, et al: Outcome of234 pregnancies in 140 renal transplant recipients from five Middle Eastern countries. Transplantation 85:840, 2008

Alexander GR, Himes JH, Kaufman RB, et aI: A United States national reference for fetal growth. Obstet Gynecol 87:163, 1996

Alsuwaida A, Mousa D, Al-Harbi A, et al: Impact of early chronic kidney disease on maternal and fetal outcomes of pregnancy. J Matern Fetal Neonatal Med 24(12):1432, 2011

American Academy of Pediatrics and American College of Obstetricians and Gynecologists: Guidelines for Perinatal Care, 8th ed. Elk Grove Village, P, 2017 Asrat T, Roossin M, Miller EI: Ultrasonographic detection of ureteral jets in normal pregnancy. Am J Obstet Gynecol 178: 1194, 1998

Audibert F, Friedman SA, Frangieh AY, et al: Diagnostic criteria for HELLP syndrome: tedious or "helpful"? Am J Obstet Gynecol 174:454, 1996 Balofsky A, Fedarau M: Renal failure in pregnancy. Crit Care Clin 32(1):73, 2016

Banhidy F, Acs N, Puho EH, et al: Pregnancy complications and birth outcomes of pregnant women with urinary tract infections and related drug treatments. Scand J Infect Dis 39:390, 2007

Banks N, Bryant J, Fischer R, et al: Pregnancy in autosomal recessive polycystic kidney disease. Arch Gynecol Obstet 291(3):705,t2015

Bargman JM, Skorecki K: Chronic kidney disease. In Kasper DL, Fauci AS, Hauser SL, et aI (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill Education, 2015

Baylis C: Impact of pregnancy on underlying renal disease. Adv Ren Replace her 10:31, 2003

Beck LH, Salant DJ: Tubulointerstitial diseases of the kidney. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill Education, 2015

Boggess A, Benedetti TJ, Raghu G: Nitrofurantoin-induced pulmonary toxicity during pregnancy: a report of a case and review of the literature. Obstet Gynecol Surv 41t:367, 1996

Bramham K, Nelson-Piercy C, Gao H, et al: Pregnancy in renal transplant recipients: a UK National Cohort Study. Clin J Am Soc Nephrol 8(2):290, 2013

Bramham K, Soh Me, Nelson-Piercy C: Pregnancy and renal outcomes in lupus nephritis: an update and guide to management. Lupus 21(12):1271, 2012

Brandes JC, Fritsche C: Obstructive acute renal failure by a gravid uterus: a case report and review. m J Kidney Dis 18:398, 1991

Briggs GG, Freeman RK: Drugs in Pregnancy and Lactation, 10th ed. Philadelphia, Lippincott Williams & Wilkins, 2014

Brosens I, Pijnenborg R, Benagiano G: Risk of obstetrical complications in organ transplant recipient pregnancies. Transplantation 96(3):227,t2013 Brown MA, Holt JL, Mangos GK, et al: Microscopic hematuria in pregnancy: relevance to pregnancy outcome. Am J Kidney Dis 45:667, 2005

Butler EL, Cox SM, Eberts E, et al: Symptomatic nephrolithiasis complicating pregnancy. Obstet Gynecol 96:753, 2000

Cabiddu G, Castellino S, Gernone G, et aI: A best practice position statement on pregnancy in chronic kidney disease: the Italian study group on kidney and pregnancy. J Nephrol 29(3):277, 2016

Cavenee MR, Cox SM, Mason R, et aI: Erythropoietin in pregnancies complicated by pyelonephritis. Obstet Gynecol 84:252, 1994

Chaemsaithong P, Romero R. Korzeniewski SJ, et al: Soluble TRAIL in normal pregnancy and acute pyelonephritis: a potential explanation for the susceptibility of pregnant women to microbial products and infection. J Matern Fetal Neonatal Med 26(16):1568,t2013

Chao AS, Huang JY, Lien R, et al: Pregnancy in women who undergo longterm hemodialysis. Am J Obstet Gynecol 187(1):152,t2002

Chapman AB, Johnson AM, Gabow PA: Pregnancy outcome and its relationship to progression of renal failure in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 5: 1178, 1994

Chen HH, Lin HC, Yeh Je, et al: Renal biopsy in pregnancies complicated by undetermined renal disease. Acta Obstet Gynecol Scand 80:888, 2001

Chen TK, Gelber Ae, Witter FR, et aI: Renal biopsy in the management of lupus nephritis during pregnancy. Lupus -54,t2015

Chou CY, Ting IW, Lin TH, et al: Pregnancy in patients on chronic dialysis: a single center experience and combined analysis of reported results. Eur J Obstet Gynecol Reprod Bioi 136: 165, 2008

Chung SD, Chen H, Keller J, et I: Urinary calculi increased the risk for adverse pregnancy outcomes: a nationwide study. Acta Obstet Gynecol Scand 921:69,t2013

Coscia A, Constantinescu S, Moritz !J, et aI: Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl 65, 2010 Cowgill D, Bishop J, Norgaard AK, et aI: Obstetric istula in low-resource countries: an under-valued and under-studied problem-systematic review of its incidence, prevalence, and association with stillbirth. BMC Pregnancy Childbirth 15:193,t2015 Cox SM, Cunningham FG: Acute focal pyelonephritis (lobar nephronia) complicating pregnancy. Obstet Gynecol 71:510,t1988

Cox SM, Shelburne P, Mason R, et al: Mechanisms of hemolysis and anemia associated with acute antepartum pyelonephritis. Am J Obstet Gynecol 164:58 , 1991

Cruz Lemini MC, Ibarguengoitia Ochoa F, Villanueva Gonzalez MA: Perinatal outcome following renal transplantation. Int J Gynecol Obstet 95:76, 2007

Cunningham FG, Cox SM, Harstad W, et al: Chronic renal disease and pregnancy outcome. Am J Obstet Gynecol 163:453, 1990

Cunningham FG, Lucas MJ, Hankins GC: Pulmonary injury complicating antepartum pyelonephritis. Am J Obstet Gynecol 156:797, 198 Cunningham FG, Morris GB, Mickal A: Acute pyelonephritis of pregnancy: a clinical review. Obstet Gynecol 42: 112, 1973

Curhan GC: Nephrolithiasis. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles ofInternal Medicine, 19th ed. New York, McGrawHill Education, 2015

Czaja CA, Rutledge BN, Cleary PA, et al: Urinary tract infections in women with type 1 diabetes mellitus: survey of female participants in the epidemiology of diabetes interventions and complications study cohort. J Urol 181(3):1129,t2009

Davison JM, Lindheimer MD: Pregnancy and chronic kidney disease. Semin NephroI31(1):86,t2011

Debska-Sliziei A, Galgowska J, Chamienia A, et al: Pregnancy after kidney transplantation: a single-center experience and review of the literature. Transplant Proc 46(8):2668,t2014

Diamond DA, Mattoo TK: Endoscopic treatment of primary vesicoureteral relux. N Engl J Med 366(13):1218, 2012

DiMarco CS, DiMarco DS, Klingele CJ, et al: Vesicouterine istula: a review of eight cases. In Utogynecol J Pelvic Floor Dysfunct (4):395,t2006 Donadio JV, Grande JP: IA nephropathy. N Engl J Med 347:738,t2002

Drakeley AJ, Le Roux PA, Anthony J, et al: Acute renal failure complicating severe preeclampsia requiring admission to an obstetric intensive care unit. Am J Obstet Gynecol 186:253,t2002

Dudderidge TJ, Haynes SV, Davies AJ, et I: Vesicocervical istula: rare complication of cesarean section demonstrated by magnetic resonance imaging. Urology 65(1):174,t2005

Dwarkasing RS, Dinkelaar W, Hop We, et al: MRI evaluation of urethral diverticula and diferential diagnosis in symptomatic women. AJR Am J Roentgenol 197(3):676,t2011

Eckford SD, Gingell JC: Ureteric obstruction in pregnancy-diagnosis and management. BJOG 98:1137, 1991

EI-Khatib M, Packham DK, Becker GJ, et al: Pregnancy-related complications in women with reflux nephropathy. Clin Nephrol 41:50, 1994

Erman Akar M1, Ozekinci M, Sanhal e, et al: A retrospective analysis of pregnancy outcomes after kidney transplantation in a single center. Gynecol Obstet Invest 79(1):13,t2015

Farwell J, Emerson J, Wyatt S, et al: Outcomes of pregnancies complicated by chronic kidney disease. Abstract No. 346. Am J Obstet Gynecol 208(1 Suppl):S153,t2013

Faundes A, Bricola-Filho \1, Pinto e Silvat]C: Dilatation of the urinary tract during pregnancy: proposal of a curve of maximal caliceal diameter by gestational age. Am J Obstet Grnecol 178: 1 082, 1998

Feng Z, Minard C, Raghavan R: Pregnancy outcomes in advanced kidney disease. Clin Nephrol 83(5):272, 2015

Fihn SO: Acute uncomplicated urinaty ttact infection in women. N Engl ] Med 349:259, 2003

Foxman B: he epidemiology of urinary tract infection. Nat Rev Urol (12):653,t2010

French VA, Davis ]B, Savies HS, et al: Contraception and fertility awareness among women with solid organ transplants. Obstet Gynecol 122:809, 2013

Friend S, Carlan SJ, Wilson], et al: Reactivation of Goodpasture disease during the third trimester of pregnancy: a case report. J Reprod Med 60(9-10):449, 2015

Frimat M, Decambron M, Lebas C, et al: Renal cortical necrosis in postpartum hemorrhage: a case series. Am J Kidney Dis 68(1):50, 2016

Ganesan C, Maynard SE: Acute kidney injury in pregnancy: the thrombotic microangiopathies.t] Nephrol 24(5):554, 2011

Garg X, Nevis IF, McArthur E, et al: Gestational hypertension and preeclampsia in living kidney donors. N Engl] Med 372(15):1469,t2015 Ghafari A, Sanadgol H: Pregnancy after renal transplantation: ten-year singlecenter experience. Transplant Proc 40:251, 2008 Gilstrap LC III, Cunningham FG, Whalley PJ: Acute pyelonephritis in pregnancy: an anterospective study. Obstet Gynecol 57:409, 1981a

Gilstrap LC III, Leveno KJ, Cunningham FG, et al: Renal infection and pregnancy outcome. Am J Obstet GynecoIt141t:708, 1981b

Goes NB, Calvin RB: Case 12-2007: A 56-year-old woman with renal failure after heart-lung transplantation. N Engl ] Med 356: 1657,

Gomi H, Goto Y, Laopaiboon M, et al: Routine blood cultures in the managemem of pyelonephritis in pregnancy for improving outcomes. Cochrane Database Syst Rev 2:CD009216, 2015

Graham JM, Oshiro BT, Blanco ]0, et al: Uterine contractions after antibiotic therapy for pyelonephritis in pregnancy. Am ] Obstet Gynecol 7, 1993

Grunfeld JP, Pertuiset N: Acute renal failure in pregnancy: . Am] Kidney Dis 9:359, 1987

Gurrieri C, Garovic VO, Gullo A, et al: Kidney injury during pregnancy: associated comorbid conditions and outcomes. Arch Gynecol Obstet 286(3):567,t2012

Harfouche M, Kaliti S, Hosseinipour M, et al: Pregnancy in a patient with a vesicouterorectal fistula and obliterated vagina: a case report. J Reprod Med 59(9-10):515,t2014

Harris E,

Gilstrap LC III: Cystitis during pregnancy: a distinct clinical entity. Obstet 8,t1981

Helal I, Fick-Brosnahan GM, Reed-Gitomer B, et al: Glomerular hyperiltration: deinitions, mechanisms, and clinical implications. Nat Rev Nephrol 8:293,t2012

Hendricks SK, Ross SO, Krieger IN: An algorithm for diagnosis and therapy of management and complications of urolithiasis during pregnancy. Surg Gynecol Obstet 2:49, 1991

Higby K, Suiter CR, Phelps JY, et al: Normal values of urinary albumin and total protein excretion during pregnancy. Am] Obstet Gynecol 171:984, 1994

Hildebrand AM, Liu K, Sharif SZ, et al: Characteristics and outcomes of AKI treated with dialysis during pregnancy and the postpartum period. ] Am Soc NephroIt26(12):3085,t2015

Hill ]B, Sheield JS, McIntire DO, et al: Acute pyelonephritis in pregnancy.

Obstet Gynecol 105:38,t2005

Hill ]B, Yost NP, Wendel GO Jr: Acute renal failure in association with severe hyperemesis gravidarum. Obstet Gynecol 100: 11t19, 2002

Hladunewich MA, Herca AE, Keunen ], et al: Pregnancy in end stage renal disease. Semin Dial 24(6):634, 2011

Hladunewich A, Lafayette A, Derby Gc, et al: The dynamics of glomerular filtration in the puerperium. Am ] Physiol Renal Physiol 286:F496, 2004 Hladunewich MA, Melamad N, Bramham K: Pregnancy across the spectrum of chronic kidney disease. Kidney Int 89(5):995, 2016a

Hladunewich vIA, Schatell 0: Intensive dialysis and pregnancy. Hemodial Int 20(3):339,t2016b

Hooton TM: Uncomplicated urinary tract infection. N Engl ] Med 366(1t1): 1028,t2012

Huser M, Wagnerova K, ]anku P, et al: Clinical management of pregnancy in women with Goodpasture syndrome. Gynecol Obstet 3, 2015 Hussein W, Lafayette A: Renal function in normal and disordered pregnancy.

Curr Opin Nephrol Hypertens 23:46,t2014

Ibrahim HN, Foley R, Tan L, et al: Long-term consequences of kidney donation. N Engl ] Med 360:459, 2009

Imbasciati E, Gregorini G, Cabiddu G, et al: Pregnancy in CKD stages 3 to 5: fetal and maternal outcomes. Amt] Kidney Dis 53, 2007

Iyer S, Minassian VA: Resection of urethral diverticulum in pregnancy. Obstet Gynecol 122(2 Pt 2):46 ,2013

Jacobsson B, Hagberg G, Hagberg B, et al: Cerebral palsy in preterm infants: a population-based case-control study of antenatal and intrapartal risk factors. Acta Paediatr 91 :946, 2002

Jain AB, Shapiro R, Scantlebury VP, et al: Pregnancy after kidney and kidney-pancreas transplantation under tacrolimus: a single center's experience. Transplantation , 2004

Jesudason S, Grace BS, McOonald SP: Pregnancy ourcomes according to dialysis commencing before or after comraception in women with ESRD. Clint] Am Soc Nephrol 9:143, 2014

Jim B, Bramham K, Maynard SE, et al (eds): Management of the pregnant dialysis patient. In Pregnancy and Kidney Disease. NephSAP Nephrology Assessment Program 15(2):75,t2016

Jim B, Garovic VO: Acute kidney injury in pregnancy. Semin Nephrol 3 :P378,t2017

Jolley]A, Kim S, Wing DA: Acute pyelonephritis and associated complications during pregnaicy in 2006 in US hospitals. J Matern Fetal Neonatal Med 25(12):2494,t2012

Johnson EB, Krambeck AE, White WM, et al: Obstetric complications of ureteroscopy during pregnancy.t] Urol 188(1):151,t2012

Jones DC, Hayslett JP: Outcome of pregnancy in women with moderate or severe renal insuiciency. N Engl J Med 335:226, 1996

Josephson MA, McKay OB: Pregnancy and kidney transplantation. Semin Nephrol 31(1):100, 2011

Jungers P, Houil\ier P, Chauveau 0, et al: Pregnancy in women with relux nephropathy. Kidney Int 50:593, 1996

Jungers P, Houillier P, Forget 0, et al: Inluence of pregnancy on the course of primary chronic glomerulonephritis. Lancet 346: 1122, 1995

Kazemier BM, Koningstein FN, Schneeberger C, et al: Maternal and neonatal consequences of treated and untreated asymptomatic bacteriuria in pregnancy: a prospective cohort study with an embedded randomized controlled trial. Lancet Infect Dis 15(11):1324,t2015

Kendrickt], Sharma S, Holment], et al: Kidney disease and maternal and fetal outcomes in pregnancy. Am J Kidney Dis 66(1):55,t2015

Kim H, Jeong ]C, Yang], et al: The optimal therapy of calcineurin inhibitors for pregnancy in kidney transplantation. Clin Transplant 29(2): 142, 2015

Koh JH, Ko HS, Lee], et al: Pregnancy and patients with preexisting lupus nephritis: 15 years of experience at a single center in Korea. Lupus 24(7):764,t2015 Kohler ]R, Tencer ], Thysell H, et al: Long-term efects of relux nephropathy on blood pressure and renl function in adults. Nephron Clin Pract 93:c35, 2003 Kuklina EV, Meikle SF, Jamieson OJ, et al: Severe obstetric morbidity in the United States: 1998-2005. Obstet GynecoI113:293, 2009

Kuper SG, Tita AT, Youngstrom ML, et al: Baseline renal function tests and adverse outcomes in pregnant patients with chronic hypertension. Obstet Gynecol 128(1):93,t2016

Lamom RF: he pathophysiology of pulmonary edema with the use of betaagonists. B]OG 107:439,t2000

Lewis OF, Robichaux AG III, ]aekle RK, et al: Urolithiasis in pregnancy: diagnosis, management and pregnancy outcome. J Reprod Med 48:28, 2003

Lewis JB, Neilson EG: Glomerular disease. In Kasper OL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, 1cGraw-Hill Education, 2015

Lim LM, Tsai KB, Hwang DY, et al: Anuric acute renal failure after elective abortion. Intern Med 50(16):1715, 2011

Lindheimer MO, Conrad KP, Karumanchi SA: Renal physiology and diseases in pregnancy. In Alpern R, Hebert S (eds): Seldin and Giebisch's he Kidney, 4th ed. London, Academic Press, 2007a

Lindheimer MO, Davison JM: Pregnancy and CKD: Any progress? Am ] Kidney Dis 49:729, 2007b

Lindheimer MD, Grunfeld ]P, Davison JM: Renal disorders. In Barron WM, Lindheimer MD (eds): Medical Disorders During Pregnancy, 3rd ed. St. Louis, Mosby, 2000

Liu Y, Ma X, Lvt], et al: Risk factors for pregnancy outcomes in patients with 19A nephropathy: a matched cohort study. Am J Kidney Dis 64(5): 30,2014 Lo JO, Kerns E, Rueda], et al: Minimal change disease in pregnancy.] Matern Fetal Neonatal Med 27(12):1282, 2014

Lopez LF, Martinez C], Castaneda DA, et al: Pregnancy and kidney transplantation, triple hazard? Current concepts and algorithm for approach of preconception and perinatal care of the patient with kidney transplantation. Transplant Proc 46(9):3027,t2014

Lucas M], Cunningham FG: Urinary infection in pregnancy. Clin Obstet Gynecol 36:855, 1993

Lucas M], Cunningham FG: Urinary tract infections complicating pregnancy.

Williams Obstetrics, 19th ed. (Suppl 5). Norwalk, Appleton & Lange, February/v[arch 1994

Luders C, Martins MC, Titak SM, et al: Obstetric outcome in pregnancy women on long-term dialysis: a case series. Am] Kidney Dis 56( 1): 77, 2010

Lumbiganon P, Villar ], Laopaiboon M, et al: One-day compared with 7-day nitrofurantoin for asymptomatic bacteriuria in pregnancy. Obstet Gynecol 113:339, 2009

Maikranz P, Coe FL, Parks], et al: Nephrolithiasis in pregnancy. Am] Kidney Dis 9:354, 1987

Manjunatha YC, Sonwalkar P: Spontaneous antepartum vesicouterine istula causing severe oligohydramnios in a patient with a previous cesarean delivery.s] Ultrasound Med 31(8):1294, 2012

Maruotti GM, Sarno L, Napolitano R, et al: Preeclampsia in women with chronic kidney disease.s] Matern Fetal Neonatal Med 25(8):1367,s2012 Masselli G, Weston M, Spencer]: he role ofimaging in the diagnosis and man agement of renal stone disease in pregnancy. Clin Radiol 70(12): 1462, 2015

Massengill ]c, Baker TM, Von Pechmann WS, et al: Commonalities of cerclage-related genitourinary istulas. Female Pelvic Med Reconstr Surg 18(6):362,s2012

McAleer S], Loughlin KR: Nephrolithiasis and pregnancy. Curr Opin Urol 14:123,s2004

McDonnold M, Friedman A, Raker C, et al: Is postpartum pyelonephritis associated with the same maternal morbidity as antepartum pyelonephritis? ] Matern Fetal Neonatal Med 25(9):1709, 2012

Mignini L, Carroli G, Abalos E, et al: Accuracy of diagnostic tests to detect asymptomatic bacteriuria during pregnancy. Obstet Gynecol 113(1):346, 2009

Millar LK, DeBuque L, Wing DA: Uterine contraction frequency during treatment of pyelonephritis in pregnancy and subsequent risk of preterm birth. ] Perinat Med 31:41, 2003

Mor Y, Leibovitch I, Zalts R, et al: Analysis of the long-term outcome of surgically corrected vesicoureteric relux. B]U Int 92:97, 2003

Moretti ME, Sgro M, Johnson DW, et al: Cyclosporine excretion into breast milk. Transplantation 75:2144, 2003

National High Blood Pressure Education Program: Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am] Obstet GynecoIs183(1):Sl, 2000

Nelson DB, Yost NP, Cunningham FG: Acute fatty liver of pregnancy: clinical outcomes and expected durations of recovery. Am ] Obstet Gynecol 209(5):456.e1,s2013

Nevis IF, ReitsmaA, DominicA, et al: Pregnancy outcomes in women with chronic kidney disease: a systematic review. Clin] Am Soc NephroI6:2587, 2011

Nzerue CM, Hewan-Lowe K, Nwawka C: Acute renal failure in pregnancy: a review of clinical outcomes at an inner city hospital from 1986-1996.] Natl Med Assoc 90:486, 1998

Orihuela S, Nin M, San Roman S, et al: Successful pregnancies in kidney transplant recipients: Experience of the National Kidney Transplant Program from Uruguay. Transplant Proc 48(2):643,s2016

Packham DK, North A, Fairley KF, et al: Primary glomerulonephritis and pregnancy. Q] Med 71:537, 1989

Pathi SD, Rahn DD, Sailors ]L, et al: Utility of clinical parameters, cystourethroscopy, and magnetic resonance imaging in the preoperative diagnosis of urethral diverticula. Int Urogynecol] 24(2):319, 2013

Piccoli GB, Attini R, Vasario E, et al: Pregnancy and chronic kidney disease: a challenge in all CKD stages. Clin] Am Soc Nephrol 5:844, 2010a

Piccoli GB, Conijn A, Attini R, et al: Pregnancy in chronic kidney disease: need for a common language.s] Nephrol 24(03)282,s2011

Piccoli GB, Conijn A, Consiglio V, et al: Pregnancy in dialysis patients: is the evidence strong enough to lead us to change our counseling policy? Clin ] Am Soc Nephrol 5:62, 2010b

Piccoli GB, Daidola G, Attini R, et al: Kidney biopsy in pregnancy: evidence for counseling? A systematic narrative review. B]OG 120(4):412,s2013 Putra LG, Minor TX, Bolton DM, et al: Improved assessment of renal lesions in pregnancy with magnetic resonance imaging. Urology 74:535,s2009 Rai], Smith RB: Acute lobar nephronia in pregnancy: a rarely reported entity in obstetric renal medicine. Arch Gynecol Obstet 286(3):797,s2012

Ramin SM, Vidaef AC, Yeomans ER, et al: Chronic renal disease in pregnancy. Obstet Gynecol 108(6):1531,2006

Rao S, Ghanta M, Moritz M], et al: Long-term functional recovery, quality of life, and pregnancy after solid organ transplantation. Ied Clin North Am 100(3):613,s2016

Raz R, Sakran W, Chazan B, et al: Long-term follow-up of women hospitalized for acute pyelonephritis. Clin Infect Dis 37:1014,s2003

Reddy SS, Holley ]L: Management of the pregnant chronic dialysis patient.

Adv Chronic Kidney Dis 14: 146, 2007

Reinstatler L, Khaleel S, Pais VM ] r: Association of pregnancy with stone formation among women in the United States: a NHANES analysis 2007 to 2012.s] Urol February 24,s2017 [Epub ahead of print]

Rocha A, Cardoso A, Malheiro ], et al: Pregnancy ater kidney transplantation: grat, mother, and newborn complications. Transplant Proc 45(3): 1088,2013 Rodriguez PN, Klein AS: Management of urolithiasis during pregnancy. Surg Gynecol Obstet 166: 103, 1988

Rogozinska E, Formina S, Zamora], et al: Accuracy of onsite tests to detect asymptomatic bacteriuria in pregnancy. Obstet Gynecol 128:495,2016

Rosenberg E, Sergienko R, Abu-Ghanem S: Nephrolithiasis during pregnancy: characteristics, complications, and pregnancy outcome. World ] Urol 29(6):743,s2011

Ross AE, Handa S, Lingeman ]E, et al: Kidney stones during pregnancy: an investigation into stone composition. Urol Res 36:99, 2008

Rouse D], Andrews W, Goldenberg L, et al: Screening and treatment of asymptomatic bacteriuria of pregnancy to prevent pyelonephritis. A costefectiveness and cost beneit analysis. Obstet GynecoI86:119, 1995

Ruan ]M, Adams SR, Carpinito G, et al: Bladder calculus presenting as recurrent urinary tract infections: a late complication of cervical cerclage placement: a case report.] Reprod Med 56(3-4):172, 2011

Sadan 0, Berar M, Sagiv R, et al: Ureteric stent in severe hydronephrosis of pregnancy. Eur] Obstet Gynecol Reprod BioI 56:79, 1994

Saliem S, Patenaude V, Abenhaim HA: Pregnancy outcomes among renal transplant recipients and patients with end-stage renal disease on dialysis. ] Perinat Med 44(3):321, 2016

Sanchez-Ramos L, Mlpine K], Adair CD, et al: Pyelonephritis in pregnancy: once a day ceftriaxone versus multiple doses of cefazolin. A randomized double-blind trial. Am ] Obstet Gynecol 172: 129, 1995

Satin A], Seiken GL, Cunningham FG: Reversible hypertension in pregnancy caused by obstructive uropathy. Obstet GynecoI81:823, 1993

Schieve A, Handler A, Hershow R, et al: Urinary tract infection during pregnancy: its association with maternal morbidity and perinatal outcome. Am ] Public Health 84:405, 1994

Schneeberger C, Geerlings SE, Middleton P, et al: Interventions for preventing recurrent urinary tract infection during pregnancy. Cochrane Database Syst Rev 7:CD009279, 2015

Schneeberger C, Kazemier BM, Geerlins SE: Asymptomatic bacteriuria and urinary tract infections in special patient groups: women with diabetes mellitus and pregnant women. Curr Opin Infect Dis 27:106, 2014

Seidman DS, Soriano D, Dulitzki M, et al: Role of renal ultrasonography in the management of pyelonephritis in pregnant women. ] Perinatol 18:98, 1998 Semins M], Matlaga BR: Kidney stones during pregnancy. Nat Rev Urol 11(3):163,s2014

Shahir AK, Briggs N, Katsoulis ], et al: n observational outcomes study from 1966-2008, examining pregnancy and neonatal outcomes from dialysed women using data from theANZDATA Registry. Nephrology 18(4):276, 2013

Sheield ]S, Cunningham FG: Urinary tract infection in women. Obstet Gynecol 106: 1085, 2005

Shehata A, Hussein N, El Halwagy A, et al: Ileo-uterine istula in a degenerated posterior wall ibroid after caesarean section. Clin Exp Reprod Med 43(1):51,s2016

Sibai BM: Imitators of severe preeclampsia. Obstet Gynecol 109:956,2007

Sibai BM, Villar A, Mabie BC: Acute renal failure in hypertensive disorders of pregnancy. Pregnancy outcome and remote prognosis in thirry-one consecutive cases. Am] Obstet Gynecol 162(3):777, 1990

Sledzinska A, Mielech A, Krawczyk B, et al: Fatal sepsis in a pregnant woman with pyelonephritis caused by Escherichia coli bearing Dr and P adhesions: diagnosis based on postmortem strain genotyping. B]OG 118(2):266,2011

Smail! FM, Vazquez ]C: Antibiotics for asymptomatic bacteriuria in pregnancy. Cochrane Database Syst Rev 8:CD000490, 2015 Snyder CC, Barton ]R, Habli M, et al: Severe sepsis and septic shock in pregnancy: indications for delivery and maternal and perinatal outcomes. ] Matern Fetal Neonatal Med 26(5):503,s2013 Spencer ]A, Chahal R, Kelly A, et al: Evaluation of painful hydronephrosis in pregnancy: magnetic resonance urographic patterns in physiological dilatation versus calculous obstruction. ] U rol 171 :256, 2004 Srinil S, Panaput T: Acute kidney injury complicating septic unsafe abortion: clinical course and treatment outcomes of 44 cases. ] Obstet Gynaecol Res 37(11):1525,s2011 Stehman-Breen CO, Levine R], Qian C, et al: Increased risk of preeclampsia among nulliparous pregnant women with idiopathic hematuria. Ams] Obstet :703,s2002 Stettler RW, Cunningham FG: Natural history of chronic proteinuria complicating pregnancy. Am] Obstet GynecoIs167:1219, 1992 Stoumpos S, McNeill SH, Gorrie M, et al: Obstetric and long-term kidney outcomes in renal transplant recipients: a 40 year single-centre study. Clin Transplant 30(6):673, 2016 Stratta P, Canavese C, Quaglia M: Pregnancy in patients with kidney disease. Nephrol 19:135, 2006

Strevens H, Wide-Swensson D, Hansen A, et al: Glomerular endotheliosis in normal pregnancy and pre-eclampsia. BJOG 110:831,2003

Sturgiss SN, Davison JM: Efect of pregnancy on long-term function of renal allografts. Am J Kidney Dis 26:54, 1995

Su X, Lv J, Liu Y, et al: Pregnancy and kidney outcomes in patients with IgA nephropathy: a cohort study. Am J Kidney Dis 70:762, 2017

Surian M, Imbasciati E, Cosci P, et al: Glomerular disease and pregnancy: a study of 123 pregnancies in patients with primary and secondary glomerular diseases. Nephron 36:101,s1984

Swartz A, Lydon-Rochelle MT, Simon D, et al: Admission for nephrolithiasis in pregnancy and risk of adverse birth outcomes. Obstet Gynecol 109(5):1099,s2007

Tan LK, Kanagalingam D, Tan HK, et al: Obstetric outcomes in women with endstage renal failure requiring renal dialysis. Int J Gynaecol Obstet 94: 17, 2006 Tan K, Cha DY, Gupta M: Management of stones in abnormal situations.

Urol Clin North Am 40(1):79, 2013

Toth C, Toth G, Varga A, et al: Percutaneous nephrolithotomy in early pregnancy. Int Urol NephroI37:1, 2005

Towers CV, Kaminskas CM, Garite TJ, et al: Pulmonary injury associated with antepartum pyelonephritis: can patients at risk be identified? Am J Obstet Gynecol 164:974, 1991

Trevisan G, Ramos JG, Martins-Costa S, et al: Pregnancy in patients with chronic renal insuiciency at Hospital de Clinicas of Porto Alegre, Brazil. Ren Fail 26:29, 2004

Turney JH, Ellis CM, Parsons FM: Obstetric acute renal failure 1956-1987.

BJOG 96:679, 1989

U.S. Preventive Services Task Force. Screening for asymptomatic bacteriuria in adults. Reairmation recommendation statement. 2008. Available at: http://ww. uspreven tiveservicestaskforce.org/ uspstf08/ asym ptbact/ asbactrs. htm. Accessed September 22,2016

Van Dorsten JP, Lenke RR, Schifrin BS: Pyelonephritis in pregnancy: the role of in-hospital management and nitrofurantoin suppression. ] Reprod Med 32:897, 1987

Van Hook JW: Acute kidney injury during pregnancy. Clin Obstet Gynecol (4):851-61,s2014

Waikar SS, Bonventre J\\1: Acute kidney injury. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill Education, 2015

Wall LL: Preventing obstetric fistulas in low-resource countries: insights from a Haddon matrix. Obstet Gynecol Surv 67(2):111,s2012 %alley PJ: Bacteriuria of pregnancy. Am J Obstet Gynecol 97:723, 1967

White WM, Zite NB, Gash J, et al: Low-dose computed tomography for the evaluation of flank pain in the pregnant population. J Endourol 21(11):1255,s2007

Widmer M, Lopez 1, Gulmezoglu AM, et al: Duration of treatment for asymptomatic bacteriuria during pregnancy. Cochrane Database Syst Rev II:CD000491,s2015

Wing DA, Fassett MJ, Getahun D: Acute pyelonephritis in pregnancy: an 18-year retrospective analysis. Am J Obstet Gynecol 210(3):219.el, 2014

Wing DA, Hendershott CM, Debuque L, et al: A randomized trial of three antibiotic regimens for the treatment of pyelonephritis in pregnancy. Am J Obstet Gynecol 92:249, 1998

Wing DA, Hendershott CM, Debuque L, et al: Outpatient treatment of acute pyelonephritis in pregnancy after 24 weeks. Obstet Gynecol 94:683, 1999

Wing DA, Park AS, DeBuque L, et al: Limited clinical utiliry of blood and urine cultures in the treatment of acute pyelonephritis during pregnancy. Am J Obstet GynecoIs182:1437, 2000

Wright A], Gill JS: Strategies to prevent BK virus infection in kidney transplant recipients. Curr Opin Infect Dis 29(4):353, 2016

Wyatt RJ, Julian BA: IgA nephropathy. N Engl J Med 368(25):2402,s2013 Wyld ML, Clayton PA, Jesudason S, et al: Pregnancy outcomes for kidney transplant recipients. Am J Transplant 13:3173,s2013

Zanconato G, Bergamini V, Baggio S, et al: Successful pregnancy outcomes after laparoscopic cerclage in a patient with cervicovaginal fistula. Case Rep Obstet GynecoIs2015:784025, 2015

Zeeman GG, Cunningham GC, PritchardJA: he magnitude ofhemoconcentration with eclampsia. Hypertens Pregnancy 28(2):127,s2009

Zeeman GG, Wendel GO Jr, Cunningham FG: A blueprint for obstetric critical care. Am J Obstet Gynecol 188:532,2003

Zhang n, MaX, Hao L, et al: A systematic review and meta-analysis of outcomes of pregnancy in CKD and CKD outcomes in pregnancy. Clin J Soc Nephrols10(11):1964,s2015

Zhao C, Zhao J, Huang Y, et al: New-onset systemic lupus erythematosus during pregnancy. Clin Rheumatol 32(6):815, 2013

Zhou J, Pollak MR: Polycystic kidney disease and other inherited disorders of tubule growth and development. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill Education, 2015

GENERAL CONSIDERATIONS . . . . . . . ............. 1042

UPPER GASTROINTESTINAL TRACT DISORDERS ..... 1043

HYPEREMESIS GRAVIDARUM.. . . . . . . ............. 1043

GASTROESOPHAGEAL REFLUX DISEASE ........... 1046

PEPTIC ULCER DISEASE.. . . . . . . . . . . . ............. 1047

SMALL BOWEL AND COLON DISORDERS .......... 1047

ACUTE DIARRHEA.. . . . . . . . . . . . . . . . ............. 1047

INFLAMMATORY BOWEL DISEASE ....i....i........i.... 1048

INTESTINAL OBSTRUCTION . . . . . . . . ............. 1051

APPENDICITIS ..................i.............. 1052

The diagnosis of acute appendicitis is more dficult than at other times, as the enlarged uterus renders it almost impossible to explore the right iliac region satiactoriy.

-J. Whitridge Williams (1903) hese words summarize that during normal pregnancy, the gastrointestinal tract and its appendages undergo remarkable anatomical, physiological, and functional alterations. hese changes, which are discussed in detail in Chapter 4 (p. 68), can appreciably alter clinical findings normally relied on for diagnosis and treatment of gastrointestinal disorders such as appendicitis. Moreover, as pregnancy progresses, gastrointestinal symptoms become more diicult to assess. Physical findings are often obscured by a large uterus that displaces abdominal organs and can alter the location and intensity of pain and tenderness.

Fiberoptic endoscopic instruments have revolutionized diagnosis and management of most gastrointestinal conditions, and these are particularly well suited for pregnancy. Endoscopy in pregnancy is associated with a slightly increased risk for preterm birth, but this is likely due to the disease itself (Ludvigsson, 2017). With endoscopy, the esophagus, stomach, duodenum, and colon can be inspected (Cappell, 2011; Savas, 2014). The proximal jejunum can also be studied, and the ampulla of Vater cannulated to perform endoscopic retrograde cholangiopancreatography-ERCP (Akcakaya, 2014; Fogel, 2014). Preliminary data suggest that postendoscopic pancreatitis following gallstone removal may have a higher incidence in pregnant women (Inamdar, 2016). Experience in pregnancy with videocapsule endoscopy for small-bowel evaluation remains limited (Storch, 2006).

Upper gastrointestinal endoscopy is used for management as well as diagnosis of several problems. Common bile duct exploration and drainage are used for choledocholithiasis as described in Chapter 55 (p. 1070). It is also used for sclerotherapy and for placement of percutaneous endoscopic gastrostomy (PEG) tubes. Several concise reviews have been provided (Cappell, 2011; Fogel, 2014; Gilinsky, 2006).

For visualization of the large bowel, lexible sigmoidoscopy can be used safely in pregnant women (Siddiqui, 2006). Coonoscopy is indispensible for viewing the entire colon and distal ileum to aid diagnosis and management of several bowel disorders. Except for the midtrimester, reports of colonoscopy during pregnancy are limited, but most results indicate that it should be performed if indicated (Cappell, 2010, 2011; De Lima, 2015). Bowel preparation is completed using polyethylene glycol electrolyte or sodium phosphate solutions. With these, serious maternal dehydration that may cause diminished uteroplacental perusion should be avoided.

he obvious ideal technique for gastrointestinal evaluation during pregnancy is abdominal sonography. Because computed tomography (CT) use is limited in pregnancy due to radiation exposure, magnetic resonance (MR) imaging is now commonly used to evaluate the abdomen and retroperitoneal space (handelwal, 2013). One example is magnetic resonance cholangiopancreatography-MRCP (Oto, 2009). Another is magnetic resonance enterography-MRE (Stern, 2014). These and other imaging modalities, and their safe use in pregnancy, are considered in more detail in Chapter 46.

Surgery is lifesaving for certain gastrointestinal conditionsperforative appendicitis being the most common example. Laparoscopic procedures have replaced traditional surgical techniques for many abdominal disorders during pregnancy. hese are shown in detail with descriptions of surgical technique in Chapter 46 (p. 903) and in Cunningham and Gilstrap 5 Operative Obstetrics, 3rd edition (Kho, 2016). Guidelines for diagnosis, treatment, and use of laparoscopy for surgical problems during pregnancy have been provided by the Society of American Gastrointestinal and Endoscopic Surgeons-SAGES (Pearl, 2017).

Specialized nutritional support can be delivered enteraly, usually via nasogastric tube feedings, orparenteraly with nutrition given by venous catheter access, either peripherally or centrally.

When possible, enteral alimentation is preferable because it has fewer serious complications (Bistrian, 2012; Stokke, 2015). In obstetrical patients, very few conditions prohibit enteral nutrition as a first efort to prevent catabolism. For extreme cases, such as recalcitrant hyperemesis gravidarum, percutaneous endoscopic gastrostomy with a jejunal port (PEG-J tube) has been described (Saha, 2009).

he purpose of parenteral eeding, or hyperalimentation, is to provide nutrition when the intestinal tract must be quiescent. Central venous access is necessary for total parenteral nutrition because its hyperosmolarity requires rapid dilution in a highflow vascular system. hese solutions provide 24 to 40 kcall kg/ d, principally as a hypertonic glucose solution.

Not surprisingly, gastrointestinal disorders are the most common indication, and in the many studies cited, feeding duration averaged approximately 33 days.

Importantly, complications of parenteral nutrition are frequent, and they may be severe (Guglielmi, 2006). n early report of 26 pregnancies described a 50-percent rate of complications, which included pneumothorax, hemothorax, and brachial plexus injury (Russo-Stieglitz, 1999). he most frequent serious complication is catheter sepsis, and Folk (2004) reported a 25-percent incidence in 27 women with hyperemesis gravidarum. Although bacterial sepsis is most common, Candia septicemia has been described (Paranyuk, 2006). he Centers for Disease Control and Prevention has updated its detailed guidelines to prevent catheter-related sepsis, and these serve to lessen the dangers of serious infections (O'Grady, 2011). Perinatal complications are

TABLE 54-1. Some Conditions Treated with Enteral or Parenteral Nutrition During Pregnancya aOisorders are listed alphabetically.

Data from Folk, 2004; Guglielmi, 2006; Manliadevan, 2015;

Ogura, 2003; Porter, 2014; Russo-Stieglitz, 1999; Saha, 2009;

Spiliopoulos, 201n3 .

uncommon, however, fetal subdural hematoma caused by mater nal vitamin K deiciency has been described (Sakai, 2003).

Appreciable morbidity is also associated with long-term use of a peripheraly inserted central catheter (PICC). Infection is the most common serious long-term complication (Holmgren, 2008;

Ogura, 2003). In a series of84 such catheters inserted in 66 preg nant women, Cape and coworkers (2014) reported a 56-percent complication rate, of which bacteremia was the most frequent.

From a review of 48 reports of nonpregnant adults, Turcotte and associates (2006) concluded that peripherally placed catheters provided no advantages compared with centrally placed ones. Still, for short-term nutrition lasting a few weeks, it seems reasonable that PICC placement has a greater beneit-versusrisk ratio (Bistrian, 2012).

Mild to moderate nausea and vomiting are especially common in pregnant women until approximatel) 16 weeks' gestation (Chap. 9, p. 174). In a small but significant proportion of these, however, it is severe and unresponsive to simple dietary modiication and antiemetics. Severe unrelenting nausea and vomiting-hyperemesis gravidarum-is deined variably as being suiciently severe to produce weight loss, dehydration, ketosis, alkalosis from loss of hydrochloric acid, and hypokalemia. Acidosis develops from partial starvation. In some women, transient hepatic dysfunction develops, and biliary sludge accumulates (Matsubara, 2012). Other causes should be considered because ultimately hyperemesis gravidarum is a diagnosis of exclusion (Benson, 2013).

Study criteria have not been homogeneous, thus reports of population incidences vary. here does, however, appear to be an ethnic or familial predilection (Grjibovski, 2008). In population-based studies from California, Nova Scotia, and Norway, the hospitalization rate for hyperemesis gravidarum was 0.5 to 1 percent (Bailit, 2005; Fell, 2006; Vikanes, 2013). Up to 20 percent of those hospitalized in a previous pregnancy for hyperemesis will again require hospitalization (Dodds, 2006; Trogstad, 2005). In general, obese women are less likely to be hospitalized for this (Cedergren, 2008).

The etiopathogenesis of hyperemesis gravidarum is unknown and is likely multifactorial. It apparently is related to high or rapidly rising serum levels of pregnancy-related hormones. Putative culprits include human chorionic gonadotropin (hCG), estrogen, progesterone, leptin, placental growth hormone, prolactin, thyroxine, and adrenocortical hormones (Verberg, 2005). More recently implicated are other hormones that include ghrelins, leptin, nesfatin-1, and peptide Y (3-36) (Albayrak, 2013; Gungor, 2013).

Superimposed on this hormonal cornucopia are an imposing number of biological and environmental factors. Moreover, in some but not all severe cases, interrelated psychological components playaa major role (Christodoulou-Smith, 20a11a; McCarthy, 2011). Other factors that increase the risk for admission include hyperthyroidism, previous molar pregnancy, diabetes, gastrointestinal illnesses, some restrictive diets, and asthma and other allergic disorders (Fell, 2006; Mullin, 2012). n association of Helicobacter pylori infection has been proposed, but evidence is not conclusive (Goldberg, 2007). Chronic marijuana use may cause the similar cannabinoid hyperemesis syndrome (Alaniz, 2015; Andrews, 2015). And for unknown reasons-perhaps estrogenrelated-a female fetus increases the risk by 1.5-fold (Schif, 2004; Tan, 2006; Veenendaal, 2011). Finally, some but not all studies have reported an association between hyperemesis gravidarum and preterm labor, placental abruption, and preeclampsia (Bolin, 2013; Vandraas, 2013; Vikanes, 20l3).

Vomiting may be prolonged, frequent, and severe, and a list of potentially fatal complications is given in Table 54-2. Various

TABLE 54-2. Some Serious and Life-Threatening Complications of Recalcitrant Hyperemesis Gravidarum

Acute kidney injury-may require dialysis Depression-cause versus efect? Diaphragmatic rupture

Esophageal rupture-Boerhaave syndrome Hypoprothrombinemia-vitamin K deficiency Hyperalimentation complications Mallory-Weiss tears-bleeding, pneumothorax, pneumomediastinum, pneumopericardium Rhabdomyolysis degrees of acute kidney injury from dehydration are encountered (Nwoko, 2012). An extreme example was a woman we cared for who required 5 days of dialysis when her serum creatinine level rose to 10.7 mg/dL (Hill, 2002). One complication from continuous retching is a Mallory-Weiss tear. Others are pneumothorax, pneumomediastinum, diaphragmatic rupture, and gastroesophageal rupture-Boerhaave syndrome (American College of 0bstetricians and Gynecologists, 2015; Chen, 2012).

At least two serious vitamin deiciencies have been reported with hyperemesis in pregnancy. One is Wernicke encephalopathy from thiamine deiciency that has been recognized with increasing frequency (Di Gangi, 2012; Palacios-vIarques, 2012). In two reviews, ocular signs, confusion, and ataxia were common, but only half had this triad (Chiossi, 2006; Selitsky, 2006). With this encephalopathy, an abnormal electroencephalogram (EEG) may be seen, and usually MR imaging shows findings (Vaknin, 2006; Zara, 2012). At least three maternal deaths have been described, and long-term sequelae include blindness, convulsions, and coma (Selitsky, 2006). he second is vitamin K deicieny that has been reported to cause maternal coagulopathy and fetal intracranial hemorrhage, as well as vitamin K embryopathy (Kawamura, 2008; Lane, 2015; Sakai, 2003).

One algorithm for management of nausea and vomiting of pregnancy is shown in Figure

Most women with mild

Mild Dietary management; Ginger extract; Vitamin 86 plus doxylamine, diphenhydramine, or dimenhydrinate Moderate Severe Promethazine, Intravenous hydration prochlorperazine, with thiamine; trimethobenzamide, Parenteral: chlorpromazine, metoclopramide, metoclopramide, or promethazine, or ondansetron ondansetron (oral, rectal, parenteral) Intractable Enteral or parenteral nutrition ment of hyperemeSis gravidarum.

TABLE 54-3. Medications for Gastric Disorders in Pregnancy

At bedtime; up to 4 times daily 12.5-25 mg 1M, IV, PO, PR 1M, IV, PO, PR

IV, PO 1M, IV, PO

Pantoprazole (Protonix)b Lansoprazole (Prevacid)b Omeprazole (Prilosec, Zegeridr Dexlansoprazole (Dexilant)C 400 mg 4 times daily for up to 12 wks 800 mg twice daily for up to 12 wks 150 mg twice daily 20 mg twice daily up to 6 wks 40 mg daily for up to 8 wks 15 mg daily for up to 8 wks 20 mg daily for 4-8 wks 30 mg daily for up to 4 wks aFood and Drug Administration category A. bFood and Drug Administration category B. (Food and Drug Administration category C.

to moderate symptoms respond as outpatients to any of several irst-line antiemetic agents (Clark, 2014; Matthews, 2014). One that is becoming a mainstay is Diclegis-a combination of doxylamine (10 mg) plus pyridoxine (10 mg). It has been proven safe and efective (Briggs, 2015; Koren, 2014). The usual dose is two tablets orally at bedtime. If relief is insufficient, then additional doses, first in the morning, and then in the morning and midafternoon can be added each day to the bedtime dose. At our institution, for cost savings, we prescribe these two agents individually: Unisom (doxylamine) Y2 of a 50-mg tablet plus a 25-mg vitamin B6 tablet. The same graduated dosing is used but does not exceed three total daily doses.

Ondansetron (Zofran) also does not appear to be teratogenic.

It was slightly more eicacious than a combination of doxylamine and pyridoxine in a randomized trial (Oliveira, 2014; Pasternak, 2013). Its drawbacks include potential maternal efects from prolonged QT-interval and serotonin syndrome (Koren, 2014).

When simple measures fail, intravenous crystalloid solutions are given to correct dehydration, ketonemia, electrolyte deicits, acid-base imbalances, and hypokalemia. No benefits are gained by infusing 5-percent dextrose along with crystalloids (Tan, 20l3). Thiamine, 100 mg, is given to prevent Wernicke encephalopathy (Giugale, 2015; Niebyl, 2010). his is usually diluted in 1 L of the selected crystalloid and infused at the maintenance rate desired for patient hydration.

If vomiting persists after rehydration and failed outpatient management, hospitalization is recommended (American College of Obstetricians and Gynecologists, 2015). Day care has also been shown to be efective in one randomized study (McCarthy, 2014). Intravenous hydration is continued and antiemetics such as promethazine, prochlorperazine, chlorpromazine, or metoclopramide are given parenterally (Table 54-3). The bulk of evidence is that treatment with glucocorticosteroids is not efective (Yost, 2003). Because of their putative teratogenicity, they are not routinely recommended (American College of Obstetricians and Gynecologists, 2015).

With persistent vomiting after hospitalization, appropriate steps should be taken to exclude possible underlying diseases as a cause of hyperemesis. That said, in one study, endoscopy did not change management in 49 women (Debby, 2008). Other potential causes of vomiting include gastroenteritis, cholecystitis, pancreatitis, hepatitis, peptic ulcer, and pyelonephritis. In addition, severe preeclampsia and fatty liver are more likely after midpregnancy. And although clinical thyrotoxicosis has been implicated as a cause of hyperemesis, it is more likely that abnormally elevated serum thyroxine levels are a surrogate for higher-than-average serum hCG levels (Sun, 2014). This is discussed further in Chapter 5 (p. 100). In our experiences, serum free thyroxine levels normalize quickly with hydration and emesis treatment.

With treatment, most women will have a salutary response and may be sent home with antiemetic therapy. Their readmission rate is 25 to 35 percent in most prospective studies. If associated psychiatric and social factors contribute to the illness, the woman usually improves remarkably while hospitalized (Swallow, 2004). That said, symptoms may relapse in these women, and some go on to develop posttraumatic stress syndrome (Christodoulou-Smith, 2011; McCarthy, 2011). For some women, hyperemesis can be an indication for elective termination (Poursharif, 2007).

In the small percentage of women who continue to have recalcitrant vomiting after intensive therapy, consideration is given for enteral nutrition (p. 1043). Stokke and associates (2015) described successful use of nasojejunal feeding for up to 41 days in 107 such women. Use of sonography to conirm correct placement of the tube has been described (Swartzlander, 2013). Percutaneous endoscopic gastrostomy with a jejunal port has also been reported (Saha, 2009; Schrag, 2007). A randomized trial failed to show any advantages from early enteral feeding (Grooten, 2017).

In our experiences, only a very few women will require parenteral nutrition (Yost, 2003). In a study of 599 women, however, Peled and coworkers (2014) reported that 20 percent required central venous access to be established for nutrition.

Symptomatic reflux is seen in up to 15 percent of nonpregnant individuals (Kahrilas, 2015). he spectrum of sequelae includes esophagitis, stricture, Barrett esophagus, and adenocarcinoma. The main symptom of relux is heartburn, or pyrosis, which is especially common in pregnancy. Its prevalence rose from 26 percent in the irst trimester to 36 percent in the second and 51 percent in the third trimesters (Malfertheiner, 2012). The retrosternal burning sensation stems from esophagitis caused by gastroesophageal relux related to relaxation of the lower esophageal sphincter.

Reflux symptoms usually respond to tobacco and alcohol abstinence, small meals, head of the bed elevation, and avoidance of postprandial recumbency. So-called "trigger" foods are also avoided and usually include fatty foods, tomato-based foods, and cofee. Oral antacids are first-line therapy. If severe symptoms persist, sucralfate (Carafate) is given along with a protonpump inhibitor or an H2-receptor antagonist (see Table 54-3). Both classes are generally safe for use in pregnancy (Briggs, 2015; Mahadevan, 2006b). Of these, a 1-g sucralfate tablet is taken orally 1 hour before each of the three meals and at bedtime for up to 8 weeks. Antacids are not used within Y2 hour before or after sucralfate doses. If relief is not attained, then endoscopy should be considered. Misoprostol is contraindicated because it stimulates labor (Chap. 26, p. 508).

In nonpregnant patients, surgical fundoplication is performed (Kahrilas, 2015). Although the procedure is not done during pregnancy, Biertho and colleagues (2006) described 25 women who had undergone laparoscopic Nissen fundoplication before pregnancy. Only 20 percent had relux symptoms during pregnancy.

he older literature is informative regarding hiatal hernias in pregnancy. Upper gastrointestinal radiographs performed in 195 women in late pregnancy showed that 20 percent of 116 multiparas and 5 percent of 79 nulliparas had a hiatal hernia (Rigler, 1935). Of 10 women studied postpartum, hernia persisted in three at 1 to 18 months.

he relationship of hiatal hernia with reflux esophagitis, and thus symptoms, is not clear. One study demonstrated no relationship between reflux and hernia and showed that the lower esophageal sphincter functioned efectively even when displaced intrathoracically (Cohen, 1971) . Nevertheless, during pregnancy, these hiatal hernias may cause vomiting, epigastric pain, and bleeding from ulceration. Schwentner (201a1) reported severe herniation requiring surgical repair in a woman with a 12-week gestation. Curran and coworkers (1999) described a 30-week pregnancy complicated by gastric outlet obstruction from a paraesophageal hernia.

These are caused by herniations of abdominal contents through either the foramen of Bochdalek or vforgagni. Fortunately, they rarely complicate pregnancy. Kurzel and associates (1988) reviewed the outcomes of 18 pregnant women with such a hernia and who developed acute obstruction. Because the maternal mortality rate was 45 percent, they recommend repair during pregnancy even if a woman is asymptomatic. Herniation has been reported in one pregnant woman from a previous traumatic diaphragmatic defect and in another who had antirelux surgery in early pregnancy (Brygger, 2013; Flick, 1999). Several case reports also describe spontaneous diaphragmatic rupture from increased intraabdominal pressure during delivery (Chen, 2012; Sharifah, 2003).

his is a rare motility disorder in which the lower esophageal sphincter does not relax properly with swallowing. There is also nonperistaltic contraction activity of the esophageal muscularis to cause symptoms (Kahrilas, 2015; Khudyak, 2006). The defect is caused by inflammatory destruction of the myenteric (Auerbach) plexus within smooth muscle of the lower esophagus and its sphincter. Postganglionic cholinergic neurons are unafected, thus, sphincter stimulation is unopposed. Symptoms are dysphagia, chest pain, and regurgitation. Barium swallow radiography demonstrates bird beak or ace of spades narrowing at the distal esophagus. Endoscopy is performed to exclude gastric carcinoma, and manometry is confirmatory. If dilatation of the esophagus and medical therapy does not provide relief, myotomy is considered (Torquati, 2006).

During pregnancy, normal relaxation of the lower esophageal sphincter in women with achalasia theoretically should not occur. Even so, in most women, pregnancy does not seem to worsen achalasia. One report of 20 afected pregnant women found no excessive relux esophagitis (Mayberry, 1987). Khudyak and coworkers (2006) reviewed 35 cases and described most women as symptom free, although esophageal dilatation was needed in a few. A maternal death was reported at 24 weeks' gestation associated with perforation of a 14-cm diameter megaesophagus (Fassina, 1995).

Management of achalasia includes soft diet and anticholinergic drugs. With persistent symptoms, other options include nitrates, calcium-channel antagonists, and botulinum toxin A injected locally (Hooft, 2015; Kahrilas, 2015). Balloon dila tation of the sphincter may be necessary, and 85 percent of nonpregnant patients respond to this. Satin (1a992) and Fiest (1993) and their associates reported successful use of pneu matic dilatation in pregnancy. One caveat is that esophageal peroration is a serious complication of dilatation. Spiliopoulos and colleagues (2013) described a 29-week pregnant woman with achalasia treated for 10 weeks with parenteral nutrition. Surgical correction was performed postpartum.

he lifetime prevalence of acid peptic disorders in women is 10 percent (Del Valle, 2015). Erosive ulcer disease involves the stomach and duodenum. Gastroduodenal ulcers may be caused by chronic gastritis from H pylori, or they develop from nonsteroidal antiinlammatory drug (NSAID) use. Neither is common in pregnancy (McKenna, 2003; Weyermann, 2003). Acid secretion is also important, and thus underlies the eicacy of antisecretory agents (Suerbaum, 2002). Gastroprotection during pregnancy probably originates from physiological changes that include reduced gastric acid secretion, decreased motility, and considerably increased mucus secretion (Hytten, 1991). Despite this, ulcer disease may be underdiagnosed because of frequent treatment for reflux esophagitis (Mehta, 2010). In the past 50 years at Parkland Hospital, during which time we have cared for more than 500,000 pregnant women, we have encountered very few who had proven ulcer disease. Perforation is rare (Goel, 2014). Before appropriate therapy was commonplace, Clark (1953) studied 313 pregnancies in 11a8 women with ulcer disease and noted a clear remission during pregnancy in almost 90 percent. However, beneits were short lived. Symptoms recurred in more than half by 3 months postpartum and in almost all by 2 years.

The mainstay of management is eradication of H pylori and prevention of NSAID-induced disease. Antacids are usually self-prescribed, but irst-line therapy is with HTreceptor blockers or proton-pump inhibitors (Del Valle, 2015). Sucraote is the aluminum salt of sulfated sucrose that inhibits pepsin. It provides a protective coating at the ulcer base. Approximately 10 percent of the aluminum salt is absorbed, and it is considered safe for pregnant women (Briggs, 2015).

With active ulcers, a search for H pylori is undertaken.

Diagnostic aids include the urea breath test, serological testing, or endoscopic biopsy. If any of these yield positive results, combination antimicrobial and proton-pump inhibitor therapy is indicated. Several efective oral treatment regimens do not include tetracycline and can be used during pregnancy. hese 14-day regimens include amoxicillin, 1000 mg twice daily plus clarithromycin, 250 to 500 mg twice daily, plus metronidazole, 500 mg twice daily given along with the proton-pump inhibitor omeprazole (Del Valle, 2015).

In some women, persistent vomiting is accompanied by worrisome upper gastrointestinal bleeding. Occasionally, a peptic ulceration is the source. However, most of these women have small linear mucosal tears near the gastroesophageal junction-Malloy-Weiss tears, described earlier. Bleeding usually responds promptly to conservative measures, including iced-saline irrigations, topical antacids, and intravenously administered HTblockers or protonpump inhibitors. Transfusions may be needed, and if bleeding persists, then endoscopy is usually indicated (O'Mahony, 2007). With sustained retching, the less common, but more serious, esophageal rupture-Boerhaave syndrome-may develop from greatly increased esophageal pressure.

The small bowel has diminished motility during pregnancy.

Using a nonabsorbable carbohydrate, Lawson (1985) showed that small bowel mean transit times were 99, 125, and 137 minutes in each trimester, compared with 75 minutes when nonpregnant. In a study cited by Everson (1992), mean tran sit time for a mercury-illed balloon from the stomach to the cecum was 58 hours in term pregnant women compared with 52 hours in nonpregnant women.

Muscular relaxation of the colon is accompanied by increased absorption of water and sodium that predisposes to consti pation. This complaint is reported by almost 40 percent of women at some time during pregnancy (Everson, 1992). Such symptoms are usually only mildly bothersome, and preventive measures include a high-iber diet and bulk-forming lxatives.

Wald (2003) has reviewed treatment options. We have encoun impacted stool. These women almost invariably had chronically abused stimulatory laxatives.

he estimated monthly prevalence of diarrhea among adults is 3 to 7 percent (DuPont, 2014). Diarrhea can be classiied as acute «2 weeks), persistent (2 to 4 weeks), and chronic (>4 weeks). Most cases of acute diarrhea are caused by infectious agents, and a third result from foodborne pathogens. The large variety of viruses, bacteria, helminths, and protozoa that cause diarrhea in adults inevitably also alict pregnant women. Some of these are discussed in Chapter 64. Evaluation of acute diarrhea depends on its severity and duration. Some indications for evaluation include profuse watery diarrhea with dehydration, grossly bloody stools, fevera> 38°C, duration >48 hours without improvement, recent antimicrobial use, and diarrhea in the immunocompromised patient (Camilleri, 2015; DuPont, 2014). Cases of moderately severe diarrhea with fecal leukocytes or gross blood may best be treated with empirical antibiotics rather than evaluation. Some features of the more common acute diarrheal syndromes and their treatment are shown in Table 54-4.

The mainstay of treatment is intravenous hydration using normal saline or Ringer lactate with potassium supplementation in amounts to restore maternal blood volume and to ensure uteroplacental perfusion. Vital signs and urine output are monitored for signs of sepsis syndrome. For moderately severe nonfebrile illness without bloody diarrhea, antimobility agents such as loperamide (Imodium) may be useful. Bismuth subsalicylate (Pepto-Bismol) may also alleviate symptoms.

TABLE 54-4. Etiology, Clinical Features, and Treatment of Common Acute Diarrheal Syndromes

Toxin producers 1-72 hr 3-4+ 1-2+ 0-1 + 3-4+, watery 1.

Staphylococcus 1. None 2.

C perfringens 2. None 3.

1-2+ 1-3+, watery, 1.

C difficile then bloody 1. Metronidazole 2.

3. Salmonella bloody 4. Campylobacter 5. Vibrio 5. Doxycycline

Severe 1-8 days 0-1 + 3-4+ 3-4+ 1-2+, bloody 6.

Shigella 6. Ciprofloxacin 7.

E coli 7. Ciprofloxacin 8. Entamoeba histolytica 8. Metronidazole

B cereus = Bacillus cereus; C difficile = Clostridium difficile; C perfringens = Clostridium perfringens; E coli = Escherichia coli.

Data from Camilleri, 201 5; DuPont, 201 4.

Judicious use of antimicrobial agents is warranted. For moderate to severely ill women, some recommend empirical treatment with ciprofloxacin, 500 mg twice daily for 3 to 5 days. Speciic pathogens are treated as needed when identiied (see Table 54-4). Syndromes for which treatment is usually unnecessary include those caused by Escherichia coli, staphylococcal species, Bacilus cereus, and Norwalk-like virus. Severe illness caused by Salmonela spp is treated with ciprofloxacin or trimethoprim-sulfamethoxazole; by Campylobacter spp with azithromycin; by Clostridium diicile with oral metronidazole or vancomycin; and by Giardia spp and Entamoeba histoytica with metronidazole (DuPont, 2014; Rocha-Castro, 2016).

his anaerobic gram-positive bacillus is transmitted by the fecal-oral route. It is the most frequent nosocomial infection in the United States. In 2011, 453,000 cases of C dicile and 29,000 associated deaths were reported by the Centers for Disease Control and Prevention (CDC) (Lessa, 2015). he most important risk factor is antibiotic use, and the highest risk is with aminopenicillins, clindamycin, cephalosporins, and luoroquinolones. Other risk factors include inlammatory bowel disease, immunosuppression, advanced age, and gastrointestinal surgery. Most cases are hospital-acquired, however, community-acquired cases are becoming common (Leler, 2015). With severe colitis, the infection-related mortality rate is 5 percent.

Diagnosis is by enzyme immunoassay for toxins in the stool, or by DNA-based tests that identiy toxin genes. Only patients with diarrhea should be tested, and posttreatment testing is not recommended. Prevention is by soap-and-water hand washing, and infected individuals are isolated. Treatment is oral vancomycin or metronidazole. The risk of recurrence after an initial episode is 20 percent. Fecal microbial transplantation may become standard for recurrent clostridial colitis.

Two presumably noninfectious forms of intestinal inlammation are ulcerative colitis and Crohn disease. Diferentiation between these is important because treatment difers. That said, they both share common features, and sometimes are indistinguishable if Crohn disease involves the colon. he salient clinical and laboratory features shown in Table 54-5 permit a reasonably confident diagnostic diferentiation in most cases. he etiopathogenesis is enigmatic in both, but a genetic predisposition is suspected. Inlammation is thought to result from dysregulated mucosal immune function in response to commensal microbiota, with or without an autoimmune component (Friedman, 2015).

TABLE 54-5. Some Shared and Diferentiating Characteristics of Inflammatory Bowel Disease

Hereditary More than 100 disease-associated genetic loci-a third shared; Jewish predominance; familial in 5-10% of cases; Turner syndrome; immune dysregulation

Other Chronic and intermittent with exacerbations and remissions; extraintestinal manifestations: arthritis, erythema nodosum, uveitis

Major symptoms Diarrhea, tenesmus, rectal bleeding, cramping pain; Fibrostenotic-recurrent RLQ colicky pain; fever chronic, intermittent bladder, interenteric Bowel involvement Mucosa and submucosa of large bowel; usually begins Deep layers small and large bowel; at rectum (40% proctitis only); continuous disease commonly transmural; discontinuous involvement; strictures and fistulas

RLQ = right lower quadrant; S cerevisiae = Saccharomyces cerevisiae. Data from Friedman, 201n5; Lichtenstein, 2009; Podolsky, 2002.

Ulcerative Colitis and erythema nodosum. Another serious problem is that the risk of colon cancer approaches 1 percent per year. With either

This is a mucosal disorder with inflammation confined to the ulcerative colitis or Crohn disease, there is also concern for possuperficial luminal layers of the colon. It typically begins at the sible increased risks for venous thromboembolism (Kappelman, rectum and extends proximally for a variable distance. In approx2011; Novacek, 2010).

imately 40 percent of cases, disease is conined to the rectum and rectosigmoid, but 20 percent have pancolitis. For unknown reasons, prior appendectomy protects against development of ulcerative coli tis (Friedman, 2015). Endoscopic indings include Also known as regional enteritis, Crohn ileitis, and granulomucosal granularity and friability that is interspersed with mucomatous colitis, Crohn disease has more protean manifestations sal ulcerations and a mucopurulent exudate (Fig. 54-2). than ulcerative colitis. It involves not only the bowel mucosa but

Major symptoms of ulcerative colitis include diarrhea, rectal also the deeper layers, and sometimes involvement is transmural bleeding, tenesmus, and abdominal cramps. The disease can be (see Fig. 54-2). Lesions can be seen throughout the entire gasacute or intermittent and is characterized by exacerbations and trointestinal tract, from the mouth to the anus, but it typically remissions. Toxic megacolon and catastrophic hemorrhage are is segmental (Friedman, 2015). Approximately 30 percent of particularly dangerous complications that may necessitate colpatients have small-bowel involvement, 25 percent have isolated ectomy. Extraintestinal maniestations include arthritis, uveitis, colonic involvement, and 40 percent have both, usually with the terminal ileum and colon involved. Perianal fistulas and abscesses develop in a third of those with colonic involvement.

Symptoms depend on which bowel segment(s) is involved. Thus, complaints may include lower-right-sided cramping abdominal pain, diarrhea, weight loss, lowgrade fever, and obstructive symptoms. The disease is chronic with exacerbations and remissions, and importantly, it cannot be cured medically or surgically. Approximately a third of patients require surgery within the first year ater diagnosis, and thereater, 5 percent per year. Reactive arthritis is common, and the gastrointestinal cancer risk, although not as great as. with ulcerative colitis, is increased substantially.

FIGURE 54-2 Causes of colitis. A.Chronic ulcerative colitis with diffuse ulcerations and exudates. B. Crohn colitis with deep ulcers. (Reproduced with permission from Song LM Topazian M: Gastointestinal endoscopy. Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York: McGraw-Hili Education; 201o5.)

Subfertility is commonly linked to chronic medical disease, but 1VIahadevan (2006a) cited a normal fertility rate for inflammatory bowel disease unless severe disease warranted surgery. Similarly, Alstead (2003) reported that decreased female fertility from active Crohn disease returned to normal with remission. For women requiring surgical resection, laparoscopic anastomosis has a higher subsequent fertility rate (Beyer-Berjot, 2013). With colectomy, however, even though fertility is improved, up to half of women will be persistently infertile (Bartels, 2012). Sexual function and fertility are only modestly afected by ileal pouch-anal anastomosis (Hor, 2016). Subfertility may also be partially due to sulfasalazine, which causes reversible sperm abnormalities (Feagins, 2009).

Because ulcerative colitis and Crohn disease are relatively common in young women, they are encountered with some frequency in pregnancy. In this regard, a few generalizations can be made. First, consensus supports that pregnancy does not increase the likelihood of an inlammatory bowel disease flare (.1ahadevan, 2015). Indeed, in a 10-year surveillance of women in the European Collaborative on Inflammatory Bowel Disease, the likelihood of a lare during pregnancy was decreased compared with the preconceptional rate (Riis, 2006). Although most women with quiescent disease in early pregnancy do not have relapses, when a lare develops, it may be severe. lso, active disease in early pregnancy increases the likelihood of poor pregnancy outcome, which is discussed subsequently. In general, most usual treatment regimens may be continued during pregnancy. Diagnostic evaluations should be undertaken if needed to direct management, and surgery should be performed if indicated. For women who successfully complete pregnancy, about half experience improvement in their health-relate.d q uali ty of life (Ananthakrishnan, 2012).

At first glance, it appears that adverse pregnancy outcomes are increased with inflammatory bowel disease (Boyd, 2015; Cornish, 2012; Getahun, 2014). Initially, this was attributed to the fact that most studies included women with either form of disease. Specifically, Crohn disease was noted to be linked to excessive morbidity (Dominitz, 2002; Stephansson, 2010). But, according to Reddy (2008) and others, these adverse outcomes were in women with severe disease and multiple recurrences. Indeed, in the prospective European case-control ECCO-EpiCom study of 332 pregnant women with inflammatory bowel disease, Bortoli and coworkers (2011) found similar outcomes in women with ulcerative colitis or Crohn disease compared with normally pregnant women. Importantly, perinatal mortality rates are not appreciably increased.

Ulcerative Colitis and Pregnancy. Ulcerative colitis does not signiicantly alter the course of pregnancy in afected women. In one review of 755 pregnancies, colitis that was quiescent at conception worsened in approximately a third of pregnancies (Fonager, 1998). In women with active disease at the time of conception, approximately 45 percent worsened, 25 percent remained unchanged, and only 25 percent improved. hese observations are similar to those previously described in an extensive review by Miller (1986) and a later report from Oron and colleagues (2012).

Osteoporosis is a signiicant complication in up to a third of these women, and thus vitamin D-800 IU daily-and calcium-1200 mg daily-are given. Folic acid, 4 mg orally daily, is recommended preconceptionally and during the first trimester for neural-tube defect prevention. his high dose counteracts the antifolate actions of sulfasalazine. Flares may be caused by psychogenic stress, and reassurance is important.

Management for colitis for the most part mirrors that outside of pregnancy. Treatment of active colitis and maintenance therapy incorporate drugs that deliver 5-aminosalicyclic acid (5-ASA) or mesalamine. Suasalazine (Azuidine) is the prototype, and its 5-ASA moiety inhibits prostaglandin synthase in colonic mucosa. Others include olsalazine (Dipentum), balsalazide (Colazal), and delayed-release 5-ASA derivatives (Apriso, Asacol Pentasa, Lialda). Glucocorticoids are given orally, parenterally, or by enema for moderate or severe disease that does not respond to 5-ASA. However, these latter drugs are not given for maintenance therapy. Recalcitrant disease is managed with immunomodulating drugs, including azathioprine, 6-mercaptopurine, or cyclosporine, which appear relatively safe in pregnancy (Briggs, 2015; Mozafari, 2015). Importantly, methotrexate is contraindicated in pregnancy.

In the past, biological therapy was reserved for recalcitrant moderate to severe disease. Because of their considerable eicacy, these medications are now frequently given initialy for severe disease to prevent future complications. These agents are antibodies against tumor necrosis factor-alpha (TNF-alpha). Those approved for treatment of ulcerative colitis include inf liximab (Rem icade) , adalimumab (Hum ira), and golinumab (Simponi). These drugs are administered intravenously or subcutaneously. Several studies indicate that they are safe for use in pregnancy, although there are concerns that their discontinuance may prompt a relapse (Torres, 2015). Another worry is that they may cause immunosuppression in the neonate (Brams, 2016; Diav-Citrin, 2014; Gisbert, 20l3).

Colorectal endoscopy is performed as indicated (Katz, 2002).

During pregnancy, colectomy and ostomy creation for fulminant colitis may be needed as a lifesaving measure, and it has been described during each trimester. Dozois (2006) reviewed 42 such cases and found that, in general, outcomes have been good in recent reports. Most women underwent partial or complete colectomy, but Ooi and colleagues (2003) described decompression colostomy with ileostomy in a 10-and a 16-week pregnancy. Parenteral nutrition discussed on page 1043 is occasionally necessary for women with prolonged exacerbations.

For women with an ileal pouch and an anal anastomosis performed before pregnancy, sexual function and fertility are improved (Cornish, 2007). Disadvantages that temporarily worsen in pregnancy include frequent bowel movements, fecal incontinence, and pouchitis. he last is an inflammatory condition of the ileoanal pouch probably due to bacterial proliferation and stasis. Pouchitis usually responds to cephalosporins or metronidazole. In one rare case, adhesions to the growing uterus led to ileal pouch perforation (Aouthmany, 2004).

(Ravid, 2002). Hahnloser (2004) reviewed routes of delivery in women with 235 pregnancies before and 232 pregnancies after ileoanal pouch surgery. Functional outcomes were similar, for obstetrical indications. Postcesarean delivery ileoanal pouch obstruction has been described (Malecki, 2010).

To reiterate, ulcerative colitis likely has minimal adverse efects on pregnancy outcome. Modigliani (2000) reviewed to be not substantively diferent from those in the general obstetrical population. Speciically, the incidences of spontane ous abortion, preterm delivery, and stillbirth were remarkably low. In a population-based cohort study of 107 women from

Washington state, perinatal outcomes, with two exceptions, were similar to those of 1308 normal pregnancies (Dominitz, 2002). One exception was an inexplicably increased incidence of congenital malformations. These authors and others also compared with that for normal controls (Mahadevan, 2015).

lar outcomes in 187 gravidas with ulcerative colitis compared with normal pregnant controls (Bortoli, 2011).

Crohn Disease and Pregnancy. In general, Crohn disease activity during pregnancy is related to its status around the time of conception. In a cohort study of 279 pregnancies in 186 women whose disease was inactive at conception, a fourth relapsed during pregnancy (Fonager, 1998). In 93 with active disease at conception, however, two thirds either remained active or worsened. Miller (1986) had described similar findings from his earlier review, as did Oron and associates (20a12).

Calcium, vitamin D, and folic acid supplementation mirror that for ulcerative colitis. For maintenance during asymptomatic periods, no regimen is universally efective. Suasalazine is efective for some, but the newer 5-ASA formulations are better tolerated. Prednisone therapy may control moderate to severe lares but is less efective for small-bowel involvement. Immunomodulators such as azathioprine, 6-mercaptopurine, and cyclosporine are used for active disease and for maintenance. These appear relatively safe during pregnancy (Briggs, 2015; Chande, 2015). As discussed in Chapter 12 (pp. 242 and 244), methotrexate, mycophenolate mofetil, and mycophenolic acid are contraindicated in pregnancy (Briggs, 2015; Food and Drug Administration, 2008).

As with ulcerative colitis, treatment with antitumor necrosis factor monoclonal antibodies is often used initially for active Crohn disease and maintenance (Casanova, 2013; Cominelli, 2013; Friedman, 2015). These biological compounds include inliximab, adalimumab, certolizumab (Cimzia), natalizumab (Tysabri), and vedolizumab (Enyvio). As discussed on page 1050, this class of immunomodulators is considered safe in pregnancy (Briggs, 2015; Clowse, 2015). heir discontinuance may be followed by a relapse (Torres, 2015).

Endoscopy or conservative surgery is indicated for complications. Patients with small-bowel involvement are more likely to require surgery for complications that include istulas, strictures, abscesses, and intractable disease. An abdominal surgical procedure was required during 5 percent of pregnancies described by Woolfson (1990). Parenteral hyperalimentation

Stieglitz, 1999). hose with an ileal loop colostomy may have signiicant problems. Women with a perianal istula-unless these are rectovaginal-usually can undergo vaginal delivery without complications (Forsnes, 1999; Takahashi, 2007).

As discussed, the likelihood is greater that Crohn disease is associated with adverse pregnancy outcomes compared with ulcerative colitis (Stephansson, 2010). Outcomes are probably related to disease activities. In a case-control Danish study,

Norgard (2007) reported a twofold risk of preterm births.

preterm delivery, low birthweight, fetal growth restriction, and cesarean delivery in 149 women with Crohn disease. Recall, however, that the prospective ECCO-EpiCom study found outcomes to be similar to those for normal pregnancies.

A colostomy or an ileostomy can be problematic during pregnancy because of its location (Hux, 2010). In a report of 82 pregnancies in 66 women with an ostomy, stomal dyfunction was common, but it responded to conservative management in most cases (Gopal, 1985). Surgical intervention was necessary, however, in three of six women who developed boweliobstruction and in another four with ileostomy prolapse-almost 10 percent overall. In this older study, only a third of 82 women underwent cesarean delivery, but Takahashi (2007) described six of seven cesarean deliveries in women with Crohn disease and a stoma. Although adhesions usually are involved with an obstructed ileostomy, the enlarging uterus may act to obstruct (Porter, 2014). Finally, Farouk and coworkers (2000) reported that pregnancy did not worsen long-term ostomy function.

The incidence of bowel obstruction is not increased during pregnancy, although it generally is more diicult to diagnose.

Meyerson (1995) reported a 20-year incidence of 1 in 17,000 deliveries at two Detroit hospitals. In one study, adhesive dis ease leading to small-bowel obstruction was the second most common cause of an acute abdomen in pregnancy following appendicitis-15 versus 30 percent, respectively (Unal, 2011). Approximately half of cases are due to adhesions from previous pelvic surgery that includes cesarean delivery (Al-Sunaidi, 2006; Andolf, 2010; Lyell, 2011). Another 25 percent of bowel obstruction cases are caused by volvulus-sigmoid, cecal, or small bowel. hese have been reported in late pregnancy or early puerperium (Bade, 2014; Biswas, 2006; l Maksoud, 2015). Small-bowel obstruction has been reported in pregnancy following the currently popular Roux-en-Y gastric bypass for weight loss (Bokslag, 2014; Wax, 2013). Intussusception is occasionally encountered (Bosman, 2014; Harma, 201l). Bowel obstruction subsequent to colorectal surgery for cancer was increased threefold in women who had open versus laparoscopic surgery (Haggar, 2013). Finally, Serra and colleagues (2014) described a massive ventral hernia with intestinal obstruction.

FIGURE 54-3 Characteristic "bent inner tube" seen with sigmoid volvulus on abdominal radiograph. (Reproduced with permission from Song LM, Topazian M: Gastointestinal endoscopy. Kasper

DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York: McGraw-Hili Education; 2015.)

Most cases of intestinal obstruction during pregnancy result from pressure of the growing uterus on intestinal adhesions. According to Davis and Bohon (1983), this more likely occurs around midpregnancy when the uterus becomes an abdominal organ; in the third trimester when the fetal head descends; or immediately postpartum when uterine size acutely shrinks. Perdue (1992) reported that 98 percent of afected pregnant women had either continuous or colicky abdominal pain, and 80 percent had nausea and vomiting. Abdominal tenderness was found in 70 percent, and abnormal bowel sounds noted in only 55 percent. Plain abdominal radiographs following soluble contrast showed evidence of obstruction in 90 percent of women (Fig. 54-3). Plain radiographs, however, are less accurate for diagnosing small-bowel obstruction, and we and others have found that CT and MR imaging can be diagnostic (Biswas, 2006; Essilie, 2007; McKenna, 2007). Colonoscopy can be both diagnostic and therapeutic for colonic volvulus (Dray, 2012; Khan, 2012).

During pregnancy, mortality rates with obstruction can be excessive because of diicult and thus delayed diagnosis, reluctance to operate during pregnancy, and the need for emergency surgery (Firstenberg, 1998; Shui, 2011). In an older report of 66 pregnancies, Perdue and associates (1992) described a 6-percent maternal mortality rate and 26-percent fetal mortality rate. Two of the four women who died were in late pregnancy, and they had bowel perforation from sigmoid or cecal volvulus caused by adhesions.

Also known as Ogilvie syndrome, pseudo-obstruction is caused by adynamic colonic ileus. It is characterized by massive abdominal distention with cecal and right-hemicolon dilatation. Approximately 10 percent of all cases are associated with pregnancy, and its frequency has been reported as high as 1 in 1500 deliveries (Reeves, 2015). he syndrome usually develops postpartum-most commonly after cesarean delivery-but it has been reported antepartum (Tung, 2008). Rarely, the large bowel may rupture (Singh, 2005). Treatment with an intravenous infusion of neostigmine, 2 mg, usually results in prompt decompression (Song, 2015). In some cases, colonoscopic decompression is performed, and laparotomy is needed for perforation (De Giorgio, 2009; Rawlings, 2010).

The lifetime incidence for appendicitis ranges from 7 to 10 percent (Flum, 2015). hus, it is not surprising that an evaluation for possible appendicitis is relatively common during pregnancy. heilen and colleagues (2015) studied 171 such women during a 5-year period, but only 12 women ultimately were found to have pathologically confirmed appendicitis. After clinical and imaging evaluation, the frequency of suspected appendicitis is much lower and that of confirmed appendicitis in more than 8 million women ranged from 1 in 1000 to 1 in 5500 births (Abbasi, 2014; Hee, 1999; Mazze, 1991).

It is repeatedly-and appropriately-emphasized that pregnancy makes the diagnosis of appendicitis more diicult. Nausea and vomiting accompany normal pregnancy, but also, as the uterus enlarges, the appendix commonly moves upward and outward from the right lower quadrant (Baer, 1932; Erkek, 2015; Pates, 2009). Another often-stated reason for late diagnosis is that some degree of leukocytosis accompanies normal pregnancy. For these and other reasons, pregnant womenespecially those late in gestation-frequently do not have clinical findings "typical" for appendicitis. Thus, it commonly is confused with cholecystitis, labor, pyelonephritis, renal colic, placental abruption, or uterine leiomyoma degeneration.

Most reports indicate increasing morbidity and mortality rates with advancing gestational age. nd as the appendix is progressively delected upward by the growing uterus, omental containment of infection becomes increasingly unlikely. It is indisputable that appendiceal perforation is more common during later pregnancy (Abbasi, 2014). In the studies by Andersson (2001) and Ueberrueck (2004), the incidence of perforation was approximately 8, 12, and 20 percent in successive trimesters.

Persistent abdominal pain and tenderness are the most reproducible findings. Right-lower quadrant pain is the most frequent, although pain migrates upward with appendiceal displacement CMourad, 2000). For initial evaluation, sonographic abdominal imaging is reasonable in suspected appendicitis, even if to exclude an obstetrical cause of pain (Butala, 2010). hat said, graded compression sonography is diicult because of cecal displacement and uterine imposition (Pedrosa, 2009). Appendiceal computed tomography is more sensitive and accurate than

FIGURE 54-4 Anterior-posterior magnetic resonance image of a periappendiceal abscess in a midtrimester pregnancy. The abscess is approximately 5 x 6 cm, and the appendiceal lumen (arow) is visible within the right-lower quadrant mass. The gravid uterus is seen to the right of this mass.

sonography to conirm suspected appendicitis (Katz, 2012; Raman, 2008). Specific views can be designed to diminish fetal radiation exposure (Chap. 46, p. 907). It is generally accepted that when available, MR imaging is the preferred modality for evaluation of suspected appendicitis in pregnancy (Fig. 54-4). MR imaging has high diagnostic yield and accuracy, and it also provides alternative diagnoses (Fonseca, 2014; Theilen, 2015). One metaanalysis cited positive-and negativepredictive values for MR imaging of 90 and 99.5 percent, respectively (Blumenfeld, 2011). Burke and associates (2015) reported similar indings. Using a decision-analysis model, CT and MR imaging were found to be cost efective (Kasten berg, 2013). This was verified in the clinical study of more than 7000 cases reported by Fonseca and coworkers (2014).

When appendicitis is suspected, treatment is prompt surgical exploration. Although diagnostic errors may lead to removal of a normal appendix, surgical evaluation is preferable to postponed intervention and generalized peritonitis (Abbasi, 2014). In earlier reports, the diagnosis was veriied in only 60 to 70 percent of pregnant women. As indicated above, however, with CT and MR imaging, these igures have improved (Blumenfeld, 2011; Theilen, 2015). Still and importantly, the accuracy of diagnosis is inversely proportional to gestational age.

Currently, laparoscopy is almost always used to treat suspected appendicitis during the irst two trimesters. In a report from a Swedish database of nearly 2000 laparoscopic appendectomies, perinatal outcomes were similar to those of more than 1500 open laparotomies done before 20 weeks' gestation (Reedy, 1997). Conversely, in their review, Wilasrusmee and coworkers (2012) reported a higher rate of fetal loss with laparoscopy. Authors of a more recent systematic review indicate that the level of evidence is not strong enough to demonstrate a preferred approach to appendectomy. They concede that laparoscopy may be associated with a higher risk of miscarriage (Walker, 2014). It has evolved that in many centers, laparo scopic appendectomy is also performed in most cases during the third trimester (Donkervoort, 2011). This is encouraged by the Society of American Gastrointestinal and Endoscopic

Surgeons (Pearl, 2017; Soper, 2011). That said, most are of the gestation should be performed only by the most experienced endoscopic surgeons (Parangi, 2007).

Before exploration, intravenous antimicrobial therapy is begun, usually with a second-generation cephalosporin or third generation penicillin. Unless there is gangrene, perforation, or a periappendiceal phlegmon, antimicrobial therapy can usually be discontinued after surgery. Without generalized peritonitis, the prognosis is excellent. Seldom is cesarean delivery indicated at the time of appendectomy. Uterine contractions are common, and although some clinicians recommend tocolytic agents, we do not. De Veciana (1994) reported that tocolytic use substantially increased the risk for pulmonary-permeability edema caused by sepsis syndrome (Chap. 47, p. 917).

Because of European studies, some have advocated that many cases of appendicitis can be treated successfully with intravenous antimicrobials alone (Flum, 2015; J00, 2017). At this time, we discourage this practice until appropriate studies have been done with pregnant women. In one study, 6 percent of pregnant women with appendicitis were treated medically, and these gravidas had "considerably" elevated risks for septic shock, peritonitis, and venous thromboembolism compared with surgically managed cases (Abbasi, 2014).

Appendicitis increases the likelihood of abortion or preterm labor, especially if peritonitis has developed. In two studies, spontaneous labor after 23 weeks ensued with greater frequency following surgery for appendicitis compared with surgery for other indications (Cohen-Kerem, 2005; Mazze, 1991). In one study, the fetal loss rate was 22 percent if surgery was performed after 23 weeks' gestation. Two large population-based studies attest to the adverse outcomes from appendicitis in pregnancy. From the California Inpatient File of 3133 pregnant women undergoing surgery for suspected appendicitis, the fetal loss rate was 23 percent, and it was doubled-6 versus 11 percent-with simple versus complicated disease (McGory, 2007). A nationwide study from Taiwan found that risks for low birthweight and preterm delivery rose 1.5-to 2-fold when outcomes in 908 women with acute appendicitis were compared with those of controls (Wei, 2012).

Long-term complications are not common. The possible link between sepsis and neonatal neurological injury has not been veriied (Mays, 1995). Finally, appendicitis during pregnancy does not appear to be associated with subsequent infertility (Viktrup, 1998).

Abbasi N, Patenaude V, Abenhaim HA: Management and outcomes of acute appendicitis in pregnancy-population-based study of over 7000 cases.

BlOC 121(12): 1509,2014

Akcakaya A, Koc B, Adas G, et al: he useofERCP during pregnancy: is it safe and efective? Hepatogastroenterology 61(130):296,s2014

Alaniz \, Liss J, Metz TD, et al: Cannabinoid hyperemesis syndrome: a cause of refractory nausea and vomiting in pregnancy. Obstet Gynecol 125(6): 1484, 2015

Albayrak M, Karatas A, Demiraran Y, et al: Ghrelin, acylated ghrelin, leptin, and PYY-3 levels in hyperemesis gravidarum. J Matern Fetal Neonatal vIed 26(9):866,s2013

Alsvlaksoud AM, Barsoum AK, Moneer MM: Sigmoid volvulus during pregnancy: a rare non-obstetric complication. Report of a case and review of the literature. Int J Surg Case Rep 17:51, 2015

Alstead EM, Nelson-Piercy C: Inlammatory bowel disease in pregnancy. Gut 52: 159, 2003

Al-Sunaidi M, Tulandi T: Adhesion-related bowel obstruction after hysterectomy for benign conditions. Obstet Gynecol 108: 1162, 2006

American College of Obstetricians and Gynecologists: Nausea and vomiting of pregnancy. Practice Bulletin No. 153, September 2015

AnanthakrishnanN, Zadvornova Y, Naik AS, et al: Impact of pregnancy on health-related quality of life of patients with inflammatory bowel disease. J Dig Dis 13(9):472,s2012

Andersson E, Lambe M: Incidence of appendicitis during pregnancy. Int J Epidemiol 30:1281, 2001

Andolf E, Thorsell M, Kakken K: Cesarean delivery and risk for postoperative adhesions and intestinal obstruction: a nested case-control study of the Swedish Medical Birth Registry. Am J Obstet GynecoIs203(4):406, 2010

Andrews KH, Bracero A: Cannabinoid hyperemesis syndrome during pregnancy: a case report. J Reprod Med 60(9-10):430,s2015

Aouthmany A, Horattas MC: Ileal pouch perforation in pregnancy: report of a case and review of the literature. Dis Colon Rectum 47:243, 2004

Bade K, Omundsen M: Caecal volvulus: a rare cause of intestinal obstruction in pregnancy. ANZ J Surg 84(4):298,s2014

Baer JL, Reis A, Arens A: Appendicitis in pregnancy with changes in position and axis of normal appendix in pregnancy. JAA 98: 1359, 1932 Bailit JL: Hyperemesis gravidarum: epidemiologic findings from a large cohort.

Am J Obstet Gyneco1s193:811, 2005

Bartels SA, D'Hoore A, Cuesta A, et al: Significantly increased pregnancy rates after laparoscopic restorative proctocolectomy: a cross-sectional study. Ann Surg 256(6):1045,s2012

Benson Be, Guinto E, Parks JR: Primary hyperparathyroidism mimicking hyperemesis gravidarum. Hawaii J Med Public Health 72(1):11, 2013

Beyer-Berjot L, Maggiori L, Birnbaum D, et al: A totalslaparoscopic approach reduces the infertility rate after ileal pouch-anal anastomosis: a 2-center study. Ann Surg 258(2):275,s2013

Biertho L, Sebajang H, Bamehriz F, et al: Efect of pregnancy on efectiveness of laparoscopic Nissen fundoplication. Surg Endosc 20:385, 2006

Bistrian BR, Driscoll DF: Enteral and parenteral nutrition therapy. In Longo DL, Fauci AS, Kasper DL, et al (eds): Harrison's Principles ofInternal Medicine, 18th ed. New York, McGraw-Hill Education, 2012, p 612

Biswas S, Gray KD, Cotton BA: Intestinal obstruction in pregnancy: a case of small bowel volvulus and review of the literature. Am Surg 72: 1218, 2006

Blumenfeld YJ, Wong AE, Jafari A, et al: MR imaging in cases of antenatal suspecred appendicitis-a meta-analysis. J Matern Fetal Neonatal Med 24(3):485,s2011

Bokslag A, Jebbink J, De Wit L, et al: Intussusception during pregnancy after laparoscopic Roux-en-Y gastric bypass. BMJ Case Rep, November 18,s2014

Bolin M, Akerud H, Cnattingius S, et al: Hyperemesis gravidarum and risks of placental dysfunction disorders: a population-based cohort study. BJOG 120(5):541,2013 .

Bortoli A, Pedersen N, Duricova D, et al: Pregnancy outcome in inflammatory bowel disease: prospective European case-control ECCO-Epicom study, 2003-2006. Aliment Pharmacol Ther 34(7):724,s2011

Bosman W, Veger HT, Hedeman Joosten PP, et al: Ileocaecal intussusception due to submucosl lipoma in a pregnant woman. BMJ Case Rep 2014: pii:bcr2013203110, 2014

Boyd HA, Basit S, Harpsoe MC, et al: Inflammatory bowel disease and risk of adverse pregnancy outcomes. PLoS One 10(6) :eO 129567, 2015 Briggs GG, Freeman RK: Drugs in Pregnancy and Lactation, 10th ed. Baltimore, Williams & Wilkins, 2015

Broms G, Granath F, Ekbom A, et al: Low risk of birth defects for infants whose mothers are treated with anti-tumor necrosis factor agents during pregnancy. Clin Gastroenterol Hepatol 14(2):234,2016

Brygger L, Fristrup CW, Harbo FS, et al: Acute gastric incarceration from thoracic herniation in pregnancy following laparoscopic antireflux surgery. BMJ Case Rep pii: bcr20 12008391, 2013

Burke LM, Bashir MR, Miller FH, et al: Magnetic resonance imaging of acute appendicitis in pregnancy: a 5-year multinstitution study. Am J Obstet GynecoIs213:693.el,s2015

Butala P, Greenstein AJ, Sur MD, et al: Surgical management of acute right lower-quadrant pain in pregnancy: a prospective cohort study. J Am Coil Surg 211(4):491,s2010

Camilleri M, Murray JA: Diarrhea and constipation. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles ofInternal Medicine, 19th ed. New York, McGraw-Hill Education, 2015, p 264

Cape A V, Mogensen KM, Robinson MK, et al: Peripherally inserted central catheter (PICC) complications during pregnancy. JPEN J Parenter Enteral Nutr 38(5):595,s2014

Cappell MS: Risks versus benefits of gastrointestinal endoscopy during pregnancy. Nat Rev Gastroenterol Hepatol 8(11):610, 2011

Cappell MS, Fox SR, Gorrepati N: Safety and eicacy of colonoscopy during pregnancy: ananalysis of pregnancy outcome in 20 patients. J Reprod Med 55(3-4):115,s2010

Casanova MJ, Chaparro M, Domenech E, et al: Safety of thiopurines and anti-TNF-a drugs during pregnancy in patients with inflammatory bowel disease. Am J Gastroenterols108(3):433, 2013

Cedergren M, Brynhildsen, Josefsson A, et al: Hyperemesis gravidarum that requires hospitalization and the use of antiemetic drugs in relation to maternal body composition. Am J Obstet Gynecol 198:412.e1, 2008

Chen X, Yang X, Cheng W: Diaphragmatic tear in pregnancy induced by intractable vomiting: a case report and review of the literature. J Matern Fetal Neonatal Med 25(9):1822,s2012

Chiossi G, Neri I, Cavazzuti M, et al: Hyperemesis gravidarum complicated by Wernicke encephalopathy: background, case report, and review of the literature. Obstet Gynecol Surv 61 :255, 2006

Christodoulou-Smith J, Gold JI, Romero R, et al: Posttraumatic stress symptoms following pregnancy complicated by hyperemesis gravidarum. J Matern Fetal Neonatal Med 24(11): 1307,s2011

Clark DH: Peptic ulcer in women. BMJ 1:1254, 1953

Clark SM, Dutta E, Hankins GD: The outpatient management and special considerations of nausea and vomiting in pregnancy. Semin Perinatol 38(8):496,s2014

Clowse ME, Wolf De, Forger F, et al: Pregnancy outcomes in subjects exposed to certolizumab pegol. J RheumatoIs42(12):2270, 2015 Cohen S, Harris LD: Does hiatus hernia afect competence of the gastroesophageal sphincter? N Engl J Med 284(19):1053, 1971

Cohen-Kerem R, Railton C, Oren D, et al: Pregnancy outcome following nonobstetric surgical intervention. Am J Surg 190:467,s2005

Cominelli F: Inhibition ofleukocyte traicking in inlammatory bowel disease.

N Engl J Med 369(8):775, 2013

Cornish J, Wooding K, Tan E, et al: Study of sexual, urinary, and fecal function in females following restorative proctocolectomy. Inflamm Bowel Dis 18(9):1601,s2012

Cornish JA, Tan E, Teare J, et al: The efect of restorative proctocolectomy on sexual function, urinary function, fertility, pregnancy and delivery: a systematic review. Dis Colon Rectum 50:1128, 2007

Curran D, Lorenz R, Czako P: Gastric outlet obstruction at 30 weeks' gestation. Obstet Gynecol 93:851, 1999

Davis MR, Bohon CJ: Intestinal obstruction in pregnancy. Clin Obstet Gynecol 26:832, 1983

Debby A, Golan A, Sadan 0, et al: Clinical utility of esophagogastroduodenoscopy in the management of recurrent and intractable vomiting in pregnancy. J Reprod Med 53:347, 2008

De Giorgio R, Knowles CH: Acute colonic pseudo-obstruction. Br J Surg 96(3):229, 2009

De Lima A, Galjart B, Wisse PH, et al: Does lower gastrointestinal endoscopy during pregnancy pose a risk for mother and child?-a systematic review. BiC GastroenteroIs15:15, 2015

Del Valle J: Peptic ulcer disease and related disorders. In: Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill Education, 2015, p 1911 de Veciana M, Towers CV, Major CA, et al: Pulmonary injury associated with appendicitis in pregnancy: who is at risk? Am J Obstet Gynecol 171(4):1008,s1994

Di Gangi S, Gizzo S, Patrelli TS, et al: Wernicke's encephalopathy complicating hyperemesis gravidarum: from the background to the present. J Matern Fetal Neonatal Med 25(8):1499,s2012

Diav-Citrin 0, Otcheretianski-Volodarsky A, Shechtman S, et al: Pregnancy outcome following gestational exposure to TNF-alpha-inhibitors: a prospective, comparative, observational study. Reprod Toxicol 43:78, 2014

Dodds L, Fell DB, Joseph KS, et al: Outcomes of pregnancies complicated by hyperemesis gravidarum. Obstet Gynecol 107:285,2006

DominitzJA, YoungJe, Boyko EJ: Outcomes of infants born to mothers with inflammatory bowel disease: a population-based cohort study. Am J Gastroenterol 97:641, 2002

Donkervoort Sc, Boerma D: Suspicion of acute appendicitis in the third trimester of pregnancy: pros and cons of a laparoscopic procedure. JSLS 15(3):379,s2011

Dozois EJ, Wolf BG, Tremaine WJ, et al: Maternal and fetal outcome after colectomy for fulminant ulcerative colitis during pregnancy: case series and literature review. Dis Colon Rectum 49:64, 2006

Dray X, Hamzi L, Lo Dico R, et al: Endoscopic reduction of a volvulus of the sigmoid colon in a pregnancy woman. Dig Liver Dis 44(5):447,s2012 DuPont HL: Acute infectious diarrhea in immunocompetent adults. N Engl J

Med 370:1532,s2014

Erkek A, Anik Ilhan G, Yidixhan B, et al: Location of the appendix at the third trimester of pregnancy: a new approach to old dilemma. J Obstet Gynaecol 35(7):688,s2015

Essilie P, Hussain M, Stokes 1M: Small bowel infarction secondary to volvulus duting pregnancy: a case report. J Reprod Med 52:553, 2007

Everson GT: Gastrointestinal motility in pregnancy. Gastroenterol Clin North Am 51, 1992

Farouk R, Pemberton JH, Wolf BG, et al: Functional outcomes after ileal pouch-anal anastomosis for chronic ulcerative colitis. Ann Surg 231:919, 2000

Fassina G, Osculati A: Achalasia and sudden death: acase report. Forensic Sci Int75:133,s1995

Feagins LA, Kane SV: Sexual and reproductive issues for men with inlammatoty bowel disease. Am J Gasrroenterol 68,2009

Fell DB, Dodds L, Joseph KS, et al: Risk factors for hyperemesis gravidarum requiring hospital admission duting pregnancy. Obstet Gynecolsl07:277, 2006 Fiest TC, Foong A, Chokhavatia S: Successful balloon dilation of achalasia during pregnancy. Gastrointest Endosc 39:810, 1993

Firstenberg MS, Malangoni MA: Gastrointestinal surgery duting pregnancy.

Gastroenterol Clin North Am 27:73, 1998

Flick RP, Boill JA, King JC: Pregnancy complicated by traumatic diaphragmatic rupture. A case report. J Reprod Med , 1999

Flum DR: Acute appendicitis-appendectomy or the "antibiotics irst" strategy. N Engl J Med ,2015

Fogel EL, Sherman S: ERCP for gallstone pancreatitis. N Engl J Med 370: 150, 2014

Folk JJ, Leslie-Brown HF, Nosovitch JT, et al: Hyperemesis gravidarum: outcomes and complications with and without total parenteral nutrition. J Reprod Med 49:49 , 2004

Fonager K, Sorensen HT, Olsen J, et al: Pregnancy outcome for womenwith Crohn's disease: a follow-up study based onlinkage between national registries. Am J Gastroenterol 93:2426, 1998

Fonseca AL, Schuster M, Kaplan LJ, et al: he use of magnetic resonance imaging in the diagnosis of suspected appendicitis in pregnancy: shortened length of stay without increase in hospital charges. JAMA Surg ):687, 2014

Food and Drug Administration: Information for healthcare professionals: mycophenolate mofetil (marketed as CellCept) and mycophenolic acid (marketed as Myfortic), 2008. Available at: http://www.fda.gov/drugs/ drugsafety / postmarketdrugsafetyinfo rmation forpa tien tsand providers/ ucmI24776.htm. Accessed March 28, 2016

Forsnes EV, Eggleston MK, Heaton JO: Enterovesical istula complicating pregnancy: a case report. J Reprod Med 44:297, 1999

Friedman S, Blumberg RS: Inflammatory bowel disease. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles ofInternal Medicine, 19th ed. New York, McGraw-Hili Education, 2015, p 1947

Getahun 0, Fassett MJ, Longstreth GF, et al: Association between maternal inlammatory bowel disease and adverse perinatal outcomes. J Perinatol 34(6):435,s2014

Gilinsky NH, Muthunayagam N: Gastrointestinal endoscopy in pregnant and lactating women: emerging standard of care to guide decision-making. Obstet Gynecol Surv 91,2006

Gisbert JP, Chaparro M: Safety of anti-TNF agents during pregnancy and breastfeeding in women with inlammatory bowel disease. m J Gastroenterol 108(9):1426,2013

Giugale LE, Young OM, Streitman DC: Iatrogenic Wernicke encephalopathy in a patient with severe hyperemesis gravidarum. Obstet Gynecol 125(5):1150,s2015

Goel B, Rani J, Huria A, et al: Perforated duodenal ulcer-a rare cause of acute abdomen in pregnancy. J Clin Diagn Res 8(9):OD03, 2014

Goldberg 0, Szilagyi A, Graves L: Hyperemesis gravidarum and Helicobacter pylori infection. Obstet Gynecol 110:695,2007

GopalA, Amshel AL, Shonberg IL, et al: Ostomy and pregnancy. Dis Colon Rectum 28:912, 1985

Grjibovski Al, Vikanes A, Stoltenberg C, et al: Consanguinity and the risk of hyperemesis gravidarum in Norway. Acta Obstet Gynecol Scand 87:20, 2008

Grooten IJ, Koot MH, van der Post JA, et al: Early enteral tube feeding in optimizing treatment of hyperemesis gravidarum: the Maternal and Ofspring outcomes after Treatment of HyperEmesis by Refeeding (MOTHER) randomized controlled trial. Am J Clin N utr 106:812, 2017

Guglielmi FW, Baggio-Bertinet 0, Federico A, et al: Total parenteral nutritionrelated gastroenterological complications. Digest Liver Dis 38:623, 2006

Gungor S, Gurates B, Aydin S, et al: Ghrelins, obestatin, nesfatin-1 and leptin levels in pregnant women with and without hyperemesis gravidarum. Clin Biochem 46(9):828,s2013

Haggar F, Pereira G, Preen 0, et al: Maternal and neonatal outcomes in pregnancies following colorectal cancer. Surg Endosc 27( ):2327,2013

Hahnloser 0, Pemberton JH, Wolf BG, et al: Pregnancy and delivery before and after ileal pouch-anal anastomosis for inlammatory bowel disease: immediate and long-term consequences and outcomes. Dis Colon Rectum 47: 1127, 2004

Harma M, Harma MI, Karadeniz G, et al: Idiopathic ileoileal invagination two days after cesarean section. J Obstet Gynaecol Res 37(2):160,s2011

Hee P, Viktrup L: The diagnosis of appendicitis during pregnancy and maternal and fetal outcome after appendectomy. Int J Gynaecol Obstet 65: 129, 1999 Hill JB, Yost NP, Wendel GW Jr: Acute renal failure in association with severe hyperemesis gravidarum. Obstet Gynecol 100: 1119, 2002

Holmgren C, Aagaard-Tillery KM, Silver M, et al: Hyperemesis in pregnancy: an evaluation of treatment strategies with maternal and neonatal outcomes. Am J Obstet Gynecol 198:56.e1, 2008

Hooft N, Schmidt ES, Bremner RM: Achalasia in pregnancy: botulinum toxin A injection of lower esophageal sphincter. Case Rep Surg 2015:328970, 2015

Hor T, Lefevre JH, Shields C, et al: Female sexual function and fertility after ileal-anal pouch anastomosis. Int J Colorectal Dis 31(3):593,2016

Hux C: Ostomy and pregnancy. Ostomy Wound Manage 56(1):48, 2010 Hytten FE: he alimentary system. In Hytten F, Chamberlain G (eds): Clinical Physiology in Obstetrics. London, Blackwell, 1991, p 137

Inamdar S, Berzin TM, Sejpal DV, et al: Pregnancy is a risk factor for pancreatitis after endoscopic retrograde cholangiopancreatography in a national cohort study. Clin Gasrroenterol Hepatol 14: 1 07, 2016

Joo JI, Park HC, Kim MJ, et al: Outcomes of antibiotic therapy for uncomplicated appendicitis in pregnancy. Am J Med June 9, 2017 [Epub ahead of print]

Kahrilas PJ, Hirano I: Diseases of the esophagus. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles ofInternal Medicine, 19th ed. New York, McGraw-Hill Education, 2015, p 1900

Kappelman MD, Horvath-Puho E, Sandler RS, et al: Thromboembolic risk among Danish children and adults with inflammatory bowel diseases: a population-based nationwide study. Gut 60(7):937,2011

Kastenberg ZJ, Hurley MP, Luan A, et al: Cost-efectiveness of preoperative imaging ultrasonography in the second or third trimester of pregnancy. Obstet Gynecolsl22:821, 2013

Katz OS, Klein A, Ganson G, et al: Imaging of abdominal pain in pregnancy.

Radiol Clin North Am 50(1):149, 2012

Katz JA: Endoscopy in the pregnant patient with inlammatory bowel disease.

Gastroinrest Endosc Clin North Am 12:635, 2002

Kawamura Y, Kawamata K, Shinya M, et al: Vitamin K deiciency in hyperemesis gravidarum as a potential cause of fetal intracranial hemorrhage and hydrocephalus. Prenat Diagn 28:59, 2008

Khan MR, Ur Rehman S: Sigmoid volvulus in pregnancy and puerperium: a surgical and obstetric catastrophe. Report of a case and review of the world literature. World J Emerg Surg 7(1):10,s2012

Khandelwal A, Fasih N, Kielar A: Imaging of the acute abdomen in pregnancy.

Radiol Clin North Am 51:1005, 2013

Kho A: Diagnostic and operative laparoscopy. In Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 2016, In press

Khudyak V, Lysy J, Mankuta 0: Achalasia in pregnancy. Obstet Gynecol Surv 61:207,s2006

Koren G: Treating morning sickness in the United States-changes in prescribing are needed. Am J Obstet Gynecol 211(6):602, 2014

Kurzel RB, Naunheim KS, Schwartz A: Repair of symptomatic diaphragmatic hernia during pregnancy. Obstet Gynecol 71 :869, 1988

Lane AS, Stallworth JL, Eichelberger Y, et al: Vitamin K deiciency embryopathy from hyperemesis gravidarum. Case Rep Obstet Gynecol 2015:324173, 2015

Lawson M, Kern F, Everson GT: Gastrointestinal transit time in human pregnancy: prolongation in the second and third trimesters followed by postpartum normalization. Gastroenterology 89:996, 1985

Leier DA, Lamont JT: Clostridium diicile infection. N Engl J Med 372(16):1539,s2015 Lessa FC, Mu Y, Bamberg WM, et al: Burden of Clostridium dficile infection in the United States. N Engl J Med 372(9):825, 2015

Lichtenstein Gc, Hanauer SB, Sandborn W], et al: Management of Crohn's disease in adults. Am] Gastroenterol 104(2):465,2009

Ludvigsson ]F, Lebwohl B, Ekbom A, et al: Outcomes of pregnancies for women undergoing endoscopy while they were pregnant: a nationwide cohort study. Gastroenterology 152:554, 2017

Lyell D]: Adhesions and peri operative complications of repeat cesarean delivery. Am] Obstet Gynecols205(6 Suppi):Sll, 2011

Mahadevan U: Fertiliry and pregnancy in the patient with inflammatory bowel disease. Gut 55:1198, 2006a

Mahadevan U, Kane S: American Gastroenterological Association Institute technical review on the use of gastrointestinal medications in pregnancy. Gastroenterology 131(1):283, 2006b

Mahadevan U, Matro R: Care of the pregnant patient with inlammatory bowel disease. Obstet GynecoIs126(2):401, 2015

Malecki A, Skagen CL, Frick T], et al: Ileoanal pouch inlet obstruction following cesarean section. Am] Gastroenterols105(8):1906, 2010

Malfertheiner SF, Malfertheiner lvIV, Kropf S, et al: A prospective longitudinal cohort study: evolution of GERD symptoms during the course of pregnancy. BvIC Gastroenterols12:131, 2012

Matsubara S, Kuwata T, Kamozawa C, et al: Connection between hyperemesis gravidarum, jaundice or liver dysfunction, and biliary sludge. ] Obstet Gynaecol Res 38(2):446, 2012

Matthews A, Haas DM, O'Mathuna DP, et al: Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev Mar 3:

CD007575,s2014

Mayberry ]F, Atkinson M: Achalasia and pregnancy. B]OG 94:855, 1987

Mays ], Verma U, Klein S, et al: Acute appendicitis in pregnancy and the occurrence of major intraventricular hemorrhage and periventricular leukomalacia. Obstet Gynecol 86:650, 1995

Mazze R., Kallen B: Appendectomy during pregnancy: a Swedish registry study of7 8 cases. Obstet Gynecol :835, 1991

McCarthy FP, Khashan AS, North A, et al: A prospective cohort study investigating associations between hyperemesis gravidarum and cognitive, behavioural and emotional well-being in pregnancy. PLoS One 6(1l):e27678, 2011

McCarthy FP, Murphy A, Khashan AS, et al: Day care compared with inpatient management of nausea and vomiting of pregnancy. Obstet Gynecol 43,s2014

McGory ML, Zingmond DS, Tillou A, et al: Negative appendectomy in pregnant women is associated with a substantial risk of fetal loss. ] Am Coli Surg 205:534, 200

McKenna D, Watson P, Dornan]: Helicobacter pylori infection and dyspepsia in pregnancy. Obstet Gynecol 102:845, 2003

McKenna DA, Meehan CP, Alhajeri N, et al: The use of MRI to demonstrate small bowel obstruction during pregnancy. Br] Radiol 80:e11, 2007

Mehta N, Saha S, Chien EK, et al: Disorders of the gastrointestinal tract in pregnancy. In Powrie R, Greene M, Camann W (eds): de Swiet's Medical Disorders in Obstetric Practice, 5th ed. New]ersey, Wiley-Blackwell, 2010, p 256

Meyerson S, Holtz T, Ehrinpresis M, et al: Small bowel obstruction in pregnancy. Am] Gastroenterol 90:299, 1995

Miller ]P: Inflammatory bowel disease in pregnancy: a review. ] R Soc Med 9:221, 1986

RM: Gastrointestinal and pancreatic disease. In Barron WM, Lindheimer MD, Davison]M (eds): Medical Disorders of Pregnancy, 3rd ed. St. Louis, Mosby, 2000, p 316

Mourad], Elliott ]P, Erickson L, et al: Appendicitis in pregnancy: new information that contradicts long-held clinical beliefs. Am ] Obstet Gynecol 185:1027,s2000

Mozafari S, Abdolghafari AH, Nikfar S, et al: Pregnancy outcomes in women with inflammatory bowel disease following exposure to thiopurines and antitumor necrosis factor drugs: a systematic review with meta-analysis. Hum Exp Toxicol 35(5):445, 2015

Mullin PM, Ching C, Schoenberg R, et al: Risk factors, treatments, and outcomes associated with prolonged hyperemesis gravidarum. ] Matern Fetal Neonatal Med 25(6):632,s2012

Niebyl ]R: Nausea and vomiting in pregnancy. N Engl] Med 363(16):1544, 2010

Norgard B, Hundborg HH, Jacobsen BA, et al: Disease activiry in pregnant women with Crohn's disease and birth outcomes: a regional Danish cohort study. Am] Gastroenterol 102:1947,s2007

Novacek G, Weltermann A, Sobala A, et al: Inflammatory bowel disease is a risk factor for recurrent venous thromboembolism. Gastroenterology 9,s2010

Nwoko R, Plecas D, Garovic VD: Acute kidney injury in the pregnant patient.

Clin Nephrol 78(6):478, 2012

O'Grady NP, Alexander M, Burns L: Guidelines for prevention of intravascular catheter-related infections. Clin Infect Dis 52(9):e162 2011

Ogura ]M, Francois E, Perlow ]H, et al: Complications associated with peripherally inserted central catheter use during pregnancy. Am ] Obstet GynecoIs188:1223,2003

Oliveira LG, Capp SM, You B, et al: Ondansetron compared with doxylamine and pyridoxine for treatment of nausea in pregnancy. Obstet Gynecol 124(4):735,s2014

O'Mahony S: Endoscopy in pregnancy. Best Pract Res Clin Gastroenterol 21:893,s2007

Ooi BS, Remzi FH, Fazio W: Turnbull-blowhole colostomy for toxic ulcerative colitis in pregnancy: report of two cases. Dis Colon Rectum 46:111, 2003

Oron G, Yogev Y, Shkolnik S, et al: Inflammatory bowel disease: risk factors for adverse pregnancy outcome and the impact of maternal weight gain. ] VIatern Fetal Neonatal Med 25(112):2256,s2012

Oto A, Ernst R, Ghulmiyyah L, et al: he role of MR cholangiopancreatography in the evaluation of pregnant patients with acute pancreaticobiliary disease. Br] Radiol 82(976):279, 2009

Palacios-Marques A, Delgado-Garcia S, Martin-Bayon T, et al: Wernicke's encephalopathy induced by hyperemesis gravidarum. BM] Case Rep June 8, 2012 Parangi S, Levine D, Henry A, et al: Surgical gastrointestinal disorders during pregnancy. Am] Surg 193:223, 2007

Paranyuk Y, Levin G, Figueroa R: Candida septicemia in a pregnant woman with hyperemesis receiving parenteral nutrition. Obstet Gynecols10 :535,2006 Pasternak B, Svanstr6m M, Henrik A: Ondansetron in pregnancy and risk of adverse fetal outcomes. N Engl] Med 368:814, 2013 Pates ]A, Avendanio TC, Zaretsky MV, et al: he appendix in pregnancy: confirming historical observations with a contemporary modaliry. Obstet Gynecol 114(4):805,2009

Pearl ]P, Price R, TonkinE, et al: SAGES guidelines for the use of laparoscopy during pregnancy. Surg Endosc 31(10):3767,s2017

Pedrosa I, Lafornara M, Pandharipande PV, et al: Pregnant patients suspected of having acute appendicitis: efect of MR imaging on negative laparotomy rate and appendiceal perforation rate. Radiology 250(3): 49, 2009

Peled Y, Melamed N, Hiersch L, et al: he impact of total parenteral nutrition support on pregnancy outcome in women with hyperemesis gravidarum. ] Matern Fetal Neonatal Med 27(11):1146, 2014

Perdue PW, Johnson HW]r, Staford PW: Intestinal obstruction complicating pregnancy. Am] Surg 164:384, 1992

Podolsky DK: Inflammatory bowel disease. N Engl] Med 347(6):417,s2002

Porter H, Seeho S: Obstructed ileostomy in the third trimester of pregnancy due to compression from the gravid uterus: diagnosis and management. BM] Case Rep August 19, 2014 Poursharif B, Korst LM, MacgibbonW, et al: Elective pregnancy termination in a large cohort of women with hyperemesis gravidarum. Contraception 76:451, 2007 Prefontaine E, Sutherland LR, Macdonald]K, et al: Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev 1:CD000067, 2009 Raman SS, Osuagwu FC, Kadell B, et al: Efect of CE on false positive diagnosis of appendicitis and perforation. N Engl ] Med 358:972, 2008 Ravid A, Richard CS, Spencer LM, et al: Pregnancy, delivery, and pouch function after ileal pouch-anal anastomosis for ulcerative colitis. Dis Colon Rectum 45:1283, 2002

Rawlings C: Management of postcaesarian Ogilvie's syndrome and their subsequent outcomes. Aust N Z] Obstet Gynaecol 50(6):5 3,2010 Reddy D, Murphy S], Kane SV, et al: Relapses of inflammatory bowel disease during pregnancy: in-hospital management and birth outcomes. Am] Gastroenterol 103: 1203, 2008 Reedy MB, Kallen B, Kuehl T]: Laparoscopy during pregnancy: a study of five fetal outcome parameters with use of the Swedish Health Registry. Am ] Obstet Gynecol 177:673, 1997 Reeves M, Frizelle F, Wakeman C, et al: Acute colonic pseudo-obstruction in pregnancy. ANZ] Surg 85(10):728,s2015 Rigler LG, Eneboe ]B: Incidence of hiatus hernia in pregnant women and its significance.] Thorac Surg 4:262, 1935 Riis L, Vind I, Politi P, et al: Does pregnancy change the disease course? A study in a European cohort of patients with inflammatory bowel disease. Am] GastroenteroIs101:1539, 2006 Rocha-Castro], Kronbauer K, Daile], et al: Characteristics of bacterial acute diarrhea among women. .nt] Gynaecol Obstet 132(3):302,s2016 Russo-Stieglitz E, Levine AB, Wagner BA, et al: Pregnancy outcome in patients requiring parenteral nutrition. ] Matern Fetal Med 8: 164, 1999

Saha S, Loranger D, Pricolo V, et al: Geeding jejunostomy for the treatment of severe hyperemesis gravidarum: a case series. ] Parenter Enteral Nutr 33(5):529, 2009

Sakai M, Yoneda S, Sasaki Y, et al: Maternal total parenteral nutrition and fetal subdural hematoma. Obstet Gynecol 101: 1142, 2003

Satin AJ, Twickler D, Gilstrap LC: Esophageal achalasia in late pregnancy.

Obstet Gynecol 79:812, 1992

Savas N: Gastrointestinal endoscopy in pregnancy. World J Gastroenterol 20(41):15241,2014

Schif MA, Reed SD, Daling JR: The sex ratio of pregnancies complicated by hospitalisation for hyperemesis gravidarum. BJOG 111:27,2004

Schrag SP, Sharma R, Jaik NP, et al: Complications related to percutaneous endoscopic gastrostomy (PEG) tubes: a comprehensive clinical review. J Gastrointest Liver Dis 16:407, 2007

Schwentner L, Wulf C, Kreienberg R, et al: Exacerbation ofa maternal hiatus hernia in early pregnancy presenting with symptoms of hyperemesis gravidarum: case report and review of the literature. Arch Gynecol Obstet 283(3):409,s2011

Selitsky T, Chandra P, Schiavello HJ: Wernicke's encephalopathy with hyperemesis and ketoacidosis. Obstet Gynecol 107:486,2006

Serra AE, Fong A, Chung H: A gut-wrenching feeling: pregnancy complicated by massive ventral hernia with bowel obstruction. Am J Obstet Gynecol 211(1):79,s2014

Sharifah H, Naidu A, Vimal K: Diaphragmatic hernia: an unusual cause of postpartum collapse. BJOG 110:701,2003

Shui LH, Rafi J, Corder A, et al: Mid-gut volvulus and mesenteric vessel thrombosis in pregnancy: case report and literature review. Arch Gynecol Obstet 283 (Suppl 1):39,2011

Siddiqui U, Denise-Proctor D: Flexible sigmoidoscopy and colonoscopy during pregnancy. Gastrointest Endosc Clin North Am 16:59,s2006

Singh S, Nadgir A, Bryan M: Post-cesarean section acute colonic pseudoobstruction with spontaneous perforation. Int J Gynaecol Obstet 89: 144, 2005

Song LM, Topazian M: Gastrointestinal endoscopy. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill Education, 2015, p 1947

Soper NJ: SAGES' guidelines for diagnosis, treatment, and use of laparoscopy for surgical problems during pregnancy. Surg Endosc 25:3477,s2011

Spiliopoulos D, Spiliopoulos M, Awala A: Esophageal achalasia: an uncommon complication during pregnancy treated conservatively. Case Rep Obstet GynecoIs2013(639698):1,s2013

Stephansson 0, Larsson H, Pedersen L, et al: Crohn's disease is a risk factor for preterm birth. Clin Gastroenterol Hepatol 8(6):509, 2010

Stern MD, Kopylov U, Ben-Horin S, et al: Magnetic resonance enterography in pregnant women with Crohn's disease: case series and literature review. BMC Gastroenterol 14: 146, 2014

Stokke G, Gjelsvik BL, Flaatten KT, et al: Hyperemesis gravidarum, nutritional treatment by nasogastric tube feeding: a 10-year retrospective cohort study. Acta Obstet Gynecol Scand 94(4):359,s2015

Storch1, Barkin JS: Contraindications to capsule endoscopy: do any still exist?

Gastrointest Endosc Clin North Am 16:329,2006

Suerbaum S, Michetti P: Helicobacter pylori infection. N Engl J Med 347: 1175, 2002

Sun S, Qiu X, Zhou J: Clinical analysis of 65 cases of hyperemesis gravidarum with gestational transient thyrotoxicosis. J Obstet Gynaecol Res 40 (6):1567,s2014

Swallow BL, Lindow SW, Masson A, et al: Psychological health in early pregnancy: relationship with nausea and vomiting.] Obstet GynaecoI24:28, 2004

Swartzlander TK, Carlan SJ, Locksmith G, et al: Sonographic conirmation of the correct placement of a nasoenteral tube in a woman with hyperemesis gravidarum: case report. J Clin Ultrasound 41(Suppls1):18, 2013

Takahashi K, Funayama Y, Fukushima K, et al: Pregnancy and delivery in patients with enterostomy due to anorectal complications from Crohn's disease. Int] Colorectal Dis 22:313, 200

Tan PC, Jacob R, Quek KF, et al: he fetal sex ratio and metabolic, biochemical, haematological and clinical indicators of severiry of hyperemesis gravidarum. B]OG 113:733,2006

Tan PC, Norazilah MJ, Omar SZ: Dextrose saline compared with normal saline rehydration of hyperemesis gravidarum: a randomized controlled trial. Obstet Gynecols121(2 Ptl):291, 2013

Theilen LH, Mellnick VM, Longman E, et al: Utiliry of magnetic resonance imaging for suspected appendicitis in pregnant women. Am J Obstet Gynecol 12(3):345, 2015

Torquati A, Luti R, Khaitan L, et al: Heller myotomy vs Heller myotomy plus Dor fundoplication: cost-utility analysis of a randomized trial. Surg Endosc 20:389, 2006

Torres J, Boyapati RK, Kennedy NA, et al: Systematic review of efects of withdrawal of immunomodulators or biologic agents from patients with inflammatory bowel disease. Gastroenterology 149(7):1716, 2015

T rogstad LI, Stoltenberg C, Magnus P, et al: Recurrence risk in hyperemesis gravidarum. BJOG 112:1641,s2005

Tung CS, Zighelboim I, Gardner MO: Acute colonic pseudo Obstruction complicating twin pregnancy. J Reprod Med 53:52, 2008

Turcotte S, Dube S, Beauchamp G: Peripherally inserted central venous catheters are not superior to central venous catheters in the acute care of surgical patients on the ward. World J Surg 30: 1603,s2006

Ueberrueck T, Koch A, Meyer L, et al: Ninety-four appendectomies for suspected acute appendicitis during pregnancy. World J Surg 28:508, 2004

Unal A, Sayherman SE, Ozel L, et al: Acute abdomen in pregnancy requiring surgical management: a 20-case series. Eur J Obstet Gynecol Reprod BioI 159(1):87,s2011

Vaknin Z, Halperin R, Schneider D, et al: Hyperemesis gravidarum and nonspeciic abnormal EEG indings. J Reprod Med 51 :623, 2006

Vandraas KF, Vikanes AV, Vangen S, et al: Hyperemesis gravidarum and birth outcomes-a population-based cohort study of 2.2 million births in the Norwegian Birth Registry. BJOG 120(13):1654,2013

Veenendaal MV, van Abeelen AF, Painter RC, et al: Consequences of hyperemesis gravidarum for ofspring: a systematic review and meta-analysis. BJOG 118(11):1302,2011

Verberg MF, Gillott JD, Fardan NA, et al: Hyperemesis gravidarum, a literature review. Hum Reprod Update ,2005

Vikanes AV, Stoer NC, Magnus P, et al: Hyperemesis gravidarum and pregnancy outcomes in the Norwegian mother and child cohort-a cohort study. BMC Pregnancy Childbirth 13:169,2013

Viktrup L, Hee P: Fertility and long-term complications four to nine years after appendectomy during pregnancy. Acta Obstet Gynecol Scand 77:746, 1998 Wald A: Constipation, diarrhea, and symptomatic hemorrhoids during pregnancy. Gastroenterol Clin North Am 32:309, 2003

Walker HG, I Samaraee A, Mills SJ, et al: Laparoscopic appendicectomy in pregnancy: a systematic review of the published evidence. Int J Surg 12(11):1235,s2014

Wax JR, Pinette MG, Cartin A: Roux-en-Y gastric bypass-associated bowel obstruction complicating pregnancy-an obstetrician's map to the clinical mineield. m J Obstet GynecoIs208(4):265, 2013

Wei PL, Keller J], Liang HH, et al: Acute appendicitis and adverse pregnancy outcomes: a nationwide population-based study. J Gastrointest Surg 16(6):1204,s2012

Weyermann M, Brenner H, Adler G, et al: Helicobacter pylori infection and the occurrence and severity of gastrointestinal symptoms during pregnancy. Am ] Obstet Gynecol 189:526, 2003

Wilasrusmee CSukrat B, McEvoy M, et al: Systematic review and meta-analysis of safety laparoscopic versus open appendectomy for suspected appendicitis in pregnancy. Br J Surg 99(11):1470,s2012

Woolfson K, Cohen Z, McLeod RS: Crohn's disease and pregnancy. Dis Colon Rectum 33:869, 1990

Yost NP, McIntire DD, Wians FH Jr, et al: A randomized, placebo-controlled trial of corticosteroids for hyperemesis due to pregnancy. Obstet Gynecol 102: 1250, 2003

Zara G, Codemo V, Palmieri A, et al: Neurological complications in hyperemesis gravidarum. Neurol Sci 33(1):133, 2012

CHAPTER 55 Hepatic, Biliary, and Pancreatic Disorders

INTRAHEPATIC CHOLESTASIS OF PREGNANCY ...... 1059

ACUTE FATY LIVER OF PREGNANCY ..i............ 1060

VIRAL HEPATITIS .....i...i.......i........i...i.....i..... 1062

NONALCOHOLIC FATY LIVER DISEASE ...........i. 1067

CIRRHOSIS.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1067

ACETAMINOPHEN OVERDOSE HEPATOTOXICITY .... 1068

HEPATIC ADENOMA .i..................i.......i. 1069

GALLBLADDER DISORDERS . . . . . . . . . . . . . . . . . . . . . 1069

PANCREATIC DISORDERS ...........i......i.......i. 1070

Prenancy is comparativey seldom complicated by jaundice. Notwithstanding the act that in most cases the jaundice disappears without treatment, too avorable a prognosis should not be ventured, or the reason that now and again the condition may represent the initial symptom of acute yellow atrophy of the liver.

-J. Whitridge Williams (1903)

Even though Williams only mentions acute hepatic fatty metamorphosis, in practice, disorders of the liver, gallbladder, and pancreas together comprise a formidable list of complications that may arise in pregnancy. Some stem from preexisting conditions and some are unique to gestation. The relationships of several of these with pregnancy can be fascinating, intriguing, and challenging.

Customarily, liver diseases complicating pregnancy are placed into three general categories. he first includes those specifically related to pregnancy that resolve either spontaneously or following delivery. Examples are intrahepatic cholestasis and acute fatty liver, both discussed in the next sections. Also, hepatic dysfunction from hyperemesis gravidarum may involve the liver. Mild hyperbilirubinemia with elevated serum transaminase levels is seen in up to half of afected women requiring hospitalization. However, these levels seldom exceed 200 U/L (Table 55-1). Liver biopsy may show minimal fatty changes. Hyperemesis gravidarum is discussed in detail in Chapter 54 (p. 1043). Another in this first category is hepatocellular damage with preeclampsia-the HELLP syndrome-which is characterized by hemolysis, �levated serum liver enzyme levels, and low 2latelet counts. hese changes are discussed in detail in Chapter 40 (p. 721).

The second category involves acute hepatic disorders that are coincidental to pregnancy, such as acute viral hepatitis. The third category includes chronic liver diseases that predate pregnancy, such as chronic hepatitis, cirrhosis, or esophageal varices.

Importantly, several normal pregnancy-induced physiological changes induce appreciable liver-related clinical and laboratory manifestations (Chap. 4, p. 68, and Appendix, p. 1257). Findings such as elevated serum alkaline phosphatase levels, palmar erythema, and spider angiomas, which might suggest liver disease, are common during normal pregnancy. Metabolism is also afected, due to altered expression of the cytochrome P450 system. This alteration is mediated by higher levels of estrogen, progesterone, and other pregnancy hormones. For example, hepatic CYFIA2 expression declines, whereas that of CYF2D6 and CYF3A4 rises. Importantly, cytochrome enzymes are expressed in many organs besides the liver, most notably the

Hepatic, Biliary, and Pancreatic Disorders 1059

TABLE 55-1 . Clinical and Laboratory Findings with Acute Liver Diseases in Pregnancy

Plat = platelets; PT = prothrombin time.

placenta. The net efect is complex and likely influenced by gestational age and organ of expression (Isoherranen, 2013). Despite all of these functional changes, no major hepatic histological changes are induced by normal pregnancy.

• Intrahepatic Cholestasis of Pregnancy his condition has been called recurrent jaundice of pregnancy, cholestatic hepatosis, and icterus gravidarum and is characterized by pruritus, icterus, or both. It may be more common in multifetal pregnancy, and there is a significant genetic influence (Lausman, 2008; Webb, 2014). Because of this, its incidence varies by population. For example, cholestasis is infrequent in North America, with an overall incidence approximating 1 case in 500 to 1000 pregnancies. But, its rate nears 5.6 percent among Latina women in Los Angeles (Lee, 2006). Historically, indigenous women from Chile and Bolivia also have a relatively high incidence. For unknown reasons, this incidence has declined since the 1970s and is now less than 2 percent (Reyes, 2016). In other countries, for example Sweden, China, and Israel, the incidence varies from 0.25 to 1.5 percent (Glantz, 2004; Luo, 2015; Sheiner, 2006).

The cause of obstetrical cholestasis is unclear, but changes in various sex steroid levels are implicated. However, current research focuses on the numerous mutations in the many genes that control hepatocellular transport systems. Examples include mutations of the ABCB4 gene, which encodes multidrug resistance protein 3 (vlDR3) associated with progressive amilial intrahepatic cholestasis, and errors of the ABCBll gene, which encodes a bile-salt export pump (Anzivino, 2013; Dixon, 2014). Other potential gene products are the farnesoid X receptor and transporting ATPase encoded by A TP8Bl (Abu-Hayyeh, 2016; Davit-Spraul, 2012). Some drugs that similarly decrease canalicular transport of bile acids aggravate the disorder. We have encountered impressive cholestatic jaundice in gravidas taking azathioprine following renal transplantation.

Whatever the inciting cause(s), bile acids are cleared incompletely and accumulate in plasma. Hyperbilirubinemia results from retention of conjugated pigment, but total plasma concentrations rarely exceed 4 to 5 mg/ dL. Alkaline phosphatase levels are usually elevated even more than in normal pregnancy. Serum transaminase levels are normal to moderately elevated but seldom exceed 250 U/L (see Table 55-1). Liver biopsy shows mild cholestasis with bile plugs in the hepatocytes and canaliculi of the centrilobular regions, but without inflammation or necrosis. These changes disappear after delivery but often recur in subsequent pregnancies or with estrogencontaining contraceptives.

Pruritus develops in late pregnancy, although it occasionally manifests earlier. Constitutional symptoms are absent, and generalized pruritus shows predilection for the soles. Skin changes are limited to excoriations from scratching. Biochemical tests may be abnormal at presentation, but pruritus may precede laboratory indings by several weeks. Approximately 10 percent of women have jaundice.

With normal liver enzymes, the diferential diagnosis of pruritus includes other skin disorders (Table 62-1, p. 1185). Findings are unlikely to stem from preeclamptic liver disease if blood pressure elevation or proteinuria is absent. Sonography may be warranted to exclude cholelithiasis and biliary obstruction. Moreover, acute viral hepatitis is an unlikely diagnosis because of the usually low serum transaminase levels seen with cholestasis. Conversely, chronic hepatitis C is associated with a significantly increased risk of cholestasis, which may be as high as 20-fold among women who test positively for hepatitis C RNA (Marschall, 2013).

Pruritus may be troublesome and is thought to result from elevated serum bile salt concentrations. Antihistamines and topical emollients may provide some relie. Although cholestyramine is reported to be efective, this compound also lowers absorption of fat-soluble vitamins, which may lead to vitamin K deficiency. Fetal coagulopathy with subsequent intracranial hemorrhage and stillbirth have been reported (Matos, 1997; Sadler, 1995).

A recent metaanalysis suggests that ursodeoxycholic acid relieves pruritus, lowers bile acid and serum enzyme levels, and may reduce certain neonatal complications. hese include preterm birth, fetal distress, respiratory distress syndrome, and neonatal intensive care unit (NICU) admission (Bacq, 2012). Kondrackiene and associates (2005) randomly assigned 84 symptomatic women to receive either ursodeoxycholic acid ($ to 10 mg/kg/d) or cholestyramine. hey reported superior relief with ursodeoxycholic acid-67 versus 19 percent, respectively. Similarly, Glantz and coworkers (2005) found superior beneits to women randomly assigned to ursodeoxycholic acid versus dexamethasone. he American College of Obstetricians and Gynecologists (2015) has concluded that ursodeoxycholic acid relieves pruritus and improves fetal outcomes, although evidence for the latter is not compelling.

Earlier reports describe excessive adverse pregnancy outcomes in women with cholestatic jaundice. That said, data accrued during the past two decades are ambiguous concerning increased perinatal mortality rates and whether close fetal surveillance is preventative. Several studies also illustrate this. In one evaluation of 693 Swedish women, perinatal mortality rates were slightly increased, but only in mothers with severe disease (Glantz, 2004). Sheiner and coworkers (2006) described no diferences in perinatal outcomes in 376 afected pregnancies compared with their overall obstetrical population. However, rates of labor induction and cesarean delivery in afected women signiicantly rose. Lee and associates (2009) described two cases of sudden fetal death not predicted by nonstress testing. In another study of 101 afected women, no term fetuses died, but 87 percent of women underwent labor induction, ostensibly to avoid adverse outcomes (Rook, 2012). Nonetheless, neonatal complications developed in a third of the pregnancies, particularly respiratory distress, fetal distress, and meconium-stained amnionic luid. These problems were noted more frequently in those with higher total bile acid levels. Herrera and coworkers (2017) reported similar results. Finally, Wikstrom Shemer and colleagues (2013) reported outcomes in 5477 women with cholestasis from a database of 1,213,668 births. They described novel associations of cholestasis with preeclampsia and gestational diabetes. Although neonates were more likely to have a low 5-minute Apgar score and to be large for gestational age, the stillbirth rate was not increased. This was thought to reflect higher induction and preterm birth rates. Thus, by this time, many had now recommended early labor induction to avoid stillbirth. Relecting this, at Parkland Hospital, some maternal-fetal specialists ofer induction at 38 weeks, whereas others suggest 39 weeks.

As discussed, some evidence supports that high serum bile acid levels may contribute to fetal death. Bile acids typically remain < 10 ILmol/L throughout normal pregnancy (Egan, 2012). Elevated levels have been associated with meconium passage and stillbirth. For example, in the prior study of 693 Swedish women, stillbirths were limited to women with bile acid levels >40 ILmollL (Glantz, 2004). More recent data indicate that adverse outcomes are associated with even higher bile acid levels. For instance, Brouwers and coworkers (2015) reported high rates of spontaneous preterm birth (19 percent), meconium-stained amnionic fluid (48 percent), and perinatal death (10 percent) with bile acids levels > 100 ILmollL despite active management leading to earlier delivery. Kawakita and colleagues (2015) found a similar stillbirth link. In particular, among 233 women followed with cholestasis of pregnancy, there were four stillbirths, all of which were among women with bile acid levels > 100 LmollL. Gao and associates (2014) implicated bile acids in cardiac dysfunction. Namely, in an exvivo preparation of cardiac myocytes, cholic acid lowered the beating rates in a dose-dependent manner, while increasing intracellular calcium levels. Intriguingly, studies have shown prolongations in the PR interval during fetal echocardiography among afected women (Rodriguez, 2016; Strehlow, 2010).

• Acute Fatty Liver of Pregnancy

The most frequent cause of acute liver failure during pregnancy is acute fatty liver-also called acute aty metamorphosis or acute yellow atrophy. It is characterized by accumulation of microvesicular fat that literally "crowds out" normal hepatocytic function (Fig.

Grossly, the liver is small, soft, yellow, and greasy. In its worst form, the incidence approximates 1 case in 10,000 pregnancies (Nelson, 2013). Fatty liver recurring in subsequent pregnancy is rare, but a few cases have been described (Usta, 1994).

Although much has been learned about this disorder, interpretation of conflicting data has led to incomplete but interesting observations. For example, some if not most cases of maternal fatty liver are associated with recessively inherited mitochondrial abnormalities of fatty acid oxidation. These are similar to those in children with Reye-like syndromes. Several mutations have been described for the mitochondrial trifunctional

FIGURE 55-1 Acute fatty liver of pregnancy. Cross section of the liver from a woman who died as the result of pulmonary aspiration and respiratory failure. The liver has a greasy yellow appearance, which was present throughout the entire specimen. Inset: Electron photomicrograph of one swollen hepatocyte containing numerous microvesicular fat droplets (*). The nuclei (N) remain centered within the cell, in contrast to the case with macrovesicular fat deposition. (Used with permission from Dr. Don Wheeler.) protein enzyme complex that catalyzes the last oxidative steps in the pathway. The most common are the G1528C and

E474Q mutations of the gene on chromosome 2 that codes for long-chain-3-hydroxyacyl-CoA-dehydrogenase-known as

LCHAD. here are other mutations for medium-chain acyl

CoA dehydrogenase-MCAD, as well as for carnitine palmito yltransferase 1 (CPT1) deficiency (Santos, 2007; Ylitalo, 2005).

Sims and coworkers (1995) observed that some homozygous LCHAD-deicient children with Reye-like syndromes had heterozygous mothers with fatty liver. This was also seen in women with a compound heterozygous fetus. Although some conclude that ony heterozygous LCHAD-deicient mothers are at risk when their fetus is homozygous, this is not always true (Baskin, 2010).

There is a controversial association between fatty acid 3-oxidation enzyme defects and severe preeclampsia-especially in women with HELLP syndrome (Chap. 40, p. 721). Most of these observations derive from retrospective study of mothers delivered of a child who later developed Reye-like syndrome. For example, one case-control study compared 50 mothers of children with a fatty-acid oxidation defect and 1250 mothers of matched control infants (Browning, 2006). During their pregnancy, 16 percent of mothers with an afected child developed liver problems compared with only 0.9 percent of control women. Problems included HELLP syndrome in 12 percent and fatty liver in 4 percent. Despite these indings, the clinical, biochemical, and histopathological findings are suiciently disparate to suggest that severe preeclampsia, with or without HELLP syndrome, and fatty liver are distinct syndromes (American College of Obstetricians and Gynecologists, 2015; Sibai, 2007).

Acute fatty liver almost always manifests late in pregnancy. Nelson and colleagues (2013) described 51 afected women at Parkland Hospital with a mean gestational age of 37 weeks (range 31.7 to 40.9). Almost 20 percent were delivered at 34 weeks' gestation or earlier. Of these 51 women, 41 percent were nulliparous, and two thirds carried a male fetus. From other data, 10 to 20 percent of cases are in women with a multifetal gestation (Fesenmeier, 2005; Vigil-De Gracia, 2011).

Hepatic, Biliary, and Pancreatic Disorders 1061

Fatty liver has a clinical spectrum of severity. In the worst cases, symptoms usually develop over several days. Persistent nausea and vomiting are major complaints, and degrees of mal aise, anorexia, epigastric pain, and progressive jaundice vary.

Perhaps half of afected women have hypertension, protein uria, and edema, alone or in combination-signs suggestive of preeclampsia. As shown in Tables 55-1 and 55-2, degrees of moderate to severe liver dysfunction are manifest by hypofi brinogenemia, hypoalbuminemia, hypocholesterolemia, and prolonged clotting times. Serum bilirubin levels usually are < 10 mgl dL, and serum transaminase levels are modestly ele vated and usually < 1000 U/L.

In almost all severe cases, profound endothelial cell activation with capillary leakage causes hemoconcentration, acute kidney injury, ascites, and sometimes pulmonary permeability edema (Bernal, 2013). With severe hemoconcentration, uteroplacental perfusion is reduced and this, along with maternal acidosis, can cause fetal death even before presentation for care. Both maternal and fetal acidemia are associated with a high incidence of fetal jeopardy and a concordantly high cesarean delivery rate.

Hemolysis can be severe and evidenced by leukocytosis, nucleated red cells, mild to moderate thrombocytopenia, and elevated serum levels of lactic acid dehydrogenase (LDH). Because of hemoconcentration, however, the hematocrit is often within the normal range. The peripheral blood smear demonstrates echinocytosis, and hemolysis is thought to stem from efects of hypocholesterolemia on erythrocyte membranes (Cunningham, 1985).

The degree of clotting dysfunction also varies and can be serious and life threatening, especially if operative delivery is undertaken. Coagulopathy is caused by diminished hepatic procoagulant synthesis, although some evidence supports increased consumption from disseminated intravascular coagulopathy. As shown in Table 55-2, hypoibrinogenemia sometimes is profound. Of 51 women with fatty liver cared for at Parkland Hospital, almost a third had a plasma fibrinogen level nadir to < 100 mg/dL (Nelson, 2014). Modest level elevations of serum D-dimers or fibrin-split products indicate an element of consumptive coagulopathy. Although usually modest, occasionally thrombocytopenia is marked (see Table 55-2). Again, among the

TABLE 55-2. Laboratory Findings in 215 Women with Acute Fatty Liver of Pregnancy

Series No. Fibrinogen (mg/dL) Platelets (103/.LL) Creatinine (mg/dL) AST (U/L)

Pereira (1n997) 32 ND 123 (26-262) 2.7 (1n.1n-8.4) 99 (25-91n1)

Fesenmeier (2005) 16 ND 88 (22-226) 3.3 (0.5-8.6) 692 (122-3195) aFibrinogen and platelet values listed reflect the nadir for each patient, whereas creatinine and AST values reflect peak values for each patient.

AST = aspartate transaminase; NO = not done.

group from Parkland Hospital, 20 percent had platelet counts < 100,000/�L and 10 percent had platelet counts <50,000/�L (Nelson, 2014).

Various liver imaging techniques have been used to confirm the diagnosis, however, none are particularly reliable. Speciically, Castro and associates (1996) reported poor sensitivity for conirmation by sonography-three of 11 patients, computed tomography (CT)-five of 10, and magnetic resonance (MR) imaging-none of ive. Similarly, in a prospective evaluation of the Swansea criteria proposed by Ch'ng and coworkers (2002), only a quarter of women had classic sonographic findings that include maternal ascites or an �chogenic hepatic appearance (Knight, 2008). Our experiences are similar (Nelson, 2013).

The syndrome typically continues to worsen after diagnosis.

Hypoglycemia is common, and obvious hepatic encephalopathy, severe coagulopathy, and some degree of renal failure each develop in approximately half of women. Fortunately, delivery arrests liver function deterioration.

We have encountered several women with a orme fruste of this disorder. Clinical involvement is relatively minor and laboratory aberrations-usually only hemolysis and a decreased plasma fibrinogen level-herald the syndrome. hus, the spectrum of liver involvement varies from milder cases that go unnoticed or are attributed to preeclampsia, to overt hepatic failure with encephalopathy.

Intensive supportive measures and good obstetrical care are essential. In some cases, the fetus may already be dead when the diagnosis is made, and the route of delivery is less problematic. Oten, living fetuses tolerate labor poorly. Because significant procrastination in efecting delivery may increase maternal and fetal risks, we prefer a trial oflabor induction with close fetal surveillance. Although some recommend cesarean delivery to hasten hepatic healing, this increases maternal risk when coagulopathy is severe. Nonetheless, cesarean delivery is common, and rates approach 90 percent. Transfusions with whole blood or packed red cells, along with fresh-frozen plasma, cryoprecipitate, and platelets, are usually necessary if surgery is performed or if obstetricalrlacerations complicate vaginal delivery (Chap. 41, p. 788).

Hepatic dysfunction resolves postpartum. It usually normalizes within a week, and in the interim, intensive medical support may be required. Two associated conditions can be seen around this time. Perhaps a fourth of women have evidence for transient diabetes insipidus. This presumably stems from elevated vasopressinase concentrations caused by diminished hepatic production of its inactivating enzyme. Finally, acute pancreatitis develops in approximately 20 percent.

With supportive care, recovery usually is complete. lvIaternal deaths are caused by sepsis, hemorrhage, aspiration, renal failure, pancreatitis, and gastrointestinal bleeding. Two women died in the series from Parkland Hospital. One was an encephalopathic woman who aspirated before intubation during transfer to our care. The other was in a woman with massive liver failure and nonresponsive hypotension (Nelson, 2013). In some centers, other measures have included plasma exchange and even liver transplantation (Fesenmeier, 2005; Franco, 2000; Martin, 2008).

Although maternal mortality rates with acute fatty liver of pregnancy have approached 75 percent in the past, the contemporaneous outlook is much better. From his review, Sibai (2007) cites an average mortality rate of 7 percent. He also cited a 70-percent preterm delivery rate and a perinatal mortality rate of 15 percent, which in the past was nearly 90 percent. At Parkland Hospital, the maternal and perinatal mortality rates during the past four decades have been 4 percent and 12 percent, respectively (Nelson, 2013).

Although most viral hepatitis syndromes are asymptomatic, during the past 30 years, acute symptomatic infections have become even less common in the United States (Daniels, 2009). There are at least ive distinct types of viral hepatitis: A (HA V), B (HBV), D (HDV) caused by the hepatitis B-associated delta agent, C (HCV) , and E (HEV). he clinical presentation is similar in all, and although the viruses themselves probably are not hepatotoxic, the immunological response to them causes hepatocellular necrosis (Dienstag, 2015a,b).

Acute infections are most often subclinical and anicteric.

When they are clinically apparent, nausea and vomiting, headache, and malaise may precede jaundice by 1 to 2 weeks. Lowgrade fever is more common with hepatitis A. By the time jaundice develops, symptoms are usually improving. Serum transaminase levels vary, and their peaks do not correspond with disease severity (see Table 55-1). Peak levels that range from 400 to 4000 U/L are usually reached by the time jaundice develops. Serum bilirubin values typically continue to rise, despite falling serum transaminase levels, and peak at 5 to 20 mgl dL.

Any evidence for severe disease should prompt hospitalization. These include persistent nausea and vomiting, prolonged prothrombin time, low serum albumin level, hypoglycemia, high serum bilirubin level, or central nervous system symptoms. In most cases, however, clinical and biochemical recovery is complete within 1 to 2 months in all cases of hepatitis A, in most cases of hepatitis B, but in only a small proportion of cases of hepatitis C.

When patients are hospitalized, their feces, secretions, bedpans, and other articles in contact with the intestinal tract should be handled with glove-protected hands. Extra precautions, such as double gloving during delivery and surgical procedures, are recommended. Due to significant exposure of health-care personnel to hepatitis B, the Centers for Disease Control and Prevention (CDC) (2016a) recommend active and passive vaccination, described later. There is no vaccine for hepatitis C, so recommendations are for postexposure serosurveillance only.

Acute hepatitis has a case-fatality rate of 0.1 percent. For patients ill enough to be hospitalized, it may reach 1 percent. Most fatalities are due to fulminant hepatic necrosis, which in later pregnancy may resemble acute fatty liver. In these cases, hepatic encephalopathy is the usual presentation, and the mortality rate is 80 percent. Approximately half of patients with fulminant disease have hepatitis B infection, and co-infection with the delta agent is common.

Hepatic, Biliary, and Pancreatic Disorders 1063

The CDC (20 16b) estimated that more than 4 million Americans were living with chronic viral hepatitis. Although most chroniclly infected persons are asymptomatic, approximately 20 percent develop cirrhosis within 10 to 20 years (Dienstag, 2015b). When present, symptoms are nonspecific and usually include fatigue. In some patients, cirrhosis with liver failure or bleeding varices may be the presenting inding. Indeed, asymptomatic chronic viral hepatitis as a group remains the leading cause of liver cancer and the most frequent reason for liver transplantation.

Chronic viral hepatitis is usually diagnosed serologically (Table 55-3). With persistently abnormal biochemical tests, liver biopsy usually discloses active inlammation, continuing necrosis, and fibrosis that may lead to cirrhosis. Chronic hepatitis is classiied by cause; by grade, defined by histological activity; and by stage, which is the degree of progression (Dienstag, 2015b).

Most young women with chronic viral hepatitis either are asymptomatic or have only mild liver disease. For seropositive asymptomatic women, there usually are no problems with pregnancy. With symptomatic chronic active hepatitis, pregnancy outcome depends primarily on disease and ibrosis severity, and especially on the presence of portal hypertension. he few women whom we have managed have done well, but their long-term prognosis is poor. Accordingly, they should be counseled regarding possible liver transplantation as well as abortion and sterilization options.

Vaccination has reduced the incidence of hepatitis by 95 percent since 1995. In 2014, the rate was 0.4 per 100,000 individuals (Centers for Disease Control and Prevention, 2016b). his 27-nm RNA picornavirus is transmitted by the fecal-oral route, usually by ingestion of contaminated food or water. The incubation period is approximately 4 weeks. Individuals shed virus in their feces, and during the relatively brief period of viremia, their blood is also infectious. Signs and symptoms are oten nonspecific and usually mild, although jaundice develops in most patients. Symptoms usually last less than 2 months, although 10 to 15 percent of patients may remain symptomatic or relapse for up to 6 months (Dienstag, 20 15a). Early serological testing identifies IgVl anti-AV antibody, which may persist for several months. During convlescence, IgG antibody predominates, and it persists and provides subsequent immunity. here is no chronic stage of hepatitis A.

Management of hepatitis A in pregnancy includes a balanced diet and diminished physical activity. Women with less severe illness may be managed as outpatients. In developed countries, the efects of hepatitis A on pregnancy outcomes are not dramatic (American College of Obstetricians and Gynecologists, 2015, 2016). Both perinatal and maternal mortality rates, however, are substantively increased in resource-poor countries. Hepatitis A virus is not teratogenic, and transmission to the fetus is negligible. Preterm birth rates may be increased, and neonatal cholestasis has been reported (Urganci, 2003). Although hepatitis A RNA has been isolated in breast milk, no cases of neonatal hepatitis A have been reported secondary to breastfeeding (Daudi, 2012).

Preventatively, vaccination during childhood with foninactivated hepatitis viral vaccine is more than 90-percent efective. HA V vaccination is recommended by the American College of Obstetricians and Gynecologists (2016) and the Advisory Committee on Immunization (Kim, 20 15a) for highrisk adults. This category includes behavioral and occupational populations and travelers to high-risk countries. These countries are listed in the CDC (2016c) Health Information for International Travel "yellow book," which is available on the CDC website. Passive immunization for the pregnant woman recently exposed by close personal or sexual contact with a person with hepatitis A is provided by a 0.02 mLlkg dose of immune globulin (Kim, 2015a). Victor and colleagues (2007) reported that a single dose of HA V vaccine given in the usual dosage within 2 weeks of contact with an afected person was as efective as immune serum globulin to prevent hepatitis A. In both groups, HA V developed in 3 to 4 percent.

This double-stranded DNA virus is found worldwide. It is endemic in Africa, Central and Southeast Asia, China, Eastern Europe, the Middle East, and certain areas of South America, where prevalence rates reach 5 to 20 percent. The World Health Organization (WHO) (2009) estimates that more than 2 billion people worldwide are infected with HBV, and of these, 370 million have

TABLE 55-3. Simplified Diagnostic Approach in Patients with Hepatitis

Acute hepatitis A with + + +

HAV = hepatitis A virus; HBc = hepatitis B core; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus.

Compiled from the Centers for Disease Control and Prevention, 2016b; Dienstag, 2015a.

chronic infection. The CDC (2016b) estimated nearly 18,100 cases of acute hepatitis B in the United States in 2014. This is a substantial decline since vaccination was introduced in the 1980s.

he hepatitis B virus is transmitted by exposure to blood or body fluids from infected individuals. In endemic countries, vertical transmission, that is, from mother to fetus or newborn, accounts for at least 35 to 50 percent of chronic HBV infections. In low-prevalence countries such as the United States, which has a prevalence <2 percent, the more frequent mode of HBV transmission is by sexual transmission or by sharing contaminated needles. HBV can be transmitted in any body luid, but exposure to virus-laden serum is the most eicient.

Acute hepatitis B develops after an incubation period of 30 to 180 days with a mean of 8 to 12 weeks. At least half of acute infections are asymptomatic. If symptoms are present, they are usually mild and include anorexia, nausea, vomiting, fever, abdominal pain, and jaundice. Acute HBV accounts for half of cases of fulminant hepatitis. Symptoms completely resolve within 3 to.4 months in more than 90 percent of patients.

Figure 55-2 details the sequence of the various HBV antigens and antibodies in acute infection. The first serological marker to be detected is the hepatitis B surface antigen (HBsAg) , often preceding the increase in transaminase levels. As HBsAg disappears, antibodies to the surface antigen develop (anti-HBs), marking complete resolution of disease. Hepatitis B core antigen is an intracellular antigen and not detectable in serum. However, anti -HBc is detectable wi thin weeks of HBsAg appearance. The hepatitis Be antigen (HBeAg) is present during times of high viral replication and often correlates with detectable HBV DNA. After acute hepatitis, approximately 90 percent of adults recover completely. The 10 percent who remain chronically infected are considered to have chronic hepatitis B.

Chronic HBV infection is oten asymptomatic but may be clinically suggested by persistent anorexia, weight loss, fatigue, and

FIGURE 55-2 Sequence of various antigens and antibodies in acute hepatitis B. ALT = alanine transaminase; anti-HBc = antibody to hepatitis B core antigen; anti-HBe = antibody to hepatitis Be antigen; anti-HBs = antibody to hepatitis B surface antigen; HBeAg = hepatitis Be antigen; HBsAg = hepatitis B surface antigen. (Reproduced with permission from Dienstag JL: Acute viral hepatitis. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hili Education, 201o5).

hepatosplenomegaly. Extrahepatic manifestations may include arthritis, generalized vasculitis, glomerulonephritis, pericarditis, myocarditis, transverse myelitis, and peripheral neuropathy. One risk factor for chronic disease is age at acquisition. It is more than 90 percent in newborns, 50 percent in young children, and less than 10 percent in immunocompetent adults. Another risk is an immunocompromised state such as those with human immunodeiciency virus (HIV) infection, transplant recipients, or persons receiving chemotherapy. Chronically infected persons may be asymptomatic carriers or have chronic disease with or without cirrhosis. Patients with chronic disease have persistent HBsAg serum positivity. he patients with evidence of high viral replication-HBV DNA with or without HBeAg-have the highest likelihood of developing cirrhosis and hepatocellular carcinoma. The WHO considers hepatitis B to be second only to tobacco among human carcinogens. HBV DNA has been found to be the best correlate of liver injury and disease progression risk.

Hepatitis B infection is not a cause of excessive maternal morbidity and mortality. It is often asymptomatic and found only on routine prenatal screening (Stewart, 2013). A review of data from the National Inpatient Sample reported a modest increase in preterm birth rates in HBV-positive mothers but no efect on fetal growth restriction or preeclampsia rates (Reddick, 2011). Others have shown similar results (Chen, 2015). Transplacental viral infection is uncommon, and Towers and associates (2001) reported that viral DNA is rarely found in amnionic luid or cord blood. Interestingly, HBV DNA has been found in the ovaries of HBV-positive pregnant women, although this may not be a significant factor in perinatal transmission Gin, 2016b). The highest HBV DNA levels were found in women who transmitted the virus to their fetuses (Dunkelberg, 2015; Society for Maternal-Fetal Medicine, 2016).

In the absence of HBV immunoprophylaxis, 10 to 20 percent of women positive for HBsAg transmit viral infection to their infant. This rate increases to almost 90 percent if the mother is HBsAg and HBeAg positive. Immunoprophylaxis and hepatitis B vaccine given to newborns ofHBV-infected mothers has decreased transmission dramatically and prevented approximately 90 percent of infections (Smith, 2012). But, women with high HBV viralloads-1 06 to 108 copies/ mL-or those who are HBeAg positive still have approximately a 10-percent vertical transmission rate, regardless of immunoprophylaxis (Yi, 2016).

The Society for Maternal-Fetal Medicine (2016) recommends antiviral therapy to decrease vertical transmission in women at highest risk because of high HBV DNA levels. Although lamivudine, a cytidine nucleoside analogue, signiicantly lowers the risk of fetal HBV infection in women with high HBV viral loads, recent data indicate that lamivudine may be less efective in the third trimester. Moreover, it is associated with the development of resistant mutations and is no longer recommended at a firstline agent. Newer drugs include the adenosine nucleoside analogue tenofovir and the thymidine analogue telbivudine. Both are associated with a lower risk of resistance than lamivudine (Ayres, 2014; Yi, 2016). T enofovir has been recommended as the irst-line agent during pregnancy by the Society for Maternal-Fetal Medicine (2016). These antiviral medications appear safe in pregnancy and are not associated with higher rates of congenital malforma tions or adverse obstetrical outcomes (Brown, 2016). Hepatitis B immunoglobulin (HBIG) given antepartum to women at highest risk of transmission is also cost-efective (Fan, 2016).

Newborns of seropositive mothers are given HBIG very soon after birth. This is accompanied by the first of a three dose hepatitis B recombinant vaccine. Hill and colleagues the 2.4-percent transmission rate was not increased with breast feeding if vaccination was completed. Although virus is present in breast milk, the incidence of transmission is not lowered by formula feeding (Shi, 201l). he American Academy of Pedi atrics and the American College of Obstetricians and Gyne contraindication to breastfeeding.

For high-risk mothers who are seronegative, hepatitis B vaccine can be given during pregnancy. he eicacy is similar to that for nonpregnant adults, and overall seroconversion rates approach 95 percent after three doses (Stewart, 2013). he traditional vaccination schedule of 0, 1, and 6 months may be diicult to complete during pregnancy, and compliance rates decline after delivery. Sheield and coworkers (2011) reported that the three-dose regimen given prenatally-initially and at 1 and 4 months-resulted in seroconversion rates of 56, 77, and 90 percent, respectively. This regimen was easily completed during routine prenatal care.

Also called delta hepatitis, this is a defective RNA virus that is a hybrid particle with an HBsAg coat and a delta core. he virus must co-infect with hepatitis B either simultaneously or secondarily. It cannot persist in serum longer than hepatitis B virus. Transmission is similar to hepatitis B. Chronic coinfection with Brand D hepatitis is more severe and accelerated than with HBV alone, and up to 75 percent of afected patients develop cirrhosis. HDV infection is detected by the presence of anti-HDV and HDV DNA. Neonatal transmission is unusual, as neonatal HBV vaccination usually prevents delta hepatitis.

This is a single-stranded RNA virus, and transmission occurs via blood and body luids, although sexual transmission is ineicient. Up to a third of anti-HCV positive persons have no identifiable risk factors (Dienstag, 2015b). Screening for HCV is recommended for HIV-infected individuals, persons with injection drug use, hemodialysis patients, children born to mothers with HCV, persons exposed to HCV-positive blood or body fluids, persons with unexplained elevations in transaminase values, and recipients of blood or transplants before July 1992. Prenatal screening is recommended for high-risk women, and in the United States, seroprevalence rates reach 1 to 2.4 percent (American College of Obstetricians and Gynecologists, 2016; Arshad, 2011). It is higher in women who are infected with HIV. Santiago-Munoz and associates (2005) found that 6.3 percent of HIV-infected pregnant women at Parkland Hospital were co-infected with hepatitis B or C.

Hepatic, Biliary, and Pancreatic Disorders 1065

Acute HCV infection is usually asymptomatic or yields mild symptoms. Only 10 to 15 percent develop jaundice. he incubation period ranges from 15 to 160 days with a mean of 7 weeks. Transaminase levels are elevated episodically during the acute infection. Hepatitis C RNA testing is now preferred for HCV diagnosis. RNA levels may be found even before elevations of transaminase and anti-HCV levels. Speciically, anti-HCV antibody is not detected for an average of 15 weeks and in some cases up to a year (Dienstag, 20 15a).

Nearly 80 to 90 percent of patients with acute HCV will be chronically infected. Although most remain asymptomatic, approximately 20 to 30 percent progress to cirrhosis within 20 to 30 years. Transaminase values fluctuate, and HCV RNA levels vary over time. Liver biopsy reveals chronic disease and fibrosis in up to 50 percent, however, these indings are oten mild. Overall, the long-term prognosis for most patients is excellent.

As expected, most pregnant women diagnosed with HCV have chronic disease. HCV infection was initially thought to have limited pregnancy efects. However, more recent reports have chronicled modestly increased fetal risks for low birthweight,

NICU admission, preterm delivery, and mechanical ventilation (Berkley, 2008; Pergam, 2008; Reddick, 201l). In some women, high-risk behaviors associated with HCV infection.

he primary adverse perinatal outcome is vertical transmission of HCV infection to the fetus-infant. This is higher in mothers with viremia (Indolfi, 2014; Joshi, 2010). Airoldi and Berghella (2006) cited a rate of 1 to 3 percent in HCV-positive, RNA-negative women compared with 4 to 6 percent in those who were RNA-positive. In a report from Dublin, the vertical transmission rate in 545 HCV-infected women was 7. I-percent in RNA-positive women compared with none in those who were RNA-negative (McMenamin, 2008). Some have found an even greater risk when the mother is co-infected with HIV (Snidjewind, 2015; T ovo, 2016). Invasive prenatal diagnostic procedures have not been reported to increase transmission to the fetus. However, Rae and Sheield (2014) note that few studies have addressed this possibility, and they recommend avoiding traversing the placenta during amniocentesis. Approximately two thirds of prenatal transmission cases occur peripartum. HCV genotype, invasive prenatal procedures, breastfeeding, and delivery mode are not associated with mother-to-child transmission. That said, invasive procedures such as internal electronic fetal heart rate monitoring are avoided. HCV infection is not a contraindication to breastfeeding.

No licensed vaccine is available for HCV prevention. The chronic HCV infection treatment has traditionally included alpha interferon (standard and pegylated), alone or in combination with ribavirin. This regimen is contraindicated in pregnancy because of the teratogenic potential of ribavirin in animals (Joshi, 2010). he initial 5-year review of the Ribavirin Pregnancy Registry found no evidence for human teratogenicity. However, the registry has enrolled fewer than half of the necessary numbers to allow a conclusive statement to be made (Roberts, 2010). The development and study of direct-acting and host-targeted antiviral drugs in the past decade shows great promise for chronic hepatitis C management (Liang, 2013; Lok, 2012; Poordad, 2013). Current interferon-free, ribavirin-free regimens are being evaluated, although no data are available for pregnant women.

This water-borne RNA virus usually is enterically transmitted by contaminated water supplies. Hepatitis E is probably the most common cause of acute hepatitis (Hoofnagle, 2012). It causes epidemic outbreaks in third-world countries with substantial morbidity and mortality rates. Pregnant women have a higher case-fatality rate than nonpregnant individuals. In a metaanalysis of nearly 4000 subjects from Asia and Africa, Jin and coworkers (2016a) reported maternal and fetal case-fatality rates of 21 and 34 percent, respectively. Fulminant hepatitis, although rare overall, is more common in gravidas and contributes to the increased mortality rates. An altered innate immune response to incipient hepatitis E infection during pregnancy, afecting macrophage function and toll-like receptor signaling, may be a factor in the development of fulminant hepatitis (Sehgal, 2015).

A recombinant HEV vaccine has been developed and licensed in China. It is >95 percent efective for 12 months after vaccination. Long-term eicacy is 87 percent, and protective titers are maintained for up to 4.5 years (Zhang, 2015). Preliminary data from inadvertently vaccinated pregnant women show no adverse maternal or fetal events (Wu, 2012). At this time, it is unclear if this Chinese-licensed vaccine is efective in other areas of the world where other genotypes predominate. Genotype 4 is most common in China, and types 2 and 3 are more common in the Americas. A Food and Drug Administration (FDA) approved vaccine is not available at this time.

Hepatitis E is found worldwide, and although the highest prevalence is in east Asia, the CDC (2015) lists Mexico as a highly endemic country. Seroprevalence rates vary by age and geography, but overall seroprevalence rates of 10 percent have been reported. Durango State has the highest rate (37 percent) (Fierro, 2016).

Hepatitis G is the former name of an RNA flavivirus now known as HPvG or human pegivirus. This blood-borne infection of the liver, spleen, bone marrow, and mononuclear cells of the peripheral blood does not actually cause hepatitis (Chivero, 2015). It is thought to infect 750 million people worldwide, with up to two times that many with evidence of past infection. It may modulate the immune response, particularly during coinfection with HIV. Currently, no treatment aside from basic blood and body luid precautions is recommended. Vertical transmission (to the fetus/infant) and horizontal transmission (to peers) has been described (Trinks, 2014).

his is a generally progressive chronic hepatitis that is important to distinguish from other forms. Autoimmune hepatitis is more common in women and frequently coexists with other types of autoimmune disease, particularly autoimmune thyroid disease and Sjogren syndrome. Symptoms are typical of acute and chronic hepatitis, but one quarter may be asymptomatic. Rates of cirrhosis vary worldwide, but in western countries autoimmune hepatitis is more common and is characterized by multiple autoimmune antibodies such as antinuclear antibodies (ANA) and anti-smooth muscle antibody. Type 2 autoimmune hepatitis has an even higher prevalence in females and typically a more aggressive presentation. he incidence peaks in childhood and adolescence, before peak reproductive years. Treatment employs corticosteroids, alone or combined with azathioprine. Failure to respond to these two agents is more frequent in those with type 2 disease, and nearly all women with type 2 disease require more intensive therapy that is sustained long term (Vierling, 2015). In some patients with progressive disease and cirrhosis, hepatocellular carcinoma develops. In general, autoimmune hepatitis-especially when severeincreases the risk of adverse pregnancy outcomes.

Westbrook and coworkers (2012) reported the outcomes of 81 pregnancies in 53 women. A third had a flare, and these were more common in those not taking medication and those with active disease in the year before conception. Maternal and fetal complications were higher among women with cirrhosis, particularly with respect to the risks of death or need for liver transplantation during the pregnancy or within 12 months postpartum. From one Swedish national database analysis, frequencies of preterm birth, low birthweight, and diabetes were higher, but not those of preeclampsia or cesarean delivery (Stokkeland, 2016). Danielsson Borssen (2016) reported stable or mild disease in 84 percent of 58 women who delivered 100 newborns. Nearly a fourth of cases were delivered before 38 weeks, and a postpartum flare developed in a third. Cirrhosis was present in 40 percent, and these women experienced more complications during pregnancy.

Chronic hepatitis and cirrhosis can result from iron and copper overload. Iron overload may stem from a primary cause that is generally inherited, such as hereditary hemochromatosis, or originates secondary to complications of certain hemoglobinopathies. Many of the gene mutations underlying hereditary hemochromatosis involve hepcidin and result in dysregulated iron transport (Chap. 4 p. 58). Some of these mutations are more common in certain populations originating from northern Europe (Pietrangelo, 2016; Salgia, 2015). Cardiomyopathy, diabetes, joint disease, and skin changes can coexist with liver disease. Pregnancy outcomes associated with iron overload in hereditary hemochromatosis are driven by the degree of liver dysfunction, although higher iron levels may afect birthweight (Dorak, 2009).

A form of neonatal hemochromatosis that does not afect the mother is now thought to be alloimmune and is called gestational aloimmune liver disease (Anastasio, 2016). With this, maternal autoantibodies cross to the fetus and mediate dysfunction of iron homeostasis, although the antigenic target of these alloantibodies remains unclear. It is associated with significant neonatal morbidity and mortality, and frequently recurs in subsequent pregnancies. In these cases, antepartum treatment with intravenous immunoglobulin (IVIG) may improve outcomes (Feldman, 2013; Roumiantsev, 2015).

Copper overload leading to chronic hepatitis and cirrhosis is Wilson disease. This systematic condition can also manifest with cardiomyopathy, renal disease, neuropsychiatric symp toms, and certain endocrine abnormalities. A Kayser-Fleischer ring surrounding the iris is highly speciic, but a suspected diagnosis generally requires genetic analysis. Autosomal reces sive mutations of the A TP7B gene underlie this disorder. his gene codes for the P-type ATPase involved in copper transport to ceruloplasmin and bile (Bandman, 2015).

With Wilson disease, infertility may be present, but preg nancy outcomes among afected women who do conceive are inluenced by disease severity. Malik and colleagues (2013) reported four cases in pregnancy, and three had associated ges tational hypertension or preeclampsia. Maternal and neonatal outcomes were good, and the authors review chelation therapy with penicillamine and zinc sulfate in pregnancy. he American

College of Gastroenterology states that few data guide which of the various chelating agents is best (Tran, 2016). These include penicillamine, zinc, and trientine, and any theoretical risks are outweighed by the risks of discontinuing therapy. he latter include not only hepatic decompensation, but also injury to the placenta and fetal liver. Accordingly, the American College continue their chelation therapy, although a dose reduction of 25 to 50 percent should be considered to promote wound heal ing in the event of a surgical delivery. As a reminder, copper ions regulate the activity of proteins essential to wound repair.

his condition is frequently comorbid with obesity and is the most common chronic liver disease in the United States (Diehl, 2017). Its most severe form-nonacoholic steatohepatitis (NASH)-is an increasingly recognized condition that may occasionally progress to hepatic cirrhosis. Nonalcoholic fatty liver disease (NAFLD) is a macrovesicular fatty liver condition that resembles alcohol-induced liver injury but is seen without this substance abuse. Obesity, type 2 diabetes, and hyperlipidemiasyndrome X-frequently coexist (Chap. 48 p. 938). The current hypothesis suggests that these conditions may interact with other unknown etiological agents to cause multiple insults or "hits" leading to hepatic injury. For example, half of persons with type 2 diabetes have NAFLD, and insulin resistance has been postulated to act as one possible "hit" (Buzzetti, 2016). Browning and associates (2004) used MR spectroscopy to determine the prevalence ofNAFLD in Dallas County and found that approximately a third of adults were afected. This varied by ethnicity, with 45 percent of Hispanics, 33 percent of whites, and 24 percent of blacks being afected. Most people-80 percent-found to have steatosis had normal liver enzymes. In a study of obese adolescents undergoing bariatric surgery, more than a third had fatty liver without hepatitis, whereas an additional 20 percent had borderline or definite NASH (Xanthakos, 2015).

Liver damage follows a progressive continuum from NAFLD to NASH and then to hepatic ibrosis that may progress to cirrhosis (Goh, 2016). Still, in most persons, the disease is usually asymptomatic, and it is a frequent explanation for elevated serum transaminase levels found in blood donors and during

Hepatic, Biliary, and Pancreatic Disorders 1067 other routine screening. Indeed, NAFLD is the cause of ele vated asymptomatic transaminase levels in up to 90 percent of cases in which other liver disease is ultimately excluded. It also is the most common cause of abnormal liver tests among adults in this country. Currently, weight loss along with control of diabetes and dyslipidemia is the only recommended treatment.

Fatty liver iniltration is probably much more common than realized in obese and diabetic gravidas. During the past decade, we encountered an increasing number of pregnant women with these disorders. Once severe liver injury, that is, acute fatty liver of pregnancy, is excluded, gravidas with fatty liver iniltra tion have no greater rates of adverse outcomes relative to liver involvement compared with pregnant women of similar weight.

That said, some emerging data indicate that this condition may portend adverse pregnancy outcomes. In 110 pregnancies with

NAFLD from the Swedish Medical Birth and the National

Patient Registries, risks of gestational diabetes, preeclampsia, pre teI'm birth, and low-birthweight newborns were two-to threefold greater than in unafected women (Hagstrom, 2016). Yarrington and associates (2016) reported a high rate of gestational diabetes among nonobese women without liver disease, alcohol use, or diabetes, and who had elevated alanine transaminase levels in the irst trimester. s the obesity endemic worsens, adverse efects of this liver disorder on pregnancy will be clarified.

Irreversible chronic liver injury with extensive fibrosis and regenerative nodules is the inal common pathway for several disorders. Laennec cirrhosis from chronic alcohol exposure is the most frequent cause in the general population. But in young women-including pregnant women-most cases are caused by postnecrotic cirrhosis from chronic hepatitis Brand C. Many cases of cryptogenic cirrhosis are now known to be caused by NAFLD (Goh, 2016). Clinical manifestations of cirrhosis include jaundice, edema, coagulopathy, metabolic abnormalities, and portal hypertension with gastroesophageal varices and with splenomegaly that may cause thrombocytopenia. The incidence of deep-vein thromboembolism is increased (S0gaard, 2009). The prognosis is poor, and 75 percent have progressive disease that leads to death in 1 to 5 years.

Women with symptomatic cirrhosis frequently are infertile.

hose who become pregnant generally have poor outcomes. Common complications include transient hepatic failure, variceal hemorrhage, preterm delivery, fetal growth restriction, and maternal death (Tan, 2008). Outcomes are generally worse if esophageal varices coexist.

Another potentially fatal complication of cirrhosis arises from associated splenic artery aneurysms. Up to 20 percent of ruptures occur during pregnancy, and 70 percent of these rupture in the third trimester (Palatnik, 2017; Tan, 2008). In a review of 32 gravidas with aneurysm rupture, the mean aneurysm diameter was 2.25 cm, and in half of cases, the diameter was <2 cm (Ha, 2009). The 22-percent maternal mortality rate was likely related to the emergent presentation of these events. Parrish and colleagues (2015) described embolization of a 13 X 9 mm aneurysm in the third trimester leading to a splenic abscess and sepsis 3 weeks later.

In pregnant women, approximately half of cases of esophageal varices originate from cirrhosis or extrahepatic portal vein obstruction, which leads to portal system hypertension. Some cases of extrahepatic hypertension develop following portal vein thrombosis associated with one of the thrombophilia syndromes (Chap. 52, p. 1005). Others follow thrombosis from umbilical vein catheterization when the woman was a neonate, especially if she was born preterm.

With either intrahepatic or extrahepatic resistance to low, portal vein pressure rises from its normal range of 5 to 10 mm Hg, and values may exceed 30 mm Hg. Collateral circulation develops that carries portal blood to the systemic circulation. Blood drains into the gastric, intercostal, and other veins to the esophageal system, where varices develop. Bleeding is usually from varices near the gastroesophageal junction, and hemorrhage can be torrential. Bleeding during pregnancy from varices occurs in a third to half of afected women and is the major cause of maternal mortality within thisrgroup (Tan, 2008).

Maternal prognosis with esophageal varices largely depends on whether these rupture. Mortality rates are higher if varices are associated with cirrhosis compared with rates for varices without cirrhosis-18 versus 2 percent, respectively. Perinatal mortality rates are high in women with varices and are worse if cirrhosis caused the varices. Increased rates of neonatal demise, preterm birth, low birthweight, preeclampsia, and postpartum hemorrhage have been reported (Puljic, 2016).

Treatment is the same as for nonpregnant patients. Preventatively, all patients with cirrhosis, including pregnant women, should undergo endoscopic screening for identification of variceal dilatation (Bacon, 2015). Beta-blocking drugs such as propranolol are given to reduce portal pressure and hence the bleeding risk (Bissonnette, 2015; Tran, 2016).

For acute bleeding and for prophylaxis, endoscopic band ligation is preferred to sclerotherapy as it avoids any potential risks of injecting sclerotherapeutic chemicals (Bissonnette, 2015; Tan, 2008). Acute medical management for bleeding varices veriied endoscopically includes the intravenous (IV) vasoconstrictors octreotide or somatostatin along with endoscopic banding. Vasopressin is less often used (Bacon, 2015). Baloon tamponade using a triple-lumen tube placed into the esophagus and stomach to compress bleeding varices can be lifesaving if endoscopy is not available. An interventional radiology procedure-tranjugular intrahepatic portosystemic stent shunting (TIPSS)-can also control bleeding from gastric varices that is unresponsive to other measures (Bissonnette, 2015; Tan, 2008). This procedure can be done electively in patients with prior variceal hemorrhage.

This drug is the most common cause of acute liver failure in the United States (Lee, 2013). Acetaminophen is often used during pregnancy, and overdose-either accidentally or by attempted suicide-may lead to hepatocellular necrosis and acute liver failure (Bunchorntavakul, 2013). Massive necrosis causes a cytokine storm and multiorgan dysfunction. Early symptoms of overdose are nausea, vomiting, diaphoresis, malaise, and pallor. With an acute overdose, after a latent period of 24 to 48 hours, liver failure ensues and usually begins to resolve in 5 days. In a prospective Danish study, only 35 percent of patients who were treated for fulminant hepatic failure spontaneously recovered before being listed for liver transplantation (Schmidt, 2007).

The antidote is N-aceycysteine, which must be given promptly. he drug is thought to increase glutathione levels, which aid metabolism of the toxic metabolite, N-acetyl-pbenzoquinoneimine. he need for treatment is based on projections of possible plasma hepatotoxic levels as a function of the time from acute ingestion. For this, many poison control centers use the nomogram established by Rumack and Matthew (1975). A plasma level is measured 4 hours after ingestion, and if the level is > 150 1g/mL, treatment is given (Smilkstein, 1988). If plasma determinations are not available, empirical treatment is given if the ingested amount exceeded 7.5 g. An oral loading dose of 140 mg/kg of N-acetylcysteine is followed by 17 maintenance doses of 70 mg/kg every 4 hours for 72 hours of total treatment time. Both the oral and an equally eicacious IV dosing regimen have been reviewed by Hodgman and Garrard (2012). he drug has been reported to reach therapeutic concentrations in the fetus (Wiest, 2014).

After 14 weeks' gestation, the fetus has some cytochrome P450 activity necessary for metabolism of acetaminophen to the toxic metabolite. Riggs and colleagues (1989) reported follow-up data from the Rocky Mountain Poison and Drug Center in 60 women sufering overdose. he likelihood of maternal and fetal survival was better if the antidote was given soon after overdose. At least one 33-week fetus appears to have died as a direct result of hepatotoxicity 2 days after maternal ingestion. In another case, Crowell and associates (2008) reported a case of acetaminophen overdose at 32 weeks' gestation. The woman had taken 9.75 grams of acetaminophen approximately 1.5 hours prior to arrival. With treatment, the patient survived and went on to deliver a healthy term neonate.

This benign lesion of the liver is characterized in most cases by a well-delineated accumulation of normal but disordered hepatocytes that surround a central stellate scar. hese usually can be diferentiated from hepatic adenomas by magnetic resonance (vIR) or computed tomographic (CT) imaging. Except in the rare situation of unremitting pain, surgery is rarely indicated, and most women remain asymptomatic during pregnancy. In one review of 20 cases in Germany, no woman had related complications during pregnancy (Rifai, 2013). hree women showed 20-percent tumor growth; in 10 patients, the tumor decreased in size; and the remaining seven were unchanged across pregnancy. Ramirez-Fuentes and associates (2013) studied 44 lesions with MR imaging in 30 women. Of the lesions, 80 percent were unchanged in size, and most of the remainder decreased in size. They concluded that size changes were unrelated to pregnancy, combination oral contraceptive (COC) use, or menopause. Notably, this lesion is not a contraindication to estrogen-containing contraceptives (Chap. 38, p. 692).

Hepatic, Biliary, and Pancreatic Disorders 1069 -This is an uncommon benign neoplasm but has a 5-percent risk of malignant transformation and a significant risk of rupture-associated hemorrhage, particularly in pregnancy. s just discussed, adenomas can usually be diferentiated from focal nodular hyperplasia by MR or CT imaging. Adenomas have a 9:1 predominance among women and are strongly linked with COC use. The rupture risk progresses with lesion size, and surgery is generally recommended for tumors measuring >5 cm (Agrawal, 2015). T ran and colleagues (2016) recommend sonographic surveillance of hepatic adenomas during pregnancy. In one review of 27 cases in pregnany, 23 became apparent in the third trimester .nd puerperium (Cobey, 2004). Bleeding complicated no tumors measuring <6.5 cm. However, 16 of27 women (60 percent) with an adenoma presented with tumor rupture that resulted in seven maternal deaths and six fetal deaths. Of note, 13 of 27 women presented within 2 months postpartum, and in hal, hemorrhage heralded rupture. Wilson and coworkers (2011) described two cases of bleeding hepatic adenoma during pregnancy. One was managed by laparoscopic segmental resection, and another, which followed liver biopsy, required open surgery. The authors discourage biopsy during pregnancy for suspected hepatic adenomas, and emphasize the feasibility of resection for problematic lesions.

In 2013 in the United States, 5921 adult liver transplants were performed, and 34 percent of patients were women (Kim, 2015b). Currently, more than 65,000 recipients of liver transplant are living, and one literature review cited 450 pregnancies in 3026 women who had undergone transplantation (Deshpande, 2012). Although their live-birth rate of 80 percent and miscarriage rate compare favorably with those of the general population, risks of preeclampsia, cesarean delivery, and preterm birth are significantly elevated. A fourth of pregnancies were complicated by hypertension, approximately a third resulted in preterm birth, and in 10 percent, there was one or more rejection episodes (Table 55-4). Importantly, 4 percent of mothers had died within a year after delivery, but this rate is comparable to that in nonpregnant liver transplantation patients. Ghazali and associates (2016) analyzed the National Inpatient Sample database and found 2.r1 liver transplants per 100,000 deliveries. Pregnancies after liver transplant had signiicantly greater risks of maternal and fetal complications, including hypertensive disorders, gestational diabetes, and postpartum hemorrhage. Rates of preterm birth, fetal growth restriction, and congenital anomalies were also increased. Mattila and colleagues (2017) found that half of the women they cared for had maternal complications.

In the United States, 20 percent of women older than 40 years have gallstones. Most stones contain cholesterol, and its overse cretion into bile is thought to be a major factor in stone forma tion. The cumulative risk of all patients with silent gallstones to require surgery for symptoms or complications is 10 percent at 5 years, 15 percent at 1° years, and 18 percent at 15 years (Greenberger, 2015). For these reasons, prophylactic cholecys tectomy is not warranted for asymptomatic stones. For symp tomatic gallstone disease, nonsurgical approaches have been used and include oral bile acid therapy with ursodeoxycholic acid and extracorporeal shock wave lithotripsy. Experience with these during pregnancy is lacking.

Acute cholecystitis usually develops when the cystic duct is obstructed. Bacterial infection plays a role in 50 to 85 percent of cases. In more than half of patients with acute cholecystitis, a history of prior right upper quadrant pain from cholelithiasis is elicited. With acute disease, pain is accompanied by anorexia, nausea and vomiting, low-grade fever, and mild leukocytosis. As shown in Figure 55-3, sonography can help visualize stones, and both false-positive and false-negative rates range from 2 to 4 percent (Greenberger, 2015). In acute cases, medical therapy consists of IV luids, antimicrobials, analgesics, and in some instances, nasogastric suction, before surgical therapy. Laparoscopic cholecystectomy is the preferred treatment for most patients.

After the irst trimester, the gallbladder fasting volume and the residual volume after postprandial emptying are doubled. Incomplete emptying may result in retention of cholesterol crystals, a prerequisite for cholesterol gallstones. Maringhini and colleagues (1993) showed that the incidence of biliary sludge-which can be a forerunner to gallstones-and gallstones in pregnancy are 31 and 2 percent, respectively. Ko and colleagues (2014), however, cited a combined incidence of <5 percent. Others have identiied asymptomatic gallstones in

FIGURE 55-3 This sonogram shows mUltiple hyperechoic gallstones filling an anechoic gallbladder.

2.5 to 10 percent of more than 1500 pregnant or postpartum women (Maringhini, 1993; Valdivieso, 1993).

Postpartum, sludge frequently regresses, and occasionally gallstones will resorb. Still, within a year ter delivery, hospitalization for gallbladder disease remains relatively common, particularly for women managed conservatively in pregnancy. Jorge and coworkers (2015) reported that half of 53 women with symptomatic gallstones in pregnancy underwent postpartum cholecystectomy. In 80 percent of these women, recurrent symptoms developed prior to surgery, requiring readmission in half.

Acute cholecystitis during pregnancy or the puerperium is common and usually associated with gallstones or biliary sludge. Symptomatic cholecystitis is initially managed in a manner similar to that for nonpregnant women. In the past, most favored medical therapy. However, the recurrence rate during the same pregnancy is high, and 25 to 50 percent of women ultimately required cholecystectomy for persistent symptoms. Moreover, if cholecystitis recurs later in gestation, preterm labor is more likely and cholecystectomy is technically more diicult.

For these reasons, operative and endoscopic interventions are increasingly favored over conservative measures. Othman and coworkers (2012) showed that women managed conservatively had more pain, more recurrent visits to the emergency department, more hospitalizations, and a higher rate of cesarean delivery. Dhupar and associates (2010) reported more complications with conservative management of gallbladder disease compared with laparoscopic cholecystectomy in pregnancy. hese included multiple admissions, prolonged total parenteral nutrition, and unplanned labor induction for worsening gallbladder symptoms. Cholecystectomy was performed safely in all trimesters. Only one of 19 patients who underwent laparoscopic cholecystectomy had a complication, which did not require further surgery. A metaanalysis found that cholecystectomy does not increase the risk of preterm labor or of maternal or fetal mortality (Athwal, 2016). Management at Parkland Hospital has evolved to a more aggressive surgical approach, especially if there is concomitant biliary pancreatitis as subsequently discussed. During the past two decades, laparoscopic cholecystectomy has evolved as the favored surgical approach and is discussed in Chapter 46 (p. 901).

Relief from symptomatic biliary duct gallstones during pregnancy has been greatly aided by use of endoscopic retrograde cholangiopancreatography (ERCP) (Fogel, 2014; Menees, 2006). he procedure is performed if common duct obstruction is suspected or proven. Approximately 10 percent of patients with symptomatic stone disease have common duct stones (Stinton, 2012). ERCP can be modiied in many cases so that radiation exposure from luoroscopy is avoided (Sethi, 2015).

Tang and associates (2009) reported results from 68 ERCP procedures performed in 65 pregnant women at Parkland Hospital. ll but two women had gallstones, and sphincterotomy was performed in all but one woman. Common duct stones were identified in half of these 65 women, and in all but one, the stones were successfully removed. A biliary stent was placed in 22 percent of cases and removed after delivery. Complications were minimal, and post-ERCP pancreatitis developed in 16 percent. Pregnancy outcomes were not diferent than for the general obstetrical population. As a less invasive approach, 1R cholangiopancreatography (MRCP) has been reported to have utility in pregnancy in small, retrospective case series. Wu and colleagues (2014) caution against its use in pregnancy, particularly for seriously ill women. Also, MRCP is not readily available, and this may lead to delayed deinitive management.

Ascending cholangitis can complicate acute biliary obstruction. Nearly 70 percent of afected patients develop Charcot triad-jaundice, abdominal pain, and fever. The diagnosis is aided by sonography, and treatment is broad-spectrum antibiotics and biliary drainage by ERCP (Greenberger, 2015).

Acute pancreatic inlammation is triggered by factors that cause activation of pancreatic trypsinogen followed by autodigestion. It is characterized by cell-membrane disruption and proteolysis, edema, hemorrhage, and necrosis (Conwell, 2015; Fogel, 2014). Up to 10 percent of women develop necrotizing pancreatitis, which carries a mortality risk of 15 percent. This rate rises if infection develops (Cain, 2015).

In nonpregnant patients, acute pancreatitis is almost equally associated with gallstones and alcohol abuse. During pregnancy, however, cholelithiasis is almost always the predisposing condition. Other causes are hyperlipidemias, usually hypertriglyceridemia; hyperparathyroidism; congenital ductal anomalies; ERCP; some drugs; and rarely autoimmune pancreatitis (Cain, 2015; Ducarme, 2014). N onbiliary pancreatitis occasionally develops postoperatively, or it is associated with trauma, drugs, or some viral infections. Certain metabolic conditions, including acute fatty liver of pregnancy and familial hypertriglyceridemia, also predispose to pancreatitis (Nelson, 2013). Cases of acute and chronic pancreatitis have been linked to numerous mutations of the cystic fibrosis transmembrane conductance regulator gene (Chang, 2015).

The incidence of pancreatitis varies with the population studied. At Parland Hospital, with a predominant Mexican American population, acute pancreatitis complicated approximately 1 in 3300 pregnancies (Ramin, 1995). At Brigham and Women's Hospital, with a more diversely ethnic population, Hernandez and colleagues (2007) reported an incidence of 1 in 4450. In a multiple-institution :Midwestern three-state review, the incidence of acute pancreatitis was 1 in 3450 (Eddy, 2008). In contrast, from California birth certificate data, the incidence approximated only 1 case in 6000 pregnancies (Hacker, 2015).

Acute pancreatitis is characterized by mild to incapacitating epigastric pain, nausea and vomiting, and abdominal distention. Patients are usually distressed and have low-grade fever, tachycardia, hypotension, and abdominal tenderness. As many as 10 percent have systemic inlammatory response syndrome (SIRS), which causes endothelial activation and can lead to acute respiratory distress syndrome (Chap. 47, p. 921).

Of laboratory tests, serum amylase levels usually measure three times values considered the upper limit of normal. In 173 pregnant women with pancreatitis, the mean amylase value approximated 2000 lUlL, and the mean lipase value approached 3000 lUlL (Table 55-5). Importanty, the degree of enzyme elevation and disease severiy do not reliaby correlate. Indeed, by 48 to 72 hours, amylase levels may return to normal despite other evidence for continuing pancreatitis. Serum lipase activity is also increased and usually remains elevated with continued inlammation. Leukocytosis is usually found, and 25 percent of patients have hypocalcemia. Elevated serum bilirubin and aspartate transaminase levels may signiY gallstone disease.

Several prognostic scoring systems have been used to classiY pancreatitis severity, but not all of these are useful in pregnancy. For instance, two of the ive Ranson criteria determined

TABLE 55-5. Laboratory Values in 173 Pregnant Women with Acute Pancreatitis

Hepatic, Biliary, and Pancreatic Disorders 1071 at admission include variables speciic to nonpregnant patients. Similarly, certain criteria for the Apache II scoring system do not account for the changes in pregnancy physiology. In contrast, the Atlanta Classiication incorporates the degree of organ failure as a measure of severity and may be more applicable in pregnancy (Banks, 2013; Cain, 2015).

Medical treatment mirrors that for nonpregnant patients. This includes analgesics, IV hydration, and measures to decrease pancreatic secretion by interdiction of oral intake. Other than supportive therapy, antibiotics when appropriate, and targeted surgical interventions in the case of gallstone pancreatitis, no particular treatment schemes have improved outcomes. In a series by Ramin and colleagues (1995), all 43 afected pregnant women responded to conservative treatment and were hospitalized for a mean of8.5 days. Nasogastric suction does not improve outcomes of mild to moderate disease, but enteral feeding may be helpul once pain improves and associated ileus resolves. For women with more severe pancreatitis and a prolonged disease course, total enteral nutrition using nasojejunl feeding is superior to total parenteral nutrition (Cain, 2015; Conwell, 2015). If there is bacterial superinfection of necrotizing pancreatitis, sepsis, or cholangitis, then broad-spectrum antimicrobials are administered. If common duct stones are found, then ERCP is indicated (Fogel, 20 14; Tang, 2010). Cholecystectomy is considered after inflammation subsides because women with galls tonic pancreatitis carry an increased risk of recurrent pancreatitis (Cain, 2015).

Pregnancy outcomes are afected by acute pancreatitis severity. Eddy and associates (2008) reported a 30-percent preterm delivery rate, and 11 percent were delivered before 35 weeks' gestation. There were two pancreatitis-related maternal deaths. Importantly, almost a third of 73 women had recurrent pancreatitis during pregnancy. Of the 342 pregnancies complicated by pancreatitis in the California study, preterm delivery and fetal mortality rates were increased (Hacker, 2015). Also, preeclampsia risk was increased fourfold.

Few reports describe pregnancy following pancreas transplantation. Of 44 pregnancies in 73 women following pancreaskidney transplantation, outcomes are encouraging, and vaginal delivery has been described CMastrobattista, 2008). Although the incidence of hypertension, preeclampsia, preterm delivery, and fetal-growth restriction are high, there was only one perinatal death. Four rejection episodes developed during pregnancy and were treated successfully. Pancreatic islet autotransplanta tion may be performed to prevent diabetes following pancre

Serum lipase 3076 36-41,824 atectomy, and at least three successful pregnancies have been 1.7 0.1-8.71 0.2-1.3 reported (J ung, 2007).

Leukocytes 10,700 1000-27,200 3900-10,700 Abu-Hayyeh S, Ovadia C, Lieu T, et al: Prognostic and mechanistic potenrial of progesterone sulfates in inrrahepatic cholestasis of pregnancy and pruritus gravidarum. Hepatology ,t2016

Agrawal S, Agarwal S, Arnason T, et al: Management of hepatocellular ade

From Ramin, 1995; Tang, 201n0; Turhan, 2010.

noma: recent advances. Clin Gastroenrerol Hepatol 13: 1221, 2015 iroldi J, Berghella V: Hepatitis C and pregnancy. Obstet Gynecol Surv 61(10):666,s2006

American Academy of Pediatrics and the merican College of Obstetricians and Gynecologists: Guidelines for Perinatal Care, 8th ed. Elk Grove Village, AAP, 2017

American College of Obstetricians and Gynecologists: Upper gastrointestinal tract, biliary, and pancreatic disorders. Clinical Updates in Women's Health Care, Vol. l, No.s4, 2012, Reairmed 2015

American College of Obstetricians and Gynecologists: Viral hepatitis in pregnancy. Practice Bulletin No. 86, October 2007, Reairmed 2016 nastasio HB, Gruncy M, Birsner ML, et al: Gestational alloimmune liver disease. A devastating condition preventable with maternal intravenous immunoglobulin. Obstet GynecoIs128:1092, 2016 nzivino C, Odoardi MR, Meschiari E, et al: ABCB4 and ABCB 11 mutations in intrahepatic cholestasis of pregnancy in an Italian population. Dig Liver Dis 45(3):226, 2013

Arshad M, El-Kamary SS, Jhaveri R: Hepatitis C virus infection during pregnancy and the newborn period-are they opportunities for treatment? J Viral Hepat 18(4):229,2011

Athwal R, Bhogal RH, Hodson J, et al: Surgery for gallstone disease during pregnancy does not increase fetal or maternal mortality: a meta-analysis. Hepatobiliary Surg Nutr 5:53, 2016

Ayres A, Yuen L, Jackson M, et al: Short duration of lamivudine for the prevention of hepatitis B virus transmission in pregnancy: lack of potency and selection of resistance mutations. J Viral Hepat 21:809,s2014 Bacon BR: Cirrhosis and its complications. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill Education, 2015 Bacq Y, Sentilhes L, Reyes HB, et al: Eicacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: a meta-analysis. Gastroenterology 143(6):1492,s2012 Bandman 0, Weiss KH, Kaler SG: Wilson's disease and other neurological copper disorders. Lancet NeuroIs14:103, 2015 Banks PA, Bollen TL, Dervenis C, et al: Acute pancreatitis classiication working group. Classiication of acute pancreatitis-20 12: revision of the Atlanta classification and definitions by international consensus. Gut 62:102,s2013 Baskin B, Geraghty M, Ray PN: Patenal isodisomy of chromosome 2 as a cause of long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. Am J Med Genet A 152A(7):1808, 2010 Berkley EM, Leslie KK, Arora S, et al: Chronic hepatitis C in pregnancy. Am J Obstet Gynecol 112(2 Pt 1):304,2008

Bernal W, Wendon J: Acute liver failure. N Engl J Med 369(26):2525, 2013 Bissonnette J, Durand F, de Raucourt E, et al: Pregnancy and vascular liver disease. J Clin Exp Hepatol 5:41, 2015 Blume C, Sensoy A, Gross MM, et al: A comparison of the outcome of pregnancies after liver and kidney transplantation. Transplantation 95(1):222, 2013 Brouwers L, Koster MP, Page-Christiaens GC, et al: Intrahepatic cholestasis of pregnancy: maternal and fetal outcomes associated with elevated bile acid levels. Am J Obstet GynecoIs212:100, 2015 Brown RS Jr, McMahon BJ, LokAS, et al: Antiviral therapy in chronic hepatitis B viral infection during pregnancy: A systematic review and meta-analysis. Hepatology 63(1):319, 2016 BrowningJD, Szczepaniak LS, Dobbins R, et al: Prevalence of hepatic steatosis in an urban population in the United States: impact of ethniciry. Hepatology 40(6):1387,s2004 Browning MF, Levy HL, Wilkins-Haug LE, et al: Fetal fatty acid oxidation defects and maternal liver disease in pregnancy. Obstet Gynecol 107:115, 2006 Bunchontavakul C, Reddy KR: Acetaminophen-related hepatotoxicity. Clin Liver Dis 17:587,2013 Buzzetti E, Pinzani M, Tsochatzis EA: he multiple-hit pathogenesis of nonalcoholic fatty liver disease (NAFLD). Metabolism 65(8):1038, 2016 Cain MA, Ellis J, Vengrove A, et al: Gallstone and severe hypertriglycerideinduced pancreatitis in pregnancy. Obstet Gynecol ,2015 Castro MA, Ouzounian JG, Colletti PM, et al: Radiologic studies in acute fatty liver of pregnancy. A review of the literature and 19 new cases. J Reprod Med 41:839, 1996 Centers for Disease Control and Prevention: Hepatitis E FAQs for health professionals. 2015. Available at: http://www.cdc.gov/hepatitis/hev/hevfaq.htm. Accessed May 2,s2016 Centers for Disease Control and Prevention: Recommended vaccines for healthcare workers. 2016a. Available at: http://www.cdc.gov/vaccines/adults/ rec-vaclhcw.html. Accessed September 30,s2016 Centers for Disease Control and Prevention: Surveillance for Viral HepatitisUnited States, 2014. 2016b. Available at: http://www.cdc.gov/hepatitis/ statistics/20 14surveillance/index.htm. Accessed September 30, 2016

Centers for Disease Control and Prevention: Yellow book: table of contents. 2016c. Available at: http://wwwnc.cdc.govltravellyellowbookl20 16ltableof-contents. Accessed September 30, 2016

Chang MC, Jan IS, Liang PC, et al: Cystic fibrosis transmembrane conductance regulator gene variants are associated with autoimmune pancreatitis and slow response to steroid treatment. J Cyst Fibros 14:661, 2015

Chen HL, Lee CN, Chang CH, et al: Eicacy of maternal tenofovir disoproxil fumarate in interrupting mother-to-infant transmission of hepatitis B virus. Hepatology 62(2):375,s2015

Chivero ET, Stapleton JT: Tropism of human pegivirus (formerly known as GB virus C/hepatitis G virus) and host immunomodulation: insights into a highly successful viral infection. J Gen Virol 96: 1521, 2015

Ch' ng CL, Morgan M, Hainsworth I, et al: Prospective study of liver dysfunction in pregnancy in Southwest Wales. Gut 51 (6):876, 2002

Christopher V, Al-Chalabi T, Richardson PO, et al: Pregnancy outcome after liver transplantation: a single-center experience of 71 pregnancies in 45 recipients. Liver Transpl 12: 1037, 2006

Cobey Fe, Salem RR: A review of liver masses in pregnancy and a proposed algorithm for their diagnosis and management. Am J Surg 187(2): 181,s2004

Conwell DL, Banks P, Greenberger NJ: Acute and chronic pancreatitis. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles ofInternal Medicine, 19th ed. New York, McGraw-Hill Education, 2015

Coscia A, Constantinescu S, Moritz MJ, et al: Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin TranspI2010:65, 2010

Crowell e, Lyew RV, Givens M, et al: Caring for the mother, concentrating on the fetus: intravenous N-acetylcysteine in pregnany. Am J Emerg Med 35, 2008

Cunningham FG, Lowe TW, Guss S, et al: Erythrocyte morphology in women with severe preeclampsia and eclampsia. Am J Obstet Gynecol 153:358, 1985

Daudi N, Shouval 0, Stein-Zamir C, et al: Breastmilk hepatitis A virus DNA in nursing mothers with acute hepatitis A virus infection. Breastfeed Med 7:313,s2012

Daniels 0, Grytdal S, Wasley A, et al: Surveillance for acute viral hepatitisUnited States, 2007. MMWR 58(3):1,s2009

Danielsson Borssen A, Wallerstedt S, Nyhlin N, et al: Pregnancy and childbirth in women with autoimmune hepatitis is safe, even in compensated cirrhosis. Scand J Gastroenterol 51 :479, 2016

Davit-Spraul A, Gonzales E, Jacquemin E: NRIH4 analysis in patients with progressive familial intrahepatic cholestasis, drug-induced cholesrasis or intrahepatic cholestasis of pregnancy unrelated to ATP8B 1, ABCB 11 and ABCB4 mutations. Clin Res Hepatol Gastroenterol 36(6):569, 2012

Deshpande NA, James NT, Kucirka LM, et al: Pregnancy outcomes of liver transplant recipients: a systematic review and meta-analysis. Liver Transpl 18(6):621, 2012 Dhupar R, Smaldone GM, Hamad GG: Is there a benefit to delaying cholecystectomy for symptomatic gallbladder disease during pregnancy? Surg Endosc 24(1):108, 2010

Diehl M, Day C: Cause, pathogenesis and treatment of nonalcoholic steatohepatitis. N Engl J Med 377:2063,2017

Dienstag JL: Acute viral hepatitis. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hili Education, 2015a

DienstagJL: Chronic hepatitis. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGrawHill Education, 2015b

Dixon PH, Wadsworth CA, Chambers J, et al: A comprehensive analysis of common genetic variation around six candidate loci for intrahepatic cholestasis of pregnancy. Am J Gastroenterol 109:76,2014

Dorak MT, Mackay RK, Relton CL, et al: Hereditary hemochromatosis gene (HFE) variants are associated with birth weight and childhood leukemia risk. Pediatr Blood Cancer 53: 1242, 2009

Ducarme G, Maire F, Chatel P, et al: Acute pancreatitis during pregnancy: a review. J Perinatol 34:87, 2014

Dunkelberg Je, Berkley EM, hiel W, et al: Hepatitis Bsand C in pregnancy: a review and recommendations for care. J Perinatol 34:882, 2014

Eddys]], Gideonsen MD, Song JY, et al: Pancreatitis in pregnancy. Obstet GynecoIs112:1075,2008

Egan N, Bartels A, Khashan AS, et al: Reference standard for serum bile acids in pregnancy. BJOG 119:493,2012

Fan L, Owusu-Edusei K ]r, Schillie SF, et al: Cost-efectiveness of activepassive prophylaxis and antiviral prophylaxis during pregnancy to prevent perinatal hepatitis B virus infection. Hepatology 63: 1471, 2016

Feldman AG, Whitington PF: Neonatal hemochromatosis. J Clin Exp Hepatology 3:313,s2013

Fesenmeier MF, Coppage KH, Lambers OS, et al: Acute fatty liver of pregnancy in 3 tertiary care centers. Am J Obstet Gynecol 192:1416,2005

Fierro NA, Realpe M, Meraz-Medina T, et al: Hepatitis E virus: an ancient hidden enemy in Latin America. World J Gastroenterol 22:2271, 2016 Fogel EL, Sherman S: ERCP for gallstone pancreatitis. N Engl J Med 3 0: 150,

Franco J, Newcomer J, Adams M, et al: Auxiliary liver transplant in acute fatry liver of pregnancy. Obstet Gynecol 95: 1042, 2000

Gao H, Chen LJ, Luo QQ, et al: Efect of cholic acid on fetal cardiac myocytes in intrahepatic choliestasis of pregnancy. J Huazhong Univ Sci Technolog Med Sci 34:736, 2014

Ghazali S, Czuzoj-Shulman N, Spence AR, et al: Pregnancy outcomes in liver transplant patients, a population-based study. J Matern Fetal Neonatal Med 25:1,s2016

Glantz A, Marschall HU, Lammert F, et al: Intrahepatic cholestasis of pregnancy: a randomized controlled trial comparing dexamethasone and ursodeoxycholic acid. Hepatology 42(6): 1399, 2005

Glantz A, Marschall H, Mattsson L: Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates. Hepatology 40:467,s2004

Goh GB, McCullough AJ: Natural history of nonalcoholic fatry liver disease.

Dig Dis Sci 61:1226, 2016

Greenberger NJ, Paumgartner G: Disease of the gallbladder and bile ducts. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles ofIreland Medicine, 19th ed. New York, McGraw-Hili Education

Ha JF, Phillips M, Faulkner K: Splenic artery aneurysm rupture in pregnancy.

Eur J Obstet Gynecol Reprod Bioi 146(2): 133, 2009

Hacker FM, Whalen PS, Lee VR, et al: Maternal and fetal outcomes of pancreatitis in pregnancy. Am J Obstet Gynecol 213:568, 2015

Hagstrom H, Hoijer J, Ludvigsson JF, et al: Adverse outcomes of pregnancy in women with non-alcoholic fatry liver disease. Liver Int 36:268, 2016 Henandez A, Petrov MS, Brooks DC, et al: Acute pancreatitis and pregnancy: a 10-year single center experience. J Gastrointest Surg 11: 1623, 200

Herrera CA, Manuck TA, Sroddard GJ, et al: Perinatal outcomes associated with intrahepatic cholestasis of pregnancy. J Maten Fetal Neonatal Med June 5, 2017 [Epub ahead of print]

Hill JB, Sheield JS, Kim MJ, et al: Risk of hepatitis B transmission in breastfed infants of chronic hepatitis B carriers. Obstet Gynecol 99(6): 1049, 2002

Hodgman MJ, Garrard AR: A review of acetaminophen poisoning. Crit Care

Indoli G, Azzari e, Resti M: Hepatitis: immunoregulation in pregnancy and perinatal transmission of HCV. Nat Rev Gastroenterol Hepatols11:6, 2014

Isoherranen N, hummel KE: Drug metabolism and transport during pregnancy: how does drug disposition change during pregnancy and what are the mechanisms that cause such changes? Drug Metab Dispos 41 (2):256, 2013

Jabiry-Zieniewicz Z, Szpotanska-Sikorska M, Pietrzak B, et al: Pregnancy outcomes among female recipients after liver transplantation: further experience. Transplant Proc 43(8):3043,2011

Jain AB, Reyes J, Marcos A, et al: Pregnancy after liver transplantation with tacrolimus immunosuppression: a single center's experience update at 13 years.

6(5):827, 2003

Jin H, Zhao Y, Zhang X, et al: Case-fataliry risk of pregnant women with acute viral hepatitis rype E: a systematic review and meta-analysis. Epidemiol Infect 144(10):2098, 2016a

Jin L, Nie R, Li Y, et al: Hepatitis B surface antigen in oocytes and embryos may not result in vertical transmission to offspring of hepatitis B virus carriers. Fertil Steril 105: 1010, 2016b Jorge AM, Keswani RN, Veerappan A, et al: Non-operative management of symptomatic cholelithiasis in pregnancy is associated with frequent hospitalizations. J Gastrointest Surg 19:598, 2015

Joshi D, James A, Quaglia A, et al: Liver disease in pregnancy. Lancet 375(9714):594,s2010

Jung HS, Choi SH, Noh JH, et al: Healthy twin birth after autologous islet transplantation in a pancreatectomized patient due to a benign tumor. Transplant Proc 39(5):1723,s2007 Kawakita T, Parikh LI, Ramsey PS, et al: Predictors of adverse neonatal outcomes in intrahepatic cholestasis of pregnancy. Am J Obstet Gynecol 0,s2015

Kim DK, Bridges CB, Harriman HK, et al: Advisory Committee on Immunization Practices recommended immunization schedule for adults aged 19 years or older: United States, 2015. Ann Intern Med 162:214, 2015a

Kim WR, Lake JR, Smith JM, et al: OPTN/SRTR 2013 annual data report: liver. AmJ Transplant 15 SuppI2:1, 2015b

Knight M, Nelson-Piercy e, Kurinczuk J], et al: A prospective national study of acute fatry liver of pregnancy in the UK. Gut ):951, 2008

Hepatic, Biliary, and Pancreatic Disorders 1073

Ko CW, Napolitano PG, Lee SP, et al: Physical activiry, maternal metabolic measures, and the incidence of gallbladder sludge or stones during pregnancy: a randomized trial. Am J PerinatoI31:39, 2014 Kondrackiene JI, Beuers U, Kupcinskas L: Eicacy and safery of ursodeoxycholic acid versus cholesryramine in intrahepatic cholestasis of pregnancy. Gastroenterology 129:894, 2005

Lausman AY, l-Yaseen E, Sam E, et al: Intrahepatic cholestasis of pregnancy in women with a multiple pregnancy: an analysis of risks and pregnancy outcomes. J Obstet Gynaecol Can 30(11): 1008, 2008

Lee RH, Goodwin TM, Greenspoon J, et al: he prevalence of intrahepatic cholestasis of pregnancy in a primarily Latina Los Angeles population. J Perinatol 26(9):527, 2006

Lee RH, Incerpi MH, Miller DA, et al: Sudden death in intrahepatic cholestasis of pregnancy. Obstet Gynecol 113(2):528, 2009

Lee WM: Drug-induced acute liver failure. Clin Liver Dis 17:575,2013

Liang CM, Hu TH, Lu SN, et al: Role of hepatitis C virus substitutions and interleukin-28B polymorphism on response to peginterferon plus ribavirin ina prospective study of response-guided therapy. J Viral Hepat 20(1s1):761, 2013

Lok AS, Gardiner DF, Lawitz E, et al: Preliminary study of two antiviral agents for hepatitis C genorype 1. N Engl J Med 366(3):216,s2012

Luo XL, Zhang Y: Obstetrical disease spectrum in China: an epidemiological study of 111,767 cases in 2011. Chin Med J (Eng!) 128: 1137,2015

Malik A, Khawaja A, Sheikh L: Wilson's disease in pregnancy: case series and review of literature. BMC Res Notes 6:421, 2013

Maringhini A, Ciambra M, Baccelliere P, et al: Biliary sludge and gallstones in pregnancy: incidence, risk factors, and natural history. Ann Intern Med 119(2):116, 1993

Marschall HU, Shemer EW, Ludvigsson JF, et al: Intrahepatic cholestasis of pregnancy and associated hepatobiliary disease: a population based cohort study. Hepatology 58(4):1385, 2013

Martin IN Jr, Briery CM, Rose CH, et al: Postpartum plasma exchange as adjunctive therapy for severe acute fa try liver of pregnancy. J Clin Apher 23(4): 138, 2008

Mastrobattista JM, Gomez-Lobo V: Pregnancy after solid organ transplantation. Obstet Gynecol 112:919,s2008

Mattila, M, Kemppainen H, Isoniemi H, et al: Pregnancy outcomes after liver transplantation in Finland. Acta Obstet Gynecol Scand 96: 1106,

Clin 28(4):499, 2012

Hoofnagle JH, Nelson E, Purcell RH: Hepatitis E. N Engl J Med 36 : 13, Matos A, Bernardes J, Ayres-de-Campos D, et al: Antepartum fetal cerebral hemorrhage not predicted by current surveillance methods in cholestasis of pregnancy. Obstet Gynecol 89:803, 199

McMenamin MB, Jackson AD, Lambert J, et al: Obstetric management of hepatitis C-positive mothers: analysis of vertical transmission in 559 mother-infant pairs. Am J Obstet Gynecol 199:315.e1, 2008

Menees S, Elta G: Endoscopic retrograde cholangiopancreatography during pregnancy. Gastrointest Endose Clin North Am 16:41,2006

Nagy S, Bush Me, Berkowitz R, et al: Pregnancy outcome in liver transplant recipients. Obstet Gynecol 102(1):121,2003

Nelson DB, Yost NP, Cunningham FG: Acute fatry liver of pregnancy: clinical outcomes and expected durations of recovery. Am J Obstet Gynecol 209(5):456.el,s2013

Nelson DB, Yost NP, Cunningham FG: Hemostatic dysfunction with acute fa try liver of pregnancy. Obstet Gynecol 124:40, 2014

Othman MO, Stone E, Hashimi M, et al: Conservative management of cholelithiasis and its complications in pregnancy is associated with recurrent symptoms and more emergency department visits. Gastrointest Endosc 76(3): 564,s2012

Palatnik A, Rinella ME: Medical and obstetric complications among pregnant women with liver cirrhosis. Obstet Gynecol 129: 1118,s2017

Parrish J, Maxwell C, Beecroft JR: Splenic artery aneurysm in pregnancy.

J Obstet Gynecol Can 37:816, 2015

Pereira SP, O'Donohue J, Wendon J, et al: Maternal and perinatal outcome in severe pregnancy-related liver disease. Hepatology 26: 1258, 1997

Pergam SA, Wang CC, Gardella C\I, et al: Pregnancy complications associated with hepatitis C: data from a 2003-2005 Washington state birth cohort. Am J Obstet Gynecol 199:38.el, 2008

Pietrangelo A: Iron and the liver. Liver Int 36: I 16, 2016

Poordad F, Lawitz E, Kowdley Y, et al: Exploratory study of oral combination antiviral therapy for hepatitis C. N Engl J Med 368(1):45, 2013

Puljic A, Salati J, Doss A, et al: Outcomes of pregnancies complicated by liver cirrhosis, portal hypertension, or esophageal varices. J Matern Fetal Med 29:506,s2016

Rac MW, Sheield JS: Prevention and management of viral hepatitis in pregnancy. Obstet Gynecol Clin North Am 41:5-3,s2014

Ramin KD, Ramin SM, Richey SD, et al: Acute pancreatitis in pregnancy. Am J Obstet Gynecol 173:187, 1995

Ramirez-Fuentes C, Marti-Bonmad L, Torregrosa A, et al: Variations in the size of focal nodular hyperplasia on magnetic resonance imaging. Radiologia 55(6):499,s2013

Reddick KLB, Jhaveri R, Gandhi M, et al: Pregnancy outcomes associated with viral hepatitis. J Viral Hepat 18(7):e394, 2011

Reyes H: What have we learned about intrahepatic cholestasis of pregnancy?

Hepatology 63:4,s2016

Rifai K, Mix H, Krusche 5, et al: No evidence of substantial growth progression orcomplications oflarge focal nodular hyperplasia during pregnancy. Scand J GastroenteroIs48(1):88, 2013

Riggs BS, Bronstein AC, Kulig K, et al: Acute acetaminophen overdose during pregnancy. Obstet Gynecol 74:247, 1989

Roberts 55, Miller RK, Jones JK, et al: The Ribavirin Pregnancy Registry: indings after 5 years of enrollinent, 2003-2009. Birth Defects Res A Clin Mol TeratoIs88(7):551,s2010

Rodriguez M, Moreno J, Marquez R, et al: Increased PR interval in fetuses of patients with intrahepatic cholestasis of pregnancy. Fetal Diagn Ther 40(4):298,s2016

Rook M, Vargas j, Caughey A, et al: Fetal outcomes in pregnancies complicated by intrahepatic cholestasis of pregnancy in a Northern California cohort. PLoS One 7(3):e28343, 2012

Roumiantsev 5, Shah V, Westra SJ, et al: Case records of the Massachusetts general hospital. Case 20-2015. A newborn girl with hypotension coagulopathy, anemia, and hyperbilirubinemia. N Engl J Med 372:2542, 2015

Rumack BH, Matthew H: Acetaminophen poisoning and toxiciry. Pediatrics 55:871, 1975

Sadler LC, Lane M, North R: Severe fetal intracranial haemorrhage during treatment with cholestyramine for intrahepatic cholestasis of pregnancy. BJOG 102:169, 1995

Salgia RJ, Brown K: Diagnosis and management of hereditary hemochromatosis. C1in Liver Dis 19:187,2015

Satiago-Munoz P, Roberts 5, Sheield j, et al: Prevalence of hepatitis Bsand C in pregnant women who are infected with human immunodeiciency virus. Am J Obstet Gynecol 193:1270,2005

Santos L, Patterson A, Moreea SM, et al: Acute liver failure in pregnancy associated with maternal MCAD deiciency. J Inherit Metab Dis 30(1): 103,s2007

Schmidt LE, Larsen FS: MELD score as a predictor ofliver failure and death in patients with acetaminophen-induced liver injury. Hepatology 45(3):789, 2007

Sehgal R, Patra 5, David P, et al: Impaired monocyte-macrophage functions and defective Toll-like receptor signaling in hepatitis E virus-infected pregnant women with acute liver failure. Hepatology 62: 1683, 2015

Sethi 5, hosani N, Banerjee 5: Radiation-free ERCP in pregnancy: a "sound" approach to leaving no stone unturned. Dig Dis Sci 60:2604, 2015 Sheield JS, Hickman A, Tang J, et al: Eicacy of an accelerated hepatitis B vaccination program during pregnancy. Obstet Gynecol 117(5): 1130, 2011 Sheiner E, Ohel I,Levy A, et al: Pregnancy outcome in women with pruritus gravidarum. J Reprod Med 51 :394, 2006

Shi Z, Tang Y, Wang H, et al: Breastfeeding of newborns by mothers carrying hepatitis B virus: a meta-analysis and systematic review. Arch Pediatr Adolesc Med 165(9):837,s2011

Sibai BM: Imitators of severe preeclampsia. Obstet Gynecol 109:956,s2007

Sims HF, Brackett JC, Powell CK, et al: he molecular basis of pediatric long chain 3-hydroxyacyl-CoA dehydrogenase deiciency associated with maternal acute fatty liver of pregnancy. Proc Nat! Acad Sci V 5 A 92:841, 1995

Smilkstein MJ, Knapp GL, Kulig W, et al: Eicacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med 319:1557,s1988

Smith EA, Jacques-Carroll L, Walker TY, et al: he National Perinatal Hepatitis B Prevention Program, 1994-2008. Pediatrics 129(4):609,2012

Snidjewind IJ, Smit C, Schutten M, et al: Low mother-to-child-transmission rate of hepatitis C virus in cART treated HIV-1 infected mothers. J C1in ViroIs68:11,s2015

Society for Maternal-Fetal Medicine (SMFM), Dionne-Odom J, Tita AT, et al: #38: Hepatitis B in pregnancy screening, treatment, and prevention of vertical transmission. Am J Obstet Gynecol 214:6, 2016

S0gaard KK, Horvath-Puh6 E, Gf0nback H, et al: Risk of venous thromboembolism in patients with liver disease: anationwide population-based casecontrol study. Am J Gastroeterol 104(1):96, 2009

Stewart RD, Sheield JS: Hepatitis B vaccination in pregnancy in the Vnited States. Vaccines 1:167,s2013 Stinton LM, Shafer A: Epidemiology of gallbladder disease: cholelithiasis and cancer. Gut Liver 6: 172, 2012 Stokkeland K, Ludvigsson JF, Hultcrantz R, et al: Increased risk of preterm birth in women with autoimmune hepatitis-a nationwide cohort study. Liver lnt 36:76, 2016

Strehlow SL, Pathak B, Goodwin TM, et al: The mechanical PR interval in fetuses of women with intrahepatic cholestasis of pregnancy. Am ] Obstet GynecoIs203:455.el,s2010

Tan], Surti B, Saab 5: Pregnancy and cirrhosis. Liver T ranspl 14(8): 1 081, 2008 Tang 5, Mayo M], Rodriguez-Frias E, et al: Safety and utility ofERCP during pregnancy. Gastrointest Endosc 69:453, 2009

Tang 5], Rodriguez-Frias E, Singh 5, et al: Acute pancreatitis during pregnancy. Clin Gastroenterol Hepatol 8(1):85, 2010

Tovo PA, Calitri C, Scolfaro C, et al: Vertically acquired hepatitis C virus infection: correlates of transmission and disease progression. World] Gastroenterol 22: 1382, 2016

Towers CV, Asrat T, Rumney P: he presence of hepatitis B surface antigen and deoxyribonucleic acid in amniotic fluid and cord blood. Am ] Obstet Gynecol 184: 1514, 2001

Tran TT, Ahn ], Reau NS: ACG clinical guideline: Liver disease and pregnancy. Am J Gastroenterol 111: 176, 2016

Trinks ], Maestri M, Oliveto F, et al: Human pegivirus molecular epidemiology in Argentina: potential contribution of Latin America migration to genotype 3 circulation. ] Med Virol 86:20 6, 2014

Turhan AN, Gonen: M, Kapan 5, et al: Acute biliary pancreatitis related with pregnancy: a 5-year single center experience. Vlus Travma Acil Cerrahi Derg 16(2):160,s2010 Vrganci N, Arapoglu M, Akyildiz B, et al: Neonatal cholestasis resulting from vertical transmission of hepatitis A infection. Pediatr Infect Dis] 22(4):381, 2003 Vsta 1M, Barton ]R, Amon EA, et al: Acute fatty liver of pregnancy: an experience in the diagnosis and management of fourteen cases. Am ] Obstet GynecoIs171:1342,s1994 Valdivieso V, Covarrubias C, Siegel F, et al: Pregnancy and cholelithiasis: pathogenesis and natural course of gallstones diagnosed in early puerperium. Hepatology 17:1,s1993

Victor ]C, Monto AS, Surdina Y, et al: Hepatitis A vaccine versus immune globulin for postexposure prophylaxis. N Engl ] Med 357: 1685, 2007 Vierling ]M: Autoimmune hepatitis and overlap syndromes: diagnosis and management. C1in Gastroenterol HepatoIs13:2088, 2015

Vigil-de Gracia P, Montufar-Rueda C: Acute fatty liver of pregnancy: diagnosis, treatment, and outcome based on 35 consecutive cases. ] Matern Fetal Neonatal Med 24(9):1143, 2011

Wang PH, Yang MJ, Lee L, et al: Acetaminophen poisoning in late pregnancy. A case report.] Reprod Med 42:367, 1997

Webb GJ, Elsharkawy AM, Hirschield G: Editorial: the etiology of intrahepatic cholestasis of pregnancy: towards solving a monkey puzzle. Am J Gastroenterol 109:85,2014

Westbrook RH, Yeoman AD, Kriese 5, et al: Outcomes of pregnancy in women with autoimmune hepatitis. J Autoimmun 38(2-3):J239, 2012

Wiest DB, Chang E, Fanning 0, et al: Antenatal pharmacokinetics and placental transfer of N-acetylcysteine in chorioamnionitis for fetal neuroprotection. J Pediatr 165:672,2014

Wikstrom Shemer E, Marschall HV, Ludvigsson JF, et al: Intrahepatic cholestasis of pregnancy and associated adverse pregnancy and fetal outcomes: a 12-year population-based cohort study. BJOG 120(6):717,s2013

Wilson CH, Manas OM, French JJ: Laparoscopic liver resection for hepatic adenoma in pregnancy.] Clin Gastroenterol 45:828, 2011

World Health Organization: Hepatitis B vaccines. Weekly Epidemiological Record 84(40):405, 2009

Wu T, Zhu FC, Huang SJ, et al: Safety of the hepatitis E vaccine for pregnant women: a preliminaty analysis. Hepatology 55(6):2038, 2012

Wu W, Faigel DO, Sun G, et al: Non-radiation endoscopic retrograde cholangiopancreatography in the management of choledocholithiasis during pregnancy. Dis Endosc 26:691, 2014

Xanthakos SA, Jenkins TM, Kleiner DE, et al: Teen-LABS consortium. High prevalence of nonalcoholic fatty liver disease in adolescents undergoing bariatric surgety. Gastroenterology 149:623, 2015

Xiong HF, Liu ]Y, Guo LM, et al: Acute fatty liver of pregnancy: over six months follow-up study of twenty-ive patients. World J Gastroenterol 21(6):1927,s2015 Yarrington CD, Cantonwine DE, Seely EW, et al: The associarion of alanine aminotransferase in early pregnancy with gestational diabetes. Metab Syndr Relat Disord 14(5):254,2016 Yi P, Chen R, Huang Y, et al: Management of mother-to-child transmission of hepatitis B virus: propositions and challenges. J Clin Virol 77:32,s2016 Ylitalo K, Vanttinen T, Halmesmaki E, et al: Serious pregnancy complications in a patient with previously undiagnosed carnitine palmitoyltransferase 1 deiciency. Am] Obstet Gynecol 192:2060,2005 Zhang J, Zhang F, Huang 5], et al: Long-term eicacy of a hepatitis E vaccine. N Engl] Med 372:914,s2015 ZhangP, Kong WQ, Zhou SP, et al: Acute fatty liver of pregnancy: a retrospective analysis of 56 cases. Chin Med J (Eng!) 129(10): 1208,2016

IRON-DEFICIENCY ANEMIA.. . . . . . . . . . . . . . . . . . . . .. 1076

MEGALOBLASTIC ANEMIA . . . . . . . . . . . . . . . . . . . . .. 1077

HEMOLYTIC ANEMIA ......i..........i...i.......i.....i. 1078 .APLASTIC AND HYPOPLASTIC ANEMIA.. . . . . . . . . . .. 1080 POL YCYTHEMIAS ..i......i...........i...i......i...... 1081

HEMOGLOBINOPATHIES ..i....i...i......i...i.....i..... 1081

THALASSEMIA SYNDROMES.. . . . . . . . . . . . . . . . . . . .. 1084

PLATELET DISORDERS.. . . . . . . . . . . . . . . . . . . . . . . . .. 1086

INHERITED COAGULATION DEFECTS ....i......i..... 1089

VON WILLEBRAND DISEASE.. . . . . . . . . . . . . . . . . . . .. 1090

In the later months of pregnancy there is a slight increase in the amount of hemoglobin and red corpuscles and a slight increase in the number of white corpuscles, which become markedy accentuated during the first ew days of the puerperium.

-J. Whitridge Williams (1903)

There is virtually nothing from the irst edition of Williams' 1903 textbook that addresses the common anemias of pregnancy. Only pernicious anemia is devoted two paragraphs to say it occasionally appeared in pregnancy. Today, it is well known that pregnant women are susceptible to hematological abnormalities that may afect any woman of childbearing age. hese include chronic disorders such as hereditary anemias, immunological thrombocytopenia, and malignancies such as leukemias and lymphomas. Other disorders arise during pregnancy because of pregnancy-induced demands. Two examples are iron deiciency and megaloblastic anemias. Pregnancy may also unmask underlying hematological disorders. Finally, any hematological disease may irst arise during pregnancy. Importantly, pregnancy induces physiological changes that often confuse the diagnosis of these hematological disorders and assessment of their treatment (Chap. 4, p. 57).

Normal values for concentrations of many cellular elements during pregnancy are listed in the Appendix (p. 1255). The Centers for Disease Control and Prevention (1998) deined anemia in iron-supplemented pregnant women using a cutof of the 5th percentile-lrl g/dL in the irst and third trimesters, and 10.5 g/dL in the second trimester (Fig.

he modest fall in hemoglobin levels and hematocrit values during pregnancy is caused by a relatively greater expansion of plasma volume compared with the increase in red cell volume. he disproportion between the rates at which plasma and erythrocytes are added to the maternal circulation is greatest during the second trimester. Late in pregnancy, plasma expansion essentially ceases, while hemoglobin mass continues to accrue.

he causes of more common anemias encountered in pregnancy are listed in Table 56-1r. Their frequency is dependent on multiple factors such as geography, ethniciry, socioeconomic level, nutrition, preexisting iron status, and prenatal iron supplementation (American College of Obstetricians and Gynecologists, 2017 a). In the United States, the prevalence of anemia in pregnancy is 3 to 38 percent (Centers for Disease Control and Prevention, 1989). In Latin America and the Caribbean, anemia prevalence ranges from 5 to 45 percent among women of :J taking iron supplements. (Data from the Centers for Disease

Control and Prevention, 1989.) childbearing age (1ujica-Coopman, 2015). Rates are also high in Israel, China, India, South Asia, and Africa (Azulay, 2015; Kumar, 2013, Stevens, 2013). Figure 56-2 highlights the global trends in hemoglobin concentrations and anemia thresholds in pregnant and nonpregnant women.

Most studies of anemia during pregnancy describe large populations and deal with nutritional anemias. Anemia is associated with several adverse pregnancy outcomes including preterm birth (Kidanto, 2009; Kumar, 2013; Rukuni, 2016). Children born to iron-deicient women and without iron supplementation are reported to have lower mental development scores (Drassinower, 2016; Tran, 2014).

A seemingly paradoxical inding is that healthy pregnant women with a higher hemoglobin concentration are also at greater risk for adverse perinatal outcomes (Murphy, 1986; von Tempelhof, 2008). This may result from lower than average plasma volume expansion of pregnancy concurrent with normal red cell mass accrual. Scanlon and associates (2000) studied the relationship between maternal hemoglobin levels and rates of preterm or growth-restricted newborns in 173,031 pregnancies.

TABLE 56-1. Causes of Anemia During Pregnancy

Anemia caused by acute blood loss Anemia of inflammation or malignancy Megaloblastic anemia 0.030 ..••. Anemia cutoff for c 0.025 0 (12.0 g/dL) : ..... Anemia cutoff for 0 0.020 . (1 1.0 g/dL) 0.015 : 0.010 0.005 04.06.0 8.010.0 18.0

FIGURE 56-2 Global trends in hemoglobin concentrations in pregnant and nonpregnant women. (Reproduced with permission from Stevens GA, Finucane MM, De-Regil LM, et al: Global, regional, and national trends in haemoglobin concentration and prevalence of total and severe anaemia in children and pregnant and nonpregnant women for 1995-201o1: a systematic analysis of populationrepresentative data, Lancet Glob Health. 2013 Jul;1(l):e16-25.)

Women whose hemoglobin concentration was three standard deviations above the mean at 12 or 18 weeks' gestation had a 1.3-to 1.8-fold greater incidence of fetal-growth restriction. Placental weight correlates negatively with maternal hemoglobin concentration (Larsen, 2016). hese indings have led some to the illogical conclusion that withholding iron supplementation to cause iron-deiciency anemia will improve pregnancy outcomes (Ziaei, 2007).

The two most common causes of anemia during pregnancy and the puerperium are iron deiciency and acute blood loss. In a study of more than 1300 women, 21 percent had thirdtrimester anemia, and 16 percent had iron-deiciency anemia (Vandevijvere, 2013). In a typical singleton gestation, the maternal need for iron averages nearly 1000 mg. Multifetal gestational requirements are considerably higher (Ru, 2016). hese amounts exceed the iron stores of most women and result in iron-deiciency anemia unless supplementation is given.

Iron deficiency is often manifested by an appreciable drop in hemoglobin concentration. In the third trimester, additional iron is needed to augment maternal hemoglobin and for transport to the fetus. Because the amount of iron diverted to the fetus is similar in a normal and in an iron-deicient mother, the newborn of a severely anemic mother does not sufer from irondeiciency anemia. Neonatal iron stores are related to maternal iron status and to timing of cord clamping.

Classic morphological evidence of iron-deiciency anemia is erythrocyte hypochromia and microcytosis (Fig. 56-3). This may be less prominent in the pregnant woman. Serum ferritin levels are lower. And, levels of hepcidin-the master regulator of iron availability-are decreased normally in pregnancy. With iron deiciency, hepcidin levels follow those of serum ferritin (Camaschella, 2015; Koenig, 2014).

FIGURE 56-3 This peripheral blood smear from a women with iron-deficiency anemia contains many scattered microcytic and hypochromic red cells with characteristic central pallor. These exhibit moderate anisopoikilocytosis, namely, varying sizes and shapes including occasional elliptocytes, which can be oval or pencil-shaped. (Reproduced with permission from Werner Cl, Richardson Dl, Chang SY, et al (eds): Perioperative Considerations. In Williams Gynecology Study Guide, 3rd ed. New York, McGrawHill Education, 201o6: Photo contributor: Dr. Weina Chen.) he initial evaluation of a pregnant woman with moderate anemia includes measurements of hemoglobin, hematocrit, and red cell indices; careful examination of a peripheral blood smear; a sickle-cell preparation if the woman has African origin; and evaluation of serum iron or ferritin levels, or both (Appendix p. 1255). Serum ferritin levels normally decline during pregnancy, and levels < 10 to 15 mg/L confirm iron-deficiency anemia.

When pregnant women with moderate iron-deficiency anemia are given adequate iron therapy, a hematological response is detected by an elevated reticulocyte count. The rate of rise of hemoglobin concentration or hematocrit is typically slower than in nonpregnant women due to the increasing and larger blood volumes during pregnancy.

Routinely in pregnancy, daily oral supplementation with 30 to 60 of iron and 400 �g of folic acid is recommended (World Health Organization, 2012). A Cochrane review found that intermittent oral iron supplementation may also be appropriate (Pena-Rosas, 2015). For iron-deficiency anemia, resolution and restitution of iron stores can be accomplished with simple iron salts that provide approximately 200 mg daily of elemental iron. hese include ferrous sulfate, fumarate, or gluconate. If a woman cannot or will not take oral iron preparations, then parenteral therapy is given. Although both are administered intravenously, ferrous sucrose is safer than iron-dextran (American College of Obstetricians and Gynecologists, 2017a; Camaschella, 2015; Shi, 2015). Hemoglobin and ferritin levels show equivalent rises in women treated with either oral or parenteral iron therapy (Breymann, 2017; Daru, 20r16).

In early pregnancy, anemia caused by acute blood loss is common with abortion, ectopic pregnancy, and hydatidiform mole. Postpartum, anemia commonly stems from obstetrical hemorrhage. Massive hemorrhage demands immediate treatment as described in Chapter 41 (p. 788). If a moderately anemic woman-defined by a hemoglobin value of approximately 7 g/dL-is hemodynamically stable, is able to ambulate without adverse symptoms, and is not septic, then blood transfusions are not indicated. Instead, oral iron therapy is given for at least 3 months (Kraft, 2005) .

• Anemia Associated with Chronic Disease

Various disorders, such as chronic renal insuiciency, cancer and chemotherapy, human immunodeficiency virus (HIV) infection, and chronic inflammation result in moderate and sometimes severe anemia, usually with slightly hypochromic and microcytic erythrocytes. It is the second most common form of anemia worldwide (Weiss, 2005).

During pregnancy, women with chronic disorders may develop anemia for the first time. In those with preexisting anemia, it may be intensified as plasma volume expands. Causes include chronic renal insuiciency, inlammatory bowel disease, and connective-tissue disorders. Others are granulomatous infections, malignant neoplasms, rheumatoid arthritis, and chronic suppurative conditions.

Chronic renal insuiciency is the most common disorder that we have encountered as a cause of this type of anemia during pregnancy. Some cases are accompanied by erythropoietin deficiency. As discussed in Chapter 53 (p. 1034), during pregnancy in women with mild chronic renal insuiciency, the degree of red cell mass expansion is inversely related to renal impairment. At the same time, plasma volume expansion usually is normal, and thus anemia is intensified (Cunningham, 1990).

For treatment, adequate iron stores must be ensured. Recombinant eythropoietin has been used successfully to treat anemia stemming from chronic disease (Weiss, 2005). In pregnancies complicated by chronic renal insuiciency, recombinant erythropoietin is usually considered when the hematocrit approximates 20 percent (Cyganek, 2011; Ramin, 2006). One worrisome side efect of this agent is hypertension, which is already prevalent in women with renal disease. Red cell aplasia and antierythropoietin antibodies have also reported (Casadevall, 2002; McCoy, 2008).

These anemias are characterized by blood and bone-marrow abnormalities from impaired DNA synthesis. This leads to large cells with arrested nuclear maturation, whereas the cytoplasm matures more normally. Worldwide, the prevalence of megaloblastic anemia during pregnancy varies considerably. It is rare in the United States.

Megaloblastic anemia developing during pregnancy almost always results from folic acid deficiency. In the past, this condition was referred to as pernicious anemia of pregnancy. It usually is found in women who do not consume fresh green leay vegetables, legumes, or animal protein. As folate deficiency and anemia worsen, anorexia often becomes intense and further aggravates the dietary deiciency. Drugs and excessive ethanol ingestion either cause or contribute (Hesdorfer, 2015).

In nonpregnant women, the folic acid requirement is 50 to 1 00 �g/ d. During pregnancy, requirements are increased, and 400 �g/ d is recommended. he earliest biochemical evidence is low plasma folic acid concentrations (Appendix, p. 1255). Early morphological changes usually include neutrophils that are hypersegmented and newly formed erythrocytes that are macrocytic. With preexisting iron deiciency, macrocytic erythrocytes cannot be detected by measurement of the mean corpuscular volume. Careful examination of a peripheral blood smear, however, usually demonstrates some macrocytes. As the anemia becomes more intense, peripheral nucleated erythrocytes appear, and bone marrow examination discloses megaloblastic erythropoiesis. Anemia may then become severe, and thrombocytopenia, leukopenia, or both may develop. he fetus and placenta extract folate from maternal circulation so efectively that the fetus is not anemic despite severe maternal anemia.

For treatment, folic acid is given along with iron, and a nutritious diet is encouraged. By 4 to 7 days after beginning folic acid treatment, the reticulocyte count is increased, and leukopenia and thrombocytopenia are corrected.

For prevention of megaloblastic anemia, a diet should contain suicient folic acid. The role of folate deiciency in the genesis of neural-tube defects has been well studied (Chap. 13, p. 270). Since the early 1990s, nutritional experts and the American College of Obstetricians and Gynecologists (2016a) have recommended that all women of childbearing age consume at least 400 �g of folic acid daily. More folic acid is given with multifetal pregnancy, hemolytic anemia, Crohn disease, alcoholism, and inflammatory skin disorders. Women with a family history of congenital heart disease may also benefit from higher doses (Huhta, 2015). Women who previously have had infants with neural-tube defects have a lower recurrence rate if a daily 4-mg folic acid supplement is given.

During pregnancy, vitamin B12 levels are lower than nonpregnant values because of decreased levels of binding proteins, namely, the transcobalamins. During pregnancy, megaloblastic anemia is rare from deficiency of vitamin B12, that is, cyanocobalamin. Instead, a typical example is Addisonian pernicious anemia, which results from absent intrinsic factor that is requisite for dietary vitamin B12 absorption. his autoimmune disorder usually has its onset after age 40 years (Stabler, 2013).

In our limited experience, vitamin Bl2 deiciency in pregnancy is more likely encountered following gastric resection. hose who have undergone total gastrectomy require 1 000 �g of vitamin B12 given intramuscularly each month. Those with a partial gastrectomy usually do not need supplementation, but adequate serum vitamin B12 levels should be ensured (Appendix, p. 1258). Other causes of megaloblastic anemia from vitamin B12 deiciency include Crohn disease, ileal resection, some drugs, and bacterial overgrowth in the small bowel (Hesdorfer, 2015; Stabler, 2013).

Several conditions feature accelerated erythrocyte destruction. Damage may be stimulated by a congenital red-cell abnormality or in other cases by antibodies directed against red-cell membrane proteins. Hemolysis may be the primary disorder, and sickle-cell disease and hereditary spherocytosis are examples. In other cases, hemolysis develops secondary to an underlying condition such as systemic lupus erythematosus or preeclampsia. Microangiopathic hemolytic anemia due to malignancy has been reported in pregnancy (Happe, 2016).

he cause of aberrant antibody production is unknown. Typically, both the direct and indirect antiglobulin (Coombs) tests are positive. Anemias caused by these factors may be due to warm-active autoantibodies (80 to 90 percent), cold-active antibodies, or a combination. hese syndromes also may be classiied as primary (idiopathic) or secondary due to underlying diseases or other factors. Examples of the latter include lymphomas and leukemias, connective-tissue diseases, infections, chronic inlammatory diseases, and drug-induced antibodies (Provan, 2000). Cold-aglutinin disease may be induced by infectious etiologies such as Mycoplasma pneumoniae or Epstein-Barr viral mononucleosis (Dhingra, 2007). Hemolysis and positive antiglobulin test results may be the consequence of either immunoglobulin M (IgM) or immunoglobulin G (IgG) antierythrocyte antibodies. When thrombocytopenia is comorbid, it is termed Evans syndrome (Wright, 2013).

In pregnancy, hemolysis can be markedly accelerated. Rituximab, along with prednisone, is first-line treatment (Luzzatto, 2015). Coincidental thrombocytopenia usually corrects with therapy. Transfusion of red cells is complicated by antierythrocyte antibodies, but warming the donor cells to body temperature may decrease their destruction by cold agglutinins.

These hemolytic anemias must be diferentiated from other causes of autoimmune hemolysis. In most cases, hemolysis is mild, it resolves with drug withdrawal, and recurrence is prevented by avoidance of the drug. One mechanism is hemolysis induced through drug-mediated immunological injury to red cells. he drug may act as a high-ainity hapten when bound to a red-cell protein to which antidrug antibodies attach-for example, IgM anti penicillin or anticephalosporin antibodies. Some other drugs act as low-ainity hap tens and adhere to cell membrane proteins. Examples include probenecid, quinidine, rifampin, and thiopental. A more common mechanism for drug-induced hemolysis is related to a congenital erythrocyte enzymatic defect. An example is glucose-6-phosphate dehydrogenase deiciency, which is common in African-American women and discussed later (p. 1080).

Drug-induced hemolysis is usually chronic and mild to moderate, but occasionally acute hemolysis is severe. Garratty and coworkers (1999) described seven women with severe Coombs-positive hemolysis stimulated by cefotetan given as prophylaxis for obstetrical procedures. Alpha-methyldopa can cause similar hemolysis (Grigoriadis, 2013). Moreover, maternal hemolysis has been reported after intravenous immune globulin therapy (Rink, 2013). Withdrawal of the ofending drug frequently halts the hemolysis.

Unexplained severe hemolytic anemia can develop during early pregnancy, and it resolves within months postpartum. A clear immune mechanism or red cell defects are not contributory (Starksen, 1983). Because the fetus-neonate also may demonstrate transient hemolysis, an immunological cause is suspected. Maternal corticosteroid treatment is often-bur not alwaysefective (Kumar, 2001). We have cared for a woman who during each pregnancy developed intense severe hemolysis with anemia that was controlled by prednisone. Her fetuses were not afected, and in all instances, hemolysis abated spontaneously after delivery.

In some cases, hemolysis is induced by conditions unique to pregnancy. Mild microangiopathic hemolysis with thrombocytopenia is relatively common with severe preeclampsia and eclampsia (Cunningham, 2015; Kenny, 2015). This HELLP (hemoysis) devated fiver enzyme levels) Low .latelet count} syndrome is discussed in Chapter 40 (p. 719). Another is acure fatty liver of pregnancy, which is associated with moderate to severe hemolytic anemia (Nelson, 2013). It is discussed in Chapter 55 (p. 1060).

Although commonly regarded as a hemolytic anemia, this hemopoietic stem cell disorder is characterized by formation of defective platelets, granulocytes, and erythrocytes. Paroxysmal nocturnal hemoglobinuria is acquired and arises from one abnormal clone of cells, much like a neoplasm (Luzzatto, 2015). One mutated X-linked gene responsible for this condition is termed PIG-A because it codes for phosphatidylinositol glycan protein A. Resultant abnormal anchor proteins of the erythrocyte and granulocyte membrane make these cells unusually susceptible to lysis by complement (Provan, 2000). The most serious complication is thrombosis, which is heightened in the hypercoagulable state of pregnancy.

Chronic hemolysis has an insidious onset, and its severity ranges from mild to lethal. Hemoglobinuria develops at irregular intervals and is not necessarily nocturnal. Hemolysis may be initiated by transfusions, infections, or surgery. Almost 40 percent of patients sufer venous thromboses and may also experience renal failure, hypertension, and Budd-Chiari syndrome. Because of the thrombotic risk, prophylactic anticoagulation is recommended (Parker, 2005). The treatment of choice is eculizumab, an antibody that inhibits complement activation (Kelly, 2015). Median survival after diagnosis is 10 years, and bone marrow transplantation is the deinitive treatment.

During pregnancy, paroxysmal nocturnal hemoglobinuria can be serious and unpredictable. Complications have been reported in up to three fourths of afected women, and the maternal mortality rate in the past was 10 to 20 percent (De Gramont, 1987; de Guibert, 2011). Complications more often develop postpartum, and half of afected women develop venous thrombosis (Fieni, 2006; Ray, 2000). Kelly and colleagues (2015) described 75 pregnancies in 61 afected women treated with eculizumab. In half of these, the dose was increased during pregnancy. They described no maternal deaths but 4 percent stillbirths.

he most fulminant acquired hemolytic anemia encountered during pregnancy is caused by the exotoxin of Clostridium petingens or by group A J-hemolytic streptococcus (Chap. 47, p. 922). Endotoxin of gram-negative bacteria, that is, lipopolysaccharide, may be accompanied by hemolysis and mild-to-moderate anemia (Cox, 1991). For example, anemia often accompanies acute pyelonephritis. With normal erythropoietin production, red cell mass is restored following infection resolution as pregnancy progresses (Cavenee, 1994; Dotters-Katz, 2013).

he normal erythrocyte is a lexible biconcave disc that allows numerous cycles of reversible deformations. Several genes encode expression of erythrocyte structural membrane proteins or intraerythrocytic enzymes. Various mutations of these genes may result in inherited membrane defects or enzyme deiciencies that destabilize the lipid bilayer. The loss of lipids from the erythrocyte membrane causes a surface area deficiency and poorly deformable cells that undergo hemolysis. Anemia severity depends on the degree of rigidity or decreased distensibility. Erythrocyte morphology similarly is dependent on these factors, and these disorders are usually named after the most dominant red-cell shape characteristic of the disorder. hree examples are hereditary spherocytosis) pyropoikilocytosis, and ovalocytosis.

Hereditary Spherocytosis. Hemolytic anemias that compose this group of inherited membrane defects are among the most common hemolytic anemias found in gravidas. Mutations are usually an autosomally dominant, variably penetrant spectrin deiciency. Others are autosomally recessive or de novo gene mutations that result from deiciency of ankyrin) protein 4.2, moderate band 3, or combinations of these (Gallagher, 2010; Rencic, 2017; Yawara, 2000). The degrees of anemia and jaundice vary, and diagnosis is conirmed by identiication of spherocytes on peripheral smear and increased osmotic fragility.

Spherocytic anemias may be associated with a so-called crisis that is characterized by severe anemia from accelerated hemolysis, and it develops in patients with an enlarged spleen. Infection can also accelerate hemolysis or suppress erythropoiesis to worsen anemia. An example of the latter is infection with parvovirus B19 (Chap. 64, p. 1216). In severe cases, splenectomy reduces hemolysis, anemia, and jaundice.

Pregnancy. In general, women with inherited red-cell membrane defects do well during pregnancy. Folic acid supplementation of 4 mg daily is given orally to sustain erythropoiesis. Women with hereditary spherocytosis cared for at Parkland Hospital had hematocrits ranging from 23 to 41 volumes percent mean 31 (Maberry, 1992). Reticulocyte counts ranged from 1 to 23 percent. Among 50 pregnancies in 23 women, eight women miscarried. Four of 42 infants were born preterm, but none was growth restricted. Infection in four women intensified hemolysis, and three of these required transusions. Similar results were reported by Pajor and coworkers (1993).

Because these disorders are inherited, the newborn may be afected. Celkan and Alhaj (2008) report prenatal diagnosis via cordocentesis at 18 weeks' gestation and testing for osmotic fragility. Newborns with hereditary spherocytosis may manifest hyperbilirubinemia and anemia shortly after birth.

n intraerythrocytic deficiency of enzymes that permit anaerobic glucose metabolism may cause hereditay nonspherocytic anemia. Most of these mutations are autosomal recessive traits. As discussed earlier (p. 1078), most episodes of severe anemia with enzyme deficiencies are induced by drugs or infections.

Pyruvate kinase deficiency is associated with variable anemia and hypertensive complications (Wx, 2007). Due to recurrent transfusions in homozygous carriers, iron overload is frequent, and associated myocardial dysfunction should be monitored (Dolan, 2002). The fetus that is homozygous for this mutation may develop hydrops ttalis from anemia and heart failure (Chap. 15, p. 309).

Glucose-6-phosphate dehydrogenase (G6PD) deiciency is complex because there are more than 400 known enzyme variants. he most common are caused by a base substitution that leads to an amino acid replacement and a broad range of phenotypic severity (Luzzatto, 2015; Puig, 2013). In the homozygous or A variant, both X chromosomes are afected, and erythrocytes are markedly deicient in G6PD activity. Approximately 2 percent of African-American women are afected, and the heterozygous variant is found in 10 to 15 percent (Mockenhaupt, 2003). In both instances, random X-chromosome inactivation-yonization-results in variable enzyme activity.

During pregnancy, infections or drugs can induce hemolysis in G6PD deficiency heterozygotes or homozygotes, and severity is related to enzyme activity. Anemia is usually episodic, although some variants induce chronic nonspherocytic hemolysis. Because young erythrocytes contain more enzyme activity, anemia ultimately stabilizes and is corrected soon after the inciting cause is eliminated. Newborn screening for G6PD deiciency is not recommended by the American College of Obstetricians and Gynecologists (20 16b).

Aplastic anemia is a grave complication that is characterized by pancytopenia and markedly hypocellular bone marrow (Young, 2015). There are multiple etiologies, and at least one is linked to autoimmune diseases (Stalder, 2009). he inciting cause can be identified in approximately a third of cases. These include drugs and other chemicals, infection, irradiation, leukemia, immunological disorders, and inherited conditions such as Fanconi anemia and Diamond-Backon syndrome (Green, 2009; Lipton, 2009). The functional defect appears to be a marked decrease in committed marrow stem cells.

Hematopoietic stem-cell transplantation is optimal therapy in a young patient (Killick, 2016). Immunosuppressive therapy is given, and in some nonresponders, eltrombopag has been successful (Olnes, 2012; Townsley, 2017). Deinitive treatment is bone marrow transplantation, and approximately three fourths of patients have a good response and long-term survival (Rosenfeld, 2003). Umbilical cord blood-derived stem cells can also serve as a potential transplant source (Moise, 2005; Pinto, 2008). Previous blood transfusions and even pregnancy enhance the risk of graft rejection (Young, 2015).

Hypoplastic or aplastic anemia complicating pregnancy is rare. A study of 60 pregnancies complicated by aplastic anemia found that half were diagnosed during pregnancy (Bo, 2016). There are a few well-documented cases of pregnancy-induced hypoplastic anemia, and the anemia and other cytopenias improve or remit following delivery or pregnancy termination (Bourantas, 1997; Choudhry, 2002). In some cases, anemia recurred in a subsequent pregnancy.

Diamond-Blackon anemia is a rare form of pure red-cell hypoplasia. Approximately 40 percent of cases are familial and have autosomal dominant inheritance (Orfali, 2004). The response to glucocorticoid therapy is usually good. Continuous treatment is necessary, and most become at least partially transfusion dependent (Vlachos, 2008). In 64 pregnancies complicated by this syndrome, Faivre and associates (2006) reported that two thirds had problems related to placental vascular etiologies that included miscarriage, preeclampsia, preterm birth, fetal-growth restriction, or stillbirth.

Gaucher disease is an autosomally recessive lysosomal enzyme deficiency characterized by deficient activity of acid >-glucosidase. Afected women have anemia and thrombocytopenia that is usually worsened by pregnancy (Granovsky-Grisaru, 1995). Elstein and colleagues (1997) described six pregnant women whose disease improved when they were given alglucerase enzyme replacement. Imiglucerase therapy, which is human recombinant enzyme replacement therapy, has been available since 1994. European guidelines recommend treatment in pregnancy, whereas the Food and Drug Administration states it may be given with "clear indications" (Granovsky-Grisaru, 2011).

he major risks with hypoplastic anemia are hemorrhage and infection. Rates of preterm labor, preeclampsia, fetal-growth restriction, and stillbirth are increased (Bo, 2016). Management depends on gestational age, and supportive care includes continuous infection surveillance and prompt antimicrobial therapy. Granulocyte transfusions are given only during infections. Red cells are transfused to improve symptomatic anemia and routinely to maintain the hematocrit at or above 20 volumes percent. Platelet transfusions may be needed to control hemorrhage. Maternal mortality rates reported since 1960 have averaged nearly 50 percent, however, better outcomes have been reported more recently (Choudhry, 2002; Kwon, 2006).

Several reports describe successful pregnancies in women who have undergone bone marrow transplantation (BorgnaPignatti, 1996; Eliyahu, 1994). In their review, Sanders and coworkers (1996) reported 72 pregnancies in 41 women who had undergone transplantation. In the 52 pregnancies resulting in a liveborn neonate, almost half were complicated by preterm delivery or hypertension. Our experiences with a few of these women indicate that they have normal pregnancy-augmented erythropoiesis and total blood volume expansion.

Excessive erythrocytosis during pregnancy is usually related to chronic hypoxia from maternal congenital cardiac disease or a chronic pulmonary disorder. Unusually heavy cigarette smoking can cause polycythemia. We have encountered otherwise healthy pregnant women who were heavy smokers, had chronic bronchitis, and had hematocrits ranging from 55 to 60 volumes percent! If polycythemia is severe, the probability of a successful pregnancy outcome is low.

This is a primary clonal myeloproliferative hemopoietic stemcell disorder characterized by excessive proliferation of erythroid, myeloid, and megakaryocytic precursors (Spivak, 2015; Vannucchi, 2015). Virtually all patients have either aJA2V617F or aJA2 exon 12 gene mutation (Harrison, 2009). Symptoms are related to increased blood viscosity, and thrombotic complications are common. Treatment of nonpregnant patients is with hydroxyurea or ruxolitinib (Vannucchi, 2015).

Fetal loss rates are high in women with polycythemia vera, and pregnancy outcome may be improved with aspirin therapy (Griesshammer, 2006; Robinson, 2005; Teferi, 2000). Women with a history of venous thrombosis are given prophylaxis with low-molecular-weight heparin. If cytoreduction is required during pregnancy, interferon alpha may be considered (Kreher, 2014).

Hemoglobin A is the most common hemoglobin tetramer and consists of two .-and two 3-chains. In contrast, sickle hemoglobin (hemoglobin S) originates from a single 3-chain substitution of glutamic acid by valine, which stems from an A-for-T substitution at codon 6 of the 3-globin gene. Hemoglobinopathies that can result in clinical features of the sickle-cell syndrome include sickle-cell anemia (Hb SS); sickle-cell hemoglobin C disease (Hb SC); sickle-cell 3-thalassemia disease (either Hb SI or Hb S/B+); and sickle-cell E disease (Hb SE) (Benz, 2015). All are also associated with increased pregnancy morbidity.

Sickle-cell anemia results from the inheritance of the gene for S hemoglobin from each parent. In the United States, 1 of 12 African-Americans has sickle-cell trait, which results from inheritance of one gene for hemoglobin S and one for normal hemoglobin A. he computed incidence of sickle-cell anemia among frican-Americans is 1 in 576 (1112 X 1112 X 114 = 11576). But, the disease is less common in adults because of earlier mortality. Hemoglobin C originates from a single 3-chain substitution of glutamic acid by lysine, which stems from a T -forC substitution at codon 6 of the 3-globin gene. Approximately 1 in 40 African-Americans has the gene for hemoglobin C. Thus, the theoretical incidence for co inheritance of the gene for hemoglobin S and an allelic gene for hemoglobin C in an frican-American child is about 1 in 2000 (1/12 X 1140 X 114). 3-halassemia minor is approximately 1 in 40, thus S-3-thalassemia also is found in approximately 1 in 2000 (1/12 X 1140 X 114).

Red cells with hemoglobin S undergo sickling when they are deoxygenated, and the hemoglobin aggregates. Constant sickling and unsickling cause membrane damage, and the cell may become irreversibly sickled. Events that slow erythrocyte transit through the microcirculation include adhesion to endothelial cells, erythrocytic dehydration, and vasomotor dysregulation. Clinically, the hallmarks of sickling episodes are periods during which there is ischemia and infarction in various organs. The sickle-cell crisis produces clinical symptoms, predominately pain, which is often severe. There may be aplastic, megaloblastic, sequestration, and hemolytic crises.

Chronic and acute changes from sickling include bony abnormalities such as osteonecrosis of femoral and humeral heads, renal medullary damage, autosplenectomy in homozygous SS patients and splenomegaly in other variants, hepatomegaly, ventricular hypertrophy, pulmonary infarctions, pulmonary hypertension, cerebrovascular accidents, leg ulcers, and a propensity for infection and sepsis (Benz, 2015; Gladwin, 2004). Other sequelae are cerebrovascular aneurysms and sickle-cell vasculopathy (Buonanno, 2016). Pulmonary hypertension can develop and is found in 20 percent of adults with SS hemoglobin (Gladwin, 2008).

Good supportive care is essential to prevent mortality. Speciic therapies are evolving, and many are still experimental. One treatment is hemoglobin F induction with drugs that stimulate gamma-chain synthesis. This increases hemoglobin F, which inhibits hemoglobin S polymerization. One example is hydroyurea, which augments hemoglobin F production and reduces the number of sickling episodes (Platt, 2008). Hydroxyurea is teratogenic in animls, although a preliminary 17 -year surveillance of antenatally exposed children was reassuring (Ballas, 2009; Briggs, 2015; Italia, 2010). A randomized trial showed no benefit from treatment with prasurel, a platelet inhibitor (Henney, 2016). Treatment with crianlizumab, an antibody against P-selectin, signiicantly lowered the incidence of adverse events (Ataga, 2017).

Various forms of hemopoietic cell transplantation are emerging as "cures" for sicle-cell syndromes and severe thalassemias (Hsieh, 2009). Oringanje and coworkers (20l3) performed a Cochrane review and found that only observational studies have been reported. Bone marrow transplantation has 5-year survival rates that exceed 90 percent (DaIle, 20l3). Cord-blood stem-cell transplantation from related donors also shows great promise (Shenoy, 2013). Finally, successful gene therapy has been accomplished by lentiviral vector-mediated addition of a beta globin gene into stem cells (Ribeil, 2017).

only after all other possible causes have been excluded. Pain

TABLE 56-2. Pregnancy Morbidity with Hemoglobin SS with sickle-cell syndromes is caused by intense sequestration of sickled erythrocytes and infarction in various organs, especially

Odds Ratios Oukome Hb.SS Hb.SC bone marrow. These episodes may develop acutely, especially

Preeclampsia 2-3.1 late in pregnancy, during labor and delivery, and early in the 2.0 puerperium.

Stillbirth 6.5 3.2

Preterm delivery 2-2.7 1.5

Growth restriction 2.8-3.9 1.5

Data from metaanalyses by Boafor, 201n6; Oteng-Ntim, 2015.

Pregnancy is a serious burden to women with any of the major sickle hemoglobinopathies, particularly those with hemoglobin SS disease. Several large studies have defined this relationship. Villers and colleagues (2008) studied 17,952 births in women with sickle-cell syndromes. Chakravarty and associates (2008) studied 4352 pregnancies. A more recent cohort study of 1526 women was reported by Boulet and coworkers (2013). Last, a cohort study taken from more than 2 million women compared those with sickle-cell disease to normal controls (Kuo, 2016). Common obstetrical and medical complications and their relative risks from a composite of most of these studies are shown in Table 56-2.

Maternal morbidity common in pregnancy includes ischemic necrosis of multiple organs, especially bone marrow that causes episodes of severe pain. Pyelonephritis, pneumonia, and pulmonary complications are frequent. Although the maternal mortality rate has improved, perinatal morbidity and mortality rates remain formidable (Boga, 2016; Lesage, 2015; Yu, 2009). Perinatal outcomes include increased risks for preterm birth, fetal-growth restriction, and perinatal mortality.

In nonpregnant women, morbidity and mortality rates from SC disease are appreciably lower than those from sickle-cell anemia. Indeed, fewer than half of these women have symptoms before pregnancy. In our experiences, afected gravidas sufer attacks of severe bone pain and episodes of pulmonary infarction and embolization more commonly than when they are not pregnant (Cunningham, 1983). Some adverse pregnancy outcomes are shown in Table 56-2.

Women with sickle-cell hemoglobinopathies require close prenatal observation. Any factor that impairs erythropoiesis or increases red cell destruction aggravates the anemia. Prenatal folic acid supplementation with 4 mg daily is needed to support rapid red blood cell turnover.

One danger is that a symptomatic woman may categorically be considered to be sufering from a "sickle-cell crisis." As a result, serious obstetrical or medical problems that cause pain, anemia, or both may be overlooked. Examples are ectopic pregnancy, placental abruption, pyelonephritis, or appendicitis. Thus, a diagnosis of sickle-cell crisis should be applied

Guidelines for care of these women have been appropriately stressed by Rees and colleagues (2003). !vIarti-Carvajal and coworkers (2009) performed a Cochrane review and reported that no randomized trials have evaluated treatment during pregnancy. At minimum, intravenous luids are given, and opioids are administered promptly for severe pain. Oxygen via nasal cannula may decrease the intensity of sickling at the capillary level. We have found that red cell transfusions after the onset of severe pain do not dramatically improve pain intensity and may not shorten its duration. Conversely, as discussed later, prophylactic transfusions almost always prevent further vasoocclusive episodes and pain crises. Recent reports suggest benefits from epidural analgesia (Verstraete, 2012; Winder, 2011). Long term, afected women can become habituated to narcotics. his problem is highlighted by the increased rates of neonatal abstinence syndrome, which is a constellation of withdrawal symptoms (Shirel, 2016).

Rates of covert bacteriuria and acute pyelonephritis are elevated substantively, and screening and treatment for bacteriuria are essential. If pyelonephritis develops, sickle cells are extremely susceptible to bacterial endotoxin, which can cause dramatic and rapid red cell destruction while simultaneously suppressing erythropoiesis. Pneumonia, especially due to Streptococcus pneumoniae, is common. he Centers for Disease Control and Prevention recommends specific vaccination for those with sickle-cell disease and all asplenic patients (Kim, 2016). hese are polyvalent pneumococcal, Haemophilus inluenzae type B, and meningococcal vaccines, and administration guidelines are found in Table 9-7 (p. 172).

Pulmonary complications are frequent. Of these, acute chest syndrome is characterized by pleuritic chest pain, fever, cough, lung infiltrates, and hypoxia, and usually also by bone and joint pain (Vichinsky, 2000). In addition to symptoms, radiographs show a new pulmonary infiltrate. There are four precipitants: infection, marrow emboli, thromboembolism, and atelectasis (Medof, 2005). Bacterial or viral infection causes approximately half of cases. When acute chest syndrome develops, the mean duration of hospitalization is 10.5 days. Mechanical ventilation is required in approximately 15 percent, and the mortality rate approximates 3 percent (Gladwin, 2008). At least for nonpregnant adults, some recommend rapid simple or exchange transfusions to remove the "trigger" for acute chest syndromes (Gladwin, 2008). In a study of nonpregnant patients, Turner and colleagues (2009) reported that there were no increased beneits of exchange versus simple transfusions, and the former were associated with fourfold increased blood usage.

Women with sickle-cell disease usually have some degree of cardiac dysfunction from ventricular hypertrophy. Chronic hypertension worsens the dysfunction (Gandhi, 2000). During pregnancy, the basal hemodynamic state characterized by high cardiac output and increased blood volume is augmented (Veille, 1994). Although most women tolerate pregnancy with out problems, complications such as severe preeclampsia or ham, 1986). Heart failure caused by pulmonary hypertension must also be considered (Chakravarty, 2008).

In 4352 pregnancies in women with sickle-cell syndromes, pregnancy complication rates. Compared with controls, women with sickling disorders had a 63-percent rate of nondelivery related admissions. hey had a 1.8-fold greater incidence of hypertensive disorders-19 percent; a 2.9-fold higher rate of fetal-growth restriction-6 percent; and a 1.7-fold increased cesarean delivery rate-45 percent.

Prophylactic Red Cell Transfusions. Chronic transfusion therapy prevents strokes in high-risk children (DeBaun, 2014). During pregnancy, the most dramatic beneit of prophylactic transfusions has been on maternal morbidity rates (Benites, 2016). In an observational 10-year prospective study at Parkland Hospital, we ofered prophylactic transfusions to all pregnant women with sickle-cell syndromes. Transfusions were given throughout pregnancy to maintain the hematocrit above 25 volumes percent and the portion of hemoglobin S <60 percent (Cunningham, 1979). Maternal morbidity was minimal, and erythropoiesis suppression was not problematic. Their outcomes were compared with historical controls who were not routinely transfused. Overall, morbidity and hospitalization rates were signiicantly reduced in the transfused group (Asma, 2015; Cunningham, 1983; Grossetti, 2009). Still, adverse perinatal outcomes are prevalent (Ngo, 2010).

In a multicenter trial, Koshy and coworkers (1988) randomly assigned 72 pregnant women with sickle-cell syndromes to prophylactic or indicated transfusions. They reported a signiicant decline in the incidence of painful sickle-cell crises with prophylactic transfusions but no diferences in perinatal outcomes. Because of risks inherent with blood administration, they concluded that prophylactic transfusions were not indicated. A metaanalysis of 12 studies found prophylactic transfusions improved rates of some adverse maternal and neonatal outcomes, including maternal mortality, pulmonary complications, and perinatal mortality (Malinowski, 2015).

Undoubtedly, morbidity from multiple transfusions is significant. Up to 10 percent of women had a delayed hemolytic transfusion reaction, and infections are major concerns. Garratty (1997) reviewed 12 studies and found alloimmunization developed in a fourth of women. Finally, in liver biopsies in these women, we found no evidence of transfusion-related iron overload, hemochromatosis, or chronic hepatitis (Yeomans, 1990).

Because of what some consider marginal benefits, routine prophylactic transfusions during pregnancy remain controversial (American College of Obstetricians and Gynecologists, 2015; Okusayna, 2013). Current consensus is that their use should be individualized.

Fetal Assessment. Because of the high incidence offetal-growth restriction and perinatal mortality, serial fetal assessment with sonography and antepartum surveillance is recommended (American College of Obstetricians and Gynecologists, 2015).

Anyaegbunam and colleagues (1991) reported nonreactive stress tests during sickling crises, which resumed reactivity with crisis resolution. They concluded that transient efects of sicklecell crisis do not compromise umbilical blood flow.

Management is essentially identical to that for women with cardiac disease (Chap. 49, p. 953). Women should be kept comfortable, but not oversedated. Conduction analgesia is ideal (Camous, 2008). Compatible blood should be available. If a diicult vaginal or cesarean delivery is contemplated, and the hematocrit is <20 volumes percent, then packed erythrocyte transfusions are administered. There is no categorical contraindication to vaginal delivery, and cesarean delivery is reserved for obstetrical indications (Rogers, 2010).

Many clinicians do not recommend combination hormonal contraception because of potential adverse vascular and thrombotic efects. In their systematic review, however, Haddad and coworkers (2012) found that complication rates were not higher with their use in women with sickle-cell syndromes. he Centers for Disease Control and Prevention categorizes combination hormonal contraception, intrauterine devices, implants, and progestin-only contraception as having no risk or as having advantages that generally outweigh theoretical or proven risks (Curtis, 2016).

The frequency of sickle-cell trait among African-Americans averages 8 percent. Carriers have occasional hematuria, renal papillary necrosis, and hyposthenuria, which is urine of low specific gravity (Tsaras, 2009). And although controversial, sickle-cell trait does not appear to be associated with increased rates of abortion, perinatal mortality, low birthweight, or pregnancy-induced hypertension (Pritchard, 1973; Tita, 2007; Tuck, 1983). One unquestioned relationship is the twofold increased incidence of asymptomatic bacteriuria and urinary infection. Sickle-cell trait should not be considered a deterrent to pregnancy or to hormonal contraception.

Inheritance is a concern for the fetus of a mother with sickle-cell trait whenever the father carries a gene for abnormal hemoglobins that include S, C, and D or for 3-thalassemia trait. Prenatal diagnosis is discussed in Chapter 14 (p. 290).

Approximately 2 percent of African-Americans are heterozygous for hemoglobin C, but even if homozygous, hemoglobin C is innocuous (Nagel, 2003). Only when coinherited with sickle-cell trait to yield hemoglobin SC is the trait problematic. Pregnancy in women with homozygous hemoglobin CC disease or C-3-thalassemia carries relatively benign associations. Table 56-3 shows our experiences from Parkland Hospital (Maberry, 1990). Other than mild-to-moderate anemia, pregnancy outcomes were not abnormal. Supplementation with folic acid and iron is indicated.

Data from Maberry, 1990.

Although uncommon in the United States, hemoglobin E is the second most frequent hemoglobin variant worldwide. The heterozygous E trait is common in Southeast Asia. Hurst and coworkers (1983) identified homozygous hemoglobin E, hemoglobin E plus 3-thalassemia, or hemoglobin E trait in 36 percent of Cambodians and 25 percent of Laotians. Hemoglobin EE is associated with little or no anemia, hypochromia, marked microcytosis, or erythrocyte targeting. Kemthong and colleagues (2016) studied 1073 women and 2146 controls and found that hemoglobin E trait does not increase pregnancy risks other than asymptomatic bacteriuria. Conversely, doubly heterozygous E-3-thalassemia is a common cause of severe childhood anemia in Southeast Asia (DeLoughery, 2014). In a cohort study of 54 women with singleton pregnancies, Luewan and associates (2009) reported a threefold greater risk of preterm birth and fetal-growth restriction in afected women. It is unclear if hemoglobin SE disease is ominous during pregnancy.

• Hemoglobinopathy in the Newborn

Neonates with homozygous SS, SC, and CC disease can be identiied accurately at birth by cord blood electrophoresis. The United States Preventive Services Task Force recommends that all newborns be tested for sickle-cell disease (Lin, 2007). In most states, such screening is mandated by law and performed routinely (Chap. 32, p. 614).

Many tests are available to detect sickle-cell disease ante natally. Most are DNA based and use chorionic villus samples or amnionic fluid specimens (American College of Obstetricians and Gynecologists, 2015). Several mutations that encode hemoglobin S and other abnormal hemoglobins can be detected by targeted mutation analysis and polymerase chain reaction-based techniques (Chap. 13, p. 270).

Hundreds of mutations afect genes that control hemoglobin production. Some of these impair synthesis of one or more of the normal globin peptide chains and may result in a clinical syndrome characterized by varying degrees of inefective erythropoiesis, hemolysis, and anemia (Benz, 2015). Thalassemias are classiied according to the globin chain that is deficient. The two major forms involve impaired production or instability of a-peptide chains to cause a-thalassemia or of 3-chains to cause 3-thalassemia. hese may form from point mutations, deletions, or translocations involving the .-or non-a-globin gene (Leung, 2012).

Because there are four a-globin genes, the inheritance of a-thalassemia is more complicated than for 3-thalassemia (Piel, 2014). Possible genotypes and phenotypes are shown in

Table 56-4. Clinical severity closely correlates with the degree of a-globin chains synthesis impairment. In most populations, the a-globin chain "cluster" or gene loci are doubled on chromosome 16. Similarly, ther, chains are duplicated. Thus, the normal genotype for diploid cells can be expressed as ../.. and "r /,,. here are two main groups of a-thalassemia determinants: .0-thalassemia is the deletion of both loci from one chromosome (--/..), whereas .+ -thalassemia is the loss of a single locus from one allele (-./.. heterozygote) or a loss from each allele (-./-.homozygote).

here are two major phenotypes. he deletion of all four a-globin chain genes (--/--) characterizes homozygous a-thalassemia. Because a-chains are contained in fetal hemoglobin, the fetus is afected. When none of the four genes

TABLE 56-4. Genotypes and Phenotypes of .-Thalassemia Syndromes

Normal ../.. Normal .+-Thalassemia heterozygote -'/.. } Normal; silent carrier ../-. .+-Thalassemia homozygotea -./-. } a-Thalassemia minor-mild .°-Thalassemia heterozygoteb --/.. hypochromic microcytic anemia Compound heterozygous .0/.+ --/-. Hgb H (34) with moderate-to severe hemolytic anemia Homozygous .-thalassemia --/--Hgb Bart ('4) disease, hydrops fetalis

African Americans. bMore common in Asian Americans.

are expressed, no a-globin chains are produced, and instead hemoglobin Bart (14) and hemoglobin H (34) are formed as abnormal tetramers that cannot transport oxygen (Chap. 7, p. 131).

he relative frequency of a-thalassemia minor, hemoglobin H disease, and hemoglobin Bart disease varies remarkably among racial groups. All of these variants are encountered in Asians.

In those of African descent, although a-thalassemia minor has a frequency approximating 2 percent, hemoglobin H disease is rare and hemoglobin Bart disease is unreported. This is because

Asians usually have .0-thalassemia minor inherited with both gene deletions typically from the same chromosome (--/..), whereas blacks usually have .+-thalassemia minor in which one gene is deleted from each chromosome (-xl-x).

Diagnosis of 3-thalassemia minor and a-thalassemia major in the fetus can be accomplished by DNA analysis using molec ular techniques (Piel, 2014). Fetal diagnosis of hemoglobin yakul, 2009; Srivorakun, 2009). Molecular genetic testing for

HBAl and HBA2 identifies 90 percent of deletions and 10 percent of point mutations in afected individuals (Galanello, 2011 b).

Important obstetrical aspects of some a-thalassemia syndromes depend on the number of gene deletions in a given woman. he silent carrier state with one gene deletion is of no consequence. Deletion of two genes resulting in a-thalassemia minor is characterized by minimal-to-moderate hypochromic micro cytic anemia. This is due to either .r_ or .+-thalassemia trait, and thus genotypes may be -xla or --la.. Diferentiation is possible only by DNA analysis (Piel, 2014). Because no other clinical abnormalities accompany either form of a-thalassemia minor, it often goes unrecognized and is usually of no maternal consequence (Hanprasertpong, 2013). The fetus with these forms of thalassemia minor will have hemoglobin Bart at birth, but as its levels drop, it is not replaced by hemoglobin H. Red cells are hypochromic and microcytic, and the hemoglobin concentration is normal to slightly depressed.

Hemoglobin H disease (34) results from the compound heterozygous state for .0_ plus .+-thalassemia with deletion of three of four alpha genes (--I-x). With only one functional a-globin gene per diploid genome, the newborn will have abnormal red cells containing a mixture of hemoglobin Bart (14), hemoglobin H (34)' and hemoglobin A. The neonate appears normal but soon develops hemolytic anemia as most of the hemoglobin Bart is replaced by hemoglobin H. In adults, anemia is moderate to severe and usually worsens during pregnancy.

Inheritance of all four abnormal a genes causes homozygous a-thalassemia with predominant production of hemoglobin Bart, which has an appreciably increased ainity for oxygen. This is incompatible with extended survival. Hsieh and colleagues (1989) reported that blood obtained by funipuncture from 20 hydropic fetuses contained 65 to 98 percent Bart hemoglobin. These fetuses are stillborn, or they are hydropic and usually die very soon after birth.

Sonographic measurement of the fetal cardiothoracic ratio at 12 to 13 weeks' gestation can be used to identiy afected fetuses (Lam, 1999; Zhen, 2015). Sonographic assessment of myocardial performance-the Tei index-in the irst half of pregnancy has been evaluated. Changes predate hydrops in afected fetuses (Luewan, 2013). Severe anemia can be detected using Doppler velocimetry of the middle cerebral artery.

ment (Galanello, 201r1a).

he 3-thalassemias are the consequences of impaired 3-globin chain production or a-chain instability. Genes that encode con trol of 3-globin synthesis are in the r3-gene "cluster" located on chromosome 11 (Chap. 7, p. 131). More than 150 point mutations in the 3-globin gene have been described (Weather all, 2010). In 3-thalassemia, 3-chain production is decreased, and excess a-chains precipitate to cause cell-membrane dam age. Other forms of3-thalassemias are caused by a-chain insta bility (Kihm, 2002).

he heterozygous trait is 3-thalassemia minor, and those

Az levels. his hemoglobin is composed of two .-and two 6-globin chains, and concentrations are usually more than 3.5 percent. Hemoglobin F-composed of two .-and two I-globin chains-also usually has increased concentrations that exceed 2 percent. Some patients with heterozygous 3-thalassemia minor do not have anemia, and others have mild-to-moderate anemia characterized by hypochromia and microcytosis.

Homozygous 3-thalassemia-also called 3-thalassemia major or Cooley anemia-is a serious and frequently fatal disorder. Hemolysis is intense and leads to severe anemia. Many patients become transfusion dependent, and the subsequent iron load, along with abnormally increased gastrointestinal iron absorption, leads to hemochromatosis, which is fatal in many cases. Stem cell transplantation has been used to treat 3-thalassemia major Gagannath, 2014). A heterozygous form of 3-thalassemia that clinically manifests as thalassemia intermedia produces moderate anemia.

During pregnancy, women with 3-thalassemia minor may have mild anemia (Charoenboon, 2016). Iron and folate supplements are given. In some women, anemia will worsen because normal plasma volume expansion may be accompanied by slightly subnormal erythropoiesis.

Thalassemia major and some of the other severe forms were uncommonly encountered during pregnancy before the advent of transfusion and iron chelation therapy. With such management, 63 pregnancies were reported and sufered no serious complications (Aessopos, 1999; Daskalakis, 1998). Pregnancy is considered reasonably safe if maternal cardiac function is normal. Transfusions are given throughout pregnancy to maintain the hemoglobin concentration at 10 g/dL. This is coupled with surveillance of fetal growth (American College of Obstetricians and Gynecologists, 2015; Sheiner, 2004).

Because 3-thalassemia major is caused by numerous mutations, prenatal diagnosis is diicult. For a given individual, targeted mutation analysis is done that requires prior identification of the familial mutation. The analysis is done using chorionic villus sampling and other techniques discussed in Chapter 14 (p. 293). Noninvasive testing of circulating fetal nucleic acids in maternal plasma for the diagnosis of 3-thalassemia has been described (Leung, 2012; Xiong, 2015).

Platelet abnormalities may precede pregnancy, develop during pregnancy coincidentally, or be induced by pregnancy. hrombocytopenia-deined by a platelet count < 150,000/�L-is identified in nearly 10 percent of gravidas (American College of Obstetricians and Gynecologists, 2016c). Of these cases, 75 percent are gestational thrombocytopenia, whereas 25 percent are due to other various causes. One other common cause is HELLP syndrome. Thrombocytopenia may be inherited or idiopathic, acute or chronic, and primary or associated with other disorders. Examples are shown in Table 56-5.

Burrows and Kelton (1993) reported that 6.6 percent of 15,471 pregnant women had a platelet count < 150,000/�L, and in 1.2 percent, it was <100,000/�L. hey further noted that almost 75 percent of 1027 women whose platelet counts were < 150,000/�L were found to have normal-variant incidental thrombocytopenia. Of the remainder, 21 percent had a hypertensive disorder of pregnancy, and 4 percent had an immunological disorder. A platelet count of <80,000/�L should trigger

TABLE 56-5. Some Causes of Thrombocytopenia in Pregnancy

APAS = antiphospholipid antibody syndrome; DIC = disseminated intravascular coagulopathy; HELLP = hemolysis, elevated liver enzyme levels, low platelet count;

MTP = massive transfusion protocol. Data from American College of Obstetrics and Gynecologists, 2016c; Aster, 2007; Diz-Ku:ukkaya, 2016.

an evaluation for etiologies other than incidental or gestational thrombocytopenia, which is unlikely to have a platelet count <50,000/�L (Gernsheimer, 2013).

he physiological decline in platelet concentration seen with gestational thrombocytopenia is usually evident in the third trimester and is thought to be predominantly due to hemodilution. The normal increased splenic mass characteristic of pregnancy may also be contributory (Maymon, 2006). Most evidence shows that platelet life span is unchanged in normal pregnancy (Kenny, 2015).

Benard-Soulier yndrome is characterized by lack of platelet membrane glycoprotein (GPIb/IX) and causes severe dysunction. Moreover, women exposed to fetal platelets carrying this glycoprotein can develop antibodies against this fetal GPIb/IX antigen to cause lloimmune fetal thrombocytopenia (Fujimori, 1999; Peng, 1991). A systematic review of 30 pregnancies in 18 women reported a 33-percent rate of primary postpartum hemorrhage, and half of women with bleeding required blood transfusion (Peitsidis, 2010). he reviewers also described six cases of neonatal lloimmune thrombocytopenia and two perinatl deaths. Close monitoring throughout pregnancy and 6 weeks postpartum is critical due to the possibility of life-threatening hemorrhage (Prabu, 2006).

May-Heglin anomay is an autosomal dominant disorder characterized by thrombocytopenia, giant platelets, and leukocyte inclusions (Chatwani, 1992). Urato and Repke (1998) described such a woman who was delivered vaginally. Despite a platelet count of 16,000/�L, she did not bleed excessively. he neonate inherited the anomaly but also had no bleeding despite a platelet count of35,000/�L. A systematic review of26 studies containing 75 pregnancies in 40 women reported four cases of postpartum hemorrhage, 34 cases of neonatal thrombocytopenia, and two fetal deaths (Hussein, 2013).

The primary form-also termed idiopathic thrombocytopenic purpura (ITP)-is usually caused by a cluster of IgG antibodies directed against one or more platelet glycoproteins (Konkle, 2015). Antibody-coated platelets are destroyed prematurely in the reticuloendothelial system, especially the spleen. Although not proven, the disorder is probably mediated by autoantibodies directed at platelet-associated immunoglobulins-P AlgG, P AIgM, and P lA.In adults, immune thrombocytopenia most often is a chronic disease that rarely resolves spontaneously.

As shown in Table 56-5, secondary forms of immunemediated chronic thrombocytopenia appear in association with systemic lupus erythematosus, lymphomas, leukemias, and several systemic diseases. Approximately 2 percent of thrombocytopenic patients have positive serological tests for lupus, and in some cases, levels of anticardiolipin antibodies are high. Finally, approximately 10 percent of HIV -positive patients have associated thrombocytopenia (Scaradavou, 2002).

Diagnosis and Management. Only a few adults with primary immune thrombocytopenia recover spontaneously, and for those who do not, platelet counts usually range from 10,000 to 100,000/�L (George, 2014). Evidence does not suggest that pregnancy increases the risk of relapse in women with women with active disease. hat said, it is certainly not unusual years to have recurrent thrombocytopenia during pregnancy.

Although this may be from closer surveillance, hyperestrogen emia has also been implicated.

Therapy is considered if the platelet count is below 30,000 to 50,000/�L (American College of Obstetricians and Gyne cologists, 20 16c). Primary treatment includes corticosteroids or intravenous immune globulin (lYlG) (Neunert, 201r1).

Initially, prednisone, 1 mg/kg daily, is given to suppress the phagocytic activity of the splenic monocyte-macrophage sys tem. IYlG given in a total dose of 2 g/kg during 2 to 5 days is also efective.

In pregnant women with no response to corticosteroid or IVIG therapy, open or laparoscopic splenectomy may be efective. In late pregnancy, cesarean delivery may be necessary for surgical exposure. Improvement usually follows splenectomy in 1 to 3 days and peaks at approximately 8 days. Cytotoxic agents are typically avoided in pregnancy due to teratogenicity risks. Azathioprine and rituximab, however, which are used in nonpregnant persons with ITP, have been used for other conditions in pregnancy. Finally, the thrombopoietin agonist romplostim has stimulated responses in some patients (Decrooq, 2014; Imbach, 2011; Kuter, 2010).

Fetal and Neonatal Efects. Pregnancy complications that are increased with ITP include stillbirth, fetal loss, and preterm birth (Wyszynski, 2016). Platelet-associated IgG antibodies cross the placenta, and fetal death from hemorrhage occurs occasionally (Webert, 2003). he severely thrombocytopenic fetus is at increased risk for intracranial hemorrhage with labor and delivery, but fortunately this is unusual. Payne and associates (1997) reviewed studies of maternal ITP published since 1973. Of 601 newborns, 12 percent had severe thrombocytopenia with counts <50,000/�L. Six infants had intracranial hemorrhage, and in three, their initial platelet count was >50,000/�L. his is consistent with a study of 127 pregnancies in women with ITP in which 10 to 15 percent of neonates had transient ITP (Koyama, 2012).

Investigators concut that fetal and maternal platelet counts lack strong correlation (George, 2009; Hachisuga, 2014). Because of this, maternal IgG free platelet antibody levels and platelet-associated antibody levels have been evaluated to predict fetal platelet counts. Again, however, there is little concurrence with these.

Investigators have also examined the association between the speciic cause of thrombocytopenia and risk of a thrombocytopenic fetus. Four researched causes include gestational th ro m bocyto penia, hypertension -associa ted thro m bocyto penia, immune thrombocytopenia, and alloimmune thrombocytopenia. Burrows and Kelton (1993) reported neonatal umbilical cord platelet counts measuring <50,000/�L in 19 of 15,932 consecutive newborns (0.12 percent). Only one of756 mothers with gestational thrombocytopenia had an afected newborn. Of 1414 hypertensive women with thrombocytopenia, five neonates had thrombocytopenia. In contrast, of 46 mothers with immunological thrombocytopenia, four infants had thrombocytopenia. Alloimmune thrombocytopenia was associated with profound thrombocytopenia and cord platelet counts <20,000/�L. One of these fetuses died, and two others had intracranial hemorrhage.

Detection of Fetal Thrombocytopenia. Because no test accurately predicts fetal platelet counts, direct fetal blood sampling is necessary. Scott and coworkers (1983) obtained intrapartum scalp blood samples and recommended cesarean delivery for fetuses with platelet counts <50,000/�L. Dafos and colleagues (1985) reported that percutaneous umbilical cord blood sampling (PUBS) for this indication had a high complication rate (Chap. 14, p. 294). Conversely, Berry and associates (1r997) reported no complications and described poor reliability to predict severe thrombocytopenia, but noted a high negative-predictive value. Payne and coworkers (1r997) summarized six studies in which fetal blood sampling was done for platelet estimation. Of the total of 195 fetuses, severe neonatal thrombocytopenia <50,000/�L was found in 7 percent. But, serious complications from cordocentesis were noted in 4.6 percent. Because of the low incidence of severe neonatal thrombocytopenia and morbidity, fetal platelet determinations and cesarean delivery are not recommended (N eunert, 2011).

Alloimmune Thrombocytopenia. Disparity between maternal and fetal platelet antigens can stimulate maternal production of antiplatelet antibodies. Such platelet alloimmunization can be severe, and its pathophysiology is identical to that caused by red cell antigens (Chap. 15, p. 307).

Also called thrombocythemia, thrombocytosis generally is deined as persistent platelet counts >450,000/�L. Common causes of seconday or reactive thrombocytosis are iron deficiency, infection, inflammatory diseases, and malignant tumors (Deutsch, 2013). Platelet counts seldom exceed 800,000/�L in these secondary disorders, and prognosis depends on the underlying disease. On the other hand, primary or essential thrombocytosis accounts for most cases in which platelet counts exceed 1 millionl �L. It is a clonal disorder frequently due to an acquired mutation in the fAQ gene (Konkle, 2015). Thrombocytosis usually is asymptomatic, but arterial and venous thromboses may develop, and thrombosis is associated with pregnancy complications (Rabinerson, 2007; Randi, 2014). hese cases must be diferentiated from the sticky platelet syndrome, which is also associated with thromboses (Rac, 2011).

Normal pregnancies have been described in women whose mean platelet counts werer> 1.25 million/�L (Beard, 1991; Randi, 1994). Others report more adverse outcomes. Niittyvuopio and associates (2004) described 40 pregnancies in 16 women with essential thrombocythemia. Almost half had a spontaneous abortion, fetal demise, or preeclampsia. In 63 pregnancies in 36 women cared for at the Mayo Clinic, a third had a spontaneous miscarriage, but other pregnancy complications were uncommon (Gangat, 2009). In this observational study, aspirin therapy was associated with a signiicantly lower abortion rate than that in untreated women-1 versus 75 percent, respectively.

Suggested treatments during pregnancy include aspmn, low-molecular-weight heparin, and interferon-a (Finazzi, 2012). Interferon-a therapy during pregnancy was successful in 11 women in the review by Delage and coworkers (1996). One of these women had transient blindness at midpregnancy when her platelet count was 2.3 million/�L.

Although not a primary platelet disorder, some degree of thrombocytopenia accompanies the thrombotic microangiopathies, which include thrombotic thrombocytopenic purpura (TTP) and hemoytic uremic syndrome (HUS). hese syndromes have an incidence of2 to 6 per million persons per year (Miller, 2004). heir similarities to HELLP syndrome allude to their obstetrical ramiications (George, 2014).

Although diferent causes account for the variable findings within these syndromes, clinically, they frequently are indistinguishable. Most cases of TTP are thought to be caused by antibodies to or a plasma deficiency of ADAMTS13 (Ganesan, 201r1; Sadler, 2010). his endothelium-derived protease cleaves von Willebrand factor (vWF) to decrease its activity. Conversely, HUS is usually due to endothelial damage incited by viral or bacterial infections and is seen primarily in children (Ardissino, 2013; George, 2014).

With TTP, intravascular platelet aggregation stimulates a cascade of events leading to end-organ failure. There is endothelial activation and damage, but it is unclear whether this is a consequence or a cause. Elevated levels of unusually large multimers of vWF are identiied with active TTP. Various defects in the ADAMTS13 gene create difering clinical presentations of thrombotic microangiopathy (Camilleri, 2007; Moake, 2002, 2004). In another scheme, antibodies raised against ADAMTS13 neutralize its action to cleave vWF multimers during an acute episode. he end result is micro thrombi of hyaline material consisting of platelets and small amounts of ibrin within arterioles and capillaries. When suicient in number or size, these aggregates produce ischemia or infarctions in various organs.

hrombotic microangiopathies are characterized by thrombocytopenia, fragmentation hemolysis, and variable organ dysfunction. TTP is characterized by the pentad of thrombocytopenia, fever, neurological abnormalities, renal impairment, and hemolytic anemia. HUS typically has more profound renal involvement and fewer neurological aberrations.

hrombocytopenia is usually severe, but fortunately, even with very low platelet counts, spontaneous severe hemorrhage is uncommon. Microangiopathic hemolysis is associated with moderate-to-marked anemia, and erythrocyte transfusions are frequently necessary. he blood smear is characterized by erythrocyte fragmentation with schizocytosis. Reticulocytes and nucleated red blood cells are increased, lactate dehydrogenase (LDH) levels are high, and haptoglobin concentrations are decreased. Consumptive coagulopathy, although common, is usually subtle and clinically insignificant.

The cornerstone of treatment is plasmapheresis with freshfrozen plasma replacement. Plasma exchange removes inhibitors and replaces the ADAMTS13 enzyme (George, 2014; Michael, 2009). Treatment with caplacizumab, the anti-vWF immunoglobulin, inhibits the interaction between ultralarge vWF multimers and platelets (Peyandi, 2016). hese treatments have remarkably improved outcomes in patients with these formerly fatal syndromes. Red cell transfusions are imperative for life-threatening anemia. Treatment is usually continued until the platelet count is > 150,OOO/�L. Unfortunately, relapses are common. Additionally, there may be long-term sequelae such as renal impairment (Dashe, 1998; Vesely, 2015). Treatment for pregnancy-associated HUS, which is complement mediated, uses the anti-C5 humanized monoclonal antibody eculizumab (Ardissino, 2013; Caiigral, 2014; Fakhouri, 2016).

As shown in the Appendix (p. 1256), ADAMTS13 enzyme activity decreases across pregnancy by up to 50 percent (S8nchez-Luceros, 2004). Levels drop even further with the preeclampsia syndrome. his is consonant with prevailing opinions that TTP is more commonly seen during pregnancy. he Parkland Hospital experiences were described by Dashe and coworkers (1998), who identified 11 pregnancies complicated by these syndromes among nearly 275,000 obstetrical patients-a frequency of 1 in 25,000.

I t seems likely that some of the disparately higher incidence in pregnancy reported by others is because of inclusion of women with severe preeclampsia and eclampsia (Hsu, 1995; Magann, 1994). Diferences that usually allow appropriate diagnosis are listed in Table 56-6. For example, moderateto-severe hemolysis is a rather constant feature of thrombotic microangiopathies. But, this is seldom severe with the preeclampsia syndrome, even when complicated by HELLP syndrome (Chap. 40, p. 719). And, although there is deposition of hyaline micro thrombi within the liver with thrombotic microangiopathy, hepatocellular necrosis with elevated serum hepatic aminotransferase levels characteristic of preeclampsia is not a common feature (Ganesan, 2011; Sadler, 2010). Importantly, whereas delivery is imperative to reverse the preeclampsia syndrome, no evidence shows that thrombotic microangiopathy is improved by delivery (Dashe, 1998; Letsky, 2000). Finally, microangiopathic syndromes are usually recurrent and frequently unassociated with pregnancy. For example, seven of 11 women described by Dashe and colleagues (1998) had recurrent disease either when not pregnant or within the first trimester of a subsequent pregnancy. George (2009) reported recurrent TTP in only five of 36 subsequent pregnancies. That said, the risk for preeclampsia in these women is increased Giang,r2014).

Unless the diagnosis is unequivocally one of these thrombotic microangiopathies, rather than severe preeclampsia, the

TABLE 56-6. Some Differential Factors between HELLP Syndrome and Thrombotic Microangiopathiesa

Thrombocytopenia Mild/mod. Mod/severe

ADAMTS 1 3 def. Mild/mod. Severe (AST, ALT) hemolytic uremic syndrome (HUS).

ADAMTS 13 = ADAM metallopeptidase with thrombospondin type 1 motif, 13; AST = aspartate transaminase; ALT = alanine transaminase; def. = deficiency; DIC = disseminated intravascular coagulopathy; HELLP = hemolysis, elevated liver enzyme levels, low platelet count; Mod. = moderate.

response to pregnancy termination should be evaluated before resorting to plasmapheresis and exchange transfusion, massivedose glucocorticoid therapy, or other therapy. Unfortunately, recall that determination of ADAMTS13 enzyme activity may be diicult to interpret with HELLP syndrome (Franchini, 2007). Plasmapheresis is not indicated or preeclampsia-eclampsia complicated by hemoysis and thrombocytopenia.

During the past two decades, and coincidental with plasmapheresis and plasma exchange, maternal survival rates from thrombotic micro angiopathy have improved dramatically (Dashe, 1998). Although previously fatal in up to half of mothers, with such treatment, Egerman and coworkers (1996) reported two maternal and three fetal deaths in 11 pregnancies. Hunt and associates (2013) reported that TTP accounted for 1 percent of maternal deaths in the United Kingdom from 2003 to 2008.

Women who are diagnosed with thrombotic micro angiopathy during pregnancy are at risk for serious long-term complications (Egerman, 1996). he Parkland experiences included a mean 9-year surveillance period (Dashe, 1998). hese women had multiple recurrences; renal disease requiring dialysis, transplantation, or both; severe chronic hypertension; and transfusion-acquired infectious diseases. Two women died remote from pregnancy-one from dialysis complications and one from transfusion-acquired HIV infection.

In nonpregnant women who have recovered from thrombotic microangiopathies, persistent cognitive defects and physical disabilities have been reported (Kennedy, 2009; Lewis, 2009). Interestingly, as discussed in Chapter 40 (p. 745), these cognitive defects are very similar to those found in long-term surveillance studies of women who had eclampsia (Aukes, 2009,r2012; Wiegman, 2012).

Obstetrical hemorrhage may infrequently be the consequence of an inherited defect in a protein that controls coagulation.

Both types of hemophilia are examples. Severity reflects plasma factor levels and is categorized as mild-levels of 6 to 30 per cent; moderate-2 to 5 percent; or severe-less than 1 percent (Arruda, 2015).

Hemophilia A is an X-linked recessively transmitted disorder characterized by a marked deiciency of factor VIII. It is rare among women compared with men, in whom the heterozygous state is responsible for the disease. Heterozygous women have diminished factor VIII levels, but almost invariably, the homozygous state is requisite for hemophilia A. In a few instances, it appears in women spontaneously from a newly mutated gene. Pregnancy-associated acquired hemophilia A from antibodies may result in severe bleeding-related morbidity (Tengborn, 2012). Christmas disease or hemophilia B is caused by severe deiciency of factor IX and has similar genetic and clinical features.

he risk of obstetrical bleeding with these is directly related to factor VIII or IX levels. Afected women have a range of activity that is determined by random X-chromosome inactivation-Iyonization-although activity is expected to average 50 percent (Letsky, 2000). Levels below 10 to 20 percent pose hemorrhage risks. If levels fall to near zero, this risk is substantial. Pregnancy does aford some protection, however, because concentrations of both these clotting factors rise appreciably during normal pregnancy (Appendix, p. 1256). Treatment with desmopressin may also stimulate factor VIII release. Risks are further reduced by avoiding lacerations, minimizing episiotomy use, and maximizing postpartum uterine contractions. Operative vaginal deliveries should be avoided.

here are few published experiences during pregnancy.

Kadir and coworkers (1997) reported that 20 percent of carriers had postpartum hemorrhage. Guy and associates (I992) reviewed five pregnancies in women with hemophilia B, and in all, outcomes were favorable. They recommended factor IX administration if levels are below 10 percent. Desmopressin has been shown in selected cases to reduce obstetrical bleeding complications (Trigg, 2012).

If a male fetus has hemophilia, the risk of hemorrhage increases after delivery in the neonate. his is especially true if circumcision is attempted.

If a mother has hemophilia A or B, all of her sons will have the disease, and all of her daughters will be carriers. If she is a carrier, half of her sons will inherit the disease, and half of her daughters will be carriers. Prenatal diagnosis of hemophilia is possible in some families using chorionic villus biopsy (Chap. 14, p. 293).

Preimplantation genetic diagnosis for hemophilia was reviewed by Lavery (2009).

Rarely, antibodies directed against factor VIII or IX are acquired and may lead to life-threatening hemorrhage. Patients with hemophilia more commonly develop antibodies, and their acquisition in patients without hemophilia is extraordinary. It has been identified rarely in women during the puerperium (Santoro, 2009). he prominent clinical feature is severe, protracted, repetitive hemorrhage from the reproductive tract starting a week or so after an apparently uncomplicated delivery (Gibson, 2016). he activated partial thromboplastin time is markedly prolonged. Treatment has included multiple transfusions of blood component, immunosuppressive therapy, and attempts at various surgical procedures, especially curettage and hysterectomy. A recombinant activated factor VII (NovoSeven) stops bleeding in up to 75 percent of patients with these inhibitors (Arruda, 2015; Gibson, 2016).

here are at least 20 heterogeneous clinical disorders involving aberrations of factor VIII complex and platelet dysfunctioncollectively termed von Willebrand disease (vWD). hese abnormalities are the most frequently inherited bleeding disorders, and their prevalence is as high as 1 to 2 percent (Arruda, 2015; Pacheco, 2010). Most von Willebrand variants are inherited as autosomal dominant traits, and types I and II are the most common. Speciically, type I accounts for 75 percent of von Willebrand variants. Type III, which is the most severe, is a recessive trait. lthough most cases of acquired vWD develop after age 50 years, some have been reported in pregnant women (Lip kind, 2005).

he von Wilebrand actor is a series of large plasma multimeric glycoproteins that form part of the factor VIII complex. It is essential for normal platelet adhesion to subendothelial collagen and formation of a primary hemostatic plug. It also plays a major role in stabilizing the coagulant properties of factor VIII. he procoagulant component is factor VIII, a glycoprotein synthesized by the liver. Conversely, von Willebrand precursor, which is present in platelets and plasma, is synthesized by endothelium and megakaryocytes. he von Willebrand factor antigen (vWF:Ag) is the antigenic determinant measured by immunoassays.

Symptomatic patients typically present with easy bruising, epistaxis, mucosal hemorrhage, and excessive bleeding with trauma, including surgery. he classic autosomal dominant forms usually cause symptoms in the heterozygous state. With vWD, laboratory features often include a prolonged bleeding time, prolonged partial thromboplastin time, decreased vWF antigen levels, decreased factor VIII immunological and coagulation-promoting activity, and inability of platelets from an afected person to react to various stimuli.

During normal pregnancy, maternal levels of both factor VIII and vWF antigen increase substantively (Appendix, p. 1256). Because of this, pregnant women with vWD often develop normal levels of factor VIII coagulant activity and vWF antigen, although their measured bleeding time still may be prolonged. If factor VIII activity is very low or if there is bleeding, treatment is recommended. Desmopressin by infusion transiently increases factor VIII and vWF levels (Arruda, 2015; Kujovich, 2005). With signiicant bleeding, 15 or 20 units of cryoprecipitate are transfused every 12 hours. Alternatively, factor VIII concentrates (Alfanate, Hemate-P) may be given that contain high-molecular-weight vWF multimers. Lubetsky and colleagues (1999) described continuous infusion with Hemate-P in a woman during a vaginal delivery. According to Chi and coworkers (2009), conduction analgesia can be provided safely if coagulation defects have normalized or if hemostatic agents are administered prophylactically.

Pregnancy outcomes in women with vWD are generally good, but postpartum hemorrhage is encountered in up to half of cases. In a fourth of 38 cases summarized by Conti and associates (1986), bleeding was reported with abortion, with delivery, or in the puerperium. Kadir and coworkers (1998) reported their experiences with 84 pregnancies. They described a 20-percent incidence of immediate postpartum hemorrhage and another 20-percent incidence of late hemorrhage. Most cases were associated with low vWF levels in untreated women, and none given treatment peripartum had hemorrhage. More recently, Stoof and colleagues (2015) reviewed 185 deliveries in 154 afected women and found the risk for postpartum hemorrhage to be highest in deliveries with lowest factor levels.

Although most patients with vWD have heterozygous variants and associated minor bleeding complications, the disease can be severe. Moreover, homozygous ofspring develop serious clotting dysfunction. Chorionic villus sampling with DNA analysis to detect the missing genes has been described. Some authorities recommend cesarean delivery to avoid trauma to a possibly afected fetus if the mother has severe disease.

In general, the activity of most procoagulant factors rises across pregnancy (Appendix, p. 1256). Factor VII deiciency is a rare autosomal recessive disorder. Levels of this factor normally increase during pregnancy, but these may rise only mildly in women with factor VII deficiency (Fadel, 1989). A systematic review of 94 births found no diference in postpartum hemorrhage rates with or without prophylaxis with recombinant factor VIla (Baumann Kreuziger, 2013).

Factor X or Stuart-Prower actor deiciency is rare and is inherited as an autosomal recessive trait. Factor X levels typically rise by 50 percent during normal pregnancy. Konje and colleagues (1994) described a woman who had 2-percent factor activity. She was given prophylactic treatment with plasmaderived factor X, which raised her plasma levels to 37 percent. Despite this, she sufered an intrapartum placental abruption.

plasma to a woman with less than I-percent factor X activity.

She delivered spontaneously without incident. Beksa: and asso ciates (20r10) described a woman with severe factor X deiciency who was successfully managed with prophylactic prothrombin complex concentrate. Nance and colleagues (2012) reported on 24 pregnancies, of which 18 resulted in a healthy baby.

Factor I-plasma thromboplastin antecedent-diciency is inherited as an autosomal trait. It manifests as severe disease in homozygotes but only as a minor defect in heterozygotes. It is most prevalent in Ashkenazi Jews and is rarely seen in pregnancy. Musclow and coworkers (1987) reported 41 deliveries in 17 afected women, and none required transfusion. In 105 pregnancies from 33 afected women, Myers and colleagues (2007) reported an uneventful pregnancy and delivery in 70 percent. hey recommended peripartum treatment with factor XI concentrate if cesarean delivery is performed and advised against epidural analgesia unless factor XI is given. From their review, Martin-Sakes and associates (2010) found that factor XI levels and bleeding severity correlated poorly in women with severe deiciency. Wiewel-Verschueren and colleagues (2015) performed a systematic review of 27 studies with 372 women and reported that 18 percent had postpartum hemorrhage.

Factor II diciency is another autosomal recessive disorder that rarely complicates pregnancy. A greater incidence of thromboembolism is encountered in nonpregnant patients with this deficiency. Lao and coworkers (1991) reported an afected pregnant woman in whom placental abruption developed at 26 weeks' gestation.

Factor III diciency is an autosomal recessive trait and may be associated with maternal intracranial hemorrhage (Letsky, 2000). In their review, Kadir and associates (2009) cited an increased risk of recurrent miscarriage and placental abruption. It has also been reported to cause umbilical cord bleeding (Odame, 2014). Treatment is fresh frozen plasma. Naderi and colleagues (2012) described 17 successful pregnancies in women receiving weekly prophylaxis with Factor XIII concentrate.

Fibrinogen abnormalities-either qualitative or quantitativealso may cause coagulation abnormalities. Autosomally inherited abnormalities usually involve the formation of a functionally defective ibrinogen-commonly referred to as dyibrinogenemia (Edwards, 2000). Familial hypoibrinogenemia and sometimes aibrinogenemia are infrequent recessive disorders. In some cases, both are found-hypodysibrinogenemia (Deering, 2003). Our experience suggests that hypoibrinogenemia represents a heterozygous autosomal dominant state. he thrombinclottable protein level in these patients typically ranges from 80 to 110 mg/ dL when nonpregnant, and this increases by 40 or 50 percent in normal pregnancy. Those pregnancy complications that give rise to acquired hypoibrinogenemia, such as placental abruption, are more common with ibrinogen deiciency. Trehan and Fergusson (1991) and Funai and coworkers (1997) described successful outcomes in two afected women in whom ibrinogen or plasma inusions were given throughout pregnancy.

Conduction Analgesia with Bleeding Disorders

Most serious bleeding disorders would logically preclude the use of epidural or spinal analgesia for labor or delivery. If the bleeding disorder is controlled, however, conduction analgesia may be considered. Chi and colleagues (2009) reviewed intrapartum outcomes in 80 pregnancies in 63 women with an inherited bleeding disorder. These included those with factor XI deiciency, hemophilia carrier status, vWD, platelet disorders, or a deiciency of factor VII, Xl, or X. Regional block was used in 41. Of these, 35 had spontaneously normalized hemostatic dysfunction, and others were given prophylactic replacement therapy. The reviewers reported no unusual complications. Singh and associates (2009) reviewed 13 women with factor XI deiciency. Nine received neuraxial analgesia without complications, but only after fresh-frozen plasma was transfused to most to correct the activated partial thromboplastin time.

Several important regulatory proteins act as inhibitors at strategic sites in the coagulation cascade to maintain blood fluidity. Inherited deiciencies of these inhibitory proteins are caused by gene mutations. Because they may be associated with recurrent thromboembolism, they are collectively referred to as thrombophilias. These are discussed in Chapter 52 (p. 1005) and reviewed by the American College of Obstetricians and Gynecologists (2017b).

Aessopos A, Karabatsos F, Farmakis D, et al: Pregnancy in patients with welltreated 3-thalassemia: outcome for mothers and newborn infants. Am J Obstet Gynecol 180:360, 1999

American College of Obstetricians and Gynecologists: Hemoglobinopathies in pregnancy. Practice Bulletin No. 78, January 2007, Reairmed 2015 American College of Obstetricians and Gynecologists: Neural tube defects. Practice Bulletin No. 44, July 2003, Reairmed 2016a

American College of Obstetrics and Gynecologists: Prenatal diagnostic testing for genetic disorders. Practice Bulletin No. 162, May 2016b

American College of Obstetricians and Gynecologists: hrombocytopenia in pregnancy. Practice Bulletin No. 166, September 20t16c

American College of Obstetricians and Gynecologists: Anemia in pregnancy.

Practice Bulletin No. 95, July 2008, Reairmed 2017a

American College of Obstetricians and Gynecologists: Inherited thrombophilias in pregnancy. Practice Bulletin No. 138, September 2013, Reaffirmed 20t17b

Anyaegbunam A, Morel MI, Merkatz IR: Antepartum fetal surveillance tests during sickle cell crisis. Am J Obstet Gynecol 165:1081, 1991

Ardissino G, Ossola MW, Bafero GM, et al: Eculizumab for atypical hemolytic uremic syndrome in pregnancy. Obstet Gynecol 122(2):487,t2013

Arruda VR, High A: Coagulation disorders. In: Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill Education, 2015

Asma S, Kozanoglu I, Tarim E, et al: Prophylactic red blood cell exchange may be beneficial in the management of sickle cell disease in pregnancy. Transfusion 55(1):36, 2015

Aster RH, Bougie DW: Drug-induced immune thrombocytopenia. N Engl J Med 357:580, 2007

Ataga U, Kutlar A, Kanter J, et al: Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med 376: 1796, 2017

Aukes AM, de Groot JC, Aarnoudse JG, et al: Brain lesions several years after eclampsia. Am J Obstet Gynecol 200:504.e1, 2009

Aukes AM, de Groot Jc, Wiegman MJ, et al: Long-term cerebral imaging after preeclampsia. BJOG 119(9):1117,t2012

Azulay CE, Pariente G, Shoham-Vardi I, et al: Maternal anemia during pregnancy and subsequent risk for cardiovascular disease. J Matern Fetal Neonatal Med 28(15):1762, 2015

Ballas SK, McCarthy WF, Guo N, et al: Multicenter study of hydroxyurea in sickle cell anemia. Exposure to hydroxyurea and pregnancy outcomes in patients with sickle cell anemia. J Natl Med Assoc 101t(10):1046,t2009

Baumann Kreuziger LM, Morton CT, Reding MT: Is prophylaxis required for delivery in women with factor VII deficiency? Haemophilia 19(6):827, 2013

Beard J, Hillmen P, Anderson CC, et al: Primary thrombocythaemia in pregnancy. Br J Haematol 77:371, 1991

Beksa: 'IS, Atak Z, Ozlii T: Severe factor X deiciency in a twin pregnancy. Arch Gynecol Obstet 281(1):151,s2010

Benites BD, Benevides TC, Valente IS, et al: he efects of exchange transfusion for prevention of complications during pregnancy of sickle hemoglobin C disease patients. Transfusion 56(1):119, 2016

Benz EJ: Disorders of hemoglobin. In: Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal l1edicine, 19th ed. New York, McGraw-Hill Education, 2015

Berry SM, Leonardi MR, Wolfe HM, et al: Maternal thrombocytopenia. Predicting neonatal thrombocytopenia with cordocentesis. J Reprod Med 42:276, 1997

Bo L, Mei-Ying L, Yang Z, et al: Aplastic anemia associated with pregnancy: mater nal and fetal complications. J Matern Fetal Neonatal Med 29(7):1120,s2016

Boafor TK, Olayemi E, Galadanci N, et al: Pregnancy outcomes in women with sickle-cell disease in low and high income countries: a systematic review and meta-analysis. BJOG 123(5):691,2016

Bofill JA, Young A, Perry KG J r: Successful pregnancy in a woman with severe factor X deficiency. Obstet Gynecol 88:723, 1996

Boga C, Ozdogu H: Pregnancy and sickle cell disease: a review of the current literature. Crit Rev Oncol Hematol 98:364, 2016

Borgna-Pignatti C, Marradi P, Rugolotto S, et al: Successful pregnancy ater bone marrow transplantation for thalassaemia. Bone Marrow Transplant 18:235, 1996

Boulet SL, Okoroh EM, Azonobi I, et al: Sickle cell disease in pregnancy: maternal complications in a Medicaid-enrolled population. Matern Child Health J 17(2):200,2013

Bourantas K, Makrydimas G, Georgiou I, et al: Aplastic anemia: report of a case with recurrent episodes in consecutive pregnancies. J Reprod Med 42:672, 1997

Breymann C, Milman N, Mezzacasa A, et al: Ferric carboxymaltose vs. oral iron in the treatment of pregnant women with iron deiciency anemia: an international, open-label, randomized controlled trial (FER-ASAP). J Perinat Med 45(4):443,s2017 Briggs GG, Freeman RK: Drugs in Pregnancy and Lactation, 9th ed. Philadelphia, Lippincott Williams & Wilkins, 2015 Buonanno FS, Schmahmann JD, Romero JM, et al: Case 10-2016: A 22-yearold man with sickle cell disease, headache, and diiculty speaking. N Engl J Med 374:1265,s2016 Burrows F, Kelton JG: Fetal thrombocytopenia and its relation to maternal thrombocytopenia. N Engl J Med 329:1463, 1993 Camaschella C: Iron-deficiency anemia. N Engl J Med 372:1832, 2015 Camilleri RS, Cohen H, Mackie I, et al: Prevalence of the ADAMTS13 missense mutation R1060W in late onset adult thrombotic thrombocytopenic purpura. J hromb Haemost 6(2):331, 2007 Camous J, N'daA, Etienne-Julan M, et al: Anesthetic management of pregnant women with sickle cell diseases-efect on postnatal sickling complications. Can J Anaesth 55:276, 2008 Caiigral C, loscard6 F, Castro C, et al: Eculizumab for the treatment of pregnancy-related atypical hemolytic uremic syndrome. Ann Hematol 93(8):1421,s2014 Casadevall N, Natataf J, Viron B, et al: Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 346:469, 2002 Cavenee MR, Cox SM, Mason R, et al: Erythropoietin in pregnancies complicated by pyelonephritis. Obstet Gynecol 84:252, 1994 Celkan T, Alhaj S: Prenatal diagnosis of hereditary spherocytosis with osmotic fragility test. Indian Pediatr 45(1):63, 2008 Centers for Disease Control and Prevention: CDC criteria for anemia in children and childbearing-aged women. MMWR 38:400, 1989 Centers for Disease Control and Prevention: Recommendations to prevent and control iron deiciency in the United States. MMWR 47:1, 1998 Chakravarty EF, Khanna D, Chung L: Pregnancy outcomes in systemic sclerosis, primary pulmonary hypertension, and sickle cell disease. Obstet Gynecols1ll:927,2008 Charoenboon C, Jatavan P, Traisrisilp K, et al: Pregnancy outcomes among women with beta-thalassemia trait. Arch Gynecol Obstet 293(4):771,s2016 Chatwani A, Bruder N, Shapiro T, et al: May-Hegglin anomaly: a rare case of maternal thrombocytopenia in pregnancy. Am J Obstet Gynecols166: 143, 1992 Chi C, Lee CA, England A, et al: Obstetric analgesia and anaesthesia in women with inherited bleeding disorders. Thromb Haemost 101(6):1104, 2009 Choudhry P, Gupta S, Gupta M, et al: Pregnancy associated aplastic anemia-a series of 10 cases with review of literature. Hematology 7(4):233, 2002

Conti M, Mari D, Conti E, et al: Pregnancy in women with diferent types of vonWillebrand disease. Obstet Gynecol 68:282, 1986

Cox SM, Shelburne P, Mason R, et al: Mechanisms of hemolysis and anemia associated with acute antepartum pyelonephritis. Am J Obstet Gynecol 164:587, 1991

Cunningham FG, Cox SM, Harstad W, et al: Chronic renal disease and pregnancy outcome. Am J Obstet Gynecol 163:453, 1990

Cunningham FG, Nelson DB: Disseminated intravascular coagulation syndromes in obstetrics. Obstet GynecoIs126(5):999, 2015

Cunningham FG, Pritchard JA: Prophylactic transfusions of normal red blood cells during pregnancies complicated by sickle cell hemoglobinopathies. Am J Obstet Gynecol 135:994, 1979

Cunningham FG, Pritchard JA, Hankins GDV, et al: Idiopathic cardiomyopathy or compounding cardiovascular events. Obstet Gynecol 67: 157, 1986

Cunningham FG, Pritchard JA, Mason R: Pregnancy and sickle hemoglobinopathy: results with and without prophylactic transfusions. Obstet Gynecol 62:419, 1983

Curtis\1, Tepper NK, Jatlaoui TC, et al: U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR 65(3):1, 2016

Cyganek A, Pietrzak B, Kociszewska-Najman B, et al: Anemia treatment with erythropoietin in pregnant renal recipients. Transplant Proc 43(8):2970, 2011

Dafos F, Capella-Pavlovsky M, Forestier F: Fetal blood sampling during pregnancy with the use of a needle guided by ultrasound: a study of 606 consecutive cases. Am J Obstet GynecoIs153:655, 1985

Dalle JH: Hematopoietic stem cell transplantation in SCD. C R Bioi 336(3):148,s2013

Daru J, Cooper NA, Khan KS: Systematic review of randomized trials of the efect of iron supplementation on iron stores and oxygen carrying capacity in pregnancy. Acta Obstet Gynecol Scand 95(3):270, 2016

Dashe JS, Ramin SM, Cunningham FG: he long-term consequences of thrombotic microangiopathy (thrombotic thrombocytopenic purpura and hemolytic uremic syndrome) in pregnancy. Obstet Gynecol 91:662, 1998

Daskalakis GJ, Papageorgiou IS, Antsaklis AJ, et al: Pregnancy and homozygous beta thalassaemia major. BJOG 105:1028, 1998

DeBaun MR, Gordon M, McKinstry RC, et al: Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med 371 :699,2014

Decrooq J, Marcellin L, Le Ray C, et al: Rescue therapy with romiplostim for refractory primary immune thrombocytopenia during pregnancy. Obstet Gynecols124(2 pt 2 Suppl1):481, 2014

Deering SH, Landy HL, Tchabo N, et al: Hypodysibrinogenemia during pregnancy, labor, and delivery. Obstet Gynecol 101: 1092, 2003

De Gramont A, Krulik M, Debray J: Paroxysmal nocturnal haemoglobinuria and pregnancy. Lancet 1 :868, 1987 de Guibert S, Pefault de Latour R, et al: Paroxysmal nocturnal hemoglobinuria and pregnancy before the eculizumab era: the French experience. Haematologica 96(9):1276, 2011

Delage R, Demers C, Cantin G, et al: Treatment of essential thrombocythemia during pregnancy with interferon-.. Obstet Gynecol 87:814, 1996 DeLoughery TG: Microcytic anemia. N Engl J Med 371:1324,s2014 Deutsch R, Tomer A: Advances in megakaryocytopoiesis and thrombopoi esis: from bench to bedside. Br J HaematoIs161(6):778, 2013

Dhingra S, Wiener JJ, Jackson H: Management of cold agglutinin-immune hemolytic anemia in pregnancy. Obstet Gynecol 110:485,2007

Diz-Kii:iikkaya R, Chen J, Geddis A, et al: Thrombocytopenia. In Kaushansky K, Lichtman A, Beutler E, et al (eds): Williams Hematology, 8th ed. New York, McGraw-Hill, 2010

Dolan LM, Ryan M, Moohan J: Pyruvate kinase deiciency in pregnancy complicated by iron overload. BJOG 109:844,2002 Dotters-Katz SK, Grotegut CA, Heine P: The efects of anemia on pregnancy outcome with pyelonephritis. InfDis Obstet GynecoIs2013:780960, 2013

Drassinower D, Lavery JA, Friedman AM, et al: The efect of maternal haematoerit on ofspring IQ at 4 and years of age: a secondary analysis. BJOG 123(13),s2087,s2016

Edwards Z, Rijhsinghani A: Dysibrinogenemia and placental abruption. Obstet Gynecol 95: 1 043, 2000

Egerman RS, Witlin AG, Friedman SA, et al: hrombotic thrombocytopenic purpura and hemolytic uremic syndrome in pregnancy: review of 11 cases. Am J Obstet Gynecol 195:950, 1996

Eliyahu S, Shalev E: A successful pregnancy after bone marrow transplantation for severe aplastic anaemia with pretransplant conditioning of total Iymphnode irradiation and cyclophosphamide. Br J HaematoI86:649, 1994

Elstein D, Granovsky-Grisaru S, Rabinowitz R, et al: Use of enzyme replacement therapy for Gaucher disease during pregnancy. Am J Obstet Gynecol 177:1509,s1997

Fadel HE, Krauss JS: Factor VII deiciency and pregnancy. Obstet Gynecol 73:453, 1989

Faivre L, Meerpohl J, Da Costa L, et al: High-risk pregnancies in DiamondBlackfan anemia: a survey of 64 pregnancies from the French and German registries. Haematologica 91 :530, 2006

Fakhouri F: Pregnancy-related thrombotic microangiopathies: Clues from complement biology. Transfus Apher Sci 54(2):199, 2016

Fieni S, Bonfanti L, Gramellini 0, et al: Clinical management of paroxysmal nocturnal hemoglobinuria in pregnancy: a case report and updated review. Obstet Gynecol Surv 61:593,t2006

Finazzi G: How to manage essential thrombocythemia. Leukemia 26(5):875, 2012

Franchini M, Montagnana M, Targher G, et al: Reduced von Willebrand factor-cleaving protease levels in secondary thrombotic micro angiopathies and other diseases. Semin Thromb Hemost 33(8):787,t2007

Fujimori K, Ohto H, Honda S, et al: Antepartum diagnosis of fetal intracranial hemorrhage due to maternal Bernard-Soulier syndrome. Obstet Gynecol 94:817,t1999

Funai EF, Klein SA, Lockwood CJ: Successful pregnancy outcome in a patient with both congenital hypoibrinogenemia and protein S deiciency. Obstet Gynecol 90:858, 1997

Galanello R, Cao A: Alpha-thalassemia. In Pagon A, Bird TD, Dolan CR, et al (eds): GeneReviews. Seattle, University of Washington, 2011a Galanello R, Cao A: Gene test review. Alpha-thalassemia. Genet vIed 13(2):83, 201t1b

Gallagher PG: The red blood cell membrane and its disorders: hereditary spherocytosis, elliptocytosis, and related diseases. In Kaushansky K, lichtman MA, Beutler E, et al (eds): Williams Hematology, 8th ed. New York, McGraw-Hill,t201O

Gandhi SK, Powers JC, Nomeir AM, et al: he pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 344: ,t2000 Ganesan C, Maynard SE: Acute kidney injury in pregnancy: the thrombotic microangiopathies.t] Nephrol 24(5):554, 2011

Gangat N, Wolanskij AP, Schwager S, et al: Predictors of pregnancy outcomes in essential thrombocythemia: a single institution study of 63 pregnancies. Eurt] Haematol 82(5):350, 2009

Garratty G: Severe reactions associated with transfusion of patients with sickle cell disease. Transfusion 37:35 , 1997

Garratt)T G, Leger M, Arndt PA: Severe immune hemolytic anemia associated with prophylactic use of cefotetan in obstetric and gynecologic procedures. Am J Obstet Gynecol 181:103, 1999

George ]N: The thrombotic thrombocytopenic purpura and hemolytic uremic syndromes: overview of pathogenesis (experience of The Oklahoma TTPHUS Registry, 1989-2007). Kidney Int 75(112):S8, 2009

George ]N, Nester CM: Syndromes of thrombotic microangiopathy. N Engl ] Med 371:654, 2014

Gernsheimer T, James AH, Stasi R: How I treat thrombocytopenia in pregnancy. Blood 121(1):38,t2013

Gibson q, Berliner N, Miller AL, et al: A bruising loss. N Engl J Med 6, 2016

Gladwin �IT, Sachdev V, ]ison ML, et al: Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl ] Med 350:886, 2004

Gladwin MT, Vichinsky E: Pulmonary complications of sickle cell disease. N Engl ] Med 359:2254, 2008

Granovsky-Grisaru S, Aboulaia Y, Diamant YZ, et al: Gynecologic and obstetric aspects of Gaucher's disease: a survey of 53 patients. Am J Obstet Gynecol 172: 1284, 1995

Granovsky-Grisaru S, Belmatoug N, vom Dahl S, et l: The management of pregnancy in Gaucher disease. Eur J Obstet Gynecol Reprod Bioi 156(1):3, 2011 Green AM, Kupfer GM: Fanconi anemia. Hematol Oncol Clin North Am 23(2):193,t2009

Griesshammer M, Struve S, Harrison CM: Essential thrombocythemia/polycythemia vera and pregnancy: the need for an observational study in Europe. Semin Thromb Hemost 32:422, 2006

Grigoriadis C, Tympa A, Liapis A, et al: Alpha-methyldopa-induced autoimmune hemolytic anemia in the third trimester of pregnancy. Case Rep Obstet Gynecol 2013:150278, 2013

Grossetti E, Carles G, El Guindi W, et al: Selective prophylactic transfusion in sickle cell disease. Acta Obstet Gynecol 88: 1 090, 2009

Guy GP, Baxi LV, Hurlet-Jensen A, et al: An unusual complication in a gravida with factor IX deiciency: case report with review of the literature. Obstet Gynecol 80:502, 1992

Hachisuga K, Hidaka N, Fujita Y, et al: Can we predict neonatal thrombocytopenia in ofspring of women with idiopathic thrombocytopenic purpura? Blood Res 49(4):259,t2014

Haddad LB, Curtis KM, Legardy-Williams JK, et al: Contraception for individuals with sickle cell disease: a systematic review of the literature. Contraception 85(6):527,t2012

Hanprasertpong T, Kor-Anantakul 0, Leetanaporn R, et al: Pregnancy outcomes amongst thalassemia traits. Arch Gynecol Obstet 288(5):1051,t2013 Happe SK, Zofkie AC, Nelson DB: Microangiopathic hemolytic anemia due to malignancy in pregnancy. Obstet Gynecol 128:1437,t2016

Harrison C: Do we know more about essential thrombocythemia because of JAK2V617F? Curr Hematol Malig Rep 4(1):25, 2009

Henney MM, Hoppe Cc, Abboud MR, et al: A multinational trial of prasugrel for sickle cell vaso-occlusive events. N Engl] Med 374:625, 2016 Hesdorfer CS, Longo DL: Drug-induced megaloblastic anemia. N Englt] Med 373:1649,t2015

Hsieh F], Chang FM, Ko TM, et al: The antenatal blood gas and acid-base status of normal fetuses and hydropic fetuses with Bart hemoglobinopathy. Obstet Gynecol 74:722, 1989

Hsieh MM, Kang EM, Fitzhugh CD, et al: Allogenic hematopoietic stem-cell transplantation for sickle cell disease. N Engl] Med 361(24):2309, 2009

Hsu HW, Belfort MA, Vernino S, et al: Postpartum thrombotic thrombocytopenic purpura complicated by Budd-Chiari syndrome. Obstet Gynecol 85:839, 1995

Huhta ]C, Linask K: When should we prescribe high-dose folic acid to prevent congenital heart defects? Curr Opin Cardiol 30(1):125, 2015

Hunt BJ, Thomas-Dewing RR, Bramham K, et al: Preventing maternal deaths due to acquired thrombotic thrombocytopenic purpura. ] Obstet Gynaecol Res 39(1):347, 2013

Hurst D, Little B, Kleman M, et al: Anemia and hemoglobinopathies in Southeast Asian refugee children. J Pediatric 102:692, 1983

Hussein BA, Gomez K, Kadir A: May-Hegglin anomaly and pregnancy: a systematic review. Blood Coagul Fibrinolysis 24(5):554, 2013

Imbach P, Crowther M: hrombopoietin-receptor agonists for primary immune thrombocytopenia. N Engl J Med 365(8):734, 2011 ltalia Y, Jijina FF, Chandrakala S, et al: Exposure to hydroxyurea during pregnancy in sickle-beta thalassemia: a report of 2 cases. ] Clin Pharmacol 50(2):231,t2010

Jagannath VA, Fedorowicz Z, Al Hajeri A, et al: Hemaropoietic stem cell transplantation for people with �-thalassaemia major. Cochrane Database Syst Rev 10:CD008708, 2014

Jiang Y, MclntoshtJ], Reese JA, et al: Pregnancy outcomes following recovery from acquired thrombotic thrombocytopenic purpura. Blood 123(11): 1674, 2014

Kadir R, Chi C, Bolton-Maggs P: Pregnancy and rare bleeding disorders. Haemophilia 15(5):990,t2009

Kadir A, Economides DL, Braithwaite J, et al: The obstetric experience of carriers ofhaemophilia. B]OG 104:803, 1997

Kadir A, Lee CA, Sabin CA, et al: Pregnancy in women with von Willebrand's disease or factor XI deiciency. B]OG 105:314, 1998

Kelly RJ, Hochsmann B, Szer J, et al: Eculizumab in pregnant patients with paroxysmal noctunal hemoglobinuria. N Engl J Med 373(11):1032, 2015

Kemthong W, ]atavan P, Traisrisilp K, et al: Pregnancy outcomes among women with hemoglobin E trait. J Matern Fetal Neonatal Med 29(7): 1146, 2016

Kennedy AS, Lewis QF, Scott ]G, et al: Cognitive deicits after recover) from thrombotic thrombocytopenic purputa. Transfusion 49(6): 1 092,t2009 Kenny L, McCrae K, Cunningham FG: Platelets, coagulation, and the liver.

In Taylor RN, Roberts JM, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. London, Academic Press, 2015

Kidanto HL, Mogren I, Lindmark G, et al: Risks for preterm delivery and low birth weight are independently increased by severity of maternal anaemia. S Afr Med ] 99(2):98, 2009

Kihm AJ, Kong Y, Hong (1, et al: An abundant erythroid protein that stabilizes free alpha-haemoglobin. Nature 417(6890):758, 2002

Killick SB, Bown N, Cavenagh j, et al: Guidelines for the diagnosis and management of adult aplastic anaemia. Br] Haematol 172(2): 187, 2016

Kim DK, Bridges CB, Harriman KH, et al: Advisory Committee on Immunization Practices recommended immunization schedule for adults aged 19 years or older-United States, 2016. MMWR 65(4):88,t2016

Koenig MD, Tussing-Humphreys LT, Day J, et al: Hepcidin and iron homeostasis during pregnancy. Nutrients 6(8):3062,t2014

Konje ]C, Murphy P, de Chazal R, et al: Severe factor X deiciency and successful pregnancy. B]OG 101:910, 1994

Konkle BA: Disorder of platelets and vessel wall. In: Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill Education, 2015

Koshy M, Burd L, Wallace D, et al: Prophylactic red-cell transfusions in pregnant patients with sickle cell disease: a randomized cooperative study. N Engl J Med 319:1447,t1988

Koyama S, Tomimatsu T, Kanagawa T, et al: Reliable predictors of neonatal immune thrombocytopenia in pregnant women with idiopathic thrombocytopenic purpura. Am J Hematol 87(1):15, 2012

Krafft A, Perewusnyk G, Hanseler E, et al: Efect of postpartum iron supplementation on red cell and iron parameters in non-anaemic iron-deicient women: a randomized placebo-controlled study. BJOG 112:445,t2005

Kreher S, Ochsenreither S, Trappe RU, et al: Prophylaxis and management of venous thromboembolism in patients with myeloproliferative neoplasms: consensus statement of the haemostasis working party of the German Society of Hematology and Oncology (DGHO), the Austrian Society of Hematology and Oncology (OGHO) and Society of hrombosis and Haemostasis Research (GTHeV) 93(12):1953, 2014

Kujovich JL: Von Willebrand disease and pregnancy. J Thromb Haemost 3:246,t2005

Kumar KJ, Asha N, Murthy DS, et a1: Maternal anemia in various trimesters and its efect on newborn weight and maturity: an obsevational study. Int J Prev Med 4(2):193,t2013

Kumar R, Advani AR, Sharan J, et al: Pregnancy induced hemolytic anemia: an unexplained entity. Ann Hematol 80:623,t2001

Kuo K, Caughey AB: Contemporary outcomes of sickle cell disease in pregnancy. Am J Obstet Gynecol 215(4):505.el, 2016

Kuter DJ, Rummel M, Boccia R, et al: Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med 363(20): 1889, 2010 Kwon JY, Lee Y, Shin Je, et a1: Supportive management of pregnancy-associated aplastic anemia. Int J Gynecol Obstet 95: 115, 2006

Lam YH, Tang MHY, Lee CP, et al: Prenatal ultrasonographic prediction of homozygous type 1 alpha-thalassemia at 12 to 13 weeks of gestation. Am J Obstet Gynecol 180: 148, 1999

Lao TT, Lewinsky RM, Ohlsson A, et al: Factor XlI deficiency and pregnancy.

Obstet Gynecol 78:491, 1991

Larsen S, Bjelland EK, Haavaldsen C, et al: Placental weight in pregnancies with high or low hemoglobin concentrations. Eur J Obstet Gynecol Reprod BioI 206:48, 2016 Lavery S: Preimplantation genetic diagnosis of haemophilia. Br J Haematol 144(3):303,t2009 Lesage N, Deneux haraux C, Saucedo M, et a1: Maternal mortality among women with sickle-cell disease in France, 1996-2009. Eur J Obstet Gynecol Reprod BioI 194: 183, 2015 Letsky EA: Hematologic disorders. In Barron WvI, Lindheimer MD (eds):

Medical Disorders During Pregnancy, 3rd ed. St. Louis, Mosby, 2000 Leung Y, Lao TT: Thalassaemia in pregnancy. Best Pract Res Clin Obstet Gynaecol 26(1):37, 2012

Lewis QF, Lanneau MS, Mathias SO, et al: Long-term deicits in health-related quality of life after recovery from thrombotic thrombocytopenia purpura. Transfusion 49(1):118,t2009

Lin K, Barton MB: Screening for hemoglobinopathies in newborns: reairmation update for the U.S. Preventative Task Force. AHRQ Publication No 07-05104-EF-1,t2007

Lipkind HS, Kurtis JD, Powrie R, et al: Acquired von Willebrand disease: management of labor and delivery with intravenous dexamethasone, continuous factor concentrate, and immunoglobulin infusion. Am J Obstet Gynecol 192:2067,t2005

Lipton JM, Ellis SR: Diamond-Blackfan anemia: diagnosis, treatmenr, and molecular pathogenesis. Hematol Oncol Clin North Am 23(2):261, 2009 Lubetsky A, Schulman S, Varon D, et al: Safety and eicacy of continuous infusion of a combined factor VIII-von Willebrand factor (vWF) concentrate (Haemate-P) in patients with von Willebrand disease. hromb Haemost 81t:229,t1999 Luewan S, Srisupundit K, Tongsong T: Outcomes of pregnancies complicated by beta-thalassemia/hemoglobin E disease. Int J Gynaecol Obstet 104(3):203,t2009 Luewan S, Tongprasert F, Srisupundit K, et 1: Fetal myocardial performance (TeO index in fetal hemoglobin Bart's disease. Ultraschall Med 34(4):355, 2013 Luzzatto L: Hemolytic anemias and anemia due to blood loss. In: Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles ofInternal Medicine, 19th ed. New York, McGraw-Hili Education, 2015 Maberry Me, Mason A, Cunningham FG, et al: Pregnancy complicated by hemoglobin CC and C-beta-thalassemia disease. Obstet Gynecol 76:324, 1990 Maberry MC, Mason A, Cunningham FG, et al: Pregnancy complicated by hereditary spherocytosis. Obstet Gynecol 79:735, 1992 Magann EF, Bass D, Chauhan SP, et al: Antepartum corticosteroids: disease stabilization in patients with the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP). Am J Obstet Gynecol 171: 1148, 1994 Malinowski AK, Shehata N, D'Souza R. et al: Prophylactic transfusion for pregnant women with sickle cell disease: a systematic review and meta-analysis. Blood 126(21):2424,t2015 Marti-Carvajal AJ, Pen a-Marti GE, Comunian-Carrasco G, et al: Interventions for treating painful sickle cell crisis during pregnancy. Cochrane Database Syst Rev 1 :CD006786, 2009

Martin-Sakes M, Jimenez-Yuste VF Alvarez MT, et a1: Factor l deiciency: review and management in pregnant women. C1in Appl Thromb Hemost 16(2):209,t2010

Maymon R, Strauss S, Vaknin Z, et al: Normal sonographic values of maternal spleen size throughout pregnancy. Ultrasound Med BioI 32(12): 1827, 2006 McCoy JM, Stonecash E, Cournoyer 0, et 1: Epoetin-associated pure red cell aplasia: past, present, and future considerations. Transusion 48(8): 1754,2008

Medof BD, Shepard JO, Smith RN, et al: Case 17-2005: a 22-year-old woman with back and leg pain and respiratory failure. N Engl J Med 352:2425, 2005

Michael M, Elliott EJ, Ridley GF, et al: Interventions for haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura. Cochrane Database Syst Rev 1:CD003595, 2009

Miller DP, Kaye JA, Shea K, et a1: Incidence of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. Epidemiology 15:208, 2004

Moake JL: Thrombotic microangiopathies. N Engl J Med 347:589, 2002 .Moake JL: Von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura. Semin Hematol 41t:4, 2004

Mockenhaupt FP, Mandelkow J, Till H, et a1: Reduced prevalence of PLasmodium aciparum infection and of concomitant anaemia in pregnant women with heterozygous G6PD deiciency. Trop Med Int Health 8: 118, 2003

Moise KJ Jr: Umbilical cord stem cells. Obstet Gynecol 106:1393,2005 Mujica-Coopman MF, Brito A, Lopez de Romana 0, et a1: Prevalence of Anemia in Latin America and the Caribbean. Food Nutr Bull 36(2 Suppl):Sl19,

Murphy JF, O'Riordan J, Newcombe RG, et al: Relation of haemoglobin levels in irst and second trimester to outcome of pregnancy. Lancet 1 :992, 1986 Musclow CE, Goldenberg H, Bernstein EP, et al: Factor XI deiciency presenting as hemarthrosis during pregnancy. Am J Obstet Gynecol 157: 178, 1987

Myers B, Pavorod S, Kean L, et al: Pregnancy outcome in Factor Xl deiciency: incidence of miscarriage, antenatal and postnatal haemorrhage in 33 women with Factor Xl deiciency. BJOG 114:643,t2007

Naderi M, Eshghi P, Cohan N, et al: Successful delivery in patients with FXlII deiciency receiving prophylaxis: report of 17 cases in I ran. Haemophilia 18(5):773,t2012

Nagel RL, Fabry ME, Steinberg MH: he paradox of hemoglobin SC disease.

Blood Rev 17(3):16,t,t2003

Nance 0, Josephson NC, Paulyson-Nunez K, et al: Factor X deiciency and pregnancy: preconception counselling and therapeutic options. Haemophilia 18(3):e277, 2012

Nelson DB, Yost NP, Cunningham FG: ACLlte fatty liver of pregnancy: clinical outcomes and expected duration of recovery. Am J Obstet Gynecol 209: I. el,t2013

Neunert C, Lim W, Crowther M, et al: The American Society of Hematology 201t1 evidence-based practice guideline for immune thrombocytopenia. Blood 117(16):4190,t2011

Ngo e, Kayem G, Habibi A, et al: Pregnancy in sickle cell disease: maternal and fetal outcomes in a population receiving prophylactic partial exchange transfusions. Eur J Obstet Gynecol Reprod Bioi 152(2): 138, 2010

Niitvuopio R, Juvonen E, Kaaja R, et a1: Pregnancy in essential thrombocythaemia: experience with 40 pregnancies. Eur J Haematol 73:431, 2004 Odame JE, Chan AK, Breakey VR: Factor XlII deiciency management: a review of the literatre. Blood Coagul Fibrinolysis 25(3): 199, 2014

Okusayna BO, Oladapo OT: Prophylactic versus selective blood transfusion for sickle cell disease in pregnancy. Cochrane Database Syst Rev 12:CD010378, 2013

Olnes MJ, Scheinberg P, Calvo KR, et al: Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med 367(1):11, 2012

Orfali A, Ohene-Abuakwa Y, Ball SE: Diamond Blackfan anaemia in the UK: clinical and genetic heterogeneity. Br J Haematol 125(2):243,t2004

Oringanje e, Nemecek E, Oniyangi 0: Hematopoietic stem cell transplantation for children with sickle cell disease. Cochrane Database Syst Rev 5:CD007001, 2013

Oteng-Ntim E, Meeks 0, Seed PT, et a1: Adverse maternal and perinatal outcomes in pregnant women with sickle cell disease: systematic review and meta-analysis. Blood 125(21):3316,t2015

Pacheco LD, Constantine MM, Saade GR: von Willebrand disease and pregnancy: a practical approach for the diagnosis and treatment. m J Obstet GynecoIt203(3):194,t2010

Pajor A, Lehoczky 0, Szakics Z: Pregnancy and hereditary spherocytosis. Arch Gynecol Obstet 253:37, 1993

Parker e, Omine M, Richards S, et al: Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood 106:3699,t2005

Payne SO, Resnik R, Moore TR, et al: Maternal characteristics and risk of severe neonatal thrombocytopenia and intracranial hemorrhage in pregnancies complicated by autoimmune thrombocytopenia. Am J Obstet Gynecol 177(1):149,t1997

Peitsidis P, Datta T, Pailis I, et al: Bernard-Soulier syndrome in pregnancy: a systematic review. Haemophilia 16(4):584,t2010

Pena-Rosas ]P, De-Regil LM, Gomez Malave H, et al: Intermittent oral iron supplementation during pregnancy. Cochrane Database Syst Rev 10: CD009997,t2015

Peng TC, Kidder TS, Bell WR, et al: Obstetric complications in a patient with Benard-Soulier syndrome. Am J Obstet Gynecol 165:425, 1991

Peyandi F, Scully M, Kremer Hovinga JA, et al: Caplacizumab for acquired thrombotic thrombocytopenic purpura. N Engl] Med 374:511, 2016

Piel FB, Weatherall 0]: he .-halassemias. N Engl J Med 371:20, 2014 Pinto FO, Roberts I: Cord blood stem cell transplantation for haemoglobinopathies. Br J Haematol 141t(3):309,t2008 Platt OS: Hydroxyurea for the treatment of sickle cell anemia. N Engl ] Med 358: 1362, 2008 Prabu P, Parapia LA: Bernard-Soulier syndrome in pregnancy. C1in Lab Haem 28:198,t2006

Pritchard JA, Scott DE, Whalley P], et al: The efects of maternal sickle cell hemoglobinopathies and sickle cell trait on reproductive performance. Am J Obstet Gynecol 117:662, 1973

Provan 0, Weatherall 0: Red cells II: acquired anaemias and polycythaemia.

Lancet 355: 1260, 2000

Puig A, Dighe AS: Case 20-2013: a 29-year-old man with anemia and jaundice. N Engl J Med 368(26):2502, 2013

Rabinerson 0, Fradin Z, Zeidman A, et al: Vulvar hematoma after cunnilingus in a teenager with essential thrombocythemia: a case report. J Reprod Med 52:458, 2007

Rac MW, Crawford NM, Worley KC: Extensive thrombosis and irst-trimester pregnancy loss caused by sticky platelet syndrome. Obstet Gynecol 117(2 part 2):501,t2011

Ramin SM, Vidaef AC, Yeomans ER, et al: Chronic renal disease in pregnancy. Obstet Gynecol 108: 1531, 2006

Randi ML, Barbone E, Rossi C, et al: Essential thrombocythemia and pregnancy. A report of six normal pregnancies in ive untreated patients. Obstet Gynecol 83:915, 1994

Randi ML, Bertozzi I, Rumi E, et al: Pregnancy complications predict thrombotic events in young women with essential thrombocythemia. Am J Hematol 89(3):306, 2014

Ray JG, Burrows RF, Ginsberg JS, et al: Paroxysmal nocturnal hemoglobinuria and the risk of venous thrombosis: review and recommendations for management of the pregnant and nonpregnant patient. Haemostasis 30(3):103, 2000

Rees DC, Olujohungbe AD, Parker NE, et al: Guidelines for the management of the acute painful crisis in sickle cell disease. Br] HaematoIt120:744, 2003 Rencic J, Zhou M, Hsu G, et a1:

Circling back for the diagnosis. N Engl J Med 8,t2017

Riebeil J-A, Hacein-Bey-Abina S, Payen E, et al: Gene therapy in a patient with sickle cell disease. N Englt] Med 376:848,t2017

Rink BD, Gonik B, Chmait RH, et al: Maternal hemolysis after intravenous immunoglobulin treatment in fetal and neonatal alloimmune thrombocytopenia. Obstet Gynecol 121(2 Pt 2 Suppl 1):471,t2013

Robinson S, Bewley S, Hunt BJ, et al: he management and outcome of 18 pregnancies in women with polycythemia vera. Haematol 90: 1477,t2005 Rogers DT, Molokie R: Sickle cell disease in pregnancy. Obstet Gynecol C1in

North Am 37(2):223, 2010

Rosenfeld S, Follmann 0, Nunez 0, et al: Antithymocyte globulin and cyclosporine for severe aplastic anemia: association between hematologic response and long-term outcome. JAMA 289: 1130, 2003

Ru Y, Pressman EK, Cooper EM, et al: Iron deiciency and anemia are prevalent in women with multiple gestations. Am J Clin Nutr 104(4):1052,2016

Rukuni R, Bhattachalya S, Murphy MF, et al: Matenal and neonatal outcomes of antenatal anemia in a Scottish population: a retrospective cohort study. Acta Obstet Gynecol Scand 95(5):555,t2016

Sadler ]E, Ponca M: Antibody-mediated thrombotic disorders: thrombotic disorders: thrombotic thrombocytopenic purpura and heparin-induced thrombocytopenia. In Kaushansky K, Lichtman MA, Beuder E, et al (eds):

Williams Hematology, 8th ed. New York, McGraw-Hill, 2010

Sanchez-Luceros A, Farias CE, Amaral MM, et al: von Willebrand factorcleaving protease (ADAMTS 13) activity in normal non-pregnant women, pregnant and post-delivery women. Thromb Haemost 92(6): 1320, 2004

Sanders JE, Hawley J, Levy W, et al: Pregnancies following high-dose cyclo phosphamide with or without high-dose busulfan or total body irradiation and bone marrow transplantation. Blood 87:3045, 1996

Santoro RC, Prejano S: Postpartum-acquired haemophilia A: a description of three cases and literature review. Blood Coagul Fibrinolysis 20(6):461, 2009

Scanlon KS, Yip R, Schieve LA, et al: High and low hemoglobin levels during pregnancy: diferential risk for preterm birth and small for gestational age. Obstet Gynecol 96:741t, 2000

Scaradavou A: HIV-related thrombocytopenia. Blood Rev 16:73,t2002

Scott JR, Rote NS, Cruikshank DP: Antiplatelet antibodies and platelet counts in pregnancies complicated by autoimmune thrombocytopenic purpura. Am] Obstet Gynecol 145:932, 1983

Sheiner E, Levy A, Yerushalmi R, et al: Beta-thalassemia minor during pregnancy. Obstet Gynecol 103: 1273, 2004

Shenoy S: Umbilical cord blood: an evolving stem cell source for sickle cell disease transplants. Stem Cells Transl Med 2(5):337, 2013

Shi Q, Leng W, Wazir R, et al: Intravenous iron sucrose versus oral iron in the treatment of pregnancy with iron deiciency anaemia: a systematic review. Gynecol Obstet 80(3): 170, 2015

Shirel T, Hubler CP, Shah R, et al: Matenalopioid dose is associated with neonatal abstinence syndrome in children born to women with sickle cell disease. Am] Hematol 91(4):416, 2016

Singh A, Hanett MJ, Connors JM, et al: Factor Xl deiciency and obstetrical anesthesia. Anesth Analg 108: 1882, 2009

Sirichotiyakul S, Saetung R, Sanguansermsri T: Prenatal diagnosis of beta-thalassemia/Hb E by hemoglobin typing compared to DNA analysis. Hemoglobin 33(1):17, 2009

Spivak JL: Polycythemia vera and other myeloproliferative neoplasms. In:

Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles ofInternal Medicine, 19th ed. New York, McGraw-Hill Education, 2015

Srivorakun H, Fucharoen G, Sae-Ung N, et al: Analysis of fetal blood using capillaty electrophoresis system: a simple method for prenatal diagnosis of severe thalassemia diseases. Eur J Haematol 9, 2009 Stabler SP: Vitamin BI2 deiciency. N Engl J Med 368(2):149, 2013

Stalder MP, Rovo A, Halter J, et al: Aplastic anemia and concomitant autoimmune diseases. Ann Hematol 88(7):659, 2009

Starksen NF, Bell WR, Kicler TS: Unexplained hemolytic anemia associated with pregnancy. Am J Obstet Gynecol 146:617, 1983

Stevens GA, Finucane M 1, De-Regil LM, et a1: Global, regional, and national trends in haemoglobin concentration and prevalence of total and severe anaemia in children and pregnant and nonpregnant women for 1995-2011: a systematic analysis of population-representation data. Lancet Glob Health 1:e16, 2013

StoofSC, van Steenbergen HW, Zwagemaker A, et al: Primary postpartum haemorrhage in women with von Willebrand disease or carriership of haemophilla despite specialized care: a retrospective survey. Haemophillia 21(4):505,2015

Teferi A, Soldberg LA, Silverstein MN: A clinical update in polycythemia vera and essential thrombocythemia. Am J Med 109: 141, 2000

Tengborn L, Baudo F, Hurh-Klihne A, et al: Pregnancy-associated acquired haemophilia A: results from the European Acquired Haemophilia (EACH2) registry. B]OG 119(12):1529,t2012

Tita AT, Biggio ]R, Chapman V, et al: Perinatal and maternal outcomes in women with sickle or hemoglobin C trait. Obstet Gynecol 110: 1113, 2007 Townsley OM, Scheinberg P, Winkler T, et al: Eltrombopag added to standard immunosuppression for aplastic anemia. N Engl J Med 6:1540,t2017

Tran TO, Tran T, Simpson JA, et al: Infant motor development in rural Vietnam and intrauterine exposures to anaemia, iron deiciency and common mental disorders: a prospective community-based study. BMC Pregnancy Childbirth 14:8,t2014

Trehan AK, Fergusson ILC: Congenital aibrinogenaemia and successful pregnancy outcome. Case report. B]OG 98:722, 1991

Trigg DE, Stergiotou I, Peitsidis P, et al: A systematic review: the use of desmopressin for treatment and prophylaxis of bleeding disorders in pregnancy. Haemophilia 18(1):25,t2012

Tsaras G, Owusu-Ansah A, Boateng FO, et al: Complications associated with sickle cell trait: a brief narrative review. Am] Med 122(6):507,t2009

Tuck SM, Studd ]W, White JM: Pregnancy in women with sickle cell trait.

B]OG 90:108, 1983

Tuner ]M, Kaplan JB, Cohen HW, et a1: Exchange versus simple transfusion for acute chest syndrome in sickle cell anemia adults. Transfusion 49(5):863, 2009 Urato AC, Repke JT: May-Hegglin anomaly: a case of vaginal delivery when both mother and fetus are afected. Am J Obstet Gynecol 179:260, 1998

Vandevijvere S, Amsalkl1ir S, Oyen HV, et al: Iron status and its determinants in a nationally representative sample of pregnant women. J Acad Nutr Diet 113(5):659,t2013

Vannucchi AM, Kiladjian J], Griesshammer M, et al: Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med 372:426, 20t15

Veille J, Hanson R: Left ventricular systolic and diastolic function in pregnant patients with sickle cell disease. Am] Obstet Gynecol 170: 1 07, 1994

Verstraete S, Verstraete R: Successful epidural analgesia for a vaso-occlusive crisis of sickle cell disease during pregnancy: a case report. J Anesth 26(5):783,t2012 Vesely SK: Life ater acquired thrombotic thrombocytopenic purpura: morbidity mortality, and risks during pregnancy.] hrom Haemost 13 Supplt1 :S216, 2015 Vichinsky EP, Neumayr LD, Earles AN, et al: Causes and outcomes of the acute chest syndrome in sickle cell disease. N Engl J Med 342:1855, 2000

Villers MS, Jamison MG, De Castro LM, et al: Morbidity associated with sickle cell disease in pregnancy. m) Obstet Gynecol 199: 125.e 1, 2008

Vlachos A, Ball S, Dahl N, et al: Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference. Br) Haematol 142(6):859,t2008 von Tempelhof GF, Heilmann L, Rudig L, et al: Mean maternal second-trimester hemoglobin concentration and outcome of pregnancy: a population based study. Clin ApplThromb/Hemost 14: 19, 2008

Wax )R, Pinette MG, Cartin A, et al: Pyruvate kinase deficiency complicating pregnancy. Obstet Gynecol 109:553, 2007

Weatherall D: he thalassemias: disorders of globin chain synthesis. In Kaushansky K, Lichtman MA, Beutler E, et al (eds): Williams Hematology, 8th ed. New York, McGraw-Hill, 2010

Webert E, Mittal R, Sigouin C, et al: A retrospective II-year analysis of obstetric patients with idiopathic thrombocytopenic purpura. Blood 102:4306, 2003 Weiss G, Goodnough LT: Anemia of chronic disease. N Engl) Med 352:1011,

Wiegman MF, DeGroott)c, )ansonius NM, et al: Long-term visual functioning after eclampsia. Obstet GynecoIt119(5):959, 2012

Wiewel-Verschueren S, Arendz I), M Knol H, et al: Gynaecological and obstetrical bleeding in women with factor XI deiciency-a systematic review. Haemophillia 2015

Winder AD, Johnson S, Murphy), et al: Epidural analgesia for treatment of a sickle cell crisis during pregnancy. Obstet Gynecol 118(2 Pt 2):495,t2011 Wright DE, Rosovsky RP, Platt MY: Case 36-2013: a 38-year-old woman with anemia and thrombocytopenia. N Englt) Med 369:21, 2013

World Health Organization: Guideline: daily iron and folic acid supplementation in pregnant women. 2012. Available at: http://apps.who.int/iris/bitstr eam/1t0665/77770/1/9789241501996_eng.pd?ua = 1. Accessed November 9, 2016

Wyszynski DF, Carman W], Cantor AB, et al: Pregnancy and birth outcomes among women with idiopathic thrombocytopenic purpura. ) Pregnancy 2016:829740 ,2016

Xiong L, Barrett AN, Hua R, et al: Non-invasive prenatal diagnostic testing for 3-thalassaemia using cell-free fetal DNA and next generation sequencing. Prenat Diagn 35(3):258, 2015

Yawata Y, Kanzaki A, Yawata A, et al: Characteristic features of the genotype and phenotype of hereditary spherocytosis in the Japanese population. Int) Hematol 71:118, 2000

Yeomans E, Lowe W, Eigenbrodt EH, et al: Liver histopathologic indings in women with sickle cell disease given prophylactic transfusion during pregnancy. m)Obstet Gynecol 163:958, 1990

Young NS: Bone marrow failure syndromes including aplastic anemia and myelodysplasia. In: Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill Education, 2015

Yu CK, Stasiowska E, Stephens A, et al: Outcome of pregnancy in sickle cell disease patients attending a combined obstetric and haematology clinic. ) Obstet Gynaecol 29(6):512, 2009

Zhen L, Pen M, Han), et al: Non-invasive prenatal detection of haemoglobin Bart's disease by cardiothoracic ratio during the irst trimester. Eurt) Obstet Gynecol Reprod Bioi 193:92, 2015

Ziaei S, Norrozi M, Faghihzadeh S, et al: A randomized placebo-controlled trial to determine the efect of iron supplementation on pregnancy outcome in pregnant women with haemoglobin : 13.2 g/dl. B)OG 114:684, 2007

TYPES OF DIABETES. . . . . . . . . . . . . . . . . . . . . . . . . . .. 1097

PREGESTATIONAL DIABETES .....i...i...i....i.....i....1098

DIAGNOSIS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1098

FETAL EFFECTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1099

MATERNAL EFFECTS.. . . . . . . . . . . . . . . . . . . . . . . . . .. 1103

MANAGEMENT OF DIABETES IN PREGNANCY . . . . .. 1104

GESTATIONAL DIABETES. . . . . . . . . . . . . . . . . . . . . . .. 1 107

SCREENING AND DIAGNOSIS .................... 1108

MATERNAL AND FETAL EFFECTS .....i............. 1110 . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1 111

Diabetes may exist bore the inception ofpregnancy, or may not appear until labour. The prognosis is generaly believed to be ominous or mother and chil, but a review of the literature shows that less than 25 percent of the mothers died from diabetic coma, while premature labour occurred in ony one third of the cases.

-J. Whitridge Williams (1903)

In the early 1900s, overt diabetes complicating pregnancy was associated with horriic morbidity and mortality for a mother and her fetus. Although tremendously mitigated by the discovery of insulin, overt and gestational diabetes still are formidable complications of pregnancy.

According to the Centers for Disease Control and Prevention (2017), the number of adults diagnosed with diabetes in the United States is 23.r1 million. And, almost a quarter of people with diabetes in the United States remain undiagnosed.

tion more likely to develop type 2 diabetes, population growth within minority group at particular risk for type 2 diabetes, and a dramatic rise in obesity rates-also referred to as diabesiy.

he term reflects the strong relationship of diabetes and the current obesity epidemic in the United States and underlines the critical need for diet and lifestyle interventions to change the trajectory of both.

here is keen interest in events that precede diabetes, and this includes the intrauterine environment. Here, early imprinting is believed to have efects later in life (Saudek, 2002). For example, in utero exposure to maternal hyperglycemia leads to fetal hyperinsulinemia, causing an increase in fetal fat cells. his leads to obesity and insulin resistance in childhood (Feig, 2002). These factors in turn lead to impaired glucose tolerance and diabetes in adulthood. This cycle of fetal exposure to diabetes leading to childhood obesity and glucose intolerance is discussed further in Chapter 48 (p. 941).

In nonpregnant individuals, the type of diabetes is based on its presumed etiopathogenesis and its pathophysiological manifestations. Absolute insulin deficiency, generally autoimmune in etiology, characterizes ype 1 diabetes. In contrast, insulin resistance, relative insulin deiciency, or elevated glucose production characterizes ype 2 diabetes (Table 57-1). Both types are generally preceded by a period of abnormal glucose homeostasis oten referred to as prediabetes. The terms insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM) are now obsolete. Pancreatic �-cell destruction can begin at any age, but type 1 diabetes is clinically apparent most often before age 30. Type 2 diabetes usually develops with advancing age but is increasingly identified in younger obese adolescents.

TABLE 57-1. Etiological Classification of Diabetes Mellitus

Type 1: �-Cell destruction, usually absolute insulin deficiency Immune-mediated

Type 2: Ranges from predominantly insulin resistance to predominantly an insulin secretory defect with insulin resistance

Genetic mutations of �-cell function-MODY 1-6, others Genetic defects in insulin action

Genetic syndromes-Down, Klinefelter, Tuner

Diseases of the exocrine pancreas-pancreatitis, cystic fibrosis Endocrinopathies-Cushing syndrome, pheochromocytoma, others

Drug or chemical induced-glucocorticosteroids, thiazides, �-adrenergic agonists, others Infections-congenital rubella, cytomegalovirus, coxsackievirus

MODY = maturit I-onset diabetes of the young. Data from Powers, 21n2.

Diabetes is the most common medical complication of pregnancy. Women can be separated into those who were known to have diabetes before pregnancy-pregestationalior overt, and those diagnosed during pregnancy-gestational diabetes. The proportion of pregnancies complicated by diabetes more than doubled between 1994 and 2008, after which rates seem to have stabilized Oovanovic, 2015). Almost 258,000-6.5 percent-of gravidas in the United States had pregnancies coexistent with some form of diabetes in 2015 (Martin, 2017). Prevalence of diabetes is highest among non-Hispanic blacks, Mexican-Americans, Puerto Rican-Americans, and Native Americans (Golden, 2012). he incidence of gestational diabetes during the past 20 years, shown in Figure 57-1, is reminiscent of similar statistics for obesity (Chap. 48, p. 936).

I:u

FIGURE 57-1 Increasing prevalence of type 2 diabetes in the United States from 1995 to 2015. (Reproduced with permission from Centers for Disease Control and Prevention, 201o7.)

Until the mid-1990s, the classification by Priscilla White (1978) for diabetic pregnant women was the linchpin of management. Today, the White classiication is used less frequently but still provides simple and useful information on pregnancy risks and prognosis (Bennett, 2015). And, because most currently cited literature also contains data from these older classifications, the one previously recommended by the American College of Obstetricians and Gynecologists (1986) is provided in Table 57-2.

Beginning several years ago, the American College of Obstetricians and Gynecologists no longer recommended the White classification. Instead, the current focus is whether diabetes antedates pregnancy or is irst diagnosed during pregnancy. Many now recommend adoption of the classiication proposed by the American Diabetes Association (ADA), which is shown in Table 57-3.

he rising prevalence of type 2 diabetes, particularly in younger people, has led to an increasing number of afected pregnancies. For example, the CDC (2015) estimates that more than 5000 new cases of type 2 diabetes are diagnosed each year in youths before the age of 20 years. Feig and coworkers (2014) reported that the incidence of pregestational diabetes doubled from 7 per 1000 women in 1996 to 15 per 1000 in 2010. When considering the previously mentioned high percentage of diabetes that is undiagnosed, then many women identified to have gestational diabetes likely have type 2 diabetes previously unrecognized. In fact,rS to 10 percent of women with gestational diabetes are found to have diabetes immediately after pregnancy.

Women with high plasma glucose levels, glucosuria, and ketoacidosis present no diagnostic challenge. Women with a

TABLE 57-2. Classification Scheme Used from 1986 through 1994 for Diabetes

Age of Onset (yr) 10 to 19 10 to 19 aWhen diagnosed during pregnancy: proteinuria :500 mg/24 hr before 20 weeks' gestation.

random plasma glucose level >200 mg/dL plus classic signs and symptoms such as polydipsia, polyuria, and unexplained weight loss, or those with a fasting glucose levelr> 125 mg/dL are considered by the ADA (2017 a) and the World Health Organization (2013) to have overt diabetes first detected in pregnancy. Women with only minimal metabolic derangement may be more diicult to identiY. To diagnose overt diabetes in pregnancy, he International Association of Diabetes and Pregnancy Study Groups (IADPSG) Consensus Panel (2010) recognizes the threshold values found in Table 57-4 for fasting or random plasma glucose and glycosylated hemoglobin (HbA1J levels at prenatal care initiation. The ADA (2017a) and the World Health Organization (2013) now also consider a plasma glucose level >200 mg/dL measured 2 hours after a 75 g oral glucose load to be diagnostic. No consensus has been reached as to whether such testing should be universal or limited to those women classiied as high risk. Regardless, the tentative diagnosis of overt diabetes during pregnancy based on these thresholds should be conirmed postpartum. isk factors for impaired carbohydrate metabolism in pregnant women include a strong familial history of diabetes, prior delivery of a large newborn, persistent glucosuria, or unexplained fetal losses.

With overt diabetes, the embryo, fetus, and mother frequently experience serious complications directly attributable to diabetes.

Peterson and colleagues (2015) estimate that thousands of these complications might be prevented each year by preconceptional care for improved glycemic control. The likelihood of successful outcomes with overt diabetes, however, is not simply related to glucose control. The degree of underlying cardiovascular or renal disease may be more important. Thus, advancing stages of the White classification, seen in Table 57-2, are inversely related to favorable pregnancy outcomes. Shown in Table 57-5 are data that chronicle the deleterious pregnancy outcomes with overt diabetes. hese maternal and fetal complications are described in the following sections.

Spontaneous Abortion. Several studies have shown that early miscarriage is associated with poor glycemic control (Chap. 18, p. 347). Up to 25 percent of diabetic gravidas have an early pregnancy loss (Galindo, 2006; Rosenn, 1994). hose whose HbA1c concentrations were > 12 percent or whose preprandial glucose concentrations were persistently > 120 mg/dL had an elevated risk. Bacon and associates (2015) reviewed 89 pregnancies in women with maturity-onset diabetes of the young (MODy), which is a monogenic form of diabetes. hese investigators found that only women with the causative glucose kinase gene (GCK) mutation were more likely to have a miscarriage. These women are characterized by hyperglycemic variability that is diicult to control.

TABLE 57-3. Proposed Classification System for Diabetes in Pregnancy

Gestational diabetes: diabetes d during pregnancy that is not clearly overt (type 1 or type 2) diabetes

Type 1 Diabetes: Type 2 Diabetes:

Diabetes resulting from �-cell destruction, usually leading to Diabetes from inadequate insulin secretion in the face of a.

Without vascular complications a. Without vascular complications b.

With vascular complications (speciy which) b. With vascular complications (speciy which)

Other types of diabetes: genetic in origin, associated with pancreatic disease, drug-induced, or chemically induced

Data from American Diabetes Association, 2017a.

TABLE 57-4. Diagnosis of Overt Diabetes in Pregnancya

Measure of Glycemia Threshold

Fasting plasma glucose At least 7.0 mmollL (126 mg/dL) Hemoglobin Ale At least 6.5% Random plasma glucose At least 11.1 mmol/L (200 mg/dL) plus confirmation aApply to women without known diabetes antedating pregnancy. The decision to perform blood testing for evaluation of glycemia all pregnant women r only on women with characteristics indicating a high risk for diabetes is based on the background frequency of abnormal glucose metabolism in the population and on local circumstances.

Data from International Association of Diabetes and Pregnancy Study Groups Consensus

Panel, 201n0.

Preterm Delivery. Overt diabetes is an undisputed risk factor for preterm birth. Eidem and associates (2011) analyzed 1307 births in women with type 1 diabetes from the Norwegian NIedical Birth Registry. More than 26 percent were delivered preterm compared with 6.8 percent in the general obstetrical population. Moreover, almost 60 percent were indicated preterm births, that is, due to obstetrical or medical complications. In one review of more than 500,000 California births, 19 percent of women with pregestational diabetes had a preterm birth compared with 9 percent in controls (Yanit, 2012). In the Canadian study shown in Table 57-5, the incidence of preterm birth was 28 percent.

Malformations. he incidence of major malformations in women with type 1 diabetes is at least doubled and approximates 11 percent Qovanovic, 2015). These account for almost half of perinatal deaths in diabetic pregnancies. As shown in Table 57-6, cardiovascular malformations accounted for more than half of the anomalies. In a cohort study of more than 2 million births in Canada, the risk of an isolated cardiac defect was ivefold higher in women with type 1 diabetes (Uu, 2013). he caudal regression sequence, described in Chapter 10 (p. 196), is a rare malformation frequently associated with maternal diabetes (Garne, 2012).

Poorly controlled diabetes, both preconceptionally and early in pregnancy, is thought to underlie this elevated severemalformation risk. s shown in Figure 57-2, increased maternal HbA[c levels and major malformations clearly correlate. To explain this, at least three interrelated molecular chain reactions have been linked to maternal hyperglycemia (Reece, 2012). hese include alterations in cellular lipid metabolism, excess production of toxic superoxide radicals, and activation of programmed cell death. In their review of molecular mechanisms underlying diabetic embryopathy, Yang and colleagues (2015) suggest that these cellular responses to oxidative stress represent potential therapeutic targets to prevent diabetes-induced embryopathy.

Altered Fetal Growth. Diminished growth may result from congenitl malformations or from substrate deprivation due to advanced maternal vascular disease. That said, fetal overgrowth is more typical of pregestational diabetes. Maternal hyperglycemia prompts fetal hyperinsulinemia, and this in turn stimulates excessive somatic growth. Except for the brain, most fetal organs are afected by the macrosomia that characterizes the fetus of a diabetic woman. Newborns such as the one shown in Figure 57-3 are described as being anthropometrically diferent from other largefor-gestational age (LGA) neonates (Catalano, 2003; Durnwald, 2004). Speciically, those whose mothers are diabetic have excesyrsive fat deposition on the shoulders and trunk, which predisposes to shoulder dystocia or cesarean delivery.

he incidence of macrosomia rises signiicantly when mean maternal blood glucose concentrations chronically exceed 130 mg/dL (Hay, 2012). Hammoud and coworkers (2013)

TABLE 57-5. Pregnancy Outcomes of Births in Nova TABLE 57-6. Major Congenital Anomalies in 36,345 Scotia from 1988 to 2002 in Women with Neonates Born to Women with Diabetes and without Pregestational Diabetes between 2004 and 201e1 (n.=.S16) (n.=.lS0,.S98) Factor P value �pe1.DM Type.2DM GDM Organ System n = 482 n = 4166 n = 31,700

Gestational 28 9 <.001 Cardiac 38 272 1129

Preterm birth 28 5 <.001 Urinary 3 28 260 <.001 CNS 13 64

FIGURE 57-3 This 6050-g macrosomic infant was born to a woman with gestational diabetes.

15.8 400.) 11.7 30 25 5 3/1e9 5 2/1e7 0 <6 6-6.9 7-7.9 �8 FIGURE 57-2 The frequency of major congenital malformations in newborns ofwomen with pregestational diabetes stratified by hemoglobin Ale levels at first prenatal visit. (Data from Galindo A, Burguillo AG, Azriel S, et al: Outcome offetuses in women with pregestational diabetes mellitus, J Perinat Med. 2006;34(4):323-331.) reported that the macrosomia rates for Nordic women with type 1, type 2, or gestational diabetes were 35 percent, 28 percent, and 24 percent, respectively. As shown in 57-4, the birthweight distribution of neonates of diabetic mothers is skewed toward consistently heavier birthweights. In the study by Hammoud and colleagues (2013), fetal growth profiles from 897 sonographic examinations in 244 women with diabetes were compared with 843 examinations in 145 control women. he abdominal circumference grew disproportionately larger in the diabetic groups. Analysis of head circumference/abdominal circumference (HC/AC) ratios shows that this disproportionate growth occurs mainly ..0

FIGURE 57-4 Distribution of birthweight standard deviations from the normal mean for gestational age in 280 newborns of diabetic mothers and in 3959 neonates of nondiabetic mothers. (Reproduced with permission from Bradley RJ, Nicolaides KH, Brudenell JM.: Are all infants ofdiabetic mothers "macrosomic"7 BMJ 1988 Dec 17;297(6663):1o583-1o584') in diabetic pregnancies that ultimately yield macrosomic newborns. hese findings comport with the observation that virtually all neonates of diabetic mothers are growth promoted, and accelerated fetal growth is particularly evident in women with poor glycemic control.

Unexplained Fetal Demise. Worldwide, the risk offetal death is three to four times higher in women with pregestational diabetes (Cardosi, 2013; Patel, 2015). Stillbirth without an identiiable cause is a phenomenon relatively limited to pregnancies complicated by overt diabetes. These stillbirths are "unexplained" because common factors such as obvious placental insuiciency, placental abruption, fetal-growth restriction, or oligohydramnios are not identified. hese fetuses are typically large for gestational age and die before labor, usually late in the third trimester.

These unexplained stillbirths are associated with poor glycemic control. Lauenborg and coworkers (2003) identiied suboptimal glycemic control in two thirds of unexplained stillbirths between 1990 and 2000. Also, fetuses ofdiabetic mothers often have elevated lactic acid levels. Salvesen and colleagues (1992, 1993) analyzed fetal blood samples and reported that mean umbilical venous blood pH was lower in diabetic pregnancies and was signiicantly related to fetal insulin levels. Such indings support the hypothesis that hyperglycemia-mediated chronic aberrations in oxygen and fetal metabolite transport may underlie these unexplained fetal deaths (Pedersen, 1977).

Aside from hyperglycemia alone, maternal ketoacidosis can cause fetal death. Explicable stillbirths due to placental insufficiency also occur with increased frequency in women with overt diabetes, usually in association with severe preeclampsia. In the prior California study of nearly a halfmillion singleton deliveries, the fetal death risk was sevenfold higher in women with hypertension and pregestational diabetes compared with the threefold increased risk associated with diabetes alone (Yanit, 2012). Stillbirth rates are also greater in women with advanced diabetes and vascular complications.

Hydramnios. Diabetic pregnancies are oten complicated by excess amnionic fluid. According to Idris and coworkers (2010), 18 percent of 314 women with pregestational diabetes were identified to have hydramnios, deined as an amnionic fluid index (AFI) >24 cm in the third trimester. And, women with elevated HbA)c values in the third trimester were more likely to have hydramnios. A likely-albeit unproven-explanation is that fetal hyperglycemia causes polyuria (Chap. 11, p. 228). In a study from Parkland Hospital, Dashe and colleagues (2000) found that the API parallels the amnionic luid glucose level among women with diabetes. Further support for this association was provided by Vink and associates (2006), who linked poor maternal glucose control to macrosomia and hydramnios.

Neonatal Efects. Before tests of fetal health and maturity became available, delivery before term was deliberately selected for women with diabetes to avoid unexplained stillbirth. Although this practice has been abandoned, a higher frequency of preterm delivery in women with diabetes persists. Most are indicated deliveries due to advanced diabetes with superimposed preeclampsia. hat said, Little and associates (2015) in their analysis of early-term delivery (37°/7 to 386/7 weeks) found a 13-percent reduction in such deliveries in women with diabetes between 2005 and 2011.

Although modern neonatal care has reduced neonatal death rates due to immaturity, neonatal morbidiy due to preterm birth continues to be a serious consequence. In one Neonatal Research Network study of 10,781 extremely preterm neonates, those born to diabetic women treated with insulin prior to pregnancy were at greater risk for necrotizing enterocolitis and late-onset sepsis than neonates of mothers without diabetes (Boghossian, 2016).

Respiratory Distress Syndrome. Gestational age rather than overt diabetes is likely the most significant factor associated with respiratory distress syndrome (Chap. 33, p. 619). Indeed, in one analysis of 19,399 very-Iow-birthweight neonates delivered between 24 and 33 weeks' gestation, rates of respiratory distress syndrome in newborns of diabetic mothers were not higher compared with rates in neonates of nondiabetic mothers (Bental, 2011).

Hypoglycemia. Newborns of a diabetic mother experience a rapid drop in plasma glucose concentration after delivery. This is attributed to hyperplasia of the fetal �-islet cells induced by chronic maternal hyperglycemia. Low glucose concentrationsdefined as <45 mg/dL-are particularly common in newborns of women with unstable glucose concentrations during labor (Persson, 2009). Frequent blood glucose measurements in the newborn and active early feeding practices can mitigate these complications.

Hypocalcemia. Deined as a total serum calcium concentration <8 mg/dL in term newborns, early onset hypocalcemia is one of the potential metabolic derangements in neonates of diabetic mothers. Its cause has not been explained. Theories include aberrations in magnesium-calcium economy, asphyxia, and preterm birth. In a randomized study, 137 pregnant women with type 1 diabetes were managed with strict versus customary glucose control (DeMarini, 1994). Almost a third of neonates in the customary control group developed hypocalcemia compared with only 18 percent of those in the strict-control group.

Hyperbilirubinemia and Polycythemia. he pathogenesis of hyperbilirubinemia in neonates of diabetic mothers is uncertain. A major contributing factor is newborn polycythemia, which raises the bilirubin load (Chap. 33, p. 626). Polycythemia is thought to be a fetal response to relative hypoxia. According to Hay (2012), the sources of this fetal hypoxia are hyperglycemia-mediated elevations in maternal ainity for oxygen and fetal oxygen consumption. Together with insulin-like growth factors, this hypoxia leads to elevated fetal erythropoietin levels and red cell production. Fetal renal vein thrombosis is reported to result from polycythemia.

Cardiomyopathy. Newborns of diabetic pregnancies may have hypertrophic cardiomyopathy that primarily afects the interventricular septum (Rolo, 2011). Huang and coworkers (2013) propose that pathological ventricular hypertrophy in neonates born to women with diabetes is due to insulin excess. In severe cases, this cardiomyopathy may lead to obstructive cardiac failure. Russell and coworkers (2008) performed serial echo cardiograms on fetuses of 26 women with pregestational diabetes. In the first trimester, fetal diastolic dysfunction was already evident in some. In the third trimester, the fetal interventricular septum and right ventricular wall were thicker in fetuses of diabetic mothers. Most afected newborns are asymptomatic following birth, and hypertrophy usually resolves in the months after delivery.

Long-Term Cognitive Development. Intrauterine metabolic conditions have long been linked to neurodevelopment in ofspring. In a study of more than 700,000 Swedish-born men, the intelligence quotient of those whose mothers had diabetes during pregnancy averaged 1 to 2 points lower (Fraser, 2014). DeBoer and associates (2005) demonstrated impaired memory performance in infants of diabetic mothers at age 1 year. Results from the Childhood Autism Risks from Genetics and the Environment (CHARGE) study indicated that autism spectrum disorders or developmental delay were also more common in children of diabetic women (Krakowiak, 2012). Adane and colleagues (2016) conirmed a consistent relationship between maternal diabetes and diminished cognitive and language development in studies of younger children but not older children. Because interpreting efects of the intrauterine environment on neurodevelopment is confounded by postnatal factors, the link between maternal diabetes, glycemic control, and long-term neurocognitive outcome remains unconfirmed.

Inheritance of Diabetes. The risk of developing type 1 diabetes if either parent is afected is 3 to 5 percent. Type 2 diabetes has a much stronger genetic component. If both parents have type 2 diabetes, the risk of developing it approaches 40 percent. Both types of diabetes develop after a complex interplay between genetic predisposition and environmental factors.

Type 1 diabetes is prompted by environmental triggers such as infection, diet, or toxins and heralded by the appearance of islet cell autoantibodies in genetically vulnerable individuals (Pociot, 2016; Rewers, 2016). Some but not all studies have shown a reduction in risk for type 1 or type 2 diabetes associated with breastfeeding (Owen, 2006; Rewers, 2016).

Diabetes and pregnancy interact signiicantly such that maternal welfare can be seriously jeopardized. With the possible exception of diabetic retinopathy, however, the long-term course of diabetes is not afected by pregnancy.

In an analysis ofmore than 800,000 pregnancies, Jovanovic and colleagues (2015) found that 1125 mothers with type 1 diabetes were at increased risk for hypertension and respiratory complications compared with nondiabetic women. And, 10,126 mothers with type 2 diabetes had an elevated risk for depression, hypertension, infection, and cardiac or respiratory complications compared with pregnant controls. Maternal death is uncommon, but rates in women with diabetes are still higher than those in unafected gravidas. In one analysis of972 women with type 1 diabetes, the maternal mortality rate was 0.5 percent, and deaths resulted from diabetic ketoacidosis, hypoglycemia, hypertension, and infection (Leinonen, 2001).

Preeclampsia. Pregnancy-associated hypertension is the complication that most often forces preterm delivery in diabetic women. he incidence of chronic and gestational hypertension-and especially preeclampsia-is remarkably increased (Chap. 40, p. 713). In a systematic review and metaanalysis of 92 studies including more than 25 million pregnancies, Bartsch and associates (2016) calculated a pooled relative risk of 3.7 for preeclampsia in women with pregestational diabetes. In the study cited earlier by Yanit and colleagues (2012), preeclampsia developed three to four times more often in women with overt diabetes. Moreover, those diabetics with coexistent chronic hypertension were 12 times more likely to develop preeclampsia. As shown in Figure 57-5, women with type 1 diabetes in more advanced White classes of overt diabetes, who typically exhibit vascular complications and have preexisting nephropathy, are more likely to develop preeclampsia. This .g:-.

.E )

FIGURE 57-5 Incidence of preeclampsia in 491 type 1 diabetic women in Sweden and the United States. (Data from Hansona, 1993; Sibaib, 2000.) rising risk with duration ofdiabetes may be related to oxidative stress, which plays a key role in the pathogenesis of diabetic complications and preeclampsia. With this in mind, the Diabetes and Preeclampsia Intervention Trial (DAPIT) randomly assigned 762 women with type 1 diabetes to antioxidant vitamin C and E supplementation or placebo in the irst half of pregnancy (McCance, 2010). Preeclampsia rates did not difer except in a few women with a low antioxidantstatus at baseline.

Diabetic Nephropathy. Diabetes is the leading cause of end stage renal disease in the United States (Chap. 53, p. 1034).

Clinically detectable nephropathy begins with microalbumin uria-30 to 300 mg/24 hours. his may manifest as early as 5 years after diabetes onset. Macroalbuminuria-more than 300 mg/24 hours-develops in patients destined to have end-stage renal disease. Hypertension almost invariably develops during this period, and renal failure ensues typically in the next 5 to 10 years. The incidence ofovert proteinuria is nearly 30 percent in individuals with type 1 diabetes and ranges from 4 to 20 per cent in those with type 2 diabetes (Reutens, 2013). Regression is common and, presumably from improved glucose control, the incidence ofnephropathy with type 1 diabetes has declined.

Approximately 5 percent of pregnant women with diabetes already have renal involvement. Approximately 40 percent of these will develop preeclampsia (Vidaef, 2008). In those with microproteinuria, this incidence may not be as high (How, 2004). However, mbia and associates (2018) reported that the rates ofpreterm delivery, birthweight <2500 g, and growth restriction were significantly higher in neonates of diabetic women with microproteinuria compared with those of diabetic gravidas without proteinuria.

In general, pregnancy does not appear to worsen diabetic nephropathy. In one prospective study of 43 women with diabetes, diabetic nephropathy did not progress through 12 months after delivery (Young, 2012). Most ofthese women had only mild renal impairment. Conversely, pregnancy in women with moderate-to-severe renal impairment may have accelerated progression of their disease (Vidaef, 2008). As in women with glomerulopathies, hypertension or substantial proteinuria before or during pregnancy is a major predictive factor for ultimate progression to renal failure in women with diabetic nephropathy (Chap. 53, p. 1033).

Diabetic Retinopathy. Retinal vasculopathy is a highly speciic complication ofboth type 1 and type 2 diabetes. In the United States, diabetic retinopathy is the most important cause ofvisual impairment in working-aged adults. he first and most common visible lesions are small microaneurysms followed by blot hemorrhages that form when erythrocytes escape from the aneurysms. hese areas leak serous fluid that creates hard exudates. Such features are termed backgroundor nonprolierative retinopathy. With increasingly severe retinopathy, the abnormal vessels of background eye disease become occluded, leading to retinal ischemia and infarctions that appear as cotton wool exuates. hese are considered preprolerative retinopathy. In response to ischemia, neovascularization begins on the retinal surface and out into the vitreous cavity. Vision is obscured when these vessels bleed. Laser photocoagulation before hemorrhage reduces the rate of visual loss progression and blindness by half. The procedure may be performed during pregnancy when indicated.

Vestgaard and coworkers (2010) reported that almost two thirds of 102 pregnant women with type 1 diabetes examined by 8 weeks' gestation had background retinal changes, proliferative retinopathy, or macular edema. A fourth of these women developed progression of retinopathy in at least one eye during pregnancy. The same group of investigators evaluated 80 type 2 diabetics and identified retinopathy, mostly mild, in 14 percent during early pregnancy. Progression was identiied in only 14 percent (Rasmussen, 2010). This complication is believed to be a rare example of a long-term adverse efect of pregnancy.

Other risk factors that have been associated with progression of retinopathy include hypertension, higher levels of insulin-like growth factor-I, placental growth factor, and macular edema identiied in early pregnancy (Bargiota, 2011; Huang, 2015; Mathiesen, 2012; Ringholm, 2011; Vestgaard, 2010). The American Academy of Ophthalmology (2016) recommends that pregnant women with preexisting diabetes should routinely be ofered retinal assessment after the first prenatal visit. Subsequent eye examinations depend on severity of retinopathy and level of diabetes control. Currently, most agree that laser photocoagulation and good glycemic control during pregnancy minimize the potential for deleterious efects of pregnancy.

Ironically, "acute" rigorous metabolic control during pregnancy has been linked to acute worsening of retinopathy. In a study of 201 women with retinopathy, almost 30 percent suffered eye disease progression during pregnancy despite intensive glucose control (11cElvy, 2001). That said, Wang and coworkers (1993) observed that although retinopathy worsened during the critical months of rigorous glucose control, long-term progression of eye disease actually slowed. Arun and Taylor (2008) found that only four women required laser photocoagulation during pregnancy, and none required laser in the next 5 years.

Diabetic Neuropathy. Peripheral symmetrical sensorimotor diabetic neuropathy is uncommon in pregnant women. But, a form of this, known as diabetic gastropathy, can be troublesome during pregnancy. It causes nausea and vomiting, nutritional problems, and diiculty with glucose control. Women with gastroparesis are advised that this complication is associated with a high risk of morbidity and poor perinatal outcome (Kitzmiller, 2008). Treatment with metoclopramide and D2-receptor antagonists is sometimes successful. Gastric neurostimulators have also been successfully used during pregnancy (Fuglsang, 2015). Treatment of hyperemesis gravidarum can be challenging, and we routinely provide insulin by continuous infusion for women who are admitted with this condition (Chap. 54, p. 1044).

Diabetic Ketoacidosis. his serious complication develops in approximately 1 percent of diabetic pregnancies and is most often encountered in women with type 1 diabetes (Hawthorne, 201r1). It is increasingly being reported in women with type 2 or even those with gestational diabetes (Bryant, 2017; Sibai, 2014). Diabetic ketoacidosis (DKA) may develop with hyperemesis gravidarum, infection, insulin noncompliance, 3-mimetic drugs given for tocolysis, and corticosteroids given to induce fetal lung maturation. DKA results from an insulin deiciency combined with an excess in counter-regulatory hormones such as glucagon. his leads to gluconeogenesis and ketone body formation. The ketone body 3-hydroxybutyrate is synthesized at a much greater rate than acetoacetate, which is preferentially detected by commonly used ketosis-detection methods. herefore, serum or plasma assays for 3-hydroxybutyrate more accurately reflect true ketone body levels.

Of gravidas with DA, fewer than 1 percent die, but perinatal mortality rates from a single episode of DKA may reach 35 percent (Guntupalli, 2015). Noncompliance is a prominent factor, and this and ketoacidosis were historically considered prognostically bad signs in pregnancy (Pedersen, 1974). Importantly, pregnant women usually develop ketoacidosis at lower blood glucose thresholds than when nonpregnant. In a study from Parkland Hospital, the mean glucose level for pregnant women with DKA was 380 mg/dL, and the mean HbA]c value was 10 percent (Bryant, 2017). Euglycemic ketoacidosis during pregnancy is possible but rare (Sibai, 2014).

One management protocol for diabetic ketoacidosis is shown in Table 57-7. An important cornerstone of management is vigorous rehydration with crystalloid solutions of normal saline or Ringer lactate.

Infections. The rates of many infections are higher in diabetic pregnancies. Common ones include candidal vulvovaginitis, urinary and respiratory tract infections, and puerperal pelvic sepsis. However, in one study of more than 1250 diabetic gravidas screened before 16 weeks' gestation, rates of bacterial vaginosis or vaginal colonization with Candida or Tricho monas species were not increased (Marschalek, 2016). But, in their population-based study of almost 200,000 pregnancies, Sheiner and coworkers (2009) found a twofold greater risk of asymptomatic bacteruria in women with diabetes. Similarly, Alvarez and associates (2010) reported positive urine culture results in 25 percent of diabetic women. In a 2-year analysis of pyelonephritis at Parkland Hospital, 5 percent of women with diabetes developed pyelonephritis compared with 1.3 percent of the nondiabetic population (Hill, 2005). Fortunately, these latter infections can be minimized by screening and eradication of asymptomatic bacteriuria (Chap. 53, p. 1027). Finally, Johnston and colleagues (2017) reported that 16.5 percent of women with pregestational diabetes had postoperative wound complications following cesarean delivery.

• Management of Diabetes in Pregnancy

Because of the close relationship between pregnancy complications and maternal glycemic control, eforts to achieve glucose targets are typically more aggressive during pregnancy. Management preferably should begin before pregnancy and include speciic goals during each trimester.

To minimize early pregnancy loss and congenital malformations in ofspring of diabetic mothers, optimal medical care and education are recommended before conception (Chap. 8, p. 147). he National Preconception Health and Healthcare Initiative Clinical Workgroup for the CDC established values

TABLE 57-7. Management of Diabetic Ketoacidosis During Pregnancy

Obtain arterial blood gases to document degree of acidosis present; measure glucose, ketones, and electrolyte levels at 1-to 2-hour intervals

Low-dose, intravenous Loading dose: 0.2-0.4 U/kg Maintenance: 2-10 U/hr

Total replacement in first 12 hours of 4-6 L 1 L in first hour

If initially normal or reduced, an infusion rate up to 15-20 mEq/hr may be required; if elevated, wait until levels decrease into the normal range, then add to intravenous solution in a concentration of 20-30 mEq/L

Add one ampule (44 mEq) to 1 L of 0.45 normal saline if pH is <7.1

Data from Bryant, 20017; Landon, 2002; Sibai, 2014.

for optimal glycemic control (Frayne, 2016). This was defined Insulin Treatment as HbA}c <6.5 percent in women with pregestational diabetes.

The overtly diabetic gravida is best treated with insulin. While Unfortunately, nearly half of pregnancies in the United States oral hypoglycemic agents have been used successfully for gesare unplanned, and diabetic women frequently begin pregnancy tational diabetes (p. 11r12), these agents are not currently recwith suboptimal glucose control (Finer, 2016; Kim, 2005).

ommended for overt diabetes, although this is controversial The ADA (20 17b) has also deined optimal preconcep(American College of 0bstetricians and Gynecologists, 20 16b).

tional glucose control using insulin. Relective values are selfMaternal glycemic control can usually be achieved with mulmonitored preprandial glucose levels of70 to 100 mg/dL, peak tiple daily insulin injections and adjustment of dietary intake.

2-hour postprandial values of 100 to 120 mg/dL, and mean he action proiles of commonly used short-and long-termdaily glucose concentrations < 110 mg/dL. In one prospective insulins are shown in Table 57-8.

population-based study of 933 pregnant women with type 1 diabetes, the risk of congenital malformations was not demonstrably higher with HbA}c levels <6.9 percent compared with the risk in more than 70,000 nondiabetic controls Qensen, 2010). These investigators also found a substantial fourfold greater risk for malformations at levels > 10 percent.

If indicated, evaluation and treatment for diabetic complica

TABLE 57-8. Action Profiles of Commonly Used Insulins Insulin Type Onset Peak (hr) Duration (hr)

Lispro <15nmin 0.5-1n.5

Glulisine <15 min 0.5-1.5 3-4 tuted before pregnancy. Finally, folate, 400 jLg/d orally, is given periconceptionally and during early pregnancy to decrease the risk of neural-tube defects.

Aspart <15 min 0.5-1n.5

Careful monitoring of glucose control is essential. For this reason, many clinicians hospitalize overtly diabetic women during early pregnancy to initiate an individualized glucose control program and provide education. This also provides an opportunity to assess the extent of diabetic vascular complications and precisely establish gestational age.

aMinimal peak activity.

NPH = neutral protamine Hagedorn; SC = subcutaneous. Data from Powers, 201 2.

Subcutaneous insulin infusion by a calibrated pump does not yield better pregnancy outcomes compared with multiple daily injections. But, an infusion pump is a safe alternative in appropriately selected patients (Farrar, 2016; Sibai, 2014). With the advent of sensor-augmented insulin pumps and closed-loop insulin delivery systems, improved glycemic control with either manual or computer-generated insulin adjustments based on continuous glucose monitoring is now possible. One small randomized, crossover study of 16 pregnant women compared these two technologies (Stewart, 2016). Those with automatic closed-loop systems had glucose values within target range for a higher percentage of time and had lower daily median glucose values. Moreover, their rates of hypoglycemic episodes were not increased. Roeder and colleagues (2012) noted with insulin pump use in women with type 1 diabetes that total daily insulin doses declined in the first trimester but later rose more than threefold. Postprandial glucose elevations prompted most of the required daily-dose increases. If a continuous-infusion insulin pump is elected, it is best started before pregnancy to avoid the hypoglycemia and ketoacidosis risk associated with the learning curve (Sibai, 2014).

Monitoring. Self-monitoring of capillary glucose levels using a glucometer is recommended because this involves the woman in her own care. he ADA (2017b) recommends fasting and postprandial glucose monitoring. Glucose goals recommended during pregnancy are shown in Table 57-9. Advances in noninvasive glucose monitoring will undoubtedly render intermittent capillary glucose monitoring obsolete. Subcutaneous continuous glucose monitoring devices have shown that pregnant women with diabetes experience signiicant periods of daytime hyperglycemia and nocturnal hypoglycemia that are undetected by traditional monitoring (Combs, 2012). Such glucose monitoring systems, coupled with a continuous insulin pump, ofer the potential of an "artificial pancreas" to avoid undetected hypo-or hyperglycemia during pregnancy.

Diet. Nutritional planning includes appropriate weight gain through carbohydrate and caloric modiications based on height, weight, and degree of glucose intolerance (merican Diabetes Association, 2017b; Bantle, 2008). he mix of carbohydrate, protein, and fat is adjusted to meet the metabolic goals and individual patient preferences. A minimum of 175 g/d of carbohydrates ideally is provided. In one analysis of more than 200 obese pregnant women with glucose intolerance, a lower carbohydrate intake, particularly late in pregnancy, was

TABLE 57-9. Self-Monitored Capillary Blood Glucose Goals

Fasting :;95 Premeal :;100 1-hr postprandial :;140 2-hr postprandial :;120

Hemoglobin Ale :;6% associated with lower fat mass in ofspring at birth (Renault, 2015). Allotted carbohydrates are distributed throughout the day in three small-to moderate-sized meals and two to four snacks. Weight loss is not recommended, but modest caloric restriction may be appropriate for overweight or obese women. An ideal dietary composition is 55 percent carbohydrate, 20 percent protein, and 25 percent fat, of which < 10 percent is saturated fat.

Hypoglycemia. Diabetes tends to be unstable in the first half of pregnancy, and the incidence of hypoglycemia peaks during the irst trimester. Chen and coworkers (2007) identified hypoglycemic events-blood glucose values <40 mg/dL-in 37 of 60 women with type 1 diabetes. A fourth of these were considered severe because the women were unable to treat their own symptoms and required assistance from another person. Caution is recommended when attempting euglycemia in women with recurrent episodes of hypoglycemia.

In a Cochrane database review, Middleton and colleagues (2016) determined that loose glycemic control, defined as fasting glucose valuesr> 120 mg/dL, was associated with greater risks for preeclampsia, cesarean delivery, and birthweight above the 90th percentile compared with women with tight or moderate control. Importantly, no obvious benefit were gained from very tight control, defined by fasting values <90 mg/dL, and there were more cases of hypoglycemia. hus, women with overt diabetes who have glucose values that are viewed by some as "considerably above" this 90 mg/dL threshold can expect good pregnancy outcomes.

Maternal serum alpha-fetoprotein determination at 16 to 20 weeks' gestation is used in association with targeted sonographic examination to detect neural-tube defects and other anomalies (Chap. 14, p. 283). hese levels may be lower in diabetic pregnancies, and interpretation is altered accordingly. Because the incidence of congenital cardiac anomalies is fivefold in mothers with diabetes, fetal echocardiography is an important part of second-trimester sonographic evaluation (Fouda, 2013). Despite advances in ultrasound technology, however, Dashe and associates (2009) cautioned that detection of fetal anomalies in obese diabetic women is more diicult than in similarly sized women without diabetes.

Regarding second-trimester glucose control, euglycemia with self-monitoring continues to be the goal in management. After the first-trimester instability, a stable period ensues. his is followed by a greater insulin requirement due to the elevated peripheral resistance to insulin described in Chapter 4 (p. 56).

During the past several decades, the threat of late-pregnancy stillbirth in women with diabetes has prompted recommendations for various fetal surveillance programs beginning in the third trimester. Such protocols include fetal movement counting, periodic fetal heart rate monitoring, intermittent biophysical profile evaluation, and contraction stress testing (Chap. 17, p. 331). None of these techniques has been subjected to prospective randomized clinical trials, and their primary value seems related to their low false-negative rates. The American

College of Obstetricians and Gynecologists (2016b) suggests initiating such testing at 32 to 34 weeks' gestation.

At Parkland Hospital, women with diabetes are seen in a specialized obstetrical clinic every 2 weeks. During these visits, glycemic control records are evaluated and insulin adjusted. Women are routinely instructed to perform fetal kick counts beginning early in the third trimester. At 34 weeks, admission is ofered to all insulin-treated women. While in the hospital, they continue daily fetal movement counts and undergo fetal heart rate monitoring three times a week. Delivery is planned for 38 weeks.

Labor induction may be attempted when the fetus is not excessively large and the cervix is considered favorable (Chap. 26, p. 503). Little and colleagues (2015) analyzed term singleton births from 2005 to 201r1 and showed a higher percentage of diabetic women were delivered each year before 39 weeks compared with the entire cohort-37 versus 29 percent. Cesarean delivery at or near term has frequently been used to avoid traumatic birth of a large fetus in a woman with diabetes. In women with more advanced diabetes, especially those with vascular disease, the reduced likelihood of successful labor induction remote from term has also contributed to an incre�sed cesarean delivery rate. In an analysis of pregnancy outcomes of diabetic women from University of labama at Birmingham according to the White classiication, the rate of cesarean delivery and preeclampsia escalated with White class (Bennett, 2015). In another study, a HbA,c level >6.4 percent at delivery was independently associated with urgent cesarean delivery. This suggests that tighter glycemic control during the third trimester might reduce late fetal compromise and cesarean delivery for fetal indications (Miailhe, 2013). The cesarean delivery rate for women with overt diabetes has remained at approximately 80 percent for the past 40 years at Parkland Hospital.

Reducing or withholding the dose of long-acting insulin to be given on the day of delivery is recommended. Regular insulin should be used to meet most or all of the insulin needs of the mother during this time, because insulin requirements typically drop markedly after delivery. We have found that continuous insulin infusion by calibrated intravenous pump is most satisfactory (Table 57-10). Throughout labor and after delivery, the woman should be adequately hydrated intravenously and given glucose in suicient amounts to maintain normoglycemia. Capillary or plasma glucose levels are checked frequently, especially during active labor, and regular insulin is administered accordingly.

Often, women may require virtually no insulin for the irst 24 hours or so postpartum. Subsequently, insulin requirements may luctuate markedly during the next few days. Infection must be promptly detected and treated. When appropriate, oral agents can be restarted.

Counseling in the puerperium should include a discussion of birth control. Efective contraception is especially important in women with overt diabetes to allow optimal glucose control before subsequent conception.

In the United States in 2010, almost 5 percent of gravidas were afected by gestational diabetes (DeSisto, 2014). W orldwide, its prevalence difers according to race, ethnicity, age, and body composition and by screening and diagnostic criteria. There continue to be several controversies pertaining to the diagnosis and treatment of gestational diabetes. A National Institutes of Health (NIH) Consensus Development Conference (2013) was convened to study this. he American College of Obstetricians and Gynecologists (2017a) has also updated its recommendations. These two authoritative sources provide an analysis of the issues surrounding the diagnosis and bolster the approach to identiying and treating women with gestational diabetes.

The word gestational implies that diabetes is induced by pregnancy-ostensibly because of exaggerated physiological changes in glucose metabolism (Chap. 4, p. 56). Gestational diabetes is deined as carbohydrate intolerance of variable severity with onset or first recognition during pregnancy (American College of Obstetricians and Gynecologists, 2017a). This deinition applies whether or not insulin is used for treatment and undoubtedly includes some women with previously unrecognized overt diabetes.

Use of the term gestational diabetes has been encouraged to communicate the need for enhanced surveillance and to

TABLE 57-1 0. Insulin Management During Labor and Delivery

Usual dose of intermediate-acting insulin is given at bedtime.

Morning dose of insulin is withheld.

Intravenous infusion of normal saline is begun.

Once active labor begins or glucose levels decrease to less than 70 mg/dL, the infusion is changed from saline to 5% dextrose and delivered at a rate of 100-150 cc/h (2.5 mg/kg/min) to achieve a glucose level of approximately 100 mg/dL.

Glucose levels are checked hourly using a bedside meter allowing for adjustment in the insulin or glucose infusion rate.

Regular (short-acting) insulin is administered by intravenous infusion at a rate of 1n.25 U/h if glucose levels exceed 100 mg/dL.

Data from Coustan DR. Delivery: timing, mode, and management. In: Reece EA, Coustan DR, Gabbe SG, editors. Diabetes in women: adolescence, pregnancy, and menopause. 3rd ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2004; and Jovanovic L, Peterson CM. Management of the pregnant, insulin-dependent diabetic woman. Diabetes Care 1980;3:63-8.

stimulate women to seek further testing postpartum. The most important perinatal correlate is excessive fetal growth, which may result in both maternal and fetal birth trauma. he likelihood of fetal death with appropriately treated gestational diabetes is not diferent from that in the general population. Importantly, more than half of women with gestational diabetes ultimately develop overt diabetes in the ensuing 20 years. And, as discussed on page 1097, evidence is mounting for long-range complications that include obesity and diabetes in their ofspring.

Despite almost 50 years of research, there is still no agreement regarding optimal gestational diabetes screening. The diiculty in achieving consensus is underscored by the controversy following publication of the single-step approach espoused by the International Association of Diabetes and Pregnancy Study Groups Consensus Panel (2010) and shown in Table 57-11. his strategy was greatly influenced by results of the Hypoglycemia and Pregnancy Outcomes (HAPO) Study, described later. Although the ADA (2017 a) supports this new scheme, the American College of Obstetricians and Gynecologists (2017a) continues to recommend a two-step approach to screen and diagnose gestational diabetes. Similarly, the NIH Consensus Development Conference in 2013 concluded that evidence is insuicient to adopt a one-step approach.

he recommended two-step approach begins with either universal or risk-based selective screening using a 50-g, I-hour oral glucose challenge test. Participants in the Fifth International

TABLE 57-1 1. Threshold Values for Diagnosis of Gestational Diabetes be equaled or exceeded for the diagnosis of gestational diabetes.

bin addition, 1.7% of participants in the initial cohort were unblinded because of fasting plasma glucose levels >5.8 mmol/L (105 mg/dL) or 2-hr OGTI values > 11n.1 mmollL (200 mg/dL), bringing the total to 17.8%.

OGI = oral glucose tolerance test.

Data from International Association of Diabetes and

Pregnancy Study Groups, 2010.

Workshop Conferences on Gestational Diabetes endorsed use ofselective screening criteria shown in Table 57-12. Conversely, the American College of Obstetricians and Gynecologists (2017a) recommends universal screening of pregnant women using a laboratory-based blood glucose test. It is suggested that attempts to identiy the 10 percent of women who should not be screened would add unnecessary complexity. Screening should

TABLE 57-12. Risk-Based Recommended Screening Strategy for Detecting GDMa

GDM risk assessment: should be ascertained at the first prenatal visit

Low Risk: Blood glucose testing not routinely required if all the following are present:

Member of an ethnic group with a low prevalence of GDM No known diabetes in first-degree relatives

No history of abnormal glucose metabolism No history of poor obstetrical outcome

Average Risk: Perform blood glucose testing at 24 to 28 weeks using either:

Two-step procedure: 50-g oral glucose challenge test (GCT), followed by a diagnostic 100-g OGI for those meeting the threshold value in the GCT One-step procedure: diagnostic 100-g OGTI performed on all subjects

High Risk: Perform blood glucose testing as soon as feasible, using the procedures described above, if one or more of these are present:

Strong family history of type 2 diabetes

Previous history of GDM, impaired glucose metabolism, or glucosuria

If GDM is not diagnosed, blood glucose testing should be repeated at 24 to aCriteria of the Fifth Intenational Workshop-Conference on Diabetes. GDM = gestational diabetes mellitus; OGTI = oral glucose tolerance test.

Reproduced with permission from Metzger BE, Coustan DR, the Organizing Committee:

Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus, Diabetes Care. 1998 Aug; 21 SuppIn2:B161n-B167.

TABLE 57-13. Diagnosis of GDM Using Threshold women not known to have glucose intolerance earlier in preg nancy. This 50-g screening test is followed by a dianostic 100-g,

Tolerance Testa,b 3-hour oral glucose tolerance test (OGT) if screening results meet or exceed a predetermined plasma glucose concentration.

For the 50-g screen, the plasma glucose level is measured 1 hour ater a 50-g oral glucose load without regard to the time

Fasting 105 5.8 95 5.3 of day or time oflast meal. In a recent review, the pooled sensitiv1-hr 190 10.6 180 2-hr 165 9.2 155 8.6 ity for a threshold of 140 mg/dL ranged from 74 to 83 percent depending on 100-g thresholds used for diagnosis (van Leeuwen, 3-hr 145 8.0 140 2012). Sensitivity estimates for a 50-g screen threshold of 135 aThe test should be performed when the patient is fasting. bTwo or more of the venous plasma glucose concentra mg/dL improved only slightly to 78 to 85 percent. Importantly, speciicity dropped from a range of 72 to 85 percent for 140 mg/dL to 65 to 81 percent for a threshold of 135 mg/dL. Using a threshold of 130 mg/dL marginally improves sensitivity with a further decline in speciicity (Donovan, 2013). That said, in the absence of clear evidence supporting one cutof value over another, the American College of Obstetricians and Gynecolo gists (2017a) sanctions using anyrone of the three 50-g screen thresholds. At Parkland Hospital, we continue to use 140 mg/dL as the screening threshold to prompt the 100-g test.

Justiication for screening and treatment of women with gestational diabetes was strengthened by the study by Crowther and coworkers (2005). They assigned 1000 women with gestational diabetes between 24 and 34 weeks' gestation to receive dietary advice with blood glucose monitoring plus insulin therapy-the intervention group-or to undergo routine prenatal care. Women were diagnosed as having gestational diabetes if their blood glucose was > 100 mg/ dL ater an overnight fast and was between 140 and 198 mg/dL 2 hours ater ingesting a 75-g glucose solution. Women in the intervention group had a signiicantly lower risk of a composite adverse outcome that included perinatal death, shoulder dystocia, fetal bone fracture, and fetal nerve palsy. Macrosomia deined by birthweight ::4000 g complicated 10 percent of deliveries in the intervention group compared with 21 percent in the routine prenatal care group. Cesarean delivery rates were almost identical in the two study groups.

Slightly diferent results were reported by the MaternalFetal Medicine Units Network randomized trial of958 women (Landon, 2009). Dietary counseling plus glucose monitoring was compared with standard obstetrical care in women with mild gestational diabetes to reduce perinatal morbidity rates. Mild gestational diabetes was identiied in women with fasting glucose levels <95 mg/dL. hey reported no diferences in rates of composite morbidity that included stillbirth; neonatal hypoglycemia, hyperinsulinemia, and hyperbilirubinemia; and birth trauma. Importantly, secondary analyses demonstrated a 50-percent reduction in macrosomia, fewer cesarean deliveries, and a signiicant decrease in shoulder dystocia rate-1.5 versus 4 percent-in treated versus control women.

Based largely on these two landmark studies, the U.S. Preventive Sevices Task Force (2014) now recommends universal screening in low-risk women after 24 weeks' gestation. However, the Task Force concluded that evidence is insuicient to assess the balance of benefits versus harms of screening before 24 weeks. For screening, the optimal OGTT ro identiy gestational diabetes has not been agreed upon. The World Health Organization (2013) and the ADA (2017a) recommend the tions listed are met or exceeded for a positive diagnosis.

(Serum glucose level.

dSerum or plasma glucose level.

NDDG = National Diabetes Data Group.

Data from American Diabetes Association, 201n7a; Ferrara, 2002.

75-g, 2-hour OGTT, but acknowledge that the diagnosis can be accomplished using the two-step strategy. In the United States, however, the 1 OO-g, 3-hour OGTT performed after an overnight fast is recommended by the American College of Obstetricians and Gynecologists (2017a). Proposed criteria for interpretation of the diagnostic 100-g OGTT are shown in Table 57-13. In a secondary analysis of the Maternal-Fetal Medicine Units Network treatment trial, Harper and colleagues (2016) showed that women diagnosed with either the National Diabetes Data Group (NDDG) or the Carpenter-Co us tan criteria beneited from treatment. However, the number needed to treat to prevent a shoulder dystocia was higher for the Carpenter-Co us tan criteria. At Parkland Hospital we continue to use the NDDG criteria for diagnosis. Criteria for the 75-g OGTT recommended are shown in Table 57-11.

The Hyperglycemia and Adverse Pregnancy Outcome Study

This was a 7 -year international epidemiological study of 23,325 pregnant women at 15 centers in nine countries (HAPO Study Cooperative Research Group, 2008). The investigation analyzed the association of various levels of glucose intolerance during the third trimester with adverse infant outcomes in women with gestational diabetes. Between 24 and 32 weeks' gestation, the general population of pregnant women underwent a 75-g OGTT after an overnight fasting. Blood glucose levels were measured fasting and then 1 and 2 hours after glucose ingestion. Caregivers were blinded to results except for women whose glucose levels exceeded values that required treatment and removal from the study. Glucose values at each of these three time posts were stratiied into seven categories (Fig. 57-6). hese values were then correlated with rates for birthweight >90th percentile (LGA) , primary cesarean delivery, neonatal hypoglycemia, and cord-serum C-peptide levels >90th percentile. Odds of each outcome were calculated using the lowest category-for example, fasting plasma glucose :;75 mg/dL-as the referent group. Their indings in general supported the supposition that increasing plasma glucose levels were associated with increasing adverse outcomes. Ecker and diagnosis rates but not with reduced macrosomia rates compared with a twostep approach. Remarkably, they identi � rate associated with adoption of the : IADPSG recommendations. he ADA ) (2013, 2017a) initially recommended ) adopting this new approach, however, ..J,approach described on page 1108, they now concede that data support a twostep strategy as well.

-1hour ; 105 106-132 133-155 156-171 172-193 194-211 ::212 Prompted by the disparate recommen -2hour ; 9091-108 109-125 126-139 140-157 158-177 ::178 dations, the NIH Consensus Development Conference on Diagnosing

FIGURE 57-6 Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. The fre quency of newborn birthweight ::90th percentile for gestational age plotted against glucose was convened. his conference included levels fasting and at 1-and 2-hr intervals following a 75-g oral glucose load. LGA = large for gestational age. (Reproduced with permission from HAPO Study Cooperative Research input from a multidisciplinary planning Group, Metzger BE, Lowe LP, et al: Hyperglycemia and adverse pregnancy outcomes, N Engl committee, a systematic evidence review

J Med. 2008 May 8;358(19):1991-2002.)

Greene (2008) concluded that it would be diicult to show that treating lesser degrees of carbohydrate intolerance would provide any meaningful improvements in clinical outcomes. We agree that changes in criteria are not justiied until clinical trials prove benefits. his position was also endorsed by the 2013 NIH Consensus Development Conference.

International Association of Diabetes and Pregnancy Study Group he IADPSG sponsored a workshop conference on the diagnosis and classiication of gestational diabetes in 2008. After reviewing the results of the HAPO study, a panel developed recommendations for the diagnosis and classiication of hyperglycemia during pregnancy. This panel allowed for the diagnosis of overt diabetes during pregnancy as shown in Table 57-4. It also recommended a single-step approach to the diagnosis of gestational diabetes using the 75-g, 2-hour OGTT. hresholds for fasting, 1-, and 2-hour values based on mean glucose concentrations from the entire HAPO study cohort were considered. hese glucose level thresholds were derived using an arbitrary 1.75 odds ratio of outcomes such as LGA birthweight and cord serum C-peptide levels >90th percentile. Only one of these thresholds, shown in Table 57-11, would need to be met or exceeded to make the diagnosis of gestational diabetes.

It is estimated that implementation of these recommendations would raise the prevalence of gestational diabetes in the United States to 17.8 percent! Said another way, the number of women with mild gestational diabetes would grow almost threefold with no evidence of treatment benefit (Cundy, 2012). Feldman and coworkers (2016) evaluated the implementation of the IADPSG paradigm in a before-ater analysis that included more than 6000 women. he new strategy was associated with a significant increase in gestational diabetes by the Agency for Healthcare Research and Quality Evidence-Based Practice Center, expert testimony, and a nonbiased panel to produce the overall report. he panel concluded that there were potential beneits to worldwide standardization. However, it found insuicient evidence to adopt a one-step diagnostic process such as the one proposed by the IADPSG. Moreover, as mentioned previously, after consideration of these indings, the American College of Obstetricians and Gynecologists (2017a) continues to recommend a two-step screening and diagnostic approach to gestational diabetes diagnosis. he College noted no significant improvements in maternal or perinatal outcomes that would ofset the tripling of gestational diabetes incidence that would derive from the one-step approach. We applaud this decision.

Adverse consequences of gestational diabetes difer from those of pregestational diabetes. Unlike in women with overt diabetes, women with gestational diabetes do not appear to have fetuses with substantially higher rates of anomalies than the general obstetrical population (Sheield, 2002). In a study of more than 1 million women from the Swedish Medical Birth Registry, major malformation rates were marginally elevated in fetuses of gestational diabetics compared with those of nondiabetic controls-2.3 versus 1.8 percent (Fadl, 2010). The stillbirth rate was not greater in this study. Similarly, the stillbirth rate was not increased in an analysis by Jovanovic and associates (2015) of more than 800,000 pregnancies from 2005 through 2011. In contrast, and not unexpectedly, women with elevatedfasting glucose levels have elevated rates of unexplained stillbirths similar to those of women with overt diabetes. This increasing risk with progressive maternal hyperglycemia emphasizes the importance of identiying women with evidence of preexisting diabetes early in pregnancy (see Table 57-4). Similar to women with overt diabetes, adverse maternal efects associated with gestational diabetes include a higher frequency of hypertension and cesarean delivery.

he primary efect attributed to gestational diabetes is exces sive fetal size or macrosomia that is variably defined and dis cussed further in Chapter 44 (p. 857). The perinatal goal is birth trauma associated with shoulder dystocia. In a retrospec tive analysis of more than 80,000 vaginal deliveries in Chinese women, Cheng and associates (2013) calculated a 76-fold greater risk for shoulder dystocia in newborns weighing :4200 g compared with the risk in those weighing <3500 g. Impor tantly, however, the odds ratio for shoulder dystocia in women with diabetes was <2. Although gestational diabetes is certainly a risk factor, it accounts for onl) a small number of pregnancies complicated by shoulder dystocia.

he excessive shoulder and trunk fat that commonly characterizes the macrosomic newborn of a diabetic mother theoretically predisposes such neonates to shoulder dystocia or cesarean delivery (Durnwald, 2004; McFarland, 2000). Landon and associates (2011) identified shoulder dystocia in approximately 4 percent of women with mild gestational diabetes compared with < 1 percent of women with a 50-g glucose screen result < 120 mg/dL. In a ptospective study of fetal adipose measurements, however, Buhling and coworkers (2012) demonstrated no diferences between measurements in 630 ofspring of women with gestational diabetes and 142 without diabetes. he authors attributed this negative inding to successful treatment of gestational diabetes.

Extensive evidence supports that insulin-like growth factors also playra role in fetal-growth regulation (Chap. 44, p. 845). hese proinsulin-like polypeptides are produced by virtually all fetal organs and are potent stimulators of cell diferentiation and division. Luo and coworkers (2012) reported that insulinlike growth factor-1 strongly correlated with birthweight. he HAPO study investigators also reported dramatic increases in cord-serum C-peptide levels with rising maternal glucose levels following a 75-g OGTT. C-peptide levels above the 90th percentile were found in almost a third of newborns in the highest glucose categories. Other factors implicated in macrosomia include epidermal growth factor, ibroblast growth factor, platelet-derived growth factor, leptin, and adiponectin (Grissa, 2010; Loukovaara, 2004; Mazaki-Tovi, 2005).

Hyperinsulinemia may provoke severe hypoglycemia within minutes of birth, but only three fourths of these episodes occur in the irst 6 hours (Harris, 2012). he deinition of neonatal hypoglycemia is controversial, with recommended clinical thresholds ranging from 35 to 45 mg/dL. An NIH workshop conference on neonatal hypoglycemia supported using a threshold of 35 mg/dL in term newborns but cautioned that this practice is not strictly evidence based (Hay, 2009). Newborns described by the HAPO study (2008) had an incidence of clinical neonatal hypoglycemia that rose with increasing maternal OGTT result values deined in Figure 57-6. The frequency varied from 1 to 2 percent, but it was as high as 4.6 percent in women with fasting glucose levels : 100 mg/ dL. Similarly,

Cho and colleagues (2016), analyzed more than 3000 Korean women who underwent a 50-g OGTT and found that neonates born to women with a screening result :200 mg/dL were 84 times more likely to have hypoglycemia than those born to women with a result < 140 mg/dL. he risk of neonatal hypoglycemia correlates with umbilical cord C-peptide levels. But, importantly, the risk also rises with birthweight, independent of a maternal diabetes diagnosis (Mitanchez, 2014).

Maternal Obesity. In women with gestational diabetes, maternal body mass index (BMI) is an independent and more substantial risk factor for fetal macrosomia than is glucose intolerance (Ehrenberg, 2004; Mission, 2013). Stuebe and associates (2012) completed a secondary analysis of women with either untreated mild gestational diabetes or normal glucose tolerance testing results. They found that higher BMI levels were associated with rising birthweight, regardless of glucose levels. In one analysis of more than 600,000 pregnant women, gestational diabetes, compared with obesity or gestational weight gain, contributed the least to the population-attributable fraction of LGA neonates (Kim, 2014). he highest fraction of LGA neonates was attributable to maternal obesity plus excessive gestational weight gain. Similarly, Egan and colleagues (2014) found that excessive gestational weight gain is common in women with gestational diabetes and confers an additive risk for fetal macrosomia. Weight distribution also seems to playra role because the risk of gestational diabetes is greater with maternal truncal obesity. Suresh and colleagues (2012) veriied that increased maternal abdominal subcutaneous fat thickness as measured by sonography at 18 to 22 weeks' gestation correlated with BMI and was a better predictor of gestational diabetes.

Women with gestational diabetes can be divided into two functional classes using fasting glucose levels. Pharmacological methods are usually recommended if diet modiication does not consistently maintain the fasting plasma glucose levels <95 mg/dL or the 2-hour postprandial plasma glucose < 120 mg/dL (American College of Obstetricians and Gynecologists, 2017 a). Whether pharmacological treatment should be used in women with lesser degrees of fasting hyperglycemia is unclear. here have been no controlled trials to identiy ideal glucose targets for fetal risk prevention. On the other hand, the HAPO study (2008) did demonstrate increased fetal risk at glucose levels below the threshold used for diagnosis of diabetes. The Fifth International Workshop Conference recommended that fasting capillary glucose levels be kept ;95 mg/ dL (Metzger, 2007).

In a systematic review, Hartling and colleagues (2013) concluded that treating gestational diabetes resulted in a signiicantly lower incidence of preeclampsia, shoulder dystocia, and macrosomia. For example, the calculated risk ratio was 0.50 for delivering a newborn >4000 g ater treatment. These investigators caution that the attributed risk for these outcomes is low, especially when glucose values are only moderately elevated. Importantly, they were unable to demonstrate an efect on neonatal hypoglycemia or on future metabolic outcomes in the ofspring.

Nutritional instructions generally include a carbohydratecontrolled diet suicient to maintain normoglycemia and avoid ketosis. On average, this includes a daily caloric intake of 30 to 35 kcallkg. Moreno-Castilla and associates (2013) randomly assigned 152 women with gestational diabetes to either a 40-or a 55-percent daily carbohydrate diet and found no diference in insulin levels and pregnancy outcomes. he American College of Obstetricians and Gynecologists (2017 a) suggests that carbohydrate intake be limited to 40 percent of total calories. The remaining calories are apportioned to give 20 percent as protein and 40 percent as fat.

The most appropriate dietary approach for women with gestational diabetes has not been established. One metaanalysis of trials of low-glycemic index diets found that diets higher in complex carbohydrates and dietary iber reduced the risk of macrosomia and likelihood of insulin use in women with gestational diabetes (Wei, 2016). That said, there clearly are limitations to what can be accomplished with various dietary approaches alone. Most and Langer (2012) found that insulin was efective in reducing the risk of excessive birthweight in ofspring of obese women with gestational diabetes. Casey and colleagues (20 15 b) also found that dietary treatment alone for morbidly obese women with mild gestational diabetes did not reduce neonatal fat mass or LGA birthweights.

Few trials have evaluated exercise speciically for women with gestational diabetes. he American College of Obstetricians and Gynecologists (2017a,b) recommends regular physical activity that incorporates aerobic and strength-conditioning exercise during pregnancy and extends this to women with gestational diabetes. Two recent metaanalyses demonstrate that structured exercise programs during pregnancy diminish weight gain during pregnancy and even reduce the risk of developing gestational diabetes (Russo, 2015; Sanabria-Martinez, 2015). Exercise during pregnancy in woman with gestational diabetes also lowers glucose levels Qovanovic-Peterson, 1989).

Hawkins and colleagues (2008) compared outcomes in 315 women with diet-treated gestational diabetes who used personal glucose monitors with those of 615 gestational diabetics who were also diet-treated but who underwent intermittent fasting glucose evaluation during weekly obstetrical visits. Women using daily blood-glucose self monitoring had significantly fewer macrosomic newborns. They also gained less weight after diagnosis than women evaluated during clinic visits only. hese indings support the common practice of blood-glucose self monitors for women with diet-treated gestational diabetes.

Postprandial surveillance for gestational diabetes has been shown to be superior to preprandial surveillance (De Veciana, 1995). At Parkland Hospital, we reviewed the impact of changing to postprandial monitoring in women with diet-treated gestational diabetes and demonstrated a signiicant reduction in maternal weight gain per week-0.63lb/week to 0.45 lb/weekin women managed with a postprandial monitoring schema. The merican College of Obstetricians and Gynecologists (2017 a) and the ADA (20 17b) recommend glucose assessment four times daily. The first check is performed fasting, and the remainder are done 1 or 2 hours ater each meal.

Historically, insulin has been considered standard therapy in women with gestational diabetes when target glucose levels cannot be consistently achieved through nutrition and exercise. It does not cross the placenta, and tight glycemic control can typically be achieved. Insulin therapy is typically added if fasting levels persistently exceed 95 mg/ dL in women with gestational diabetes. The American College of Obstetricians and Gynecologists (2017 a) also recommends that insulin be considered in women with I-hour postprandial levels that persistently exceed 140 mg/dL or those with 2-hour levelsr> 120 mg/dL. Importantly, all of these thresholds are extrapolated from recommendations for managing women with overt diabetes.

If insulin is initiated, the starting dose is typically 0.7 to 1.0 units/kg/d and is given in divided doses (American College of Obstetricians and Gynecologists, 2017a). A combination of intermediate-acting and short -acting insulin may be used, and dose adjustments are based on glucose levels at particular times of the day. At Parkland Hospital, the starting daily dose is divided so that two thirds is given in the morning before breakfast and one third in the evening before dinner. In the morning dose, one third is regular insulin and two thirds are NPH (neutral protamine Hagedorn). For the evening dose, one half is regular insulin and the other half is NPH. Insulin instruction for these women is accomplished either in a specialized outpatient clinic or during a short hospital stay. As shown in Table 57-8, insulin analogues such as insulin aspart and insulin lispro have a more rapid onset of action than regular insulin and theoretically could be helpful in postprandial glucose management. Experience with these analogues with gestational diabetes is limited, and Singh and coworkers (2009) were unable to demonstrate a beneit compared with conventional insulins.

Insulin is the preferred first-line agent for persistent hyperglycemia in women with gestational diabetes. However, both the American College of Obstetricians and Gynecologists (2017 a) and the ADA (20 17b) acknowledge that several studies support the safety and eicacy of either glyburide (Micronase) or metformin (Glucophage) (Langer, 2000; Nicholson, 2009; Rowan, 2008). Balsells and colleagues (2015) performed metaanalyses of trials comparing both agents to insulin or to each other. In the seven trials comparing glyburide with insulin, glyburide was associated with higher birthweight, more macrosomia, and more frequent neonatal hypoglycemia. In the six trials comparing metformin with insulin, metformin was associated with less maternal weight gain, more ?reterm birth, and less severe neonatal hypoglycemia. On average from all trials, treatment failures occurred in 6 percent of women treated with glyburide and 34 percent of those treated with metformin. In the two studies comparing oral hypoglycemic agents with each other, metformin treatment was associated with less maternal weight gain, lower birthweight, and less macrosomia. In contrast to trials of each agent compared with insulin, treatment failure rates of both agents in these two studies were equivalent. Importantly, in a randomized trial of glyburide treatment as an adjunct to diet therapy in 395 women with mild gestational diabetes, improvements in pregnancy outcomes in women treated with glyburide.

comes among women treated with glyburide. First, like metfor min, glyburide crosses the placenta and reaches concentrations in the fetus that are more than two thirds of maternal lev els (Caritis, 2013). Additionally, a study of more than 9000 women with gestational diabetes treated with either insulin or glyburide showed a signiicant rise in rates of neonatal intensive care unit admission, respiratory distress, and neonatal hypogly cemia associated with glyburide use (Castillo, 2015).

Metformin reaches fetal serum concentrations similar to maternal levels. However, in one study of 751 women with gestational diabetes who were randomly assigned to metformin or insulin treatment, short-term perinatal adverse events did not difer between groups (Rowan, 2008). Outcomes included neonatal hypoglycemia, respiratory distress syndrome, photo therapy, birth trauma, 5-minute Apgar score .7, and preterm birth. Overall growth of ofspring at age 2 years also did not difer (Rowan, 2011). Nevertheless, the fat distribution in chil dren exposed to metformin showed a tendency toward a more favorable pattern. From a smaller randomized metformin trial, at 18 months, ofspring exposed to metformin were slightly heavier, but markers of early motor or language development did not difer compared with those in ofspring exposed to insulin (Ijas, 2015).

The Food and Drug Administration has not approved glyburide and metformin use for treatment of gestational diabetes. However, the American College of Obstetricians and Gynecologists (2017 a) recognizes both as reasonable choices for second-line glycemic control in women with gestational diabetes. Because long-term outcomes have not been fully studied, the committee recommends appropriate counseling, which includes disclosing the limitations in current safety data.

In general, for women with gestational diabetes who do not require insulin, early delivery or other interventions are seldom required. here is no consensus regarding the value or timing of antepartum fetal testing. It is typically reserved for women with pregestational diabetes because of the greater stillbirth risk. The American College of Obstetricians and Gynecologists (2017a) endorses fetal surveillance in women with gestational diabetes and poor glycemic control. At Parkland Hospital, women with gestational diabetes are routinely instructed to perform daily fetal kick counts in the third trimester (Chap. 17, p. 332). Insulin-treated women are ofered inpatient admission after 34 weeks' gestation, and antepartum monitoring is performed three times each week.

Women with gestational diabetes and adequate glycemic control are managed expectantly. Elective labor induction to prevent shoulder dystocia compared with spontaneous labor remains controversial. Alberico and colleagues (2017) recently described their truncated randomized trial of 425 women with tation. Although underpowered, this GINEXMAL Trial dem onstrated no clinically meaningful diference in the cesarean delivery rate between the induction and expectant management groups-12.6 versus 11.8 percent. However, with early labor induction, neonatal hyperbilirubinemia rates were signiicantly higher, and ironically, there was a nonsigniicant threefold greater shoulder dystocia rate. In a retrospective cohort study of 8392 Canadian women with gestational diabetes, Melamed 39 weeks was associated with a lower rate of cesarean delivery but with an elevated rate of neonatal intensive care unit admis sion. The American College of Obstetricians and Gynecologists 39 weeks' gestation. At Parkland Hospital, women with diet treated gestational diabetes are not electively induced for this indication. However, those treated with insulin are delivered at 38 weeks' gestation.

Elective cesarean delivery to avoid brachial plexus injuries in overgrown fetuses is another important issue. The American College of Obstetricians and Gynecologists (2017a) has concluded that data are insuicient to determine whether cesarean delivery in women with gestational diabetes whose fetuses have a sonographically estimated weight �4500 g should be performed to avoid risk of birth trauma. From their systematic review, Garabedian and coworkers (2010) estimated that as many as 588 cesarean deliveries in women with gestational diabetes and an estimated fetal weight of �4500 g would be necessary to avoid one case of permanent brachial plexus palsy. Scifres and colleagues (2015), in their retrospective analysis of 903 women with gestational diabetes who underwent so nographic evaluation within 1 month of delivery, demonstrated that sonographic estimates of fetal weight typically overdiagnosed fetuses as being LGA. Only 22 percent of women estimated to have an LGA fetus actually delivered an overgrown newborn. Still, the American College of Obstetricians and Gynecologists (2016a) acknowledges that prophylactic cesarean delivery may be considered in diabetic women with an estimated fetal weight �4500 g.

Recommendations for postpartum evaluation are based on the 50-percent likelihood of women with gestational diabetes developing overt diabetes within 20 years (O'Sullivan, 1982). The Fifth International Workshop Conference on Gestational Diabetes recommended that women diagnosed with gestational diabetes undergo postpartum evaluation with a 75-g OGTT (Metzger, 2007). These recommendations are shown in Table 57-14 along with the classification scheme of the ADA (20 17b). Eggleston and colleagues (2016) reviewed insurance claim data from 2000 to 2013 and found that only 24 percent of women with a pregnancy complicated by gestational diabetes underwent postpartum screening within a year, and less than half of those underwent a 75-g OGTT. he American College

TABLE 57-14. Fifth International Workshop-Conference: Metabolic Assessments Recommended after Pregnancy with

Fasting or random plasma glucose 75-g, 2-hr OGI 75-g, 2-hr OGTI 75-g, 2-hr OGTI 75-g, 2-hr OGTI

Classification of the American Diabetes Association (2013) 2 hr <140 mg/dL 2 hr �140-199 mg/dL Hemoglobin A1c<5.7% 5.7-6.4%

OGTI = oral glucose tolerance test.

Detect persistent, overt diabetes

Postpartum classification of glucose metabolism Assess glucose metabolism 2 hr �200 mg/dL �6.5%

Data from American Diabetes Association, 2013, 2017a; Metzger, 2007.

of Obstetricians and Gynecologists (2017a) recommends either a fasting glucose or the 75-g, 2-hour OGTT at 4 to 12 weeks postpartum for the diagnosis of overt diabetes. he ADA (2017a) recommends testing at least every 3 years in women with a history of gestational diabetes but normal postpartum glucose screening.

Women with a history of gestational diabetes are also at risk for cardiovascular complications associated with dyslipidemia, hypertension, and abdominal obesity-the metabolic syndrome (Chap. 48, p. 937). In a study of 47,909 parous women, Kessous and coworkers (2013) evaluated subsequent hospitalizations due to cardiovascular morbidity. hey found that almost 5000 women with gestational diabetes were 2.6 times more likely to be hospitalized for cardiovascular morbidity. Another study evaluated 483 women between 5 and 10 years ater being diagnosed with mild gestational diabetes (Varner, 2017). Investigators found no increased risk for developing metabolic syndrome associated with additional pregnancies. However, risk for subsequent diabetes rose almost fourfold if gestational diabetes complicated at least one subsequent pregnancy.

In a metaanalysis of published reports from 1973 through 2014, the pooled gestational diabetes recurrence rate was 48 percent (Schwartz, 2015). Rates in primiparas were lower (40 percent) than in multiparas (73 percent). The same group of investigators identified maternal BMI, insulin use, fetal macrosomia, and weight gain between pregnancies as additional risk factors for gestational diabetes recurrence (Schwartz, 2016). Thus, lifestyle behavioral changes that include weight control and exercise between pregnancies would seem likely to prevent gestational diabetes recurrence. Gueli and colleagues (2016) were unable to demonstrate a lower recurrence rate in women randomized to an exercise program that started before 14 weeks' gestation in a subsequent pregnancy. Conversely, Ehrlich and colleagues (2011) found that prepregnancy loss of at least two BMI units was associated with a lower subsequent risk of gestational diabetes in women who were overweight or obese in the irst pregnancy.

Adane A, Mishra GO, Tooth LR: Diabetes in pregnancy and childhood cognitive development: a systematic review. Pediatrics 137(5):pii:e20154234, 2016 lberico S, Erenbourg A, Hod M, et al: Immediate delivery or expectant management in GDM at term: the GINEXMAL randomised controlled trial. B]OG 124(4):669,t201y

Alvarez ]R, Fechner A], Williams SF, et al: Asymptomatic bacteriuria in pregestational diabetic pregnancies and the role of group B streptococcus. Am ] Perinat 27(3):231,t2010

Ambia M, Seacely AR, Macias 0, et al: The impact of baseline proteinuria in pregnancy in a contemporary diabetic population. Presented at the 38th Annual Meeting of the Society for Maternal-Fetal Medicine, January 29-February 3,t2018

American Academy of Ophthalmology: Diabetic Retinopathy PPP-Updated 20 16 . Available at: h ttps: / /www.aao. 0rg/ preferred -p ractice-pattern/ diabeticretinopathy-ppp-updated-2016. Accessed November 5, 2017

American College of Obstetricians and Gynecologists: Management of diabetes mellitus in pregnancy. Technical Bulletin No. 92, May 1986

American College of Obstetricians and Gynecologists: Fetal macrosomia. Practice Bulletin No. 173, November 2016a

American College of Obstetricians and Gynecologists: Pregestational diabetes mellitus. Practice Bulletin No. 60, 2005, Reairmed 2016b

American College of Obstetricians and Gynecologists: Gestational diabetes mellitus. Practice Bulletin No. 180, ]uly 2017a

American College of Obstetricians and Gynecologists: Physical activity and exercise during pregnancy and the postpartum period. Committee Opinion No. 650, December 2015, Reairmed 2017b

American Diabetes Association: Classification and diagnosis of diabetes-20 17.

Diabetes Care 40(1 Suppl):S005, 2017a

American Diabetes Association: Standards of medical care in diabetes-2013.

Diabetes Care 36(Suppl 1):Sll, 2013

American Diabetes Association: Standards of medical care in diabetes-20 17.

Diabetes Care 40(1 Suppl):S 114, 2017b

Arun CS, Taylor R: Influence of pregnancy on long-term progression of retinopathy in patients with type 1 diabetes. Diabetologia 51: 1041, 2008

Bacon S, Schmid], McCarthy A, et al: The clinical management ofhyperglycemia in pregnancy complicated by maturity-onset diabetes of the young. Am ] Obstet GynecoIt213(2):236.e1, 2015

Balsells v!, Garda-Patterson A, Sola I, et al: Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BM] 350:h102, 2015

Bantle ]P, Wylie-Rosettt], Albright AL, et al: Nutrition recommendations and interventions for diabetes. Diabetes Care 31(1 Suppl):S61, 2008

Bargiota A, Kotoula M, Tsironi E, et al: Diabetic papillopathy in pregnancy. Obstet GynecoItI18:457, 2011

BartSch E, Medcalf KE, Park L, et al: Clinical risk factors for pre-eclampsia determined in early pregnancy: systematic review and meta-analysis of large cohort studies. BM] 353:i 1 53, 2016

Bennett SN, Tita A, Owen ], et al: Assessing White's classification of pregestational diabetes in a contemporary diabetic population. Obstet Gynecol 125(5):1217,t2015

Bental Y, Reichman B, Shif Y, et al: Impact of maternal diabetes mellitus on mortality and morbidity of preterm infants (24-33 weeks gestation). Pediatrics 128:e848, 2011

Boghossian NS, Hansen NI, Bell EF, et al: Outcomes of extremely preteI'm infants born to insulin-dependent diabetic mothers. Pediatrics 137(6):e20 153424, 2016 Bradley R], Nicolaides KH, Brudenell ]M: Are all infants of diabetic mothers "macrosomic"? BM] 297:1583, 1988

Bryant SN, Herrera CL, Nelson DB, et al: Diabetic ketoacidosis complicating pregnancy.t] Neonatal Perinatal Med ,t2017

Buhling K], Doll I, Siebert G, et al: Relationship between sonographically estimated fetal subcutaneous adipose tissue measurements and neonatal skinfold measurements. Ultrasound Obstet Gynecol 39:558, 2012

Caritis SN, Hebert MF: A pharmacologic approach to the use of glyburide in pregnancy. Obstet Gynecol 121(6):1309,t2013

Casey BM, Duryea EL, Abbassi-Ghanavati M, et al: Glyburide in women with mild gestational diabetes: a randomized controlled trial. Obstet Gynecol 126(2):303,t2015a

Casey BM, Mele L, Landon MB, et al: Does maternal body mass index influence treatment efect in women with mild gestational diabetes? Amt] Perinatol 32(1):93, 2015b

Castillo We, Boggess K, Sturmer T, et al: Association of adverse pregnancy outcomes with glyburide vs insulin in women with gestational diabetes. ]AMA Pediatr 169(5):452,t2015

Catalano PM, Thomas A, Huston-Presley L, et al: Increased fetal adiposity: a very sensitive marker of abnormal in utero development. Am ] Obstet GynecoIt189(6):1698,t2003

Centers for Disease Control and Prevention: Diabetes report card 2014.

Updated 2015. Available at: https://ww.cdc.gov/diabetesllibrarylreports/ reportcard.html. Accessed November 9, 2017

Centers for Disease Control and Prevention: National diabetes statistics report, 2017. Available at: https://ww.cdc.gov/diabetes/data/statistics/statisticsreport.html. Accessed November 9,t2017

Chen R, Ben-Haroush A, Weismann-Brenner A, et al: Level of glycemic control and pregnancy outcome in type 1 diabetes: a comparison between multiple daily insulin injections and continuous subcutaneous insulin infusions. Am ] Obstet Gynecol 197 :404e.tl, 2007

Cheng K, Lao TT, Sahota OS, et al: Use of birth weight threshold for macrosomia to identiY fetuses at risk of shoulder dystocia among Chinese populations. Int] Gynecol Obstet 120:249,t2013 Cho Hy, lung I, Kim S]: he association between maternal hyperglycemia and perinatal outcomes in gestational diabetes mellitus patients: a retrospective cohort study. Medicine (Baltimore) 95(36):e4712, 2016 Combs CA: Continuous glucose monitoring and insulin pump therapy for diabetes in pregnancy.t] Matern Fetal Neonatal Med 25(10):2025, 2012 Coustan DR: Delivery: timing, mode, and management. In Reece EA, Coustan DR, Gabbe SG (eds): Diabetes in Women: Adolescence, Pregnancy, and Menopause, 3rd ed. Philadelphia, Lippincott Williams & Wilkins, 2004

Crowther CA, Hiller ]E, Moss ]R, et al: Efect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Englt] Med 352:2477, 2005 Cundy T: Proposed new diagnostic criteria for gestational diabetes-a pause for thought? Diabet Med 29(2): 176, 2012

Dashe ]S, McIntire DO, Twickler OM: Efect of maternal obesity on the ultrasound detection of anomalous fetuses. Obstet Gynecol 113(5):1001,t2009

Dashe ]S, Nathan L, McIntire DO, et al: Correlation between amniotic luid glucose concentration and amniotic luid volume in pregnancy complicated by diabetes. Am ] Obstet Gynecol 182:901, 2000

DeBoer T, Wewerka S, Bauer P], et al: Explicit memory performance in infants of diabetic mothers at 1 year of age. Dev Med Child Neurol 47:525, 2005

DeMarini S, Mimouni F, Tsang Re, et al: Impact of metabolic control of diabetes during pregnancy on neonatal hypocalcemia: a randomized study. Obstet Gynecol 83:918, 1994

DeSisto CL, Kim SY, Sharma A]: Prevalence estimates of gestational diabetes mellitus in the United States, Pregnancy Risk Assessment Monitoring System (PRAMS), 2007-2010. Prev Chronic Dis II:EI04, 2014

DeVeciana M, Major CA, Morgan M, et al: Postprandial versus preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin therapy. N Englt] Med 333: 1237, 1995

Donovan L, Hartling L, Muise M, et al: Screening tests for gestational diabetes: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 159(2):115,t2013

Durnwald C, Huston-Presley L, Amini S, et al: Evaluation of body composition of large-for-gestational-age infants of women with gestational diabetes mellitus compared with women with normal glucose levels. Am ] Obstet Gynecol 191:804, 2004

Ecker ]L, Greene MF: Gestational diabetes-setting limits, exploring treatment. N Engl] Med 358(19):2061, 2008

Egan vl, Dennedy MC, Al-Ramli W: ATLANTIC-DIP: excessive gestational weight gain and pregnancy outcomes in women with gestational or pregestational diabetes mellitus.] Clin Endocrinol Metab 99(1):212, 2014

Eggleston EM, LeCates RF, Zhang F, et al: Variation in postpartum glycemic screening in women with a history of gestational diabetes mellitus. Obstet Gynecol 128(1):159,t2016

Ehrenberg HM, Mercer BM, Catalano PM: The inluence of obesity and diabetes on the prevalence of macrosomia. Amt] Obstet Gynecol 191 :964, 2004

Ehrlich SF, Hedderson MM, Feng], et al: Change in body mass index between pregnancies and the risk of gestational diabetes in a second pregnancy. Obstet Gynecol 117(6): 1323, 2011

Eidem 1, Vangen S, Hanssen KF, et al: Perinatal and infant mortality in term and preterm births among women with type 1 diabetes. Diabetologia 54(11):2{71,t2011

Fadl HE, Ostlund M, Magnusont AF, et al: Maternal and neonatal outcomes and time trends of gestational diabetes mellitus in Sweden from 1991 to 2003. Diabet vled 27:436, 2010

Farrar 0, Tufnell 0], West]: Continuous subcutaneous insulin infusion versus multiple daily injections of insulin for pregnant women with diabetes. Cochrane Database Syst Rev 6:CD005542, 2016

Feig OS, Hwee], Shah BR, et al: Trends in incidence of diabetes in pregnancy and serious perinatal outcomes: a large, population-based study in Ontario, Canada, 1996-2010. Diabetes Care 37(6):1590,t2014

Feig OS, Palda VA: Type 2 diabetes in pregnancy: a growing concern. Lancet 359: 1690, 2002

Feldman RK, Tieu RS, Yasumura L: Gestational diabetes screening: The International Association of the Diabetes and Pregnancy Study Groups compared with Carpenter-Coustan screening. Obstet Gynecol 127(1):10,t2016

Ferrara A, Hedderson MM, Quesenberry CP, et al: Prevalence of gestational diabetes mellitus detected by the National Diabetes Data Group or the Carpenter and Coustan plasma glucose thresholds. Diabetes Care 25(9): 1625, 2002

Finer LB, Zolna MR: Declines in unintended pregnancy in the United States, 2008-201t1. N Englt] Med 374(9):843, 2016

Fouda UM, Abou EIKassem MM, Hefny SM, et al: Role of fetal echocardiography in the evaluation of structure and function of fetal heart in diabetic pregnancies.t] Matern Fetal Neonatal Med 26(6):571,t2013

Fraser A, Almqvist C, Larsson H: Maternal diabetes in pregnancy and ofspring cognitive ability: sibling study with 723,775 men from 579,857 families. Diabetologia 57(1):102, 2014

Frayne 0], Verbiest S, Chelmow 0, et al: Health care system measures to advance preconception wellness: consensus recommendations of the clinical workgroup of the national preconception health and health care initiative. Obstet Gynecol 127(5):863,t2016

Fuglsang], Ovesen PG: Pregnancy and delivery in a woman with type 1 diabetes, gastroparesis, and a gastric neurostimulator. Diabetes Care 38(5):e75, 2015

Galindo A, Burguillo AG, Azriel S, et al: Outcome of fetuses in women with pregestational diabetes mellitus. ] Perinat Med 34(4):323, 2006

Garabedian C, Deruelle P: Delivery (timing, route, peripartum glycemic control) in women with gestational diabetes mellitus. Diabetes Metab 36:515, 2010

Gardosi], Madurasinghe V, Williams M, et al: Maternal and fetal risk factors for stillbirth: population based study. BM] 346:fl08, 2013

Game E, Loane M, Dolk H, et al: Spectrum of congenital anomalies in pregnancies with pregestational diabetes. Birth Defects Res A Clin Mol Teratol 94(3):134,t2012

Golden SH, Brown A, Cauley ]A, et al: Health disparities in endocrine disorders: biological, clinical, and nonclinical factors-an Endocrine Society scientific statement.t] Clin Endocrinol Metab 9z(9):EI579, 2012

Grissa 0, Yessoufou A, Mrisak I, et al: Growth factor concentrations and their placental mRNA expression are modulated in gestational diabetes mellitus: possible interactions with macrosomia. BMC Pregnancy Childbirth 10:7,2010

Gueli K], Ong M], Crisp NA, et al: Regular exercise to prevent the recurrence of gestational diabetes mellitus: a randomized controlled trial. Obstet Gynecol 128(4):819,t2016

Guntupalli KK, Karnad DR, Bandi V, et al: Critical illness in pregnancy: Part

II: common medical conditions complicating pregnancy and puerperium. Chest 148(5):1333,t2015

Hammoud NM, Visser GH, Peterst SA, et al: Fetal growth profiles of macrosomic and non-macrosomic infants of women with pregestational or gestational diabetes. Ultrasound Obstet GynecoIt41(4):390, 2013

Hanson U, Persson B: Outcome of pregnancies complicated by type 1 insulindependent diabetes in Sweden: acute pregnancy complications, neonatal mortality and morbidity. Am J Perinatol10:330, 1993

HAPO Study Cooperative Research Group: Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 358:2061,t2008

Harper LM, Mele L, Landon MB, et al: Carpenter-Coustan compared with National Diabetes Data Group criteria for diagnosing gestational diabetes. Obstet Gynecol 127(5):893,t2016

Harris DL, Weston PJ, Harding JE: Incidence of neonatal hypoglycemia in babies identified as at risk. J Pediatr 161(5):787, 2012

Hartling L, Dryden DM, Guthrie A, et al: Benefits and harms of treating gestational diabetes mellitus: a systematic review and meta-analysis for the U.S. Preventive Services Task Force and the National Institutes of Health Oice of Medical Applications of Research. Ann Intern Med 159(2):123, 2013

Hawkins JS, Lo JY, Casey BM, et al: Diet-treated gestational diabetes: comparison of early versus routine diagnosis. m J Obstet Gynecol, 198:287, 2008 Hawthorne G: Maternal complications in diabetic pregnancy. Best Pract Res Clin Obstet Gynaecol 25(1):77, 2011

Hay W: Care of the infant of the diabetic mother. Curr Diab Rep 12:4, 2012

Hay W, Raju TN, Higgins RD, et al: Knowledge gaps and research needs for understanding and treating neonatal hypoglycemia: workshop report from Eunice Kennedy Shriver National Institute of Child Health and Human Development. J Pediatrics 155(5):612,t2009

Hill JB, Sheield JS, McIntire DD, et al: Acute pyelonephritis in pregnancy.

Am J Obstet Gynecolt105(l):18, 2005

How HY, Sibai B, Lindheimer M, et al: Is early-pregnancy proteinuria associated with an increased rate of preeclampsia in women with pregestational diabetes mellitus? Am J Obstet GynecoIt190:775, 2004

Huang H, He J, Johnson D, et al: Deletion of placental growth factor prevents diabetic retinopathy and is associated with Akt activation and HIF1aVEGF pathway inhibition. Diabetes 64(3):1067, 2015

Huang T, Kelly A, Becker SA, et al: Hypertrophic cardiomyopathy in neonates with congenital hyperinsulinism. rch Dis Child Fetal Neonatal Ed 98(4):F351,t2013

Idris N, Wong SF, homae M, et al: Inluence of polyhydramnios on perinatal outcome in pregestational diabetic pregnancies. Ultrasound Obstet Gynecol 36(3):338, 2010

Ijas H, Vaarasmaki M, Saarela T, et al: A follow-up of a randomised study of metformin and insulin in gestational diabetes mellitus: growth and develop ment of the children at the age of 18 months. BJOG ):994,t2015

International Association of Diabetes and Pregnancy Study Groups Consensus Panel: Recommendations on the diagnosis and classiication of hyperglycemia in pregnancy. Diabetes Care 33(3),t2010

Jensen DM, Damm P, Ovesen P, et al: Microalbuminuria, preeclampsia, and preterm delivery in pregnant women with type 1 diabetes. Diabetes Care 33:90,t2010

Johnston RC, Gabby L, Tith T, et al: Immediate postpartum glycemic control and risk of surgical site infection. J Matern Fetal Neonatal Med 30(3):267,t2017

Jovanovic L, Liang Y, Weng W, et al: Trends in the incidence of diabetes, its clinical sequelae, and associated costs in pregnancy. Diabetes Metab Res Rev 31(7):707,t2015

Jovanovic-Peterson L, Durak EP, Peterson CM: Randomized trial of diet versus diet plus cardiovascular conditioning on glucose levels in gestational diabetes. Am J Obstet GynecoI161:415, 1989

Kessous R, Shoham-Vardi I, Pariente G, et al: An association between gestational diabetes mellitus and long-term maternal cardiovascular morbidity. Heart 99: 1118,t2013

Kim C, Ferrara A, McEwen LN, et al: Preconception care in managed care: the translating research into action for diabetes study. Am J Obstet Gynecol 192:227,t2005

Kim SY, Sharma AJ, Sappenield W, et al: Association of maternal body mass index, excessive weight gain, and gestational diabetes mellitus with large-forgestational-age births. Obstet GynecoIt123(4):737, 2014

Kitzmiller JL, Block JM, Brown FM, et al: Managing preexisting diabetes for pregnancy. Diabetes Care 31(5):1060, 2008

Krakowiak P, Walker CK, Bremer A, et l: Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. Pediatrics 129:el121,t2012

Landon MB, Catalano PM, Gabbe SG: Diabetes mellitus. In Gabbe SG, Niebyl JR, Simpson JL (eds): Obstetrics: Normal and Problem Pregnancies, 4th ed. Philadelphia, Churchill Livingstone, 2002

Landon MB, Mele L, Spong CY, et al: The relationship between maternal glycemia and perinatal outcome. Obstet Gynecol 117(2):218,t2011

Landon MB, Spong CY, Thon E, et al: A multicenter, randomized treatment trial of mild gestational diabetes. N Engl J Med 361 (14): 1339, 2009 Langer 0, Conway DL, Berkus MD, et al: A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 343: 1134, 2000 LauenborgJ, Mathiesen E, Ovesen P, et al: Audit on stillbirths in women with pregestational type 1 diabetes. Diabetes Care 26(5): 1385, 2003

Leinonen PJ, Hiilesmaa VK, Kaaja RJ: Maternal mortality in type 1 diabetes.

Diabetes Care 24(8):1501, 2001

Little SE, Zara CA, Clapp vIA, et al: A multi-state analysis of early-term delivery trends and the association with term stillbirth. Obstet Gynecol 126(6):1138,t2015

Liu S, Joseph KS, Lisonkova S, et al: Association between maternal chronic conditions and congenital heart defects: a population-based cohort study. Circulation 128(6):583,t2013 Loukovaara M, Leinonen P, Teramo K, et al: Diabetic pregnancy associated with increased epidermal growth factor in cord serum at term. Obstet Gynecol 103:240,t2004

Luo Zc, Nuyt AM, Delvin E, et al: Maternal and fetal IGF-1 and IGF-11 levels, fetal growth, and gestational diabetes. J Clin Endocrinol Metab :1720,t2012

Marschalek J, Farr A, Kiss H, et al: Risk of vaginal infections at early gestation in patients with diabetic conditions during pregnancy: a retrospective cohort study. PLoS One 11(5):e0155182, 2016

Martin JA, Hamilton BE, Osterman MJ, et al: Births: final data for 2015. Natl Vital Stat Rep 66 (1):1,t2017

Mathiesen ER, Ringholm L, Feldt-Rasmussen B, et al: Obstetric nephrology: pregnancy in women with diabetic nephropathy-the role of antihyperten sive treatment. Clin J Am Soc :2081,t2012

Mazaki-T ovi S, Kanety H, Pariente C, et al: Cord blood adiponectin in largefor-gestational age newborns. Am J Obstet Gynecol 193: 1238, 2005

McCance DR, Holmes VA, Maresh MJ, et al: Vitamins C and E for prevention of preeclampsia in women with type 1 diabetes (DAPIT): a randomised placebo-controlled trial. Lancet 3 6:259,t2010

McElvy SS, Demarini S, Miodovnik M, et al: Fetal weight and progression of diabetic retinopathy. Obstet Gynecol 97:587, 2001 vIcFariand MB, Langer 0, Fazioni E, et al: Anthropometric and body composition diferences in large-for-gestational age, but not appropriate-forgestational age infants of mothers with and without diabetes mellitus. J Soc Gynecol Investig 7:231, 2000

Melamed N, Ray JG, Geary M, et al: Induction of labor before 40 weeks is associated with lower rate of cesarean delivery in women with gestational diabetes mellitus. m J Obstet GynecoIt214(3):364.e1, 2016

Metzger BE, Buchanan TA, Coustan DR, et al: Summary and recommendations of the Fith International Workshop-Conference on Gestational Diabetes. Diabetes Care 30(SuppIt2):S251, 2007

Miailhe G, Le Ray C, Timsit J, et al: Factors associated with urgent cesarean delivery in women with type 1 diabetes mellitus. Obstet Gynecol 121:983, 2013

Middleton P, Crowther CA, Simmonds L: Diferent intensities of glycaemic control for pregnant women with pre-existing diabetes. Cochrane Database Syst Rev 5:CD008540, 2016

Mission JF, Marshall NE, Caughey AB: Obesiry in pregnancy: a big problem and getting bigger. Obstet Gynecol Sur 88(5):389,t2013

Mitanchez D, Burguet A, Simeoni U: Infants born to mothers with gestational diabetes mellitus: mild neonatal efects, a long-term threat to global health. J Pediatr 164(3):445,t2014

Moreno-Castilla C, Hernandez M, Bergua M, et al: Low-carbohydrate diet for the treatment of gestational diabetes mellitus. Diabetes Care 36:2233, 2013

Most 0, Langer 0: Gestational diabetes: maternal weight gain in relation to fetal growth, treatment modality, BMI and glycemic control. J Matern Fetal Med 25(11):2458, 2012

National Institutes of Health: NIH Consensus Development Conference on Diagnosing Gestational Diabetes Mellitus. 2013. Available at: https:llconsensus.nih.gov/2013/gdm.htm. Accessed November 11,t2017

Nicholson W, Bolen S, Witkop CT, et al: Beneits and risks of oral diabetes agents compared with insulin in women with gestational diabetes. Obstet Gynecol 113(1): 193, 2009 O'Sullivan JB: Body weight and subsequent diabetes mellitus. JAMA 248:949, 1982 Owen CG, Martin RM, Whincup PH, et al: Does breastfeeding inluence risk of type 2 diabetes in later life? A quantitative analysis of published evidence. Am J Clin N utr 84: 1043, 2006

Patel EM, Goodnight H, James AH, et al: Temporal trends in maternal medical conditions and stillbirth. Am J Obstet Gynecol 212(5):673.e1, 2015

Pedersen J: he Pregnant Diabetic and Her Newborn, 2nd ed. Baltimore, Williams & Wilkins, 1977

Pedersent], M0lsted-Pedersen L, Andersen B: Assessors of fetal perinatal mortality in diabetic pregnancy. Analysis of 1332 pregnancies in the Copenhagen series, 1946-1972. Diabetes 23:302, 1974

Persson M, Norman M, Hanson U: Obstetric and perinatal outcomes in type I diabetic pregnancies. Diabetes Care 32:2005, 2009

Peterson C, Grosse SO, Li R, et a1: Preventable health and cost burden of adverse birth outcomes associated with pregestational diabetes in the United State. Am] Obstet Gynecol 212(1):74.e1, 2015

Pociot F, Lernmark A: Genetic risk factors for type 1 diabetes. Lancet 387(10035):2331,t2016

Powers AC: Diabetes mellitus. In: Longo DL, Fauci AS, Kaspar DL, et al (eds):

Harrison's Principles of Internal Medicine, 18th ed. McGraw-Hili, New York,t2012

Rasmussen L, Laugesen CS, Ringholm L, et al: Progression of diabetic retinopathy during pregnancy in women with type 2 diabetes. Diabetologia 53:1076,t2010

Reece A: Diabetes-induced birth defects: what do we know? What can we do?

CUff Diab Rep 12:24,t2012

Renault KM, Carlsen EM, N0gaard K, et al: Intake of carbohydrates during pregnancy in obese women is associated with fat mass in the newborn ofspring. Am] Clin Nutr 102(6):1475, 2015

Reutens AT: Epidemiology of diabetic kidney disease. Med Clin North Am 97:1,t2013

Rewers M, Ludvigsson ]: Environmental risk factors for type 1 diabetes. Lancet 387(10035):2340,t2016

Ringholm L, Vestgaard M, Laugesen CS, et al: Pregnancy-induced increase in circulating IGF-1 is associated with progression of diabetic retinopathy in women with type 1 diabetes. Growth Horm IGF Res 21:25, 2011

Roeder A, Moore TR, Ramos GA: Insulin pump dosing across gestation in women with well-controlled type 1 diabetes mellitus. Amt] Obstet Gynecol 207:324.e1,t2012

Rolo LC, Nardozza LMM, Junior EA, et al: Reference curve of the fetal ventricular septum area by the STIC method: preliminary study. Arq Bras Cardiol 96(5):386, 201t1

Rosenn B, Miodovnik M, Combs CA, et al: Glycemic thresholds for spontaneous abortion and congenital malformations in insulin-dependent diabetes mellitus. Obstet Gynecol 84:515, 1994

Rowan ]A, Hague WM, Wanzhen G, et al: Metformin versus insulin for the treatment of gestational diabetes. N Engl] Med 358:2003, 2008

Rowan ]A, Rush EC, Obolonkin V, et al: Metformin in gestational diabetes: the ofspring follow-up (MiG TOFU): body composition at 2 years of age. Diabetes Care 34(10):2279,t2011

Russell NE, Foley M, Kinsley BT, et al: Efect of pregestational diabetes mellitus on fetal cardiac function and structure. Am] Obstet Gynecol 199:312. e1,t2008

Russo LM, Nobles e, Ertel A, et al: Physical activity interventions in pregnancy and risk of gestational diabetes mellitus: a systematic review and metaanalysis. Obstet Gynecol 125(3):576,t2015

Salvesen DR, Brudenell M], Nicolaides KH: Fetal polycythemia and thrombocytopenia in pregnancies complicated by maternal diabetes mellitus. Am ] Obstet Gynecol 166:1287, 1992

Salvesen DR, Brudenell M], Snijders ]M, et al: Fetal plasma erythropoietin in pregnancies complicated by maternal diabetes mellitus. Amt] Obstet Gynecol 168:88, 1993

Sanabria-Martinez G, Garda-Hermoso A, Poyatos-Le6n R, et al: Efectiveness of physical activity interventions on preventing gestational diabetes mellitus and excessive maternal weight gain: a meta-analysis. B]OG 122(9):1t167, 2015

Saudek CD: Progress and promise of diabetes research. ]AMA 287:2582, 2002

Schwartz N, Nachum Z, Green MS: Risk factors of gestational diabetes mellitus recurrence: a meta-analysis. Endocrine 53(3):662, 2016

Schwartz N, Nachum Z, Green MS: The prevalence of gestational diabetes mellitus recurrence-efect of ethnicity and parity: a metaanalysis. Am ] Obstet GynecoIt213(3):31O, 2015

Scifres CM, Feghali M, Dumont T, et al: Large-for-gestational-age ultrasound diagnosis and risk for cesarean delivery in women with gestational diabetes mellitus. Obstet Gynecol 126(5):978, 2015

Sheield ]S, Buder-Koster EL, Casey BM, et al: Maternal diabetes mellitus and infant malformations. Obstet Gynecol 100:925,t2002

Sheiner E, Mazor-Drey E, Levy A: Asymptomatic bacteriuria during pregnancy. ] Matern Fetal Neonatal Med 22(5):423, 2009

Sibai BM, Caritis S, Hauth], et al: Risks of preeclampsia and adverse neonatal outcomes among women with pregestational diabetes mellitus. Amt] Obstet Gynecol 182:364, 2000

Sibai BM, Viteri OA: Diabetic ketoacidosis in pregnancy. Obstet Gynecol 123(1):167,t2014

Singh SR, Ahmad F, Lai A, et al: Eicacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis. CMA] 180(4):385,2009 Stewart ZA, Wilinska ME, Hartnell S, et al: Closed-loop insulin delivery preg nancy in women with type 1 diabetes. N Engl] Med 375(7):644, 2016 Stuebe AM, Landon MB, Lai Y, et al: Maternal BMI, glucose tolerance, and adverse pregnancy outcomes. Amt] Obstet Gynecol 207:62.e.1, 2012

Suresh A, Liu A, Poulton A, et a1: Comparison of maternal abdominal subcutaneous fat thickness and body mass index as markers for pregnancy outcomes: a stratiied cohort study. Aust N Z] Obstet Gynecol 52:420,t2012

U.S. Preventive Services Task Force: Gestational diabetes mellitus, screening. 2014. Available at: https:llwww.uspreventiveservicestaskforce.org/Page/ Documen t/U pdateS ummaryF inall gestational-diabetes-melli tus-screeni ng. Accessed November 11, 2017

Van Leeuwen M, Louwerse MD, Opmeer Be, et al: Glucose challenge test for detecting gestational diabetes mellitus: a systematic review. B]OG 119(4):393,t2012

Varner MW, Rice MM, Landon MB, et al: Pregnancies after the diagnosis of mild gestational diabetes mellitus and risk of cardiometabolic disorders. Obstet GynecoIt129(2):273, 2017

Vestgaard M, Ringholm L, Laugesen CS, et al: Pregnancy-induced sightthreatening diabetic retinopathy in women with type 1 diabetes. Diabet Med 27:431, 2010

Vidaef AC, Yeomans ER, Ramin SM: Pregnancy in women with renal disease.

Part II: speciic underlying renal conditions. Amt] Perinatol 25:399, 2008

Vink ]Y, Poggi SH, Ghidini A: Amniotic fluid index and birth weight: is there a relationship in diabetics with poor glycemic control? Amt] Obstet Gynecol 195:848,t2006

Wang PH, Lau], Chalmers TC: Meta-analysis of efects of intensive blood-glucose control on late complications of type 1 diabetes. Lancet 341:1306,t1993

Wei ], Heng W, Gao ]: Efects of low glycemic index diets on gestational diabetes mellitus: a meta-analysis of randomized controlled clinical trials. Medicine (Baltimore) 95(22):e3792, 2016 White P: Classiication of obstetric diabetes. Am] Obstet Gynecol 130:228, 8 World Health Organization: Diagnostic criteria and classification of hyperglycemia irst detected in pregnancy. Geneva, WHO, 2013

Yang ], Cummings EA, O'Connell C, et al: Fetal and neonatal outcomes of diabetic pregnancies. Obstet Gynecol 108:644,t2006

Yang P, Reece EA, Wang F, et al: Decoding the oxidative stress hypothesis in diabetic embryopathy through proapoprotic kinase signaling. Am ] Obstet Gynecol 212(5):569, 2015

Yanit KE, Snowden ]M, Cheng W, et al: he impact of chronic hypertension and pregestational diabetes on pregnancy outcomes. Am ] Obstet Gynecol 207:333,t2012

Young EC, Pires M, Marques L, et al: Efects of pregnancy on the onset and progression of diabetic nephropathy and of diabetic nephropathy on pregnancy outcomes. Diabetes Metab Syndr 5: 13 7, 2012

THYROID PHYSIOLOGY AND PREGNANCY .i......i... 1118

HYPERTHYROIDISM. . . . . . . . . . . . . . . . . . . . . . . . . . .. 1120 HYPOTHYROIDISM . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1123

SUBCLINICAL HYPOTHYROIDISM. . . . . . . . . . . . . . . .. 1124

IODINE DEFICIENCY ...i..............i.........i..... 1126

CONGENITAL HYPOTHYROIDISM ..i....i.....i....i..... 1127

POSTPARTUM THYROIDITIS.. . . . . . . . . . . . . . . . . . . .. 1127

NODULAR THYROID DISEASE .....i...i....i.......i.....i1128

PARATHYROID DISEASE .....i.......i.......i......i.... 1128

ADRENAL GLAND DISORDERS.. . . . . . . . . . . . . . . . . .. 1130 PITUITARY DISORDERS .i....i.........i....i.....i....i... 1132

In a smal number of cases the thyroid gland increases markedy in size, though we are ignorant as to its signicance.

-J. Whitridge Williams (1903)

In 1903, little was known of many endocrine disorders. Still, endocrinopathies seem particularly closely related to pregnancy because of its gestational proclivity for prodigious hormone secretion. This is best illustrated by placental lactogen in diabetes, the most common endocrinopathy encountered in pregnancy (Chap. 57, p. 1097). Pregnancy is also interrelated with some endocrinopathies that are at least partially due to autoimmune dysregulation. Clinical manifestations of this result from complex interplay among genetic, environmental, and endogenous factors that activate the immune system against targeted cells within endocrine organs. An extraordinary example of these interactions comes from studies that implicate maternal organ engraftment by fetal cells that were transferred during pregnancy. These cells later provoke antibody production, tissue destruction, and autoimmune endocrinopathies.

Taken in aggregate, disorders of the thyroid gland are common in young women and thus frequently encountered in pregnancy. Maternal and fetal thyroid function are intimately related, and drugs that afect the maternal thyroid also afect the fetal gland. Moreover, thyroid autoantibodies have been associated with increased rates of early pregnancy wastage. Also, uncontrolled thyrotoxicosis and untreated hypothyroidism are both associated with adverse pregnancy outcomes. Finally, evidence suggests that the severity of some autoimmune thyroid disorders may be ameliorated during pregnancy, only to be exacerbated postpartum .

Maternal thyroid changes are substantial, and normally altered gland structure and function are sometimes confused with thyroid abnormalities. These alterations are discussed in detail in Chapter 4 (p. 69), and normal serum hormone level values are found in the Appendix (p. 1258). First, maternal serum concentrations of thyroid binding globulin are increased concomitantly with total or bound thyroid hormone levels (Fig. 4-16, p. 70). Second, thyrotropin, also called thyroidstimulating hormone (TSH) , currently plays a central role in screening and diagnosis of many thyroid disorders. Notably, TSH receptors are cross stimulated, albeit weakly, by massive quantities of human chorionic gonadotropin (hCG) secreted 6 2.0 1.5 1 :J0l�

Se3 1.0 �2 : 0.5 0.0 o 10 20 30 40

FIGURE 58-1 Gestational age specific values for serum thyroid stimulating hormone (TSH) levels (black lines) and free thyroxine (T4) levels (blue lines). Data were derived from 17,298 women tested during pregnancy. For each color, the dark solid lines represent the 50th percentile, whereas the upper and lower light lines represent the 25th and 975th percentiles, respectively. (Data from Casey, 2005; Dashe, 2005.) by placental trophoblast. Because TSH does not cross the placenta, it has no direct fetal efects. During the irst 12 weeks of gestation, when maternal hCG serum levels are maximal, thyroid hormone secretion is stimulated. he resulting greater serum free thyroxine (T4) levels act to suppress hypothalamic thyrotropin-releasing hormone (TRH) and in turn limit pituitary TSH secretion (Fig.

Accordingly, TRH is undetectable in maternal serum. Conversely, in fetal serum, beginning at midpregnancy, TRH becomes detectable, but levels are static and do not increase.

hroughout pregnancy, maternal thyroxine is transferred to the fetus (American College of Obstetricians and Gynecologists, 2017). Maternal thyroxine is important for normal fetal brain development, especially before the onset of fetal thyroid gland function (Bernal, 2007; Korevaar, 2016). And, even though the fetal gland begins concentrating iodine and synthesizing thyroid hormone after 12 weeks' gestation, maternal thyroxine contribution remains important. In fact, maternal sources account for 30 percent of thyroxine in fetal serum at term (horpe-Beeston, 1991). Still, developmental risks associated with maternal hypothyroidism after midpregnancy remain poorly understood (Morreale de Escobar, 2004; Sarkhail, 2016).

Most thyroid disorders are inextricably linked to autoantibodies against nearly 200 thyrocyte components. These antibodies variably stimulate thyroid function, block function, or cause thyroid inlammation that may lead to follicular cell destruction. Often, these efects overlap or even coexist.

Thyroid-stimulating autoantibodies, also called thyroidstimulating immunoglobulins (TSls), bind to the TSH receptor and activate it, causing thyroid hyperfunction and growth. Although these antibodies are identiied in most patients with classic Graves disease, simultaneous production of thyroidstimulating blocking antibodies may blunt this efect Qameson, ;C ..EJ,50 w)0:J::0 w ...•30 ..•5 -..,20

FIGURE 58-2 Incidence in percent of antithyroid peroxidase anti bodies in 16,407 women who are normal or euthyroid, in 233 with isolated maternal hypothyroxinemia (1M H), in 598 with subclinical hypothyroidism (SCH), and in 134 with overt hypothyroidism.

(Data from Casey, 2007).

2015). Thyroidperoxidase (TPO) is a thyroid gland enzyme that normally functions in the production of thyroid hormones. Thyroid peroxidase antibodies, previously called thyroid microsomal autoantibodies, are directed against TPO and, as shown in Figure 58-2, have been identiied in 5 to 15 percent of all pregnant women (Abbassi-Ghanavati, 2010; Sarkhail, 2016). These antibodies have been associated in some studies with early pregnancy loss and preterm birth (Negro, 2006; Korevaar, 2013; Plowden, 2017; Thangaratinam, 201l). In another study with more than 1000 TPO antibody-positive pregnant women, the risk for preterm birth was not elevated, however, the risk for placental abruption was greater (Abbassi-Ghanavati, 2010). These women are also at high risk for postpartum thyroid dysfunction and at lifelong risk for permanent thyroid failure (Andersen, 2016; Jameson, 2015).

Autoimmune thyroid disease is much more common in women than in men. One intriguing explanation for this disparity is fetal-to-maternal cell traicking (Greer, 201l). Fetal cells are known to enter maternal circulation during pregnancy. When fetal lymphocytes enter maternal circulation, they can live for more than 20 years. Stem cell interchange can lead to engraftment in several maternal tissues and is termed etal microchimerism. In some cases, this may involve the thyroid gland (Bianchi, 2003; Boddy, 2015; Khosrotehrani, 2004). A high prevalence of Y-chromosome-positive cells has been identiied using luorescence in situ hybridization (FISH) in the thyroid glands of women with Hashimoto thyroiditis-60 percent, or with Graves disease-40 percent (Renne, 2004). In another study of women giving birth to a male fetus, Lepez and colleagues (201l) identiied signiicantly more circulating male mononuclear cells in those with Hashimoto thyroiditis. Ironically, such micro chimerism may have a protective role for autoimmune thyroid disorders (Cirello, 2015).

TABLE 58-1. Incidence of Overt Hyperthyroidism in Pregnancy

Vaidya (2007)a United Kingdom 0.7%

Lazarus (2007)b United Kingdom 1.7%

Casey (2006r United States 0.4%

Andersen (201n6r,d Denmark 0.4-0.7% aScreened irl the first trimester. bScreened at 9-15 weeks. (Screened before 20 weeks.

dDiagnosed in early versus later pregnancy.

The incidence of thyrotoxicosis or hyperthyroidism in pregnancy is varied and complicates between 2 and 17 per 1000 births when gestational-age appropriate TSH threshold values are used (Table

Because normal pregnancy simulates some clinical findings similar to thyroxine excess, clinically mild thyrotoxicosis may be diicult to diagnose. Suggestive indings include tachycardia that exceeds that usually seen with normal pregnancy, thyromegaly, exophthalmos, and failure to gain weight despite adequate food intake. Laboratory testing is confirmatory. TSH levels are markedly depressed, while serum free T4 (IT4) levels are elevated Qameson, 2015). Rarely, hyperthyroidism is caused by abnormally high serum triiodothyronine (T 3) levels-so-called Trtoxicosis.

he overwhelming cause of thyrotoxicosis in pregnancy is Graves disease, an organ-speciic autoimmune process associated with thyroid-stimulating TSH-receptor antibodies as previously discussed'(De Leo, 2016). Because these antibodies are specific to Graves hyperthyroidism, such assays have been proposed for diagnosis, management, and prognosis in pregnancies complicated by hyperthyroidism (Barbesino, 2013). At Parkland Hospital, these receptor antibody assays are generally reserved for cases in which fetal thyrotoxicosis is suspected. With Graves disease, during the course of pregnancy, hyperthyroid symptoms may initially worsen because ofhCG stimulation but then subsequently diminish with drops in receptor antibody titers in the second half of pregnancy (Mestman, 2012; Sarkhail, 2016). Amino and coworkers (2003) have found that levels of blocking antibodies also decline during pregnancy.

Treatment. Thyrotoxicosis during pregnancy can nearly always be controlled by thionamide drugs. Propylthiouracil (PTU) has been historically preferred because it partially inhibits the conversion of T4 to T3 and crosses the placenta less readily than methimazole. he latter has also been associated with a rare methimazole embryopathy, characterized by esophageal or choanal atresia as well as aplasia cutis, a congenital skin defect. yoshihara and associates (2012, 2015) analyzed outcomes in Japanese women with irst-trimester hyperthyroidism and found a twofold increased risk of major fetal malformations in pregnancies exposed to methimazole compared with either PTU or potassium iodide. Speciically, seven of nine cases with aplasia cutis and the only case of esophageal atresia were in the group of methimazole-exposed fetuses. here have also been reports of a PTU-associated embryopathy (Andersen, 2014).

In 2009, the Food and Drug Administration issued a safety alert on PTU-associated hepatotoxicity. his warning prompted the American Thyroid Association and the American Association of Clinical Endocrinologists (201r1) to recommend PTU therapy during the first trimester followed by methimazole beginning in the second trimester. he obvious disadvantage is that this might lead to poorly controlled thyroid function. Accordingly, at Parkland Hospital, we continue to prescribe PTU treatment throughout pregnancy.

Transient leukopenia can be documented in up to 10 percent of women taing antithyroid drugs, but this does not require therapy cessation (American College of Obstetricians and Gynecologists, 2017). In approximately 0.3 percent, however, agranuloytosis develops suddenly and mandates drug discontinuance (Thomas, 2013). It is not dose related, and because of its acute onset, serial leukocyte counts during therapy are not helpul.

Thus, fever or sore throat develops, women are instructed to discontinue medication immediatey and report or a complete blood count.

herapy may have other side efects. First, as noted, hepatotoxicity is a possibility and develops in approximately 0.1 percent of treated women. Serial measurement of hepatic enzyme levels does not prevent fulminant PTU-related hepatotoxicity. Second, approximately 20 percent of patients treated with PTU develop antineutrophil cytoplasmic antibodies NC). Despite this, only a small percentage of these subsequently develops serious vasculitis (Kimura, 2013). Finally, although thionamides have the potential to cause fetal complications, these are uncommon. In some cases, thionamides may even be therapeutic for the fetus, because TSH-receptor antibodies cross the placenta and can stimulate the fetal thyroid gland to cause thyrotoxicosis and goiter.

The initial thionamide dose is empirical. For nonpregnant patients, the American hyroid Association recommends that methimazole be used at an initial higher daily dose of 10 to 20 mg orally followed by a lower maintenance dose of 5 to 10 mg. If PTU is selected, a dose of 50 to 150 mg orally three times daily may be initiated depending on clinical severity (Bahn, 2011). At Parkland Hospital, we usually initially give 300 or 450 mg of PTU daily in three divided doses for pregnant women. Occasionally, daily doses of 600 mg or higher are necessary. As discussed, we generally do not transition women to methimazole during the second trimester. he goal is treatment with the lowest possible thionamide dose to maintain thyroid hormone levels slightly above or in the high normal range, while TSH levels remains suppressed (Bahn, 2011). Serum free T 4 concentrations are measured every 4 to 6 weeks.

Subtotal thyroidectomy can be performed after thyrotoxicosis is medically controlled. This seldom is done during pregnancy but may be appropriate for the very few women who cannot adhere to medical treatment or in whom drug therapy proves toxic (Stagnaro-Green, 2012a). Surgery is best accomplished in the second trimester. Potential drawbacks of thyroidectomy include inadvertent resection of parathyroid glands and injury to the recurrent laryngeal nerve.

Thyroid ablation with therapeutic radioactive iodine is contraindicated during pregnancy. The necessary doses may also cause fetal thyroid gland destruction. Thus, when radioactive iodine is given unintentionally, many clinicians recommend abortion. Any exposed fetus must be carefully evaluated, and the incidence of fetal hypothyroidism depends on gestational age and radioiodine dose (Berlin, 2001). There is no evidence that radioiodine given before pregnancy causes fetal anomalies if enough time has passed to allow radiation efects to dissipate and if the woman is euthyroid (Ayala, 1998). The International Commission on Radiological Protection has recommended that women avoid pregnancy for 6 months after radioablative therapy (Brent, 2008). Moreover, during lactation, the breast also concentrates a substantial amount of iodine. This may pose neonatal risk due to I-containing milk ingestion and maternal risk from significant breast irradiation. To limit the latter, a delay of 3 months after breastfeeding cessation will more reliably ensure complete breast involution.

Pregnancy Outcome. Women with thyrotoxicosis have pregnancy outcomes that largely depend on whether metabolic control is achieved. For example, excess thyroxine may cause miscarriage or preterm birth (Andersen, 2014; Sheehan, 2015). In untreated women or in those who remain hyperthyroid despite therapy, incidences of preeclampsia, heart failure, and adverse perinatal outcomes are higher (Table 58-2). A prospective cohort study from China showed that women with clinical hyperthyroidism had a 12-fold greater risk of delivering an infant with hearing loss (Su, 2011).

In most cases, the perinate is euthyroid. In some, however, hyper-or hypothyroidism can develop with or without a goiter (Fig. 58-3). Clinical hyperthyroidism develops in up to 1 percent of neonates born to women with Graves disease (Barbesino, 2013; Fitzpatrick, 2010). If fetal thyroid disease is

TABLE 58-2. Pregnancy Outcomes in Women with Overt Thyrotoxicosis aData presented as n (%). Data from Davis, 1989; Kriplani, 1994; Luewan, 201n1; Medici, 2014; Millar, 1994.

FIGURE 58-3 Term hypothyroid neonate delivered of a woman with a 3-year history of thyrotoxicosis that recurred at 26 weeks' gestation. The mother was given methimazole 30 mg orally daily and was euthyroid at delivery.

suspected, nomograms are available for sonographically mea sured thyroid volume (Gietka-Czernel, 2012).

The fetus or neonate who was exposed to excessive maternal thyroxine may have any of several clinical presentations. First, goitrous thyrotoxicosis is caused by placental transfer of thyroidstimulating immunoglobulins. Nonimmune hydrops and fetal demise have been reported with fetal thyrotoxicosis (Nachum, 2003; Stulberg, 2000). The best predictor of perinatal thyrotoxicosis is presence of thyroid-stimulating TSH-receptor antibodies in women with Graves disease (Nathan, 2014). This is especially true if their levels are more than threefold higher than the upper normal limit (Barbesino, 2013). In a study of 72 pregnant women with Graves disease, Luton and associates (2005) reported that none of the fetuses in 31 low-risk mothers had a goiter, and all were euthyroid at delivery. Low risk was defined as no requirement for antithyroid medications during the third trimester or an absence of antithyroid antibodies. Conversely, in a group of 41 women who either were taking antithyroid medication at delivery or had thyroid receptor antibodies, 11 fetuses-27 percent-had sonographic evidence of a goiter at 32 weeks' gestation. Seven of these 11 fetuses were determined to be hypothyroid, and the remaining fetuses were hyperthyroid. In response to these results, the merican Thyroid Association and American Association of Clinical Endocrinologists (201r1) recommend routine evaluation of TSH-receptor antibodies between 22 and 26 weeks' gestation in women with Graves disease. he American College of Obstetricians and Gynecologists (2017), however, does not recommend such testing. If the fetus is thyrotoxic, maternal thionamide drugs are adjusted even though maternal thyroid function may be within the targeted range (Mestman, 2012). lthough usually short-lived, neonatal thyrotoxicosis may require short-course antithyroid drug treatment (Levy-Shraga, 2014; Nathan, 2014).

A second presentation is goitrous hypothyroidism caused by fetal exposure to maternally administered thionamides (see Fig. 58-3). Although there are theoretical neurological implications, reports of adverse fetal efects seem to have been exaggerated. Available data indicate that thionamides carry an extremely small risk for causing neonatal hypothyroidism (Momotani, 1997; O'Doherty, 1999). For example, in at least 239 treated thyrotoxic women shown in Table 58-1, evidence of hypothyroidism was found in only four newborns. Furthermore, at least four long-term studies report no abnormal intellectual and physical development of these children (Mestman, 1998). If maternal hypothyroidism developed, the fetus can be treated by a reduced maternal antithyroid medication dose and injections of intraamnionic thyroxine if necessary.

A third presentation, nongoitrous hypothyroidism, may develop from transplacental passage of maternal TSH-receptor blocking antibodies (Fitzpatrick, 2010; Gallagher, 2001). And finally,etal thyrotoxicosis after maternal thyroid gland ablation, usually with 1 radioiodine, may result from transplacental thyroid-stimulating antibodies. In one report of early fetal exposure to radioiodine, neonatal thyroid studies indicated transient hyperthyroidism from maternal transfer of stimulating antibodies (Tran, 2010).

Fetal Diagnosis. Evaluation of fetal thyroid function is somewhat controversial. Although the fetal thyroid volume can be measured sonographically in women taking thionamide drugs or in those with thyroid-stimulating antibodies, most investigators do not currently recommend this routinely (Cohen, 2003; Luton, 2005). Kilpatrick (2003) recommends umbilical cord blood sampling and fetal antibody testing only if the mother has previously undergone radioiodine ablation. Because fetal hyper-or hypothyroidism may cause hydrops, growth restriction, goiter, or tachycardia, fetal blood sampling may be appropriate if these are identified (Brand, 2005). he Endocrine Society clinical practice guidelines recommend umbilical cord blood sampling only when the diagnosis of fetal thyroid disease cannot be reasonably ascertained based on clinical and sonographic data (Garber, 2012). Diagnosis and treatment are considered further in Chapter 16 (p. 318).

Both of these are acute and life-threatening in pregnancy. hyroid storm is a hypermetabolic state and is rare in pregnancy. In contrast, pulmonary hypertension and heart failure from cardiomyopathy caused by the profound myocardial efects of thyroxine are common in pregnant women (Sheield, 2004). As shown in Table 58-2, heart failure developed in 8 percent of 90 women with uncontrolled thyrotoxicosis. In these women, cardiomyopathy is characterized by a high-output state, which may lead to a dilated cardiomyopathy (Fadel, 2000; Klein, 1998). The pregnant woman with thyrotoxicosis has minimal cardiac reserve, and decompensation is usually precipitated by preeclampsia, anemia, sepsis, or a combination of these. Fortunately, thyroxine-induced cardiomyopathy and pulmonary hypertension are frequently reversible (Sheield, 2004; Siu, 2007; Vydt, 2006).

Management. Treatment is similar for thyroid storm and heart failure and should be carried out in an intensive care area that may include special-care units within labor and delivery (American College of Obstetricians and Gynecologists, 2017). Shown in Figure 58-4 is our stepwise approach to medical management of thyroid storm or thyrotoxic heart failure. An hour or two ater initial thionamide administration, iodide is given to inhibit thyroidal release ofT3 and T4. It can be given intravenously as sodium iodide or orally as either saturated solution of potassium iodide (SSKI) or Lugol solution. With a history of iodine-induced anaphylaxis, lithium carbonate, 300 mg every 6 hours, is given instead. Most authorities recommend dexamethasone, 2 mg intravenously every 6 hours for four doses, to further block peripheral conversion ofT4 to T3. If a 3-blocker drug is given to control tachycardia, its efect on heart failure must be considered. Propranolol, labetalol, and esmolol have all been used successfully. Coexisting severe preeclampsia, infection, or anemia should be aggressively managed before delivery is considered.

Transient biochemical features of hyperthyroidism may be observed in 2 to 15 percent of women in early pregnancy (Fitzpatrick, 2010). Many women with hyperemesis gravidarum have abnormally high serum thyroxine levels and low TSH levels (Chap. 54, p. 1045). his results from TSH-receptor stimulation from massive-but normal for pregnancyconcentrations of hCG. This transient condition is also termed gestational transient thyrotoxicosis. Even if associated with hyperemesis, antithyroid drugs are not warranted (American College of Obstetricians and Gynecologists, 2017). The degree of hCG level elevation does not correlate with thyroxine and TSH values, which become more normal by midpregnancy (Nathan, 2014; Yoshihara, 2015).

he prevalence of increased thyroxine levels in women with a molar pregnancy ranges between 25 and 65 percent (Hershman, 2004). As discussed, abnormally high hCG levels lead to overstimulation of the TSH receptor. Because these tumors are now usually diagnosed early, clinically apparent hyperthyroidism has become less common. With molar evacuation, serum free T4 levels usually normalize rapidly in parallel with declining hCG concentrations. This is discussed further in Chapter 20 (p. 391).

hird-generation TSH assays with an analytical sensitivity of 0.002 mU/mL permit identiication of subclinical thyroid disorders. These biochemically defined extremes usually represent normal biological variations but may herald the earliest stages of thyroid dysfunction. Subclinical hyperthyroidism is characterized by an abnormally low serum TSH concentration in concert with normal thyroxine hormone levels (Surks, 2004). Long-term efects of persistent subclinical thyrotoxicosis include osteoporosis, cardiovascular morbidity, and progression

After 1-2 hours of thionamide therapy start iodine: if iodine anaphylaxis history, Lithium carbonate 300 mg PO every 6 hr

Consider corticosteroid therapy for 24 hours:

FIGURE 58-4 One management method for thyroid storm or thyrotoxic heart failure. gtt = drops; IV = intravenous; NGT = nasogastric tube; PO = orally; PTU = propylthiouracil.

to overt thyrotoxicosis or thyroid failure. Casey and Leveno (2006) reported that subclinical hyperthyroidism was found in 1.7 percent of pregnant women. Importantly, subclinical hyperthyroidism was not associated with adverse pregnancy outcomes. In separate retrospective analyses of almost 25,000 women who underwent thyroid screening throughout pregnancy, Wilson and colleagues (2012) and Tudela and coworkers (2012) also found no relationship between subclinical hyperthyroidism and preeclampsia or gestational diabetes.

Treatment of subclinical hyperthyroidism is unwarranted in pregnancy because antithyroid drugs may afect the fetus. hese women may beneit from periodic surveillance, and approximately half eventually have normal TSH concentrations.

Overt or symptomatic hypothyroidism, as shown in Table 58-3, more likely in women in areas of endemic iodine deiciency or those with Hashimoto thyroiditis. Other indings include edema, dry skin, hair loss, and prolonged relaxation phase of deep tendon relexes. Clinical or overt hypothyroidism is conirmed when an abnormally high serum TSH level is accompanied by an abnormally low thyroxine level. Subclinical

TABLE 58-3. Frequency of Overt Hypothyroidism

Wang (201n1)a China 0.3% Cleary-Goldman (2008)a United States 0.3% Vaidya (2007)d United Kingdom 1.0% Casey (200S)b United States 0.2% Andersen (2016)d Denmark 1.2% has been reported to complicate between 2 and 12 per 1000 aScreened during first trimester.

pregnancies. It is characterized by insidious nonspeciic clini bScreened before 20 weeks.

cal indings that include fatigue, constipation, cold intolerance, (Includes those treated before pregnancy.

muscle cramps, and weight gain. A pathologically enlarged thy dDiagnosed in early versus later pregnancy.

roid gland depends on the etiology of hypothyroidism and is hypothyroidism, discussed later, is defined by an elevated serum TSH level and normal serum thyroxine concentration Qameson, 2015). Sometimes included in the spectrum of subclinical thyroid disease are asymptomatic individuals with high levels of anti-TPO or anti thyroglobulin antibodies. Autoimmune euthyroid disease represents a new investigative frontier in screening and treatment of thyroid dysfunction during pregnancy.

he most common cause of hypothyroidism in pregnancy is Hashimoto thyroiditis, characterized by glandular destruction from autoantibodies, particularly anti-TPO antibodies. Another cause is postablative Graves disease. Clinical identiication of hypothyroidism is especially diicult during pregnancy because many of the signs or symptoms are also common to pregnancy itself. Thyroid analyte testing should be performed on symptomatic women or those with a history of thyroid disease (American College of Obstetricians and Gynecologists, 2017). Severe hypothyroidism during pregnancy is uncommon, probably because it is often associated with infertility and higher spontaneous abortion rates (De Groot, 2012). Even women with treated hypothyroidism undergoing in vitro fertilization have a significantly lower chance of achieving pregnancy (Scoccia,r2012).

Treatment. The American hyroid Association and American Association of Clinical Endocrinologists (2011) recommend replacement therapy for overt hypothyroidism beginning with levothyroxine in doses of 1 to 2 ILg/kgl d or approximately 100 Lg daily. Women who are athyreotic after thyroidectomy or radioiodine therapy may require higher doses. Surveillance is with TSH levels measured at 4-to 6-week intervals, and the thyroxine dose is adjusted by 25-to 50-lLg increments until TSH values become normal. Pregnancy is associated with an increased thyroxine requirement in approximately a third of supplemented women (Abalovich, 2010; Alexander, 2004). The increased demand in pregnancy is believed to be related to augmented estrogen production (Arafah, 2001).

Greater thyroxine requirements begin as early as 5 weeks' gestation. In a randomized trial that provided an increased levothyroxine dose at pregnancy confirmation in 60 mothers, Yassa and coworkers (2010) found that a 29-to 43-percent increase in the weekly dose maintained serum TSH values <5.0 mUlL during the first trimester in all women. Importantly, however, this increase caused TSH suppression in more than a third of women. Significant hypothyroidism may develop early in women without thyroid reserve, such as those with a previous thyroidectomy, those with prior radioiodine ablation, or those undergoing assisted reproductive techniques (Alexander, 2004; Loh, 2009). Anticipatory 25-percent increases in thyroxine replacement at pregnancy conirmation will reduce this likelihood. All other women with hypothyroidism should instead undergo TSH testing at initiation of prenatal care.

Pregnancy Outcome with Overt Hypothyroidism. Observational studies, although limited, indicate that excessive adverse perinatal outcomes are associated with overt thyroxine

TABLE 58-4. Pregnancy Complications in 440 Women with Hypothyroidism a,bBirthweight <2000 gr apreterm or term deliveries were the only outcomes reported by Abalovich, 2002.

SU,r2011.

COne infant died from syphilis.

Data from Abalovich, 2002; Davis, 1988; leung, 1993;

Mannistb, 2009; Su, 2011.

deficiency (Table 58-4). Preterm birth rates, for example, are higher (Sheehan, 2015). With appropriate replacement therapy, however, rates of adverse efects are not increased in most reports (Bryant, 2015; Matalon, 2006; Tan, 2006). In one dissenting study, however, risks for some pregnancy complications were greater even in women taking replacement therapy (Wikner, 2008). Most experts agree that adequate hormone replacement during pregnancy minimizes the risk of adverse outcomes and most complications.

Fetal and Neonatal Efects. Undoubtedly, maternal and fetal thyroid abnormalities are related. In both, thyroid unction is dependent on adequate iodide intake, and its deiciency early in pregnancy can cause both maternal and fetal hypothyroidism. And, as discussed, maternal TSH-receptor-blocking antibodies can cross the placenta and cause fetal thyroid dysunction. Rovelli and colleagues (2010) evaluated 129 neonates born to women with autoimmune thyroiditis. They found that 28 percent had an elevated TSH level on the third or fourth day of life, and 47 percent of these had TPO antibodies on day 15. Still, autoantibodies were undetectable at 6 months of age. It seems paradoxical that despite these transient laboratory findings in the neonate, TPO and anti thyroglobulin antibodies have little or no efect on etalthyroid function (Fisher, 1997). Indeed, prevalence of fetal hypothyroidism in women with Hashimoto thyroiditis is estimated to be only 1 in 180,000 newborns (Brown, 1996).

Although common in women, the incidence of subclinical hypothyroidism varies depending on age, race, dietary iodine intake, and serum TSH thresholds used to establish the diagnosis Qameson, 2015). In two large studies totaling more than 25,000 pregnant women screened in the first half of pregnancy, subclinical hypothyroidism was identified in 2.3 percent (Casey, 2005; Cleary-Goldman, 2008). he rate of progression to overt thyroid failure is afected by TSH level, age, other disorders such as diabetes, and presence and concentration of antithyroid antibodies.

nant women with subclinical hypothyroidism for 5 years and reported that in a third, TSH values became normal. In the other two thirds, those women whose TSH levels were 10 to 15 mUlL developed overt disease at a rate of 19 per 100 patient years. Those women whose TSH levels were < 10rm U IL devel oped overt hypothyroidism at a rate of 2 per 100 patient years.

pregnant individuals, the U.S. Preventative Services Task Force (Helfand, 2004; Karmisholt, 2008).

For gravidas, in a 20-year follow-up study of 5805 women who were screened in early pregnancy, only 3 percent developed thyroid disease. Of the 224 women identified with subclinical hypothyroidism during pregnancy, 17 percent developed thy roid disease in the next 20 years, and most of these had either

TPO or thyroglobulin antibodies during pregnancy (Mannisto, 2010). hus, the likelihood of progression to overt hypothy roidism during pregnancy in otherwise healthy women with subclinical hypothyroidism seems remote.

Earlier studies were suggestive that subclinical hypothyroidism might be associated with adverse pregnancy outcomes. In 1999, interest was heightened by two studies indicating that undiagnosed maternal thyroid hypofunction may impair fetal neuropsychological development. In one study, Pop and associates (1999) described 22 women with free T 4 levels < 10th percentile whose ofspring were at higher risk for impaired psychomotor development. In the other study, Haddow and coworkers (1999) retrospectively evaluated children born to 48 untreated women whose serum TSH values were >98th percentile. Some had diminished school performance, reading recognition, and intelligent quotient (IQ) scores. Although described as "subclinically hypothyroid," these women had an abnormally low mean serum free thyroxine level, and thus, many had overt hypothyroidism.

To further evaluate any adverse efects, Casey and colleagues (2005) identiied subclinical hypothyroidism in 2.3 percent of 17,298 women screened at Parkland Hospital before midpregnancy. hese women had small but signiicantly higher incidences of preterm birth, placental abruption, and neonates admitted to the intensive care nursery compared with euthyroid women. In another study of 10,990 similar women, however, ClearyGoldman and associates (2008) did not ind such associations.

Other studies subsequently conirmed a link between subclinical thyroid function and adverse outcomes (Chen, 2017; Maraka, 2016). One included 24,883 women screened throughout pregnancy and showed an almost twofold greater risk of severe preeclampsia (Wilson, 2012). In an analysis of the same cohort, a consistent relationship was shown between rising TSH levels and the risk for gestational diabetes (Tudela, 2012). Finally, Nelson and colleagues (2014) found an elevated risk for diabetes and stillbirth.

Lazarus and colleagues (2012) reported the indings of the international multicenter Controlled Antenatal Thyroid Screening (CATS) study. his study evaluated prenatal thyroid screening and randomized treatment of both subclinical hypothyroidism and isolated maternal hypothyroxinemia. They rior in the treated pregnancies.

Despite these indings, the unanswered question concerned whether treatment of subclinical hypothyroidism would miti gate any or all of these reported adverse outcomes. To address this, the Maternal-Fetal Medicine Units Network screened more than 97,000 pregnant women for thyroid disorders and reported that 3.3 percent had subclinical hypothyroid ism. hese 677 women were randomly assigned to thyroxine replacement therapy or placebo. As reported by Casey and col leagues (2017), and shown in Table 58-5, maternal adverse pregnancy outcomes or cognitive development in the ofspring at 5 years did not difer between groups. Annual developmental disorder results also did not difer.

Screening in Pregnancy. Because of the findings in the studies from 1999 cited above, some professional organizations began to recommend routine prenatal screening and treatment for subclinical hypothyroidism. Consequent to the Lazarus study, however, clinical practice guidelines from the Endocrine Society, the American hyroid Association, and the American Association of Clinical Endocrinologists uniformly recommended screening only those at greater risk during pregnancy (De Groot, 2012; Garber, 2012). his has been and still is the recommendation of the American College of Obstetricians and Gynecologists (2017). he indings of Casey and colleagues (2017) further buttress these recommendations.

Women with low serum free T4 values but a normal-range TSH level are considered to have isolated matenal hypothyroxinemia.

Its incidence in two large trials was l.3 to 2.1 percent (Casey, 2007; Cleary-Goldman, 2008). As shown in Figure 58-2, unlike in subclinical hypothyroidism, these women had a low preva lence of antithyroid antibodies.

Evolution of the knowledge of this thyroid disorder was similar to that seen with subclinical hypothyroidism. Initial studies reported that ofspring of women with isolated hypothyroxinemia had neurodevelopmental diiculties (Kooistra, 2006; Pop, 1999, 2003). In another study, Casey and colleagues (2007) found no higher risks for other adverse perinatal outcomes compared with those of euthyroid women. Also, the aforementioned CATS study did not ind improved neurodevelopmental outcomes in women with isolated hypothyroxinemia who were then treated with thyroxine (Lazarus, 2012).

he randomized trial conducted by the Maternal-Fetal Medicine Units Network also provided data to settle this question. Casey and colleagues (2017) noted no higher rates of adverse outcomes between groups and found that early thyroxine treatment ofered no beneits (see Table 58-5).

Autoantibodies to TPO and thyroglobulin have been identiied in 6 to 20 percent of reproductive-aged women (Thangaratinam, 201l). Most who test positive for such antibodies,

TABLE 58-5. Pregnancy and Perinatal Outcomes According to Diagnosis and Treatment Group of Thyroid Disordersa

EGA at delivery (weeks) 39.1 ± 2.5 38.9 ± 3.1 39.0 ± 2.4 38.8 ± 3.1 birth <34 weeks 9.1 % 10.9% 3.8% 2.7% Placental abruption 0.3% 1.5% 1.1% 0.8%

Preeclampsia 6.5% 5.9% 3.4% 4.2%

Diabetes 7.4% 6.5% 8.0% 9.2%

NICU admission 8.6% 6.2% 11.8% 11.9%

Birthweight < 10th centile 9.8% 8.1 % 8.8% 7.8% IQ median (25th, 75th 97 (85,105) 94 (85,107) 94(83,101) 91 (82,101) dFor all comparisons, p >0.05.

EGA = estimated gestational age; IQ = intelligence quotient; [lICU = neonatal intensive care unit. Data from Casey, 201r7.

however, are euthyroid. That said, such women carry a two-to ivefold increased risk for early pregnancy loss (Stagnaro-Green, 2004; hangaratinam, 2011). he presence of thyroid antibodies has also been associated with preterm birth (Stagnaro-Green, 2009). In a randomized treatment trial of 115 euthyroid women with TPO antibodies, Negro and coworkers (2006) reported that treatment with levothyroxine astoundingly reduced the preterm birth rate from 22 to 7 percent. Contrarily, AbbassiGhanavati and associates (2010) evaluated pregnancy outcomes in more than 1000 untreated women with TPO antibodies and did not ind an increased risk for preterm birth compared with the risk in 16,000 euthyroid women without antibodies. hese investigators, however, did find a threefold greater risk of placental abruption in these women.

As with nonpregnant subjects with TPO antibodies, these women are also at increased risk for progression of thyroid disease and postpartum thyroiditis (Jameson, 2015; StagnaroGreen, 2012a). Currently, universal screening for the thyroid autoantibodies is not recommended by any professional organization (De Groot, 2012; Stagnaro-Green, 20lla, 2012a).

Decreasing iodide fortification of table salt and bread products in the United States during the past 25 years has led to occasional iodide deficiency (Caldwell, 2005; Hollowell, 1998). Importantly, the most recent National Health and Nutrition Examination Survey indicated that, overall, the United States population remains iodine suicient (Caldwell, 201l). Even so, experts agree that iodine nutrition in vulnerable populations, such as pregnant women, requires continued monitoring. In 2011, the Oice of Dietary Supplements of the National Institutes of Health sponsored a workshop to prioritize iodine research. Participants emphasized the decline in median urinary iodine levels to 125 Lg/L in pregnant women and the serious potential efects on developing fetuses (Swanson, 2012).

Dietary iodine requirements are higher during pregnancy due to augmented thyroid hormone production, increased renal losses, and fetal iodine requirements. Adequate iodine is requisite for fetal neurological development beginning soon after conception, and abnormalities are dependent on the degree of deficiency. he World Health Organization (WHO) has estimated that 38 million children are born every year at risk of lifelong brain damage associated with iodine deiciency (Alipui, 2008).

Although it is doubtful that mild diciency causes intellectual impairment, supplementation does prevent fetal goiter (Stagnaro-Green, 2012b). Severe diciency, on the other hand, is frequently associated with damage typically encountered with endemic cretinism (Delange, 2001). It is presumed that moderate deiciency has intermediate and variable efects. Berbel and associates (2009) began daily supplementation in more than 300 pregnant women with moderate deiciency at three time periods-4 to 6 weeks, 12 to 14 weeks, and after delivery. They found improved neurobehavioral development scores in ofspring of women supplemented with 200 ILg potassium iodide very early in pregnancy. Similarly, Velasco and coworkers (2009) found improved Bayley Psychomotor Development scores in ofspring of women supplemented with 300 ILg of iodine daily in the irst trimester. In contrast, Murcia and colleagues (2011) identified lower psychomotor scores in 1-yearold infants whose mothers reported daily supplementation of more than 150 ILg. To address this, randomized controlled trial of iodine supplementation in mildly to moderately iodinedeficient pregnant women in India and hailand is nearing completion (Pearce, 2016).

Regarding daily iodine intake, the Institute of Medicine during lactation (Chap. 9, p. 168). he Endocrine Society recommends an average iodine intake of 150 �g/d in repro ductive-aged women, and this should be increased to 250 �g during pregnancy and breastfeeding (De Groot, 2012). The of iodine be added to prenatal vitamins to achieve this average daily intake (Becker, 2006). According to Leung and coworkers (2011), however, only 51 percent of the prenatal multivitamins in the United States contain iodine. It has even been suggested that because most cases of maternal hypothyroxinemia world wide are related to relative iodine deficiency, supplementation may obviate the need to consider thyroxine treatment in such women (Gyami, 2009). However, without evidence of benefit, it is hard to justiy the cost of iodine supplementation of large numbers of pregnant women in areas with mild iodine dei ciency (Pearce, 2016).

Importantly, experts caution against oversupplementa tion. T eng and associates (2006) contend that excessive iodine intake-deined as > 300 �g/ d-may lead to subclinical hypo thyroidism and autoimmune thyroiditis. he Endocrine Soci ety, in accordance with the WHO, advises against exceeding twice the daily recommended intake of iodine, or 500 �g/ d (De

Groot, 2012; Leung, 2011).

Universal newborn screening for neonatal hypothyroidism was introduced in 1974 and is now required by law in all states (Chap. 32, p. 614). This develops in approximately 1 in 3000 newborns and is one of the most preventable causes of mental retardation (LaF ranchi, 2011). Developmental disorders of the thyroid gland such as agenesis and hypoplasia account for 80 to 90 percent of these cases. he remainder is caused by hereditary defects in thyroid hormone production (Moreno, 2008).

Early and aggressive thyroxine replacement is critical for newborns with congenital hypothyroidism. Still, some neonates identified by screening programs who were treated promptly will exhibit cognitive deicits into adolescence (Song, 2001). herefore, in addition to timing of treatment, the severity of congenital hypothyroidism is an important factor in long-term cognitive outcomes. Olivieri and colleagues (2002) reported that 8 percent of 1420 newborns with congenital hypothyroidism also had other major congenital malformations.

Transient autoimmune thyroiditis is consistently found in approximately 5 to 10 percent of women during the first year after childbirth (Nathan, 2014; Stagnaro-Green, 2011b, 2012a). Postpartum thyroid dysfunction with an onset within 12 months includes hyperthyroidism, hypothyroidism, or both. The propensity for thyroiditis antedates pregnancy and is directly related to increasing serum levels of thyroid autoantibodies. Up to 50 percent of women who are thyroid-antibody positive in the irst trimester will develop postpartum thyroiditis (Stagnaro-Green, 2012a). In a Dutch study of 82 women with type 1 diabetes, postpartum thyroiditis developed in 16 percent and was threefold higher than in the general population (Gallas, 2002). Importantly, 46 percent of those identified with overt postpartum thyroiditis had TPO antibodies in the first trimester.

In clinical practice, postpartum thyroiditis is diagnosed infre quently because it typically develops months after delivery and causes vague and nonspeciic symptoms (Stagnaro-Green, 2004). he clinical presentation varies, and classically two clinical phases that may develop in succession are recognized.

The first and earliest is destruction-induced thyrotoxicosis with symptoms from excessive release of hormone from glandular disruption. The onset is abrupt, and a small, painless goiter is common. Although there may be many symptoms, only fatigue and palpitations are more frequent in thyrotoxic women com pared with normal controls. This thyrotoxic phase usually lasts only a few months. hionamides are inefective, and if symp toms are severe, a 3-blocking agent may be given. he second and usually later phase between 4 and 8 months postpartum is hypothyroidism from thyroiditis. hyromegaly and other symp toms are common and more prominent than during the thyro toxic phase. hyroxine replacement at doses of25 to 75 �g/d is typically given for 6 to 12 months.

Stagnaro-Green and associates (20 11 b) reported postpartum surveillance results in 4562 Italian gravidas who had been screened for thyroid disease in pregnancy. Serum TSH and anti-TPO antibody levels were measured again at 6 and 12 months. Overall, two thirds of 169 women (3.9 percent) with postpartum thyroiditis were identiied to have hypothyroidism only. The other third were diagnosed with hyperthyroidism. Only 14 percent of all women demonstrated the "classic" biphasic progression described above. These indings are consistent with data compiled from 20 other studies between 1982 and 2008 (Stagnaro-Green, 2012a).

Importantly, women who experience either type of postpartum thyroiditis have a 20-to 30-percent risk of eventually developing permanent hypothyroidism, and the annual progression rate is 3.6 percent (Nathan, 2014). Women at greater risk for developing hypothyroidism are those with higher titers of thyroid antibodies and higher TSH levels during the initial hypothyroid phase. Others may develop subclinical disease, but half of those with thyroiditis who are positive for TPO antibodies develop permanent hypothyroidism by 6 to 7 years (Stagnaro-Green,r2012a).

n association between postpartum thyroiditis and postpartum depression has been proposed but remains unresolved. Lucas and coworkers (2001) found a 1.7-percent incidence of postpartum depression at 6 months in women with thyroiditis as well as in controls. Pederson and colleagues (2007) found a signiicant correlation between abnormal scores on the Edinburgh Postnatal Depression Scale and total thyroxine values in the low normal range during pregnancy in 31 women. Similarly unsettled is the link between depression and thyroid antibodies. Kuijpens and associates (2001) reported that TPO antibodies were a marker for postpartum depression in euthyroid women. In a randomized trial, however, Harris and coworkers (2002) reported no diference in postpartum depression in 342 women with TPO antibodies who were given either levothyroxine or placebo.

hyroid nodules can be found in 1 to 2 percent of reproductive-aged women (Fitzpatrick, 2010). Management of a palpable thyroid nodule during pregnancy depends on gestational age and mass size. Small nodules detected by sensitive sonographic methods are more common during pregnancy in some populations. Kung and associates (2002) used high-resolution sonography and found that 15 percent of Chinese women had nodules larger than 2 mm in diameter. Almost half were multiple, and the nodules usually enlarged modestly across preg nancy and did not regress postpartum. Biopsy of thoser> 5 mmrthat persisted at 3 months usually showed nodular hyperplasia, and none were malignant. In most studies, 90 to 95 percent of solitary nodules are benign (Burch, 2016).

Evaluation of thyroid nodules during pregnancy should be similar to that for nonpregnant patients. As discussed in Chapter 46 (p. 908), radioiodine scanning in pregnancy is usually not recommended (American College of Obstetricians and Gynecologists, 2017). Sonographic examination reliably detects nodules > 5 mm, and their solid or cystic structure also is determined. According to the American Association of Clinical Endocrinologists, sonographic characteristics associated with malignancy include hypoechogenic pattern, irregular margins, and microcalcifications (Gharib, 2005). Fine-needle aspiration (FNA) is an excellent assessment method, and histological tumor markers and immunostaining are reliable to evaluate for malignancy (Hegedus, 2004). If the FNA biopsy shows a follicular lesion, surgery may be deferred until after delivery.

Evaluation of thyroid cancer involves a multidisciplinary approach (Fagin, 2016). Most thyroid carcinomas are well differentiated and pursue an indolent course. Messuti and coworkers (2014) provided evidence that persistence or recurrence of these tumors may be more common in pregnant women. When thyroid malignancy is diagnosed during the first or second trimester, thyroidectomy may be performed before the third trimester (Chap. 63, p. 1201). In women without evidence of an aggressive thyroid cancer or in those diagnosed in the third trimester, surgical treatment can be deferred to the immediate puerperium (Gharib, 2010).

The function of parathyroid hormone (PTH) is to maintain extracellular fluid calcium concentration. his 84-amino acid hormone acts directly on bone and kidney and indirectly on small intestine through its efects on synthesis of vitamin D (l,25-(OH)2D) to increase serum calcium (Potts, 2015). Secretion is regulated by serum ionized calcium concentration through a negative feedback system. Cacitonin is a potent parathyroid hormone that acts as a physiological parathyroid hormone antagonist. The interrelationships between these hormones, calcium metabolism, and PTH-related protein produced by fetal tissue are discussed in Chapter 4 (p. 71).

Of fetal demands, calcium requirements reach 300 mg/d in late pregnancy and 30 g for the entire gestation. These needs and greater renal calcium loss from augmented glomerular iltration substantively raise maternal calcium demands. Pregnancy is associated with a twofold rise in serum concentrations of 1,25-dihydroxyvitamin D, which increases gastrointestinal calcium absorption. he efectuating hormone is probably of placental and decidual origin because maternal PTH levels are low normal or decreased during pregnancy (Cooper, 2011; Molitch, 2000). Total serum calcium levels decline with serum albumin concentrations, but ionized calcium levels remain unchanged. Vargas Zapata and colleagues (2004) have suggested a role for insulin-like growth factor-1 (IGF-1) in maternal calcium homeostasis and bone turnover.

Hypercalcemia is caused by hyperparathyroidism or cancer in 90 percent of cases (Potts, 2015). Because many automated laboratory systems include serum calcium measurement, hyperparathyroidism has changed from being a condition deined by symptoms to one that is discovered on routine screening (Pallan, 2012). It has a reported prevalence of 2 to 3 per 1000 women, but some have estimated the rate to be as high as 14 per 1000 when asymptomatic cases are included. Almost 80 percent are caused by a solitary adenoma, and another 15 percent by hyperfunctioning of all four glands. In the remainder, a malignancy as the cause of increased serum calcium levels is usually obvious. Of note, PTH produced by tumors is not identical to the natural hormone and may not be detected by routine assays.

In most patients, the serum calcium level is elevated to within only 1 to 1.5 mg/dL above the upper normal limit. This may help to explain why only 20 percent of those who have abnormally elevated levels are symptomatic (Bilezikian, 2004). In a fourth, however, symptoms become apparent when the serum calcium level continues to rise. Hypercacemic crisis manifests as stupor, nausea, vomiting, weakness, fatigue, and dehydration.

All women with symptomatic hyperparathyroidism should be surgically treated (Potts, 2015). Indications for parathyroidectomy include a serum calcium level 1.0 mg/dL above the upper normal range, a calculated creatinine clearance < 60 mLi min, reduced bone density, or age >50 years (Bilezikian, 2009). Those not meeting these criteria should undergo annual serum calcium and creatinine level measurement and bone density assessment every 1 to 2 years (Pallan, 2012).

In their review, Schnatz and Thaxton (2005) found fewer than 200 reported cases of hyperparathyroidism complicating pregnancy. As in nonpregnant patients, parathyroid adenoma is the most common etiology. Ectopic parathyroid hormone production and rare cases of parathyroid carcinoma have been reported in pregnancy (Montoro, 2000; Saad, 2014). Symptoms include hyperemesis, generalized weakness, renal calculi, and psychiatric disorders. Occasionally, pancreatitis is the presenting disorder (Cooper, 2011; Hirsch, 2015).

Pregnancy theoretically improves hyperparathyroidism because of signiicant calcium shunting to the fetus and augmented renal excretion (Power, 1999). When the "protective efects" of pregnancy are withdrawn, however, postpartum hypercalcemic crisis is a significant danger. his life-threatening complication can be seen with serum calcium levels greater than 14 mgl dL and is characterized by nausea, vomiting, tremors, dehydration, and mental status changes (Malekar-Raikar, 2011).

ism. More recent reports, however, described lower rates of stillbirth, neonatal death, and neonatal tetany (Kovacs, 201r1).

Other fetal complications include miscarriage,r· fetal-growth restriction, and low birthweight (Chamarthi, 2011). Schnatz (2005) reported a 25-percent incidence of preeclampsia.

Management in Pregnancy. Surgical removal of a symptomatic parathyroid adenoma is preferable. This should prevent fetal and neonatal morbidities and postpartum parathyroid crises (Kovacs, 2011). Elective neck exploration during pregnancy is usually well tolerated, even in the third trimester (Hirsch, 2015; Schnatz, 2005; Stringer, 2017). In at least two cases, a mediastinal adenoma was removed at midpregnancy (Rooney, 1998; Saad, 2014).

Medical management may be appropriate in asymptomatic pregnant women with mild hypercalcemia (Hirsch, 2015). If so, patients are careully monitored in the puerperium for hypercalcemic crisis. Initial medical management might include cacitonin to decrease skeletal calcium release, or oral phosphate, 1 to 1.5 g daily in divided doses, to bind excess calcium. For women with dangerously elevated serum calcium levels or those who are mentally obtunded with hypercacemic crisis, emergency treatment is instituted. Diuresis with intravenous normal saline is begun so that urine low exceeds 150 mLlhr. Furosemie is given in conventional doses to block tubular calcium reabsorption. Importantly, hypokalemia and hypomagnesemia should be prevented. Adjunctive therapy includes mithramycin, which inhibits bone resorption.

Neonatal Efects. Normally, cord blood calcium levels are higher than maternal levels (Chap. 7, p. 139). With maternal hyperparathyroidism, abnormally elevated maternal and thus fetal levels further suppress fetal parathyroid function. Because of this, newborn calcium levels rapidly drop after birth, and 15 to 25 percent of these neonates develop severe hypocalcemia with or without tetany (Molitch, 2000). Neonatal hypoparathyroidism caused by maternal hyperparathyroidism is usually transient and is treated with calcium and 1,25-dihydroxyvitamin D3 (calcitriol). he latter will not be efective in preterm infants, however, because the intestinal vitamin D receptor is not suiciently expressed (Kovacs, 2011) . Neonatal tetany or seizures should stimulate an evaluation for maternal hyperparathyroidism (Beattie, 2000; Ip, 2003).

The most common cause of hypocalcemia is hypoparathyroidism that usually follows parathyroid or thyroid surgery. Hypoparathyroidism is estimated to follow up to 7 percent of total thyroidectomies (Shoback, 2008). It is characterized by facial muscle spasms, muscle cramps, and paresthesias of the lips, tongue, fingers, and feet. This can progress to tetany and seizures (Potts, 2015). Chronically, hypocalcemic pregnant women may also have a fetus with skeletal demineralization resulting in multiple bone fractures in the neonatal period (Alikasifoglu, 2005).

Maternal treatment includes calcitriol, dihydrotachysterol, or large vitamin D doses of 50,000 to 150,000 U/d; calcium gluconate or calcium lactate in doses of 3 to 5 g/d; and a lowphosphate diet. Fetal risks from large doses of vitamin D have not been established. During treatment, the therapeutic challenge in women with known hypoparathyroidism is management of blood calcium levels. It is possible that the greater calcium absorption typical of pregnancy will result in lower calcium requirements or that the fetal demand for calcium will result in greater need. he goal during pregnancy is to maintain a corrected calcium level in the low normal range.

In most gravidas, even with their remarkably increased calcium requirements, it is uncertain whether pregnancy causes osteopenia (Kaur, 2003; To, 2003). In one study of200 pregnant women in which bone mass was measured, Kraemer and colleagues (2011) demonstrated a decline in bone density during pregnancy. Women who breastfed, carried twin pregnancies, or had a low body mass index were at higher risk of bone loss. From their review, Thomas and Weisman (2006) cite a 3-to 4-percent average reduction in bone mineral density during pregnancy. Lactation also represents a period of negative calcium balance that is corrected through maternal skeletal resorption. Feigenberg and coworkers (2008) found cortical bone mass reductions using ultrasound in young primiparas in the puerperium compared with nulligravid controls. Rarely, some women develop idiopathic osteoporosis while pregnant or lactating (Hellmeyer, 2007).

The most common symptom of osteoporosis is back pain in late pregnancy or postpartum. Other symptoms are hip pain, either unilateral or bilateral, and diiculty in weight bearing until the woman is nearly immobilized (Maliha, 2012). In more than half of women, no apparent reason for osteopenia is found. Some known causes include heparin (unfractionated only), prolonged bed rest, and corticosteroid therapy (Cunningham, 2005; Galambosi, 2016). In a few cases, overt hyperparathyroidism or thyrotoxicosis eventually develops.

Treatment is problematic and includes calcium and vitamin D supplementation and standard pain management. Shown in Figure 58-5 is a hip radiograph from a woman

FIGURE 58-5 Anteroposterior plain hip radiograph of a 25-yearold woman at 26 weeks' gestation. She complained of left hip and knee pain and progressive weakness. Transient osteoporosis of the left femur responded over 3 months to physical therapy combined with vitamin 0 and calcium supplementation.

treated at Parkland Hospital during the third trimester for transient osteoporosis of pregnancy. For women with pregnancy-associated osteopenia, long-term surveillance indicates that although bone density improves, these women and their ofspring may have chronic osteopenia (Carbone, 1995). Related, prenatal supplementation of normal women with cholecalciferol, 1000 IU / d, did not increase ofspring bone mineral content, although it did ensure maternal vitamin D repletion (Cooper, 2016).

Pregnancy has profound efects on adrenal cortical secretion and its control or stimulation. These interrelationships were reviewed by Lekarev and New (2011) and are discussed in detail in Chapter 4 (p. 71).

Pheochromocytomas are chromain tumors that secrete catecholamines and usually are located in the adrenal medulla, although 10 percent are located in sympathetic ganglia. They are called the 10-percent tumor because approximately 10 percent are bilateral, 10 percent are extraadrenal, and 10 percent are malignant. These tumors can be associated with medullary thyroid carcinoma and hyperparathyroidism in some of the autosomally dominant or recessive multiple endocrine neoplasia syndromes, as well as in neurofibromatosis and von HippelLindau disease (Neumann, 2015).

These tumors complicate approximately 1 per 50,000 pregnancies (Quartermaine, 2017). Notably, they are found in 0.1 percent of hypertensive patients (Abdelmannan, 2011). However, they are more commonly found at autopsy but with infrequent clinical recognition. Symptoms are usually paroxysmal and manifest as hypertensive crisis, seizure disorders, or anxiety attacks. Hypertension is sustained in 60 percent of patients, but half of these also have paroxysmal crises. Other symptoms during paroxysmal attacks are headaches, profuse sweating, palpitations, chest pain, nausea and vomiting, and pallor or flushing.

The standard screening test is quantification of metanephrines and catecholamine metabolites in a 24-hour urine specimen (Neumann, 2015). Diagnosis is established by measurement of a 24-hour urine collection with at least two of three assays for free catecholamines, metanephrines, or vanillylmandelic acid (VMA). Determination of plasma catecholamine levels is the most sensitive test. In nonpregnant patients, adrenal localization is usually successful with either computed tomography (CT) or magnetic resonance (MR) imaging. For most cases, preferred treatment is laparoscopic adrenalectomy (Neumann, 2015).

These tumors are rare but result in dangerous pregnancy complications. Geelhoed (1983) provided an earlier review of 89 cases in which 43 mothers died. Maternal death was much more common if the tumor was not diagnosed antepartum-58 versus 18 percent. As seen in Table 58-6, maternal mortality rates are now lower but still formidable. In their review of 77 cases, Biggar and Lennard (2013) reported that antepartum diagnosis is the most important determinant of maternal mortality risk. That said, Salazar-Vega and colleagues (2014) described good outcomes in women diagnosed after delivery.

TABLE 58-6. Outcomes of Pregnancies Complicated by Pheochromocytoma and Reported in Four Contiguous Epochs

Diagnosis of pheochromocytoma in pregnancy is similar to that for nonpregnant patients. MR imaging is the preferred technique because it almost always locates adrenal and extraadrenal pheochromocytomas (Fig. 58-6). In many cases, the principal challenge is to diferentiate preeclampsia from the hypertensive crisis caused by pheochromocytoma. Grimbert and colleagues (1999) diagnosed two pheochromocytomas during 56 pregnancies in 30 women with von Hippel-Lindau disease.

FIGURE 58-6 Coronal magnetic resonance image taken in a 32-week pregnant woman shows a right-sided pheochromocytoma (arrow) and its position relative to the liver above it.

Immediate control of hypertension and symptoms with an .-adrenergic blocker such as phenoxybenzamine is impera tive. he dose is 10 to 30 mg, two to four times daily. After .-blockade is achieved, 3-blockers may be given for tachycar dia. In many cases, surgical exploration and tumor removal are performed during pregnancy, preferably during the second trimester (Biggar, 2013; Dong, 2014). Successfulrlaparoscopic removal of adrenal tumors has become the norm (Miller, 2012;

Zuluaga-G6mez, 2012). If diagnosed later in pregnancy, either planned cesarean delivery with tumor excision or postpartum resection is appropriate.

Recurrent tumors are troublesome, and even with good blood pressure control, dangerous peripartum hypertension may develop. We have cared for three women in whom recur rent pheochromocytoma was identiied during pregnancy.

Hypertension was managed with phenoxybenzamine in all three. Two newborns were healthy, but a third was stillborn in a mother with a massive tumor burden who was receiving phenoxybenzamine, 100 mg daily. In all three women, tumor was resected postpartum.

his syndrome is rare and the female:male ratio is 3: 1 (Arit, 2015). Most cases are iatrogenic from long-term corticosteroid treatment. Cushing disease refers to bilateral adrenal hyperplasia stimulated by corticotropin-producing pituitary adenomas. Corticotropin is also called adrenocorticotropic hormone (ACTH). Most adenomas are microadenomas measuring < 1 em, and half measure <5 mm. Rarely, abnormal secretion of hypothalamic corticotropin-releasing factor may cause corticotropic hyperplasia. Such hyperplasia may also be caused by nonendocrine tumors that produce polypeptides similar to either corticotropin-releasing factor or corticotropin. Less than a fourth of cases of Cushing syndrome are corticotropin independent, and most of these are caused by an adrenal adenoma. Tumors are usually bilateral, and half are malignant. Occasionally, associated androgen excess may lead to severe virilization.

he typical cushingoid body habitus is caused by adipose tissue deposition that characteristically results in moon acies, a builo hump, and truncal obesiy. Fatigability and weakness, hypertension, hirsutism, and amenorrhea are each encountered in 75 to 85 percent of nonpregnant patients (Hatipoglu, 2012). Personality changes, easy bruisability, and cutaneous striae are common. Up to 60 percent may have impaired glucose tolerance. Diagnosis can be diicult and is suggested by elevated plasma cortisol levels that cannot be suppressed by dexamethasone or by elevated 24-hour urine free cortisol excretion (Arit, 2015; Loriaux, 2017). Neither test is totally accurate, and each is more diicult to interpret in obese patients. Serum corticotropin levels and CT and MR imaging are used to localize pituitary and adrenal tumors or hyperplasia.

Because most women have corticotropin-dependent Cushing syndrome, associated androgen excess may cause anovulation,

TABLE 58-7. Maternal and Perinatal Complications

Data from Lindsay, 2005.

and pregnancy is rare. In their review, Lekarev and New (2011) identiied fewer than 140 reported cases of Cushing syndrome in pregnancy. These difer compared with nonpregnant women in that half are caused by corticotropin-independent adrenal adenomas (Kamoun, 2014; Lacroix, 2015). Approximately 30 percent of cases are from a pituitary adenoma, and 10 percent from adrenal carcinomas. All reports stress diiculties in diagnosis because of pregnancy-induced increases in plasma cortisol, corticotropin, and corticotropin-releasing factor levels. Measurement of24-hour urinary free cortisol excretion is recommended, with consideration for the normal elevation seen in pregnancy.

Pregnancy outcomes in women with Cushing syndrome are listed in Table 58-7. Heart failure is common during pregnancy and is a major cause of maternal mortality (Buescher, 1992). Hypercortisolism in pregnancy may also cause poor wound healing, osteoporotic fracture, and psychiatric complications (Kamoun, 2014).

Long-term medical therapy for Cushing syndrome usually is inefective, and deinitive therapy is resection of the pituitary or adrenal adenoma or bilateral adrenalectomy for hyperplasia (Lacroix, 2015; Motivala, 2011). During pregnancy, management of hypertension in mild cases may suice until delivery. In their review, Lindsay and associates (2005) described primary medical therapy in 20 women with Cushing syndrome. Most were successfully treated with meyrapone as an interim treatment until deinitive surgery after delivery. A few cases were treated with oral ketoconazole. However, because this drug also blocks testicular steroidogenesis, treatment during pregnancy with a male fetus is worrisome. Miepristone, the norethindrone derivative used for abortion and labor induction, has shown promise for treating Cushing disease but should not be used in pregnancy for obvious reasons. If necessary, pituitary adenomas can be treated by transsphenoidal resection (Boscaro, 2001; Lindsay, 2005). Unilateral adrenalectomy has been safely performed in the early third trimester and can also be curative (Abdelmannan, 2011).

Primary adrenocortical insuiciency is rare because more than 90 percent of total gland volume must be destroyed for symptoms to develop. Autoimmune adrenalitis is the most common cause in the developed world, but tuberculosis is a more frequent etiology in resource-poor countries (Arit, 2015; Kamoun, 2014). The incidence has been cited as being as high as 1 in 3000 births in Norway (Lekarev, 2011). In the United States, the prevalence was 1 per 10,000 to 20,000 pregnancies (Schneiderman, 2017). here is an increased incidence of concurrent Hashimoto thyroiditis, primary ovarian insuiciency, type 1 diabetes, and Graves disease. These poyglandular autoimmune syndromes also include pernicious anemia, vitiligo, alopecia, nontropical sprue, and myasthenia gravis.

Untreated adrenal hypofunction frequently causes infertility, but with replacement therapy, ovulation is restored. If untreated, symptoms often include weakness, fatigue, nausea and vomiting, and weight loss. Because serum cortisol levels are increased during pregnancy, the inding of a low value should prompt a cosyntropin test to document the lack of response to infused corticotropin (Salvatori, 2005).

In a large Swedish cohort study, 1188 women with Addison disease were compared with more than 11,000 age-matched controls who delivered between 1973 and 2006 (Bjornsdottir, 2010). Women diagnosed with adrenal insuiciency within 3 years of delivery were signiicantly more likely to deliver preterm, to deliver a low-birthweight newborn, and to undergo cesarean delivery. Others have reported similar adverse outcomes (Quartermaine, 2017). Most pregnant women with Addison disease are already taking glucocorticoid and mineralocorticoid replacement drugs. hese should be continued and women observed for evidence of either inadequate or excessive corticosteroid replacement (Lebbe, 2013). During labor, delivery,r and postpartum, or after a surgical procedure, corticosteroid replacement must be increased appreciably to approximate the normal adrenal response-the so-called stress dose. Hydrocortisone, 100 mg, is usually given intravenously every 8 hours for 48 hours. It is important that shock from causes other than adrenocortical insuiciency-for example, hemorrhage or sepsis-be recognized and treated promptly.

Hyperaldosteronism is caused by an adrenal adenoma-Conn syndrome-in approximately 75 percent of cases. Idiopathic bilateral adrenal hyperplasia makes up the remainder, except for rare cases of adrenal carcinoma (Abdelmannan, 2011; Eschler, 2015). Findings include hypertension, hypokalemia, and muscle weakness. High serum or urine levels of aldosterone confirm the diagnosis.

In normal pregnancy, as discussed in Chapter 4 (p. 72), progesterone blocks aldosterone action, and thus there are very high aldosterone levels (Appendix, p. 1258). Accordingly, the diagnosis of hyperaldosteronism during pregnancy can be diicult. Since renin levels are suppressed in pregnant women with hyperaldosteronism, a plasma aldosterone-to-renin activity ratio may be helpful for diagnosis (Kamoun, 2014). Hypertension worsens as pregnancy progresses, and medical management includes potassium supplementation and antihypertensive therapy. In many cases, hypertension responds to spironolactone, but 3-blockers or calcium-channel blockers may be preferred because of the potential fetal antiandrogenic efects of spironolactone. Mascetti and coworkers (201r1) reported successful use of amiloride in a pregnant woman. Use of eplerenone, a selective aldosterone-receptor antagonist, has also been reported (Cabassi, 2012). Laparoscopic tumor resection is curative (Eschler, 2015; Miller, 2012).

The pituitary enlarges impressively during pregnancy, predominately from lactotrophic cellular hyperplasia induced by estrogen stimulation (Chap. 4, p. 68). Several pituitary disorders can also complicate pregnancy.

These adenomas are found often in nonpregnant women since the advent of widely available serum prolactin assays. Serum levels <25 pg/mL are considered normal in nonpregnant women (Nlotivala, 2011). Adenoma symptoms and indings include amenorrhea, galactorrhea, and hyperprolactinemia. Tumors are classiied arbitrarily by their size measured by CT or MR imaging. A micro adenoma is :;10 mm, and a macro adenoma is >10 mm. Treatment for microadenomas is usually with bromocriptine, a dopamine agonist and powerful prolactin inhibitor, which frequently restores ovulation. For suprasellar macroadenomas, most recommend surgical resection before pregnancy is attempted (Araujo, 2015).

In a pooled analysis of more than 750 pregnant women with prolactinomas, only 2.4 percent with microadenomas developed symptomatic enlargement during pregnancy (Molitch, 2015). Symptomatic enlargement of macroadenomas, however, is more frequent and was found in 21 percent of 238 pregnant women. Schlechte (2007) also reported that 15 to 35 percent of suprasellar macroadenomas have tumor enlargement that causes visual disturbances, headaches, and diabetes insipidus. Nonfunctioning adenomas can also cause symptoms of pituitary expansion in pregnancy (Lambert, 2017).

Pregnant women with microadenomas should be queried regularly for headaches and visual symptoms. Those with macroadenomas are followed more closely and have visual field testing during each trimester. CT or MR imaging is recommended only if symptoms develop (Fig. 58-7). Serial serum prolactin levels serve little use because of normal rises during pregnancy (Appendix, p. 1259). Symptomatic tumor enlargement should be treated immediately with a dopamine antagonist. he safety of bromocriptine in pregnancy is well established. The safety profile is less well known for cabergoline, which is increasingly used in nonpregnant women because it is better tolerated and more efective. Cabergoline is generally considered safe for use in pregnancy (Araujo, 2015; Auriemma, 2013). Lebbe and colleagues (2010) described 100 pregnancies exposed to cabergoline and found no adverse efects. Similar indings were reported in 85 exposed Japanese pregnant women (Ono, 2010). Surgery is recommended for women with no response.

suprasellar mass (arrow). Note the layering of complex fluid within the mass, which was found during surgery to be hemorrhage.

(Used with permission from Dr. April Baily.) his is caused by excessive growth hormone, usually from an acidophilic or a chromophobic pituitary adenoma. In normal pregnancy, pituitary growth hormone levels decrease as placental epitopes are secreted. Diagnosis is confirmed by elevated IGF-1 serum levels (Katznelson, 2014). Fewer than 100 cases of acromegaly have been reported during pregnancy (Cheng, 2012; Dias, 2013; Motivala, 2011). Pregnancy is probably rare in women with acromegaly because half are hyperprolactinemic and anovulatory. During pregnancy, afected women are at marginally greater risk for gestational diabetes and hypertension (Caron, 2010; Dias, 20l3).

Management is similar to that for prolactinomas, with close monitoring for symptoms of tumor enlargement. Dopamine agonist therapy is less efective than for prolactinomas. And, transsphenoidal resection, generally considered irst-line treatment outside of pregnancy, may be necessary for symptomatic tumor enlargement during pregnancy (Motivala, 2011). Guven and associates (2006) reported a case of pituitary apoplexy necessitating emergent transsphenoidal adenoma resection and cesarean delivery at 34 weeks. Successful treatment of pregnant women with the somatostatin-receptor ligand octreotide and with the GH analogue pegvisomant has also been reported (Dias, 2013; Fleseriu, 2015).

The vasopressin deficiency evident in diabetes insipidus is usually due to agenesis or destruction of the neurophypophysis (Robertson, 2015). True diabetes insipidus is a rare complication of pregnancy.

Diabetes insipidus therapy is intranasal administration of a synthetic analogue of vasopressin, desmopressin, which is 1-deamino8-D-arginine vasopressin (DDA P). Ray (1998) reviewed 53 cases in which DDAP was used during pregnancy with no adverse sequelae. Most women require increased doses during pregnancy because of an increased metabolic clearance rate stimulated by placentl vasopressinase (Lindheimer, 1994). By this same mecha nism, subclinicaL diabetes inspidus may become symptomatic or cases of transient diabetes inspidus may be encountered during pregnancy (Bellastella, 2012; Robertson, 2015). he prevalence of vasopressinase-induced diabetes insipidus is estimated at 2 to 4 per 100,000 pregnancies (Wallia, 20l3).

In our experiences, as described in Chapter 55 (p. 1062), transient secondary diabetes insipidus is more likely encoun tered with acute atty Liver of pregnancy (Nelson, 20 l3). This probably is due to altered vasopressinase clearance because of hepatic dysfunction.

Sheehan (1937) reported that pituitary ischemia and necrosis associated with obstetrical blood loss could result in hypopituitarism. With modern methods of hemorrhagic shock treatment, Sheehan syndrome is now seldom encountered (Feinberg, 2005; Pappachan, 2015; Robalo, 2012). Afected women may have persistent hypotension, tachycardia, hypoglycemia, and lactation failure. Because deficiencies of some or all pituitary-responsive hormones may develop after the initial insult, Sheehan syndrome can be heterogenous and may not be identified for years (Tessnow, 2010). In one cohort study of 60 women from Costa Rica with Sheehan syndrome, the average time to diagnosis was 13 years (Gei-Guardia, 2011). Because adrenal insuiciency is the most life-threatening complication, adrenal function should be immediately assessed in any woman suspected of having Sheehan syndrome. Mter glucocorticoid replacement, subsequent analyses and replacement of thyroid, gonadal, and growth hormones is considered.

This rare autoimmune pituitary disorder is characterized by massive iniltration by lymphocytes and plasma cells with parenchymal destruction of the gland. vIany cases are temporally linked to pregnancy (Foyouzi, 2011; Honegger, 2015; Melmed, 2015). here are varying degrees of hypopituitarism or symptoms of mass efect, including headaches and visual ield defects. A sellar mass is seen with CT or MR imaging. A mass accompanied by a modestly elevated serum prolactin level-usually < 100 pgl mL-suggests lymphocytic hypophysitis. In contrast, levels >200 pg/mL are encountered with a prolactinoma. he etiology is unknown, but nearly 30 percent have a history of coexisting autoimmune diseases including Hashimoto thyroiditis, Addison disease, type 1 diabetes, or pernicious anemia. Treatment is with glucocorticoids and pituitary hormone replacement. he disease may be self-limited, and a careful withdrawal of hormone replacement is attempted after inflammation subsides (Foyouzi, 2011; Melmed, 2015).

Abalovich I, Alcaraz G, Kleiman-Rubinsztein ], et al: he relationship of preconception thyrotropin levels to requirements for increasing the levothyroxine dose during pregnancy in women with primary hypothyroidism. Thyroid 5,t2010

Abalovich , Gutierrez S, Alcaraz G, et al: Overt and subclinical hypothyroidism complicating pregnancy. hyroid 12(1):63,t2002

Abbassi-Ghanavati M, Casey B, Spong C, et al: Pregnancy outcomes in women with thyroid peroxidase antibodies. Obstet Gynecol 116(2, Pt 1) :381, 2010

Abdelmannan D, ron D: Adrenal disorders in pregnancy. Endocrinol Metab Clin North Am 40:779,t2011

Ahlawat SK, Jain S, Kumari S, et al: Pheochromocytoma associated with pregnancy: case report and review of the literature. Obstet Gynecol Surv 54:728, 1999

Alexander EK, Marquesee E, Lawrence ], et al: Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl] Med 351:241,t2004

Alikasifoglu A, Gone EN, Yalcin E, et al: Neonatal hyperparathyroidism due to maternal hypoparathyroidism and vitamin D deficiency: a cause of multiple bone fractures. Clin Pediatr 44:267, 2005

Alipui N: Sustained elimination of iodine deficiency. World Health Organization, 2008. Available at: https:llwww.unicef.org/publications/files/Sustain able_Elimination_oCIodine_Deficiency. pdf. Accessed] anuary 7, 2017 American College of Obstetricians and Gynecologists: Thyroid disease in pregnancy. Practice Bulletin No. 148, April 2015, Reairmed 2017

American hyroid Association and American Association of Clinical Endocrinologists: Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the merican hyroid Association and merican Association of Clinical Endocrinologists. Endocr Pract 17(3):456, 2011

Amino N, Izumi Y, Hidaka Y, et al: No increase of blocking type anti-thyrotropin receptor antibodies during pregnancy in patients with Graves' disease. ] Clin Endocrinol Metab 88(12):5871, 2003

Andersen SL, Olsen ], Laurberg P: Maternal thyroid disease in the Danish National Birth Cohort: prevalence and risk factors. Eur ] Endocrinol 174(2):203,t2016

Andersen SL, Olsen], W u CS, et al: Severity of birth defects after propylthiouracil exposure in early pregnancy. hyroid 24(10):1533,t2014

Arafah BM: Increased need for thyroxine in women with hypothyroidism during estrogen therapy. N Englt] Med 344:t1743,t2001

Araujo PB, Vieira Neto L, Gadelha MR: Pituitary tumor management in pregnancy. Endocrinol Metab Clin North Am 44(1):181, 2015

Arit W: Disorders of the adrenal cortex. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, cGraw-Hill Education, 2015

Auriemma RS, Perone Y, Di Sarno A, et al: Results of a single-center observational 10-year survey study on recurrence of hyperprolactinemia after pregnancy and lactation.] Clin Endocrinol Metab 98(1):372, 2013

Ayala C, Navarro E, Rodriguez]R, et al: Conception after iodine-131 therapy for diferentiated thyroid cancer. hyroid 8: 1009, 1998

Bahn RS, Burch HB, Cooper OS, et al: Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American hyroid Association and American Association of Clinical Endocrinologists. Endocr Pract 17(3):456, 2011

Barbesino G, Tomer Y: Clinical utility of TSH receptor antibodies. ] Clin Endocrinol Metab 98(6):2247, 2013

Beattie Gc, Ravi NR, Lewis M, et al: Rare presentation of maternal primary hyperparathyroidism. BM] 321 :223, 2000

Becker DV, Braverman LE, Delange F, et al: Iodine supplementation for pregnancy and lactation-United States and Canada: recommendations of the American hyroid Association. hyroid 16:949,t2006

Bellastella A, Bizzarro A, Colella C, et al: Subclinical diabetes insipidus. Best Pract Res Clin Endocrinol Metab 26(4):471,t2012

Berbel P. Mestre ]L, Santamaria A, et al: Delayed neurobehavioral development in children born to pregnant women with mild hypothyroxinemia during the first month of gestation: the importance of early iodine supplementation. Thyroid 19:511, 2009

Berlin L: Malpractice issues in radiology: iodine-131 and the pregnant patient.

A]RAm] RoentgenoIt176:869, 2001

Bernal ]: Thyroid hormone receptors in brain development and function. Nat Clin Pract Endocrinol Metab 3(3):249, 2007

Bianchi DW, Romero R: Biological implications of bi-directional fetomaternal cell traicking summary of a National Institute of Child Health and Human Development-sponsored conference.] Matern Fetal Neonatal Med 14: 123, 2003

Biggar viA, Lennard TW: Systematic review of phaeochromocytoma in pregnancy. Br] Surg 100(2):182, 2013

Bilezikian ]P, Khan A, Potts]T]r: Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement of the Third International Workshop. ] Clin Endocrinol Metab 94(2):335, 2009

Bilezikian ]P, Silverberg S]: Asymptomatic primary hyperparathyroidism.

N Engl] Med 350:1746,2004

Bjornsdottir S, Cnattingius S, Brandt L, et al: Addison's disease in women is a risk factor for an adverse pregnancy outcome. ] Clin Endocrinol Metab 95(12):5249,t2010

Boddy AM, Fortunato A, Wilson Sayres M, et al: Fetal micro chimerism and maternal health: a review and evolutionary analysis of cooperation and conlict beyond the womb. Bioessays 37(10):1106,t2015

Boscaro M, Barzon L, Fallo F, et al: Cushing's syndrome. Lancet 357:783,t2001 Brand F, Liegeois P, Langer B: One case of fetal and neonatal variable thyroid dysfunction in the context of Graves' disease. Fetal Diagn Ther 20: 12, 2005 Brent GA: Graves' disease. N Engl ] Med 358:2594, 2008

Brown RS, Bellisario L, Botero 0, et al: Incidence of transient congenital hypothyroidism due to maternal thyrotropin receptor-blocking antibodies in over one million babies. ] Clin Endocrinol Metab 81: 1147, 1996

Bryant SN, Nelson DB, McIntire DD, et al: n analysis of population- based prenatal screening for overt hypothyroidism. Am ] Obstet Gynecol 213(4):565.e1,t2015 Buescher A, McClamrock HD, Adashi EY: Cushing syndrome in pregnancy.

Obstet Gynecol 79:t130, 1992

Burch HB, Burman KD, Cooper OS, et al: A 2015 survey of clinical practice patterns in the management of thyroid nodules. ] Clin Endocrinol Metab 101(7):2853,t2016

Cabassi A, Rocco R, Berretta R, et al: Eplerenone use in primary aldosteronism during pregnancy. Hypertension 59(2):e18, 2012

Caldwell L, Jones R, Hollowell ]G: Urinary iodine concentration: United States National Health and Nutrition Examination Survey 2001-2002. hyroid 15(7):692,t2005

Caldwell KL, Makhmudov A, Ely E, et al: Iodine status of the U.S. population, National Health and Nutrition Examination Survey, 2005-2006 and 2007-2008. Thyroid 21(4):419,t2011

Carbone LD, Palmieri GviA, Graves SC, et al: Osteoporosis of pregnancy: long-term follow-up of patients and their ofspring. Obstet Gynecol 86:664, 1995

Caron P, Broussaud S, Bertherat ], et al: Acromegaly and pregnancy: a retrospective multicenter study of 59 pregnancies in 46 women. ] Clin Endocrinol Metab 95(10):4680, 2010

Casey BM, Dashe ]S, Spong CY, et al: Perinatal significance of isolated maternal hypothyroxinemia identified in the first half of pregnancy. Obstet Gynecol 109:1129,t2007

Casey BM, Dashe ]S, Wells CE, et al: Subclinical hypothyroidism pregnancy outcomes. Obstet Gynecol 105:38,t2005

Casey BM, Leveno K]: Thyroid disease in pregnancy. Obstet Gynecol 108:1283,t2006

Casey BM, Thon A, Peaceman AM, et al: Treatment of subclinical hypothyroidism or hypothyroxinemia during pregnancy. N Engl] Med 376:815,2017 Chamarthi B, Greene M, Dluhy R: A problem in gestation. N Engl ] Med 365(9):843,t201t1

Chen S, Zhou X, Zhu H, et al: Preconception TSH levels and pregnancy outcomes: a population-based cohort study in 184,611 women Clin Endocrinol (Oxf) 86(6):816,t2017

Cheng S, Grasso L, Martinez-Orozco ]A, et al: Pregnancy in acromegaly: experience from two referral centers and systematic review of the literature. Clin Endocrinol (Oxf) 76(2):264, 2012

Cirello V, Rizzo R, Crippa M, et al: Fetal cell microchimerism: a protective role in autoimmune thyroid diseases. Eur] EndocrinoIt173(1):111, 2015 Cleary-Goldman], Malone FD, Lambert-Messerlian G, et al: Maternal thyroid hypofunction and pregnancy outcome. Obstet Gynecol 112(1):85,2008

Cohen 0, Pinhas-Haniel 0, Sivian E, et al: Serial in utero ultrasonographic measurements of the fetal thyroid: a new complementary tool in the management of maternal hyperthyroidism in pregnancy. Prenat Diagn 23:740,t2003

Cooper C, Harvey NC, Bishop N], et al: Maternal gestational vitamin D supplementation and ofspring bone health CMAVIDOS): a multicentre, double-blind, randomised placebo-controlled trial. Lancet Diabetes Endocrinol 4:393, 2016

Cooper MS: Disorders of calcium metabolism and parathyroid disease. Best Pract Res Clin Endocrinol Metabol 25:975, 2011

Cunningham FG: Screening for osteoporosis. N Engl ] Med 353: 1975, 2005

Dashe ]S, Casey BM, Wells CE, et al: Thyroid-stimulating hormone in singleton and twin pregnancy: importance of gestational age-specific reference ranges. Obstet Gynecol 107(1):205, 2005 Davis LE, Leveno L, Cunningham FG: Hypothyroidism complicating pregnancy. Obstet Gynecol 72:108, 1988 Davis LE, Lucas M], Hankins GD, et al: hyrotoxicosis complicating pregnancy. Am] Obstet Gynecol 160:63, 1989 De Groot L, Abalovich M, Alexander EK, et al: Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. ] Clin Endocrinol Metab 97(8):2543, 2012 Delange F: Iodine deiciency as a cause of brain damage. Postgrad Med ] 77:21 ,2001 De Leo S, Lee SY, Braverman LE: Hyperthyroidism. Lancet 388(10047):906, 2016

Dias M, Boquszewski C, Gadelha M, et al: Acromegaly and pregnancy: a prospective study. Eur J EndocrinoIt170(2):301, 2013

Diez J], Iglesias P: Spontaneous subclinical hypothyroidism in patients older than 55 years: an analysis of natural course and risk factors for the development of overt thyroid failure. J Clin Endocrinol Metab 89:4890, 2004

Dong 0, Li H: Diagnosis and treatment of pheochromocytoma during pregnancy. J Matern Fetal Neonatal Med 2 (18):1930,t2014

Eschler DC, Kogekar N, Pessah-Pollack R: Management of adrenal tumors in pregnancy. Endocrinol Metab Clin North Am 44(2):381,t2015

Fadel BM, Ellahham S, Ringel MD, et al: Hyperthyroid heart disease. Clin Cardiol 23:402, 2000

Fagin JA, Wells SA Jr: Biologic and clinical perspectives on thyroid cancer. N Engl J Med 375(11):1054,t2016

Feigenberg T, Ben-Shushan A, Daka K, et al: Ultrasound-diagnosed puerperal osteopenia in young primiparas. J Reprod Med 53(4):287, 2008

Feinberg EC, Molitch ME, Endres LK, et al: The incidence of Sheehan's syndrome after obstetric hemorrhage. Fertil Steril 84:975, 2005

Fisher DA: Fetal thyroid function: diagnosis and management of fetal thyroid disorders. Clin Obstet Gynecol 40: 16, 1997

Fitzpatrick DL, Russell MA: Diagnosis and management of thyroid disease in pregnancy. Obstet Gynecol Clin North Am 37(2): 173,t2010

Fleseriu M: Medical treatment of acromegaly in pregnancy, highlights on new reports. Endocrine 49(3):577,t2015 Foyouzi N: Lymphocytic adenohypophysitis. Obstet Gynecol Surv 66(2): 109, 201t1

Galambosi P, Hilsemaa V, Ulander VM, et al: Prolonged low-molecularweight heparin use during pregnancy and subsequent bone mineral density. Thromb Res 143:122,t2016

Gallagher MP, Schachner HC, Levine LS, et al: Neonatal thyroid enlargement associated with propylthiouracil therapy of Graves' diseases during pregnancy: a problem revisited. J Pediatr 139:896,t2001

Gallas PRJ, Stolk RP, Bakker K, et al: Thyroid function during pregnancy and in the irst postpartum year in women with diabetes mellitus type 1. Eur J Endocrinol 147(4):443, 2002

Garber JR, Cobin RH, Gharib H, et al: Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American hyroid Association. Thyroid 22(12):1200,t2012

Geelhoed GW: Surgery of the endocrine glands in pregnancy. Clin Obstet Gynecol 26:865, 1983

Gei-Guardia 0, Soto-Herrera E, Gei-Brealey A, et al: Sheehan syndrome in Costa Rica: clinical experience with 60 cases. Endocr Pract 17(3):337, 201t1

Gharib H, Papini E, Paschke R, et al: American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European hyroid Association medical guidelines for clinical practice for the diagnosis and management of thyroid nodules: executive summary of recommendations. J Endocrinol Invest 33(5):287,t2010

Gharib H, Turtle RM, Baskin HJ, et al: Subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and The Endocrine Society. J Clin Endocrinol Metab 90:581, 2005

Gietka-Czernel M, Debska M, Kretowicz P, et al: Fetal thyroid in two-dimensional ultrasonography: nomograms according to gestational age and biparietal diameter. Eur J Obstet Gynecol Reprod Bioi 162(2):131, 2012

Greer LG, Casey BM, Halvorson LM, et al: Antithyroid antibodies and parity: further evidence for microchimerism in autoimmune thyroid disease. Am J Obstet GynecoIt205(5):471, 2011

Grimbert P, Chauveau D, Richard S, et al: Pregnancy in von Hippel-Lindau disease. Am J Obstet Gynecol 180: 10, 1999

Guven S, Durukan T, Berker M, et al: A case of acromegaly in pregnancy: concomitant transsphenoidal adenomectomy and cesarean section. J Matern Fetal Neonatal Med 19:69,t2006

Gyami C, Wapner RJ, D'Alton ME: Thyroid dysfunction in pregnancy. he basic science and clinical evidence surrounding the cotroversy in management. Obstet Gynecol 113t:702, 2009

Haddow JE, Palomaki GE, Allan WC, et al: Maternal thyroid deiciency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 341:549, 1999

Harper v1A, Munaghan GA, Kennedy L, et al: Pheochromocytoma in pregnancy. Five cases and a review of the literature. Br J Obstet Gynaecol 96:594, 1989

Harris B, Oretti R, Lazarus J, et al: Randomised trial of thyroxine to prevent postnatal depression in thyroid-antibody-positive women. Br J Psychiatry 180:327,t2002 Hatipoglu B: Cushing's syndrome. J Surg Oncol 106(5):565,t2012

Hegedus L: he thyroid nodule. N Engl J Med 64,t2004 Helfand M: Screening for subclinical thyroid dysfunction in nonpregnant adults: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 140: 128, 2004

Hellmeyer L, Kuhnert M, Ziller V, et al: The use of LV. bisphosphonate in pregnancy-associated osteoporosis-case study. Exp Clin Endocrinol Diabetes 115:139,2007

Hershman J: Physiological and pathological aspects of the efect of human chorionic gonadotropin on the thyroid. Best Pract Res Clin Endocrinol Metab 18(2):249,t2004

Hirsch D, Kopel V, Nadler V, et al: Pregnancy outcomes in women with primary hyperparathyroidism. J Clin Endocrinol Metab 100:2115, 2015

Hollowell JG, Staehling NW, Hannon H, et al: Iodine nutrition in the United States. Trends and public health implications: iodine excretion data from National Health and Nutrition Examination Surveys I and III (1971]974 and 1988-1994). J Clin Endocrinol Metab 83:3401,t1998

Honegger J, Schlafer S, Menzel C: Diagnosis of primary hypophysitis in Germany. J Clin Endocrinol Metab 100(10):3841, 2015

Institute of Medicine: Dietary Reference Intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, National Academies Press, 200t1

Ip P: Neonatal convulsion revealing maternal hyperparathyroidism: an unusual case of late neonatal hypoparathyroidism. Arch Gynecol Obstet 268:227, 2003

Jameson JL, Mandel S], Weetman AP: Disorders of the thyroid gland. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles ofInternal Medicine, 19th ed. New York, McGraw-Hill Education, 2015

Kamoun M, Mnif M, Chari N, et al: Adrenal diseases during pregnancy: pathophysiology, diagnosis and management strategies. Am J Med Sci 347(1):64,t2014

Karmisholt J, Andersen S, Laurberg P: Variation in thyroid function tests in patients with stable untreated subclinical hypothyroidism. Thyroid 18(3):303, 2008

Katznelson L, Laws ER Jr, Melmed S, et al: Acromegaly: an Endocrine Society clinical practice guideline.t] Clin Endocrinol Metab 99(11):3933,t2014 Kaur M, Pearson 0, Godber I, et al: Longitudinal changes in bone mineral density during normal pregnancy. Bone 32:449, 2003

Khosrotehrani K, Johnson L, Cha DH, et al: Transfer of fetal cells with multilineage potential to maternal tissue. JAMA 292:75,t2004

Kilpatrick S: Umbilical blood sampling in women with thyroid disease in pregnancy: is it necessary? Am] Obstet Gynecol 189:1,t2003

Kimura M, Seki T, Ozawa H, et al: The onset of atineutrophil cytoplasmic antibody-associated vasculitis immediately after methimazole was switched to propylthiouracil in a woman with Graves' disease who wished to become pregnant. Endocr J 60(3):383, 2013

Klein I, Ojamaa K: hyrotoxicosis and the heart. Endocrinol Metab Clin North Am 27:51,t1998

Kooistra L, Crawford S, van Baar AL, et al: Neonatal efects of maternal hypothyroxinemia during early pregnancy. Pediatrics 117: 161, 2006

Korevaar TI, Muetzel R, Chaker L, et al: Association of maternal thyroid function dring early pregnancy with ofspring IQ and brain morphology in childhood: a population-based prospective cohort srudy. Lancet Diabetes EndocrinoIt4(1):35,t2016

Korevaar TI, Schalekamp-Timmermans S, de Rijke YB, et al: Hypothyroxinemia and TPO-antibody positivity are risk factors for premature delivery: the Generation R Study. J Clin Endocrinol Metab 98:4382-90, 2013

Kovacs CS: Calcium and bone metabolism disorders during pregnancy and lactation. Endocrinol Metab Clin North Am 40:795,t201t1

Kraemer B, Schneider S, Rothmund R, et al: Influence of pregnancy on bone density: a risk factor for osteoporosis? Measurements of the calcaneus by ultrasonometry. Arch Gynecol Obstet 285:907, 2011

Kriplani A, Buckshee K, Bhargava L, et al: Maternal and perinatal outcome in thyrotoxicosis complicating pregnancy. Eur J Obstet Gynecol Reprod BioI 54:159, 1994

Kuijpens JL, Vader HL, Drexhage HA, et al: Thyroid peroxidase antibodies during gestation are a marker for subsequent depression postpartum. Eur J Endocrinol 145:5 9,t2001

Kung A WC, Chau MT, LAO TT, et al: The efect of pregnancy on thyroid nodule formation. J Clin Endocrinol Metab 87:1010, 2002

Lacroix A, Feelders A, Stratakis CA, et al: Cushing's syndrome. Lancet 386(9996):913,t2015

LaFranchi SH: Approach to the diagnosis and treatment of neonatal hypothyroidism. ] Clin Endocrinol Metab 96(10):2959, 2011 Lambert K, Rees K, Seed PT, et al: Macroprolactinomas and nonfunctioning piruitary adenomas and pregnancy outcomes. Obstet Gynecol 129: 185, 2017

Lazarus J, Kaklamanou K: Signiicance of low thyroid-stimulating hormone in pregnancy. Curr Opin Endocrinol Diabetes Obes 14:389,t2007

Lazarus JH, Bestwick-JP, Channon S, et al: Antenatal thyroid screening and childhood cognitive function. N Engl J Med 366(6):493,t2012

Lebbe M, Arlt W: What is the best diagnostic and therapeutic management strategy for an Addison patient during pregnancy? Clin Endocrinol (Ox£) 78(4):497,t2013

Lebbe M, Hubinot C, Bernard P, et al: Outcome of 100 pregnancies initiated under treatment with cabergoline in hyperprolactinaemic women. Clin Endocrinol 73:236, 2010

Lekarev 0, New MI: Adrenal disease in pregnancy. Best Pract Res Clin Endocrinol Metab 25(6):959, 2011

Lepez T, Vandewoestryne M, Hussain S, et al: Fetal micro chimeric cells in blood of women with an autoimmune thyroid disease. PLoS One 6(12):1, 2011

Leung AM, Pearce EN, Braverman LE: Iodine nutrition in pregnancy and lactation. Endocrinol Metab Clin North Am 40:765, 201t1

Leung AS, Millar LE, Koonings PP, et al: Perinatal outcome in hypothyroid pregnancies. Obstet GynecoIt81:349, 1993

Levy-Shraga Y, Tamir-Hostovsky L, Boyko V, et al: Follow-up of newborns of mothers with Graves' disease. hyroid 24(6):1032,t2014

Lindheimer MD, Barron WM: Water metabolism and vasopressin secretion duting pregnancy. Baillieres Clin Obstet Gynaecol 8:311, 1994

Lindsay JR, Jonklaas J, Oldfield EH, et al: Cushing's syndrome duting pregnancy: personal experience and review of literature. J Clin Endocrinol Metab 90:3077, 2005

Loh JA, Wartofsky L, Jonklaas J, et al: The magnitude of increased levothyroxine requirements in hypothyroid pregnant women depends upon the etiology of the hypothyroidism. Thyroid 19(3):269,2009

Loriaux DL: Diagnosis and diferential diagnosis of Cushing's syndrome. N Engl J Med 376:1421,t2017

Lucas A, Pizarro E, Granada ML, et al: Postpartum thyroid dysfunction and postpartum depression: are they two linked disorders? Clin Endocrinol 55:809,t2001

Luewan S, Chakkabut P, Tongsong T: Outcomes of pregnancy complicated with hyperthyroidism: a cohort study. Arch Gynecol Obstet 283:243,t2011

Luton D, Le Gac I, Vuillard E, et al: Management of Graves' disease during pregnancy: the key role of fetal thyroid gland monitoring. J Clin Endocrinol Metab 90:6093, 2005

Malekar-Raikar S, Sinnott B: Primary hyperparathyroidism in pregnancy-a rare case of life-threatening hypercalcemia: case report and literature review. Case Rep Endocrinol 2011:520516, 2011

Maliha G, Morgan J, Varhas M: Transient osteoporosis of pregnancy. Int J Care Injured 43:1237,t2012

Mannist6 T, Vaarasmaki M, Pouta A, et al: Perinatal outcome of children bon to mothers with thyroid dysfunction or antibodies: a prospective populationbased cohort study. J Clin Endocrinol Metab 94:772, 2009

Mannisto T, Vaarasmaki M, Pouta A, et al: hyroid dysfunction and autoantibodies during pregnancy as predictive factors of pregnancy complications and maternal morbidity in later life. J Clin Endocrinol Metab 95: 1 084, 2010 Maraka S, Ospina NM, O'Keefe DT, et al: Subclinical hypothyroidism in pregnancy: a systematic review and meta-analysis. hyroid 26(4):580, 2016 Mascetti L, Bettinelli A, Simonetti GO, et al: Pregnancy in inherited hypokalemic salt-losing renal tubular disorder. Obstet Gynecol 117(2 Pt 2):512, 2011 Matalon S, Sheiner E, Levy A, et al: Relationship of treated maternal hypothyroidism and perinatal outcome.t] Reprod Med 51:59, 2006 Medici M, Korevaar TI, Schalekamp-Timmermans S, et al: Maternal earlypregnancy thyroid function is associated with subsequent hypertensive disorders of pregnancy: the Generation R Study. ] Clin Endocrinol Metab 99(12):E2591,t2014 Melmed S, Jameson ]L: Hypopituitarism. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill Education, 2015 Messuti 1, Corvisieri S, Bardesono F, et al: Impact of pregnancy on prognosis of diferentiated thyroid cancer: clinical and molecular features. Eutt] Endocrinol 170(5):659,t2014 Mestman JH: Hyperthyroidism in pregnancy. Curr Opin Endocrinol Diabetes Obes 19:394,t2012 Mestman ]H: Hyperthyroidism in pregnancy. Endocrinol Metab Clin North Am 27:127,t1998 Millar LK, Wing DA, Leung AS, et al: Low birth weight and preeclampsia in pregnancies complicated by hyperthyroidism. Obstet GynecoI84:946, 1994 Miller MA, Mazzaglia P], Larson L, et al: Laparoscopic adrenalectomy for pheochromocytoma in a twin gestation.] Obstet GynecoIt32(2):186, 2012 Molitch ME: Endocrinology in pregnancy: management of the pregnant patient with a prolactinoma. Eur] EndocrinoIt172(5):R205, 2015 Molitch ME: Pituitary, thyroid, adrenal, and parathyroid disorders. In Barron WM, Lindheimer MD (eds): Medical Disorders Outing Pregnancy, 3rd ed. St. Louis, Mosby, 2000

Momotani N, Noh ]H, Ishikawa N, et al: Efects of propylthiouracil and methimazole on fetal thyroid status in mothers with Graves' hyperthyroidism. ] Clin Endocrinol Metab 82:3633, 1997

Montoro MN, Paler R], Goodwin TM, et al: Parathyroid carcinoma during pregnancy. Obstet Gynecol 96: 841, 2000

Moreno ]c, Klootwijk W, van Toor H, et al: Mutations in the iodotyrosine deiodinase gene and hypothyroidism. N Engl] Med 358(17):1811,t2008 Morreale de Escobar G, Obregon M], Escobar Del Rey F: Role of thyroid hormone during early brain development. Eur] Endocrinol 151: U25, 2004 Motivala S, Gologorsky Y, Kostandinov], et al: Pituitary disorders during preg nancy. Endocrinol Metab Clin North Am 40:82 ,201t1

Murcia M, Rebagliato M, Iniguez C, et al: Efect of iodine supplementation during pregnancy on infant �eurodevelopment at 1 year of age. Am ] Epidemiol 173:804,2011

Nachum Z, Rakover Y, Weiner E, et al: Graves' disease in pregnancy: prospective evaluation of a selective invasive treatment protocol. Am ] Obstet GynecoIt189:159,t2003

Nathan N, Sullivan SD: hyroid disorders during pregnancy. Endocrinol Metab Clin North Am 43(2): 573, 2014

Negro T, Formoso G, Mangieri T, et al: Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: efects on obstetrical complications.t] Clin Endocrinol Metab 91(7):2587, 2006

Nelson DB, Casey BM, McIntire DO, et al: Subsequent pregnancy outcomes in women previously diagnosed with subclinical hypothyroidism. Amt] Peri,2014

Nelson DB, Yost NP, Cunningham FG: Acute fatty liver of pregnancy: clinical outcomes and expected durations of recovery. Am ] Obstet Gynecol 209(5):456.e1,t2013

Neumann HP: Pheochromocytoma. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill Education, 2015

O'Doherty M], McElhatton PR, Thomas SH: Treating thyrotoxicosis in pregnant or potentially pregnant women. BM] 318:5, 1999

Olivieri A, Stazi MA, Mastroiacovo P, et al: A population-based study on the frequency of additional congenital malformations in infants with congenital hypothyroidism: data from the Italian Registry for Congenital hypothyroidism (1991-1998).t] Clin Endocrinol Metab 87:557, 2002

Ono M, Miki N, Amano K, et al: Individualized high-dose cabergoline therapy for hyperprolactinemic infertility in women with micro-and macroprolactinomas.t] Clin Endocrinol Metab 95(6):2672, 2010

Pallan S, Rahman M, Khan A: Diagnosis and management of primary hyperparathyroidism. BM] 344:elO13, 2012

Pappachan ]M, Raskauskiene 0, Kutty VR, et al: Excess mortality associated with hypopituitarism in adults: a meta-analysis of observational studies. J Clin Endocrinol Metab 100(4):1405,t2015

Pearce EN, Lazarus ]H, Moreno-Reyes R, et al: Consequences of iodine deficiency and excess in pregnant women: an overview of current knowns and unknowns. Am] Clin Nutr 104(SuppI3):918S, 2016 Pederson CA, Johnson ]L, Silva S, et al: Antenatal thyroid correlates of postpartum depression. Psychoneuroendocrinology 32:235, 2007 Plowden TC, Schisterman EF, Sjaarda A, et al: Thyroid-stimulating hormone, anti-thyroid antibodies, and pregnancy outcomes. Am ] Obstet Gynecol September 14, 2017 [Epub ahead of print] Pop V], Brouwers EP, Vader HL, et al: Maternal hypothyroxinemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol 59:282, 2003 Pop V], Kujipens ]L, van Baar AL, et al: Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin EndocrinoIt50:149, 1999 Potts ]T, Jiippner H: Disorders of the parathyroid gland and calcium homeostasis. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles ofInternal Medicine, 19th ed. New York, McGraw-Hill Education, 2015 Power ML, Heaney RP, KalkwarftH], et al: he role of calcium in health and disease. Am] Obstet Gynecol 181:1560, 1999 Quartermaine G, Lambert K, Rees K, et al: Hormone-secreting adrenal tumours cause severe hypertension and high rates of poor pregnancy outcome; a UK Obstetric Surveillance System study with case control comparisons. B]OG Spetember 5, 2017 [Epub ahead of print] Ray]G: DDA VP use during pregnancy: an analysis of its safety for mother and child. Obstet Gynecol Surv 53:450, 1998 Renne C, Lopez ER, Steimle-Grauer SA, et al: Thyroid fetal male microchimerisms in mothers with thyroid disorders: presence of Y-chromosomal immunoluorescence in thyroid-iniltrating lymphocytes is more prevalent in Hashimoto's thyroiditis and Graves' disease than in follicular adenomas. ] Clin Endocrinol Metab 89:5810, 2004 Robalo R, Pedroso C, Agapito A, et al: Acute Sheehan's syndrome presenting as central diabetes insipidus. BM] Case Rep Nov 6,t2012

Robertson GL: Disorders of the neurohypophysis. In Kasper L, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill Education, 2015

Rooney DP, Traub AI, Russell CF], et al: Cure of hyperparathyroidism in pregnancy by sternotomy and removal of a mediastinal parathyroid adenoma. Postgrad Med] 74:233, 1998

Rovelli R, Vigone M, Giovanettoni C, et al: Newborns of mothers afected by autoimmune thyroiditis: the importance of thyroid function monitoring in the irst months of life. Ital ] Pediatr 36:24, 2010

Saad AF, Pacheco LD, Costantine MM: Management of ectopic parathyroid adenoma in pregnancy. Obstet GynecoIt124:478, 2014

Salazar-Vega ]L, Levin G, Sanso G: Pheochromocytoma associated with pregnancy: unexpected favourable outcome in patients diagnosed after delivery. ] Hypertens 32(7):1458, 2014

Salvatori R: Adrenal insuiciency. ]AMA 294:2481, 2005

Sarathi V, Lila A, Bandgar T, et al: Pheochromocytoma and pregnancy: a rare but dangerous combination. Endocr Pract 16(2):300,t2010

Sarkhail P, Mehran L, Askari S, et al: Maternal thyroid function and autoimmunity in 3 trimesters of pregnancy and their ofspring's thyroid function. Horm Metab Res 48:20,t2016

Schlechte ]A: Long-term management of prolactinomas. ] Clin Endocrinol Metab 92:2861, 2007

Schnatz PF, haxton S: Parathyroidectomy in the third trimester of pregnancy.

Obstet Gynecol Surv 60:672, 2005

Schneiderman M, Czuzoj-Shulman N, Spence AR, et al: Maternal and neonatal outcomes of pregnancies in women with Addison's disease: a populationbased cohort study on 7.7 millions births. B]OG 124:1772,t2017

Scoccia B, Demir H, Kang Y, et al: In viro fertilization pregnancy rates in levothyroxine-treated women with hypothyroidism compared to women without thyroid dysfunction disorders. TIlyroid 22(6):631, 2012

Sheehan HL: Post-partum necrosis of the anterior pituitary. ] Pathol Bacteriol 45:189, 1937

Sheehan PM, Nankervis A, Araujo ]linior E, et al: Maternal thyroid disease and preterm birth: systematic review and meta-analysis. ] Clin Endocrinol Metab 100(11):4325, 2015

Sheield ]S, Cunningham FG: Thyrotoxicosis and heart failure that complicate pregnancy, Am ] Obstet Gynecol 190:211, 2004

Shoback 0: Hypoparathyroidism. N Engl] Med 359:391, 2008

Siu CW, Zhang XH, Yung C, et al: Hemodynamic changes in hyperthyroidismrelated pulmonary hypertension: a prospective echocardiographic study. ] Clin Endocrinol Metab 92: 1736, 2007

Song SI, Daneman D, Rovet]: he inluence of etiology and treatment factors on intellectual outcome in congenital hypothyroidism. ] Dev Behav Pediatr 6,t2001

Stagnaro-Green A: Maternal thyroid disease and preterm delivery.t] Clin Endocrinol Metab 94:21, 2009

Stagnaro-Green A: Overt hyperthyroidism and hypothyroidism during pregnancy. Clin Obstet Gynecol 54(3):478, 2011a

Stagnaro-Green A, Glinoer 0: Thyroid autoimmunity and the risk of miscarriage. Baillieres Best Pract Res Clin Endocrinol Metab 18: , 2004 Stagnaro-Green A, Pearce E: hyroid disorders in pregnancy. Nat Rev Endocrinol 8:650, 20t12a

Stagnaro-Green A, Schwartz A, Gismondi R, et al: High rate of persistent hypothyroidism in a large-scale prospective study of postpartum thyroiditis in southern Italy. ] Clin Endocrinol Metab 96(3):652, 201t1 b

Stagnaro-Green A, Sullivan S, Pearch EN: Iodine supplementation during pregnancy and lactation.t]AMA 308(23):2463, 2012b

Stringer KM, Gought], Gough IR: Primary hyperparathyroidism during pregnancy: management by minimally invasive surgery based on ultrasound localization. ANZ] Surg 87(10):E134, 2017

Stulberg RA, Davies GAL: Maternal thyrotoxicosis and fetal nonimmune hydrops. Obstet Gynecol 95: 1036, 2000

Su PY, Huang K, Hao ]H, et al: Maternal thyroid function in the first rwenry weeks of pregnancy and subsequent fetal and infant development: a prospective population-based cohort study in China. ] Clin Endocrinol Metab 96(10):3234,t201t1

Surks MI, Ortiz E, Daniels GH, et al: Subclinical thyroid disease: scientiic review and guidelines for diagnosis and management.]AMA 291(2):228,t2004

Swanson CA, Zimmerman MB, Skeaf S, et al: Summary of an NIH workshop to identiy research needs to improve the monitoring of iodine status in the United States and to inform the DRIl-3.] Nutr 142:1175S, 2012

Tan TO, Cheng W, Caughey AB: Are women who are treated for hypothyroidism at risk for pregnancy complications? Am] Obstet Gynecol 194:el, 2006

T eng W, Shan Z, T eng X, et al: Efect of iodine intake on thyroid diseases in China. N Englt] Med 354:2783, 2006

Tessnow A, Wilson ]: The changing face of Sheehan's syndrome. Am] Med Sci 340(5):402, 2010

Thangaratinam S, Tan A, Knox E, et al: Association berween thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. BM] 342:d2616, 2011

Thomas M, Weisman SM: Calcium supplementation during pregnancy and lactation: efects on the mother and the fetus. Am ] Obstet Gynecol 194:937,t2006

Thomas SK, Sheield ]S, Roberts SW: Thionamide-induced neutropenia and ecthyma in a pregnant patient with hyperthyroidism. Obstet Gynecol 122:940,t2013

Thorpe-Beeston ]G, Nicolaides KH, Snijders RJ, et al: Thyroid function in small for gestational age fetuses. Obstet Gynecol 77: 701, 1991

To W, Wong MW, Leung TW: Relationship berween bone mineral density changes in pregnancy and maternal and pregnancy characteristics: a longitudinal study. Acta Obstet Gynecol Scand 82:820, 2003

Tran P, DeSimone S, Barrett M, et al: 1-131 treatment of Graves' disease in an unsuspected irst trimester pregnancy; the potential for adverse efects on the fetus and a review of the current guidelines for pregnancy screening. Int ] Pediatr EndocrinoIt2010:858359, 2010

Tudela CM, Casey BM, McIntire DD, et al: Relationship of subclinical thyroid disease to the incidence of gestational diabetes. Obstet Gynecol 119(5):983,t2012

Vaidya B, Anthony S, Bilous M, et al: Detection of thyroid dysfunction in early pregnancy: universal screening or targeted high-risk case finding? ] Clin Endocrinol Metab 92(1):203, 2007

Vargas Zapata CL, Donangelo CM, Woodhouse LR, et al: Calcium homeostasis during pregnancy and lactation in Brazilian women with low calcium intakes: a longitudinal study. Am] Clin Nutr 80:417,t2004

Velasco I, Carreira M, Santiago P, et al: Efect of iodine prophylaxis during pregnancy on neurocognitive development of children during the first rwo years of life. ] Clin Endocrinol Metab 94:3234, 2009

Vydt T, Verhelst ], De Keulenaer G: Cardiomyopathy and thyrotoxicosis: tachycardiomyopathy or thyrotoxic cardiomyopathy? Acta Cardiol 61:1t15, 2006

Wallia A, Bizhanova A, Huang W, et aI: Acute diabetes insipidus mediated by vasopressinase after placental abruption. ] Clin Endocrinol Metab 98:881, 20t13

Wang W, Teng W, Shan Z, et al: he prevalence of thyroid disorders during early pregnancy in China: the beneits of universal screening in the irst trimester of pregnancy. Eur] Endocrinol 164(2):263, 2011

Wikner BN, Sparre LS, Stiller CO, et al: Maternal use of thyroid hormones in pregnancy and neonatal outcome. Acta Obstet Gynecol Scand 87(6):617, 2008

Wilson KL, Casey BM, McIntire DO, et al: Diagnosis of subclinical hypothyroidism early in pregnancy is a risk factor for the development of severe preeclampsia. Clin Thyroidol 24(5):15, 2012

Yassa L, Marqusee E, Fawcett R, et al: hyroid hormone early adjustment in pregnancy (the THERAPy) trial. ] Clin Endocrinol Metab 95(7):3234, 2010

Yoshihara A, Noh ]Y, Mukasa K, attel: Serum human chorionic gonadotropin levels and thyroid hormone levels in gestational transient thyrotoxicosis: is the serum hCG level useful for diferentiating berween active Graves' disease and GTT? Endocr] 62(6):557,t2015

Yoshihara A, Noh ]Y, Yamaguchi T, et al: Treatment of Graves disease with antithyroid drugs in the irst trimester of pregnancy and the prevalence of congenital malformation. ] Clin Endocrinol Metab 9 :2396, 2012

Zuluaga-Gomez A, Arrabal-Polo A, Arrabal-Martin M, et al: Management of pheochromocytoma during pregnancy: laparoscopic adrenalectomy. Am 8(3):E156,t2012

IMMUNE-MEDIATED CONNECTIVE TISSUE DISEASES.. 1138

SYSTEMIC LUPUS ERYTHEMATOSUS ............... 1139

ANTI PHOSPHOLIPID SYNDROME ......i.......i.... 1i143 ..RHEUMATOID ARTHRITIS .....i................i.... 1146 SYSTEMIC SCLEROSIS-SCLERODERMA.. . . . . . . . . .. 1148 VASCULITIS SYNDROMES.. . . . . . . . . . . . . . . . . . . . . .. 1149 INFLAMMATORY MYOPATHIES .........i......... 1150

HEREDITARY CONNECTIVE TISSUE DISORDERS.. . . .. 1151

Owing to the great vasculariy incident to pregnancy, the various pelvic joints always show a somewhat increased motiliy. In rare instances, particulary when the pelvis is contracted in the lower portion, spontaneous rupture of the symphysis pubis or one or both sacro-iliac joints has been observe.

-]. Whitridge Williams (1903)

The principal concerns in the 1st edition of Williams Obstetrics with disorders of the joints were the obstructed pelvis caused by rickets. There is no mention of the arthritides complicating pregnancy. And of course, immune-mediated disease had not yet been elucidated.

Connective tissue disorders, which are also termed collagen vascular disorders, have two basic underlying causes. First are the immune-complex diseases in which connective tissue damage is caused by deposition of immune complexes. Because these are manifest by sterile inflammation-predominately of the skin, joints, blood vessels, and kidneys-they are referred to as rheumatic diseases. Many of these immune-complex diseases are more prevalent in women, for example, systemic lupus erythematosus (SLE) and rheumatoid arthritis. Second are the inherited disorders of bone, skin, cartilage, blood vessels, and basement membranes. Some examples include Marfan syndrome, osteogenesis imperfecta, and Ehlers-Danlos syndrome.

hese disorders can be separated into those associated with and those without autoantibody formation. The rheumatoid actor (F) is an autoantibody found in many autoimmune inflammatory conditions such as SLE, rheumatoid arthritis, systemic sclerosis (scleroderma), mixed connective tissue disease, dermatomyositis, polymyositis, and various vasculitis syndromes. he F-seronegative spondyloarthropathies are strongly associated with expression of the human leukocyte antigen B27 (HLAB27) antigen and include ankylosing spondylitis, psoriatic arthritis, Reiter disease, and other arthritis syndromes.

Pregnancy may mitigate activity in some of these syndromes as a result of the immunosuppression that also allows successful engraftment of fetal and placental tissues. These changes are discussed in detail in Chapters 4 (p. 58) and 5 (p. 95). One example is pregnancy-induced predominance ofT2 helper cells compared with cytokine-producing T 1 helper cells (Keeling, 2009). Pregnancy hormones also alter immune cells. Namely, estrogens upregulate and androgens down regulate T-cell response, and progesterone is immunosuppressive (Cutolo, 2006; Haupl, 2008a; Robinson, 2012).

In contrast, immune-mediated disease may contribute to obstetrical complications. One longitudinal cohort study found that unrecognized autoimmune systemic rheumatic disorders are associated with significant risk for preeclampsia and fetalgrowth restriction (Spinillo, 2016). In this study, the prevalence of unrecognized rheumatic arthritis was 0.4 percent, and was 0.3 percent each for SLE, Sjogren syndrome, and antiphospholipid syndrome.

Last, some immune-mediated diseases may either be caused or activated as a result of prior pregnancies. To explain, fetal cells and free fetal DNA are detectable in maternal blood beginning early in pregnancy (Simpson, 2013; Sitar, 2005; Waldorf, 2008). Fetal cell microchimerism is the persistence of fetal cells in the maternal circulation and in organs following pregnancy. These fetal cells may become engrafted in maternal tissues and stimulate autoantibodies. This raises the possibility that fetal cell micro chimerism leads to the predilection for autoimmune disorders among women (Adams, 2004). Evidence for this includes fetal stem cells engrafted in tissues in women with autoimmune thyroiditis and systemic sclerosis Gimenez, 2005; S;ivatsa, 2001). Such microchimerism has also been described in women with SLE and those with rheumatoid arthritis-associated HLA alleles (da Silva, 2016; Lee, 2010; Rak, 2009a). Conversely, engrafted maternal cells may provoke autoimmune conditions in a woman's ofspring (Ye, 2012; Stevens, 2016).

Lupus is a heterogeneous autoimmune disease with a complex pathogenesis that results in interactions between susceptibility genes and environmental factors (Hahn, 2015). Immune system abnormalities include overactive B lymphocytes that are responsible for autoantibody production. hese result in tissue and cellular damage when autoantibodies or immune complexes are directed at one or more cellular nuclear components (T sokos, 201r1). In addition, immunosuppression is impaired, including regulatory T-cell function (Tower, 2013). Some autoantibodies produced in patients with SLE are shown in Table

Almost 90 percent of SLE cases are in women, and its prevalence in those of childbearing age approximates 1 in 500 (Lockshin, 2000). Accordingly, the disease is encountered relatively frequently during pregnancy. The 10-year survival rate is 70 to 90 percent (Tsokos, 201r1). Infection, lupus lares, endorgan failure, hypertension, stroke, and cardiovascular disease account for most deaths.

Genetic inluences are implicated by a higher concordance with monozygotic compared with dizygotic twins-25 versus 2 percent, respectively. Moreover, frequency in patients with one afected family member is 10 percent. he relative risk of disease rises if there is inheritance of the "autoimmunity gene" on chromosome 16 that predisposes to SLE, rheumatoid arthritis, Crohn disease, and psoriasis. Susceptibility genes such as HA-Al, -B8, -D3, -DBl, and -TET3 explain only a portion of the genetic heritability (Tsokos, 201r1; Yang, 2013). Interestingly, even maternal exposure to fetal genes elevates susceptibility to SLE development. A case-control study found that a child's HLA-DRB1 genotype increases the risk of SLE in the mother (Cruz, 2016). Furthermore, neonatal lupus erythematosus has been reported in an infant conceived via oocyte donor to a mother with autoimmune disease with circulating anti-Ro and anti-La antibodies (Chiou, 2016).

Lupus is notoriously variable in its presentation, course, and outcome (Table 59-2). Findings may be conined initially to one organ system, and others become involved later. Or, the disease may irst be multisystem. Frequent findings are malaise, fever, arthritis, rash, pleuropericarditis, photosensitivity, anemia, and cognitive dysfunction. At least half of patients have renal involvement. SLE is also associated with declines in attention, memory, and reasoning (Hahn, 2015; Kozora, 2008).

Identification of antinuclear antibodies (ANA) is the best screening test, however, a positive result is not speciic for SLE. For example, low titers are found in normal individuals, other autoimmune diseases, acute viral infections, and chronic inlammatory processes. Several drugs can also cause a positive reaction. Antibodies to double-stranded DNA (dsDNA) and to Smith (Sm) antigens are relatively speciic for SLE, whereas other antibodies are not (see Table 59-1). Although hundreds of autoantibodies have been described in SLE, only a few have been shown to participate in tissue injury (Sherer, 2004; Tsokos, 2011). Currently, micro array proiles are being developed for more accurate SLE diagnosis (Putterman, 2016).

TABLE 59-1. Some Autoantibodies Produced in Patients with Systemic Lupus Erythematosus (SLE)

Best screening test, multiple antibodies; a second negative test makes SLE unlikely High titers SLE-specific; may correlate with disease activity, nephritis, and vasculitis Specific for SLE

Not SLE-specific, high titers associated with rheumatic syndromes

Not SLE-specific; associated with sicca syndrome, predisposes to cutaneous lupus, neonatal lupus with heart block, reduced risk of nephritis Associated with anti-Ro Common in drug-induced lupus

Lupus anticoagulant and anticardiolipin antibodies associated with thrombosis, fetal loss, thrombocytopenia, valvular heart disease; false-positive test for syphilis Direct Coombs test, may develop hemolysis

Thrombocytopenia in 15%; poor clinical test dsDNA = double-stranded DNA; RNP = ribonucleoprotein. Data from Arbuckle, 2003; Hahn, 2015.

TABLE 59-2. Some Clinical Manifestations of Systemic Lupus Erythematosus

Modified from Kasper, 201r5.

Anemia develops frequently, and there may be leukopenia and thrombocytopenia. Proteinuria and casts are found in the half of patients with glomerular lesions. Lupus nephritis can also cause renal insuiciency, which is more common if there are anti phospholipid antibodies (Moroni, 2004). Other laboratory indings include false-positive syphilis serology, prolonged partial thromboplastin time, and higher RF levels. Elevated serum D-dimer concentrations often follow a lare or infection, but unexplained persistent elevations are associated with a high risk for thrombosis (Wu, 2008).

The diagnostic criteria for SLE are listed in Table 59-3. If any four or more of these 11 criteria are present, serially or

TABLE 59-3. Clinical Criteria for Classification of Systemic Lupus Erythematosus

Renal: proteinuria, casts, biopsy

Neurological: seizures, psychosis, myelitis, neuropathies,

ANA = antinuclear antibodies; dsDNA = double-stranded DNA; Sm = Smith.

Data from Hahn, 201r5; Hochberg, 1997.

simultaneously, the diagnosis of lupus is made. Importantly, numerous drugs can induce a lupus-like syndrome. These include proton-pump inhibitors, thiazide diuretics, antifungals, chemotherapeutics, statins, and antiepileptics. Druginduced lupus is rarely associated with glomerulonephritis and usually regresses when the medication is discontinued (Laurinaviciene, 2017).

Of nearly 16.7 million pregnancies from 2000 to 2003 in the United States, 13,555 were complicated by lupus-an incidence of approximately 1 in 1250 pregnancies (Clowse, 2008). During pregnancy, lupus improves in a third of women, remains unchanged in a third, and worsens in the remaining third. Thus, in any given pregnancy, the clinical condition can worsen orlare without warning (Hahn, 2015; Khamashta, 1997).

Petri (1998) reported a 7 -percent risk of major morbidity during pregnancy. In a cohort of 13,555 women with SLE during pregnancy, the maternal mortality and severe morbidity rate was 325 per 100,000 (Clowse, 2008). In a review of 13 studies with 17 maternal deaths attributable to SLE and lupus nephritis, all occurred in those with active disease (Ritchie, 2012). Results of a prospective cohort study of 385 women are shown in Figure

During the past several decades, pregnancy outcomes in women with SLE have improved remarkably. For most women with inactive or mild/moderate SLE, pregnancy outcomes are relatively favorable. Women who have conined cutaneous lupus do not usually have adverse outcomes (Hamed, 2013). However, newly diagnosed SLE during pregnancy tends to be severe (Zhao, 2013). In general, pregnancy outcome is best in women for whom: (1) lupus activity has been quiescent for at least 6 months before conception; (2) there is no lupus nephritis manifest by proteinuria or renal dysfunction; (3) anti phospholipid syndrome or lupus anticoagulant is absent; and (4) superimposed preeclampsia does not develop (Peart, 2014; Stojan, 2012; Wei, 2017; Yang, 2014).

SLE, low risk (n = 129) . 10

FIGURE 59-1 Frequency of adverse pregnancy outcomes. All women with systemic lupus erythematosus (SLE) in the PROMISSE study are compared with a subset of low-risk SLE patients and with control patients without SLE. (Data from Buyon, 201o5.)

Active nephritis is associated with adverse pregnancy outcomes, ease remains in remission (Moroni, 2002, 2005; Stojan, 2012).

Of complications, women with renal disease have a high inci dence of gestational hypertension and preeclampsia. Of 80 gravidas with SLE reported by Lockshin (1989), 63 percent of women with preexisting renal disease developed preeclampsia compared with only 14 percent of those without underlying renal disease. In a review of 309 pregnancies complicated by lupus nephritis, 30 percent sufered a lare, and 40 percent of these had associated renal insuiciency (Moroni, 2005). he maternal mortality rate was 1.3 percent. These indings were corroborated in a subsequent prospective study (Moroni, 2016b). In addition, a third of the 113 pregnancies were delivered preterm (Imbasciati, 2009; Moroni, 2016a). Wagner and coworkers (2009) compared outcomes of 58 women with 90 pregnancies and found that active nephritis was linked with a signiicantly higher incidence of maternal complications-57 versus 11 percent.

Most recommend continuation during pregnancy of immunosuppressive therapy for nephritis. New-onset nephritis or severe renal lare is treated aggressively with intravenous corticosteroids and consideration of immunosuppressive drugs or intravenous immunoglobulin (Lazzaroni, 2016).

Chronic hypertension complicates up to 30 percent of pregnancies in women with SLE (Egerman, 2005). Also, as mentioned, preeclampsia is common, and superimposed preeclampsia is encountered even more often, and earlier, in those with nephritis or antiphospholipid antibodies (Bertsias, 2008). Preeclampsia and lupus nephritis share features of hypertension, proteinuria, edema, and renal function deterioration. However, the management is distinct, as lupus nephritis is treated with immunosuppression, and severe preeclampsia/eclampsia requires delivery (Lazzaroni, 2016). It may be diicult, if not impossible, to diferentiate lupus lare with nephropathy from severe preeclampsia if the kidney is the only involved organ (Petri, 2007). Central nervous system involvement with lupus may culminate in convulsions similar to those of eclampsia. One proposed schema for diferentiating the two is shown in Table 59-4. Management for preeclampsia-eclampsia is described in Chapter 40 (p. 728).

Lupus management consists primarily of monitoring fetal well-being and maternal clinical and laboratory status (Lateef, 2012). Pregnancy-induced thrombocytopenia and proteinuria resemble SLE disease activity, and the identiication of a lupus lare is confounded by the increased facial and palmar erythema of normal pregnancy (Lockshin, 2003).

For SLE activity monitoring, various laboratory techniques have been recommended, but interpretation may be challenging. The sedimentation rate may be misleading because of pregnancy-induced hyperibrinogenemia. Serum complement levels are also normally increased in pregnancy (Appendix, p. 1259). And, although falling or low levels of complement components C3, C4, and CH50 are more likely to be associated with active disease, higher levels provide no assurance against disease activation. Our experiences and those of others suggest that clinical manifestations of disease and complement levels correlate poorly (Lockshin, 1995; Varner, 1983).

Serial hematological studies may detect changes in disease activity. Hemolysis is characterized by a positive Coombs test, anemia, reticulocytosis, and unconjugated hyperbilirubinemia. hrombocytopenia, leukopenia, or both may develop. According to Lockshin and Druzin (1995), chronic thrombocytopenia

Data from Andreoli, 2012.

in early pregnancy may be due to anti phospholipid antibodies. Later, thrombocytopenia may indicate preeclampsia.

Urine is tested frequently to detect new-onset or worsening proteinuria. The fetus is closely observed for adverse efects such as growth restriction and oligohydramnios. Many recommend screening for anti-SS-A (anti-Ro) and anti-SS-B (anti-La) antibodies, because of associated fetal complications described subsequently. Antepartum, the fetus is surveilled as outlined by the American College of Obstetricians and Gynecologists (2016a) and described in Chapter 17 (p. 331). Unless hypertension or evidence of fetal compromise or growth restriction develops, pregnancy is allowed to progress to term. Peripartum corticosteroids in "stress doses" are given to women who are taking these drugs or who recently have done so.

here is no cure for SLE, and complete remissions are rare. Approximately a fourth of pregnant women have mild disease, which is not life threatening, but may be disabling because of pain and fatigue. Arthralgia and serositis can be managed by nonsteroidal antiinflammatory drugs (NSAIDs). However, chronic or large intermittent dosing is avoided due to related oligohydramnios or ductus arteriosus closure (Chap. 12, p. 241). Low-dose aspirin can be used throughout gestation. Severe disease is managed with corticosteroids such as prednisone, 1 to 2 mg/kg/d orally. Mter the disease is controlled, this dose is tapered to a daily morning dose of 10 to 15 mg. Corticosteroid therapy can lead to gestational diabetes.

Immunosuppressive agents such as azathioprine are beneicial for active disease. These are usually reserved for lupus nephritis or disease that is corticosteroid resistant. Azathioprine has a good safety record during pregnancy (Fischer-Betz, 2013; Petri, 2007). Its recommended daily oral dose is 2 to 3 mg/kg. Teratogenic medications to be avoided include mycophenolate mofetil, methotrexate, and cyclophosphamide (Gotestam Skorpen, 2016). However, cyclophosphamide can be considered in the second or third trimester for severe disease (Lazzaroni, 2016). In some situations, mycophenolate is the only treatment that achieves disease stability. In these cases, counseling is essential regarding fetal risks described in Chapter 12 (p. 244) (Bramham, 2012).

Antimalarials reduced dermatitis, arthritis, and fatigue (Hahn, 2015). Although these agents cross the placenta, hydroxychloroquine is not associated with congenital malformations. Because of the long half-life of antimalarials and because discontinuing therapy can precipitate a lupus lare, most recommend their continuation during pregnancy (Borden, 2001).

'When severe disease supervenes-usually a lupus larehigh-dose glucocorticoid therapy is given. Petri (2007) recommends pulse therapy consisting of methylprednisolone, 1000 mg given intravenously over 90 minutes daily for 3 days, then a return to maintenance doses if possible.

In nonpregnant subjects, antihypertensive therapy oten includes an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker. For pregnancy, these should be changed to safer fetal options such as calcium-channel blockers, alpha methyldopa, or labetalol (Cabiddu, 2016).

Adverse perinatal outcome rates are signiicantly elevated in pregnancies complicated by SLE. Among these are preterm delivery, fetal-growth restriction, stillbirth, and neonatal lupus syndrome (Madazli, 2014; Phansenee, 2017). Perinatal outcome rates worsen in mothers with a lupus flare, significant proteinuria, or renal impairment and in those with chronic hypertension, preeclampsia, or both (Lazzaroni, 2016). Adverse outcomes are also more common in women with neuropsychiatric lupus (de Jesus, 2017). Reasons at least partially responsible for adverse fetal consequences include decidual vasculopathy with placental infarction and decreased perfusion (Hanly, 1988).

This is characterized by newborn skin lesions-lupus dermatitis; a variable number of hematological and systemic derangements; and occasionally congenital heart block (Hahn, 2015). Cutaneous manifestations can be present in 30 to 40 percent of infants and appears at 4 to 6 weeks of age (Silverman, 2010). hese are usually associated with anti-SS-A and SS-B antibodies, and approximately 40 percent of women with SLE are positive for these (Buyon, 2015). Thrombocytopenia and hepatic involvement are seen in 5 to 10 percent of afected infants.

In a review of outcomes in 91 infants born to women with lupus, eight of these were possibly afected-four had deinite neonatal lupus and four had possible disease (Lockshin, 1988). Cutaneous lupus, thrombocytopenia, and autoimmune hemolysis are transient and clear within a few months (Zuppa, 2017). This is not always so for congenital heart block, discussed next. In subsequent ofspring, the recurrence risk for neonatal lupus may near 25 percent Qulkunen, 1993).

Fetal and neonatal heart block results from difuse myocarditis and ibrosis in the region between the atrioventricular (A ) node and bundle of His. Congenital heart block develops almost exclusively in fetuses of women with antibodies to the SS-A or SS-B antigens (Buyon, 1993). Even in the presence of such antibodies, however, the incidence of fetal myocarditis is only 2 to 3 percent but rises to 20 percent with a prior afected child (Bramham, 2012; Lockshin, 1988). Fetal cardiac monitoring is performed between 18 and 26 weeks' gestation in pregnancies with either of these antibodies. The cardiac lesion is permanent, and a pacemaker is generally necessary. Long-term prognosis is poor. Of 325 infants with cardiac neonatal lupus, nearly 20 percent died, and of these, one third was stillborn (Izmirly, 2011).

Maternal administration of corticosteroids, plasma exchange, or intravenous immunoglobulin does not reduce the risk of congenital heart block. Maternal corticosteroid administration for treatment congenital heart block is controversial, is currently not recommended, and is discussed further in Chapter 16 (p. 316). Although this therapy to treat fetal heart block has not been studied in randomized trials, some evidence suggests that early fetal exposure to the mother's corticosteroid treatment for SLE may mitigate fetal myocarditis. Namely, Shinohara and coworkers (1999) reported no heart block in 26 neonates whose mothers received corticosteroids before 16 weeks' gestation as part of SLE maintenance therapy. By contrast, 15 of 61 neo nates with heart block were born to women in whom corticoste roid therapy was begun after 16 weeks for an SLE exacerbation.

There are reports that maternal treatment with hydroxychlo roquine (Plaquenil) is associated with a lower incidence of fetal heart block (Izmirly, 2012). Research in this area is ongoing.

The survival rate for women with SLE is 95 percent at 5 years, 90 percent at 10 years, and 78 percent at 20 years (Hahn, 2015). In general, women with lupus and chronic vascular or renal disease may limit family size because of morbidity associated with the disease and greater risks for adverse perinatal outcomes. For contraception, combination oral contraceptives did not increase the incidence oflupus lares in two large multicenter trials (Petri, 2005; Sanchez-Guerrero, 2005). Progestinonly implants and injections provide efective contraception with no known efects on lupus lares (Sammaritano, 2014). Concerns that intrauterine device (IUD) use and immunosuppressive therapy lead to greater infection rates in these patients are not evidenced-based. Notably, comorbid antiphospholipid antibodies are a contraindication to hormonal methods. Tubal sterilization may be advantageous and is performed with greatest safety postpartum or whenever SLE is quiescent.

his syndrome is an autoantibody-mediated acquired thrombophilia with recurrent thrombosis or pregnancy morbidity as part of its clinical constellation (Moutsopoulos, 2015). Speciically, antiphospholipid syndrome (APS) is diagnosed in women with persistently positive serum tests for antiphospholipid antibodies andwith arterial and/or venous thromboses or obstetrical morbidity. Antibodies include lupus anticoagulant, anti cardiolipin antibody, and anti-32 glycoprotein-I antibody.

Phospholipids are the main lipid constituents of cell and organelle membranes. There are proteins in plasma that associate noncovalently with these phospholipids. Antiphospholipid antibodies are directed against these phospholipids or phospholipid-binding proteins (Giannakopoulos, 2013; Tsokos, 201r1). his antibody group may be ofIgG, IgM, and IgA classes, alone or in combination. Antiphospholipid antibodies are most common with SLE, other connective tissue disorders, and APS. However, a small proportion of otherwise normal women and men have low levels of these antibodies.

The stimulus for autoantibody production is unclear, but it possibly is due to a preceding infection. he pathophysiology encountered is mediated by one or more of the following: (1) activation of various procoagulants, (2) inactivation of natural anticoagulants, (3) complement activation, and (4) inhibition of syncytiotrophoblast diferentiation (Tsokos, 2011). Clinically, these actions lead to arterial or venous thromboses or to pregnancy morbidity. Virtually every organ system may be afected.

Central nervous system involvement is one of the most prominent clinical manifestations. In addition to cerebrovascular arterial and venous thrombotic events, there may be psychiatric features and even multiple sclerosis (Binder, 2010).

Renovascular involvement may lead to renal failure that can be diicult to diferentiate from lupus nephritis (D'Cruz, 2009).

Peripheral and visceral thromboses are also a feature. For example, Ahmed and associates (2009) reported a postpartum ing a mesenteric vessel infarction. Obstetrical complications relected by fetal-growth restriction, stillbirth, preeclampsia, and preterm birth. Treatment using aspirin, anticoagulation, and close monitoring has increased live birth rates to more than 70 percent in these women (Schreiber, 2016).

A small proportion of these patients develop the catastrophic drome. his is deined as a rapidly progressive thromboembolic or tissues (Schreiber, 2016). It has a high mortality rate from activation of a cytokine storm. In half of cases, a "triggering" event is identiied.

As mentioned, several antibodies in APS are directed against a speciic phospholipid or phospholipid-binding protein: 1.

32-Gycoprotein I-also known as apolipoprotein H-is a phospholipid-binding plasma protein that inhibits prothrombinase activity within platelets and inhibits platelet aggregation (Giannakopoulos, 2013). hus, its normal action is to limit procoagulant binding and thereby prevent coagulation cascade activation. Logically, antibodies directed against this glycoprotein would reverse its anticoagulant activity and promote thrombosis. This is important from an obstetrical viewpoint because 32-glycoprotein I is expressed in high concentrations on the syncytiotrophoblast surface. Complement activation may contribute to its pathogenesis (Avalos, 2009; Tsokos, 2011). Teleologically, this seems appropriate because the decidua intuitively should be a critical area to prevent coagulation that might lead to intervillous space thrombosis. Another possibility is that 32-glycoprotein I may be involved in implantation, and this glycoprotein may result in pregnancy loss via an inlammatory mechanism (Iwasawa, 2012; Meroni, 2011).

2.

Lupus anticoagulant (LAC) is a heterogeneous group of antibodies directed against phospholipid-binding proteins. This antibody group induces prolongation in vitro of the prothrombin, partial thromboplastin, and Russell viper venom times. hus, paradoxically, this so-called anticoagulant is actually powerfully thrombotic in vivo.

3.

Anticardiolipin antibodies (ACAs) are directed against one of the many phospholipid cardiolipins found in mitochondrial membranes and platelets.

Some anti phospholipid antibodies are also directed against the natural anticoagulant proteins C and S (Robertson, 2006). Another is directed against the anticoagulant protein annexin V, which is expressed in high concentrations by syncytiotrophoblast

TABLE 59-5. Some Clinical Features of Antiphospholipid Syndrome

Venous thrombosis-thromboembolism, thrombophlebitis, livedo reticularis

Arterial thrombosis-stroke, transient ischemic attack, Libman-Sacks cardiac vegetations, myocardial ischemia, distal extremity and visceral thrombosis and gangrene

Hematological-thrombocytopenia, autoimmune hemolytic anemia

Other-neurological manifestations, migraine headaches, epilepsy; renal artery,

Pregnancy-preeclampsia syndrome, recurrent miscarriage, preterm delivery, fetal-growth restriction, fetal death

Data from Giannakopoulos, 2013; Moutsopoulos, 2015.

(Giannakopoulos, 2013). Testing for these other antibodies is not recommended (American College of Obstetricians and Gynecologists, 2017). However, some studies have evaluated these nonconventional antiphospholipid antibodies in women who clinically meet APS criteria but do not have the classic antibody proile. In one study, treatment of women with these nonconventional antibodies ofered some beneits, such as a lower pregnancy loss rate (Mekinian, 2016).

Clinical features shown in Table 59-5 provide indications for testing. By international consensus, APS is diagnosed based on laboratory and clinical criteria found in Table 18-5 (p. 353). First, one of two clinical criteria-which are vascular thrombosis or certain pregnancy morbidity-must be present. With laboratory criteria, elevated levels of LAC, ACA, and anti-3zglycoprotein I should be conirmed on two occasions 12 weeks apart. he diagnosis can be further stratified based on the number of these tests that are positive (Miyakis, 2006).

Tests for LAC are nonspeciic coagulation tests. he partial thromboplastin time is generally prolonged because the anticoagulant interferes with conversion of prothrombin to thrombin in vitro. Tests considered more speciic are the dilute Russell vper venom test and the platelet neutralization procedure. here is currently disagreement as to which of these two is best for screening. If either is positive, then identiication of LAC is conirmed.

Branch and Khamashta (2003) recommend conservative interpretation of results based on repeated tests from a reliable laboratory that are consistent with each clinical case. Only approximately 20 percent of patients with PS have a positive LAC assay alone. Thus, ACA enzyme-linked immunosorbent assay (ELISA) testing should also be performed. Eforts have been made to standardize ACA assays, however, these remain without international standards (Adams, 2013). For each APS test, interlaboratory variation can be large, and agreement between commercial kits is poor.

As noted, nonspecific low levels of antiphospholipid antibodies are identified in approximately 5 percent of normal adults (Branch, 2010). When Lockwood and coworkers (1989) irst studied 737 normal pregnant women, they reported that 0.3 percent had LAC and 2.2 percent had elevated concentrations of either IgM or IgG ACAs. Subsequent investigations confirmed this, and taken together, they totaled almost 4000 normal pregnancies with an average prevalence for antiphospholipid antibodies of 4.7 percent. This is similar to that for normal nonpregnant individuals (Harris, 1991 ; Yasuda, 1995).

In women with high ACA levels, and especially when AC is identiied, risks for decidual vasculopathy, placental infarction, fetal-growth restriction, early-onset preeclampsia, and recurrent fetal death are increased (Saccone, 2017). Some of these women, like those with SLE, also have a high incidence of venous and arterial thromboses, cerebral thrombosis, hemolytic anemia, thrombocytopenia, and pulmonary hypertension (American College of Obstetricians and Gynecologists, 2017; Clowse, 2008). In 191 LAC-negative women with APS, women with antibodies to cardiolipin and 32-glycoprotein I had signiicantly higher miscarriage rates than if either one alone was positive (Liu, 2013). Women with higher titers tend to have more adverse outcomes (Hadar, 2017).

It is not precisely known how antiphospholipid antibodies cause damage, but it is likely that their actions are multifactorial. Platelets may be damaged directly by antiphospholipid antibody or indirectly by binding 32-glycoprotein I, which causes platelets to be susceptible to aggregation (Giannakopoulos, 2013). One theory proposes that phospholipid-containing endothelial cell or syncytiotrophoblast membranes may be damaged directly by the antiphospholipid antibody or indirectly by antibody binding to either 3z-glycoprotein lor annexin V (Rand, 1997, 1998). his prevents the cell membranes from protecting the syncytiotrophoblast and endothelium. This exposes the basement membrane, to which damaged platelets can adhere and form a thrombus.

Pierro and associates (1999) reported that antiphospholipid antibodies decreased decidual production of the vasodilating prostaglandin E2. Diminished protein C or S activity and greater prothrombin activation may also be contributory (Zangari, 1997). Evidence also supports that thrombosis with APS stems from activation of the tissue factor pathway (Amengual, 2003). Finally, uncontrolled placental complement activation by anti phospholipid antibodies may playra role in fetal loss and growth restriction (Holers, 2002).

Complications from APS cannot be completely explained by thrombosis alone. Animal models suggest that efects are due to inflammation rather than thrombosis (Cohen, 2011). Some investigators hypothesize that APS-associated clotting is triggered as a "second hit" from innate inflammatory immune responses. These investigators recommend treatment with antiinlammatory agents (Meroni, 2011).

Overall, antiphospholipid antibodies are generally associated with higher rates of fetal wastage (Chap. 18, p. 353). In most early reports that describe these outcomes, however, women were included because they had had repeated adverse outcomes.

Both antibody prevalence and miscarriage are common-recall that the incidence of antiphospholipid antibodies in the general obstetrical population is about 5 percent and early pregnancy loss approximates 20 percent. Accordingly, current data are too limited to conclude the exact risks for adverse efects of these antibodies on pregnancy outcomes. Fetal deaths, however, are more characteristic with APS than are first-trimester miscar riages (Oshiro, 1996; Roque, 2004). Moreover, women with higher titers have worse obstetrical outcomes compared with those with low titers (Hadar, 2017; Nodler, 2009).

When otherwise unexplained fetal deaths are examined, the data are mixed. One study measured ACA levels in 309 pregnancies with fetal death and found no diferences in their frequency compared with levels in 618 normal pregnancies (Haddow, 1991). In another of women with recurrent pregnancy loss, those with antiphospholipid antibodies had a higher rate of preterm delivery (Clark, 2007). In a case-control study of 582 stillbirths and 1547 live births, a three-to fivefold higher risk for stillbirth was found in women with elevated ACA and anti-3rglycoprotein I levels (Silver, 2013). In women with antiphospholipid antibodies, adverse outcomes are more common in the presence of: (1) all three classic anti phospholipid antibody types, (2) comorbid SLE or systemic autoimmune diseases, and (3) prior thrombosis and pregnancy morbidity. Logistic regression found the probability of pregnancy failure was 93 percent with two or more antiphospholipid antibody types but was 63 percent for those with only one (Rufatti, 2011).

Because of study heterogeneity, current treatment recommendations for women with antiphospholipid antibodies can be confusing. Therapy is directed at thrombosis prevention. As discussed, antiphospholipid antibodies are immunoglobulins that may be of G, M, or A classes. Those directed against the phospholipids (PL) are termed GPL, MPL, and APL, respectively. During testing, these are reported as semiquantified phospholipid binding-unit levels and expressed as negative, low-positive, medium-positive, or high-positive (American College of Obstetricians and Gynecologists, 2017). Of the three, higher titers for GPL and MPL anticardiolipin antibodies are clinically important, whereas low-positive titers are of questionable clinical signiicance.

As discussed in Chapter 52 (p. 1008), women with prior thromboembolic events who have antiphospholipid antibodies are at risk for recurrence in subsequent pregnancies. For these women, prophylactic anticoagulation with heparin throughout pregnancy and then for 6 weeks postpartum with either heparin or warfarin is recommended (American College of Obstetricians and Gynecologists, 2017). For those without prior thromboembolic events, recommendations for management from the American College of Obstetricians and Gynecologists (2017) and the American College of Chest Physicians (Bates, 2012) vary and are listed in Table 52-6 (p. 1020). Some acceptable schemes include close antepartum maternal observation with or without prophylactic or intermediate-dose heparin, and some form of postpartum anticoagulation for 4 to 6 weeks. Scias results with treatment with hydroxychloroquine.

Several trials have questioned the need for heparin for women with antibodies but no history of thrombosis (Branch, 2010). lthough this is less clear, some recommend that fetal death not attributable to other causes (Dizon-Townson, 1998; Lockshin, 1995). Some report that women with recur rent early pregnancy loss and medium-or high-positive titers of antibodies may beneit from therapy (Robertson, 2006).

Described earlier (p. 1143), catastrophic antiphospholipid syndrome is treated aggressively with full anticoagulation, high-dose corticosteroids, plasma exchange, and/or intravenous immunoglobulins (Cervera, 2010; Tenti, 2016). If needed, rituximab may be added (Sukara, 2015).

Due to the risk of fetal-growth abnormalities and stillbirth, serial sonographic assessment of fetal growth and antepartum testing in the third trimester is recommended by the American

College of Obstetricians and Gynecologists (2016a, 2017).

here are other agents used to treat pregnant women with APS, but with no prior thromboembolic event. Aspirin, in doses of 60 to 80 mg orally daily, blocks conversion of arachidonic acid to thromboxane A2 while sparing prostacyclin production. This reduces synthesis of thromboxane A2, which usually causes platelet aggregation and vasoconstriction, and simultaneously spares prostacyclin, which normally has the opposite efect. There appear to be no major side efects from low-dose aspirin other than a slight risk of small-vessel bleeding during surgical procedures. Low-dose aspirin does not reduce adverse pregnancy outcomes in anti phospholipid antibody-positive women without the complete APS syndrome (Amengual, 2015). Its use is recommended for women with SLE or APS (American College of Obstetricians and Gynecologists, 20 16b).

Unractionated heparin is given subcutaneously in dosages of 5000 to 10,000 units every 12 hours. Some prefer lowmolecular-weight heparin, such as 40 mg enoxaparin (Lovenox) once daily (Kwak-Kim, 2013). With therapeutic dosing, measurement of heparin levels may be useful because clotting tests can be altered by LAC. he rationale for heparin therapy is to prevent venous and arterial thrombotic episodes. Heparin therapy also prevents thrombosis in the microcirculation, including the decidual-trophoblastic interface (Toglia, 1996). As discussed, heparin binds to 3rglycoprotein I, which coats the syncytiotrophoblast. This prevents binding of ACAs and anti-3rglycoprotein I antibodies to their surfaces, which likely prevents cellular damage (Tsokos, 2011). Heparin also binds to antiphospholipid antibodies in vitro and likely in vivo. Aspirin plus heparin therapy is the most eicacious regimen (de

Jesus, 2014). However, heparin therapy is associated with several complications that include bleeding, thrombocytopenia,

TABLE 59-6. Pregnancy Outcomes (%) in 750 Women Treated for the Antiphospholipid Syndrome-the PREGNANTS Study

ACA = anticardiolipin antibodies; LAC = lupus anticoagulant.

aNonsevere only.

Data from Saccone, 201r7.

osteopenia, and osteoporosis. A description of various heparins and their adverse efects is found in Chapter 52 (p. 1012).

Corticosteroids generally should not be used with primary APS-that is, without an associated connective tissue disorder. For women with SLE or those being treated for APS who develop SLE, corticosteroid therapy is indicated (Carbone, 1999). In such cases ofseconday APS seen with SLE, the dose of prednisone should be maintained at the lowest efective level to prevent lares.

Intravenous immunoglobulin therapy (NIG) is controversial and has usually been reserved for women with overt diseaseincluding CAPS or heparin-induced thrombocytopenia or both (Alijotas-Reig, 2013). It is used when other first-line therapies have failed, especially in the setting of preeclampsia and fetalgrowth restriction. IlG is administered by some in doses of 0.4 g/kgl d for 5 days-total dose of 2 g/kg. This is repeated monthly, or it is given as a single dose of 1 g/kg each month. Treatment is expensive, as one course costs more than $10,000. A recent literature review found no beneits from adding IlG to low-dose aspirin and low-molecular-weight heparin (Tenti, 2016). And, a Cochrane review found no improvement in the live birth rate for immunotherapy given to women with recurrent pregnancy loss (Wong, 2014). Trials are needed before application of this expensive and cumbersome therapy becomes widespread.

Immunosuppression with hydroxychloroquine may be beneficial with APS by reducing the risk of thrombosis and improving pregnancy outcomes in women with APS (Mekinian, 2015; Sciascia, 2016). Hydroxychloroquine is commonly used with low-dose aspirin in the treatment of women with antiphospholipid antibodies and SLE.

Statins have been examined due to their protective efects on endothelium. In a small trial in 21 women with APS who developed fetal-growth restriction or preeclampsia, the addition of pravastatin to low-dose aspirin and low-molecular-weight heparin improved placental blood flow, preeclampsia features, and pregnancy outcomes (Lekou, 2016). Larger trials are needed.

Fetal loss is common in women with APS if untreated (Rai, 1995). Even with treatment, recurrent fetal loss rates remain at 20 to 30 percent (Branch, 2003; Empson, 2005; Ernest, 2011). Shown in Table 59-6 are pregnancy outcomes from 750 treated women with primary APS-the PREGNANTS study (Saccone, 2017). Participants were treated with low-dose aspirin and prophylactic low-molecular-weight heparin starting in the irst trimester. Importantly, some women with SLE and antiphospholipid antibodies have normal pregnancy outcomes without treatment. Also, it is emphasized that women with LAC and prior bad pregnancy outcomes have had liveborn neonates without treatment.

In a manner similar to neonatal lupus syndrome (p. 1142), up to 30 percent of newborns demonstrate passively acquired antiphospholipid antibodies, and thus there is concern for their adverse neonatal efects (N alii, 2017). One group found higher rates of learning disabilities in these children (Tincani, 2009). Simchen and colleagues (2009) reported a fourfold greater risk for perinatal strokes. Of 141 newborns followed in a European registry, the rate of preterm birth was 16 percent; low birthweight, 17 percent; and later behavioral abnormalities in 4 percent of the children. here were no cases of neonatal thrombosis (Motta, 2012). A 7-year study of 26 women who had APS with 36 pregnancies reported three cases of autism spectrum disorder, all associated with persistent neonatal anti �2_g1ycoprotein-1 IgG antibodies (Abisror, 2013).

This chronic inflammatory disease stems from immunological dysunction, and iniltrating T cells secrete ctokines to cause inflammation, polyarthritis, and systemic symptoms. he cardinal feature is inflammatory synovitis that usually involves the peripheral joints. he disease has a propensity for cartilage destruction, bony erosions, and joint deformities. Pain, aggravated by movement, is accompanied by swelling and tenderness. Extraarticular manifestations include rheumatoid nodules, vasculitis, and pleuropulmonary symptoms. Other complaints are fatigue, anorexia, and depression. he American College of Rheumatology criteria for rheumatoid arthritis diagnosis are shown in Table 59-7. A score of 6 or greater ulills the requirements for definitive diagnosis.

The worldwide prevalence of rheumatoid arthritis is 0.5 to 1 percent, women are afected three times more often than men, and peak onset is from 25 to 55 years (Shah, 2015). There is a genetic predisposition, and heritability is estimated at 15 to 30 percent (McInnes, 2011). Genome-wide associated studies have identified more than 30 loci involved in rheumatoid arthritis pathogenesis (Kurka, 2013). There is an association with the

TABLE 59-7. Criteria for Classification of Rheumatoid Arthritis

CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; IP = interphalangeal joint; MCP = metacarpophalangeal joint; MTP = metatarsophalangeal joint; PIP = proximal inteLphalangeal joint; RF = rheumatoid factor.

Criteria established in collaboration with the American College of Rheumatology and the European League Against Rheumatism. A scorer:::6 fulfills criteria for diagnosis. Data from Aletaha, 2010; Shah, 2015.

class II major histocompatibility complex molecule HLADR4 and HLA-DRB1 alleles (McInnes, 2011; Shah, 2015). Pregnancy provides a protection against rheumatoid arthritis development, and this may be related to HLA-disparate fetal microchimerism (Guthrie, 2010). Of other inluences, cigarette smoking raises the risk of rheumatoid arthritis (Papadopoulos, 2005).

Treatment is directed at pain relief, inlammation reduction, protection of articular structures, and preservation of function. Physical and occupational therapy and self-management instructions are essential. Until recently, aspirin and other NSAIDs were the cornerstone of therapy, but they do not retard disease progression. According to Shah and St. Clair (2015), methotrexate has become the preferred disease-modiying antirheumatic drug (DMARD). NSAIDs serve as adjunctive therapy but are important to pregnancy because methotrexate is contraindicated. Conventional NSAIDs nonspeciically inhibit both cyclooxygenase-1 (COX-I), which is an enzyme critical to normal platelet function, and COX-2, which mediates inflammatory response mechanisms. Because gastritis with acute bleeding is an unwanted side efect common to conventional NSAIDs, the more specific COX-2 inhibitors have been recommended. However, their long-term use is associated with higher risk for myocardial infarction and major vascular events (Patrono, 2016).

In one systematic review, a higher rate of cardiac malformations was found in newborns exposed to NSAIDs in the first trimester (Adams, 2012). In addition, NSAIDs are associated with early spontaneous abortions, ductus arteriosus constriction, and neonatal pulmonary hypertension. Thus, risks versus beneits of these medications must be considered.

Glucocorticoid therapy in low-to-moderate doses is given to achieve more rapid symptom control. Of these, prednisone, 7.5 mg orally daily for the first 2 years of active disease, substantively reduces progressive joint erosions (Kirwan, 1995; Shah, 201r5).

The American College of Rheumatology recommends several DMARDs that may reduce or prevent joint damage (Singh, 2016). Lelunomide, like methotrexate, is teratogenic (Briggs, 2015) (Chap. 12, p. 241). Sulfasalazine and hydroxychloroquine are safe for use in pregnancy (Pardett, 201r1). These, combined with COX-2 inhibitors and with relatively low-dose prednisone-7.5 to 20 mg daily-usually successfully treat flares. In one review of drug exposure, a fourth of women with rheumatoid arthritis took a DMARD within 6 months of conception (Kuriya, 2011). During pregnancy, 4 percent of 393 pregnant women were given a category D or X medication. Methotrexate was the most common 2.9 percent.

Biological DMARDs have revolutionized the treatment of rheumatoid arthritis. These include tumor necrosis factor alpha (TNF-.) inhibitors-infliximab, adalimumab, golimumab, certolizumab, and etanercept (Shah, 2015). Their use in pregnancy is limited, and fetal safety is a concern (Mako!, 201r1; Ojeda-Uribe, 2013). In one drug-exposure review, 13 percent of 393 women were given a biological cytokine-inhibiting DMARD-primarily etanercept (Kuriya, 2011). In another review of 300 exposures, no fetal efects were noted (Berthelot, 2009). A prospective study of 38 women found similar results (Hoxha, 2017). In 74 women exposed to adalimumab during pregnancy, no risks were identified (Burmester, 2017). There is also little known regarding pregnancy efects of anakinra, an interleukin-1 receptor antagonist, or of rituximab, an antagonist to the B-cell CD20 antigen.

In up to 90 percent of women with rheumatoid arthritis, their disease will improve during pregnancy (de .Man, 2008). Animal studies suggest this may be due to regulatory T-cell alterations (Munoz-Suano, 2012). Even so, some women develop disease during pregnancy, and others become worse (Nelson, 1997).

A downside to this respite during pregnancy is that postpartum exacerbation is common (0stensen, 2007). This may stem from postpartum alterations in innate immunity (Haupl, 2008b). In one review, a postpartum flare was more common if women were breastfeeding (Barrett, 2000a). These same investigators followed 140 women with rheumatoid arthritis during 1 to 6 months postpartum (Barrett, 2000b). There was only a modest fall in objective disease activity, and only 16 percent had complete remission. They observed that although overall disease actually did not exacerbate postpartum, the mean number of inflamed joints rose signiicantly.

Some studies report a protective efect of pregnancy against developing new-onset rheumatoid arthritis. In a case-control study of 88 afected women, there was a protective efect of pregnancy in the long term, but the likelihood of new-onset rheumatoid arthritis was increased sixfold during the irst 3 postpartum months (Silman, 1992). Pikwer and colleagues (2009) reported a significant reduction in the risk of subsequent arthritis in women who breastfed longer than 12 months.

hese indings may reflect the interference of sex hormones with several putative processes involved in arthritis pathogenesis, including immunoregulation (Haupl, 2008a,b). First, Unger and associates (1983) reported that amelioration of rheumatoid arthritis correlated with serum levels of pregnancyassociated apha2-gycoprotein. his compound has immunosuppressive properties. Second, Nelson and coworkers (1993) noted that amelioration of disease was associated with a disparity in HLA class II antigens between mother and fetus. They s�ggested that the maternal immune response to paternal HLA antigens may play a role in pregnancy-induced remission of arthritis. In addition to monocyte activations, there also may be T -lymphocyte activation (Forger, 2008).

This group of diseases is the most frequent cause of chronic arthritis in children and persists into adulthood. In 76 pregnancies of 51 afected Norwegian women, pregnancy had no efects on clinical presentation, but disease activity usually became quiescent or remained so during pregnancy (0stensen, 1991). Postpartum flares were common as was discussed for rheumatoid arthritis. Joint deformities often developed in these women, and 15 of 20 cesarean deliveries were done for contracted pelves or joint prostheses. Results from a summary of 39 Polish women with juvenile rheumatoid arthritis were similar (Musiej-Nowakowska, 1999).

This arthritis portends few adverse pregnancy outcomes. The risk for preterm birth is increased, but later fetal development is normal (Mohamed, 2016; Rom, 2014; Wallenius, 2014). Disease severity in early pregnancy was predictive of preterm delivery and fetal-growth restriction in a cohort study (Bharti, 2015). nother study of 190 pregnancies followed from first trimester to delivery found patients with low disease activity scores in the first trimester were likely to have low disease activity or remission in the third trimester (Ince-Askan, 2017). In a study of 1807 births, Remaeus and associates (2017) reported increased incidences of preterm birth, fetal-growth restriction, and preeclampsia.

Primary treatment of symptomatic women during pregnancy is with aspirin and NSAIDs. These are used with appropriate concerns for irst-trimester efects, impaired hemostasis, prolonged gestation, premature ductus arteriosus closure, and persistent pulmonary circulation. Low-dose corticosteroids are also prescribed as indicated. Gold compounds have been administered in pregnancy (Almarzouqi, 2007).

Immunosuppressive therapy with azathioprine, cyclophosphamide, or methotrexate is not routinely used during pregnancy. Only azathioprine is considered during early pregnancy because the other agents are teratogens (Briggs, 2015). As discussed on page 1147, DMARDs including sulfasalazine and hydroxychloroquine are acceptable for use in pregnancy.

If the cervical spine is involved, particular attention is warranted during pregnancy. Subluxation is common, and pregnancy, at least theoretically, predisposes to this because of joint laxity. Importantly, there are anesthesia concerns during endotracheal intubation.

Following pregnancy in women with rheumatoid arthritis and its juvenile form, contraceptive counseling may include combination oral contraceptives. These are a logical choice because of their efectiveness and their potential to improve disease (Farr, 2010). That said, all methods of contraception are appropriate.

This is a chronic multisystem connective tissue disorder of unknown etiology. It is characterized by microvascular damage, immune system activation leading to inlammation, and excessive deposition of collagen in the skin and often in the lungs, heart, gastrointestinal tract, and kidneys. It is uncommon, displays a 5-to-1 female dominance, and typically afects those aged 30 to 50 years (Meier, 2012; Varga, 2015).

This strong prevalence of scleroderma in women and its greater incidence in the years following childbirth give credence to the hypothesis that microchimerism is involved as discussed earlier (p. 1139) (Lambert, 2010). Artlett and coworkers (1998) demonstrated Y-chromosomal DNA in almost half of women with systemic sclerosis compared with only 4 percent of controls. Rak and colleagues (2009b) identiied male microchimerism in peripheral blood mononuclear cells more frequently in women with limited versus diuse scleroderma-20 versus 5 percent.

The hallmark is overproduction of normal collagen. In the more benign form-Limited cutaneous systemic sclerosis-progression is slow. With diuse cutaneous systemic sclerosis, skin thickening progresses rapidly, and skin fibrosis is followed by gastrointestinal tract ibrosis, especially the distal esophagus (Varga, 2015). Pulmonary interstitial fibrosis along with vascular changes may cause pulmonary hypertension, which develops in 15 percent of patients. Antinuclear antibodies are found in 95 percent of patients, and immunoincompetence often develops.

Raynaud phenomenon, which includes cold-induced epi sodic digital ischemia, is seen in 95 percent of patients, and there may also be swelling of the distal extremities and face.

Half of patients have symptoms from esophageal involve ment, especially fullness and epigastric burning pain. Pulmo nary involvement is frequent and causes dyspnea. The 10-year cumulative survival rate is 70 percent in those with pulmo nary fibrosis, and pulmonary arterial hypertension is the main cause of death Goven, 2010; Varga, 2015). Women with lim ited cutaneous disease such as the CEST syndrome-falcinosis,

Baynaud phenomenon, .sophageal involvement, .clerodacyy, and .elangiectasia-have milder disease.

Overlap syndrome refers to systemic sclerosis with features of other connective tissue disorders. Mixed connective tissue disease is a term used for the syndrome involving features of SLE, systemic sclerosis, polymyositis, rheumatoid arthritis, and high titers of anti-ribonucleoprotein (RNP) antibodies (see Table 59-1). he disorder is also termed undierentiated connective tissue disease (Spinillo, 2008).

Although systemic sclerosis is incurable, treatment directed improve function. Renal involvement and hypertension are often comorbid. At times, ACE inhibitors may be required for blood pressure control despite their known teratogenicity. Scleroderma renal crisis develops in up to a fourth of these patients and is characterized by obliterative vasculopathy of the renal cortical arteries. his leads to renal failure and malignant hypertension.

Interstitial restrictive lung disease is common and frequently becomes life threatening. Associated pulmonary hypertension is treated with bosentan or sildenail (Chap. 49, p. 960).

The prevalence of scleroderma in pregnancy approximates 1 in 22,000 pregnancies (Chakravarty, 2008). These women usually have stable disease during gestation if their baseline unction is good. As perhaps expected, are aggravated by pregnancy (Steen, 1999). Dysphagia results from loss of esophageal motility due to neuromuscular dysunction. A decrease in amplitude or disappearance of peristaltic waves in the lower two thirds of the esophagus is seen using manometry. Symptomatic treatment for reflux is described in Chapter 54 (p. 1046).

Women with renal insuiciency and malignant hypertension have a higher incidence of superimposed preeclampsia. With rapidly worsening renal or cardiac disease, pregnancy termination should be considered. As discussed, renal crisis is life threatening and is treated with ACE inhibitors, but it does not improve with delivery (Gayed, 2007). Pulmonary hypertension usually contraindicates pregnancy.

Vaginal delivery may be anticipated, unless the soft tissue thickening wrought by scleroderma produces dystocia requiring cesarean delivery. Tracheal intubation for general anesthesia has special concerns because of limited ability of these women to open their mouths widely (Sobanski, 2016). Because of esophageal dysfunction, aspiration is also more likely, and epidural analgesia is preferable. Warming the delivery room and intravenous fluids, extra blankets, and socks and gloves are recommended to improve impaired circulation from Raynaud phenomenon. If corticosteroids were used frequently, stress doses of hydrocortisone are recommended (Sobanski, 2016).

Maternal and fetal outcomes correlate with underlying dis ease severity. In a review of 214 gravidas with systemic sclerosis, 45 percent had difuse disease. Major complications included renal crisis in three and greater rates of preterm birth (Steen, 1989, 1999). Chung and coworkers (2006) also reported elevated rates of preterm delivery, fetal-growth restriction, and perinatal mortality. A multicenter study of 109 pregnan cies from 25 centers reported higher rates of preterm delivery, fetal-growth restriction, and very-low-birthweight newborns (Taraborelli, 2012). hese are likely related to placental abnor malities that include decidual vasculopathy, acute atherosis, and infarcts (Sobanski, 2016).

Scleroderma may be associated with subfertility (Bernatsky, 2008; Lambe, 2004). For women who do not choose preg nancy, several reversible contraceptive methods are acceptable.

However, hormonal agents, especially combination oral con traceptives, probably should not be used, especially in women with pulmonary, cardiac, or renal involvement. Due to the often unrelenting progression of systemic sclerosis, permanent sterilization is also considered.

Inlammation and damage to blood vessels may be primary or caused by another disease. Immune-complex deposition is presumed to underlie most cases (Langford, 2015). Primary types include polyarteritis nodosa, temporal or giant-cell arteritis, T akayasu arteritis, Henoch-Schonlein purpura, Behyet syndrome, and cutaneous or hypersensitivity arteritis (Goodman, 2014). Small vessel vasculitides such as granuomatosis with poyangiitis and eosinophilic granuomatosis with poyangiitis have antibodies directed against proteins in the cytoplasmic granules of leukocytes-antineutrophil ytopsmic antibodies-NA (Pagnox, 201).

This necrotizing vasculitis of small and medium-sized arteries is characterized clinically by myalgia, neuropathy, gastrointestinal disorders, hypertension, and renal disease (Goodman, 2014). Of cases, approximately a third is associated with hepatitis B antigenemia (Langford, 2015). Symptoms are nonspecific, and fever, weight loss, and malaise are present in more than half of cases. Diagnosis is made by biopsy, and treatment consists of high-dose prednisone plus cyclophosphamide. Vasculitis due to hepatitis B antigenemia responds to antivirals, glucocorticosteroids, and plasma exchange (Chap. 55, p. 1063).

Only a few reports describe polyarteritis nodosa associated with pregnancy. Of 12 afected gravidas, polyarteritis first manifested during pregnancy in seven, and it was rapidly fatal by 6 weeks postpartum (Owen, 1989). he diagnosis was not made until autopsy in six of the seven women. Four women continued pregnancy, which resulted in one stillborn and three successful outcomes.

• Granulomatosis with Polyangiitis

Formerly Wegener granulomatosis, this is a small-vessel necrotizing granulomatous vasculitis afecting the upper and lower respiratory tract and kidney (Pagnoux, 2016). Disease frequently includes sinusitis and nasal disease-90 percent; pulmonary infiltrates, cavities, or nodules-85 percent; glomerulonephritis-75 percent; and musculoskeletalrlesions-65 percent (Sneller, 1995). At least 90 percent have polyangiitis (Langford, 2015). It is uncommon and usually encountered after age 50. Koukoura and associates (2008) reviewed 36 cases in association with pregnancy and found a higher preterm birth rate. In another report, a second woman had disease-related pneumonitis, but pregnancy did not appear to afect disease activity (Pagnoux, 2011). Because subglottic stenosis is found in up to a fourth of patients, the anesthesia team is ideally consulted antepartum (Engel, 2011).

Corticosteroids are standard treatment, but azathioprine, cyclosporine, and IVIG therapy may also be used. For severe disease in the late second or third trimester, cyclophosphamide in combination with prednisolone seems acceptable.

Also called pulseless disease, this is a chronic inflammatory arteritis afecting large vessels (Goodman, 2014). Unlike temporal arteritis, which develops almost exclusively after age 55, the onset ofTakayasu arteritis is almost always before age 40. It is associated with abnormal angiography of the upper aorta and its main branches and with upper extremity vascular impairment. Death usually results from congestive heart failure or cerebrovascular events. Computed tomography or magnetic resonance angiography can detect this disorder before the development of severe vascular compromise. Takayasu arteritis may respond symptomatically to corticosteroid therapy, however, it is not curative. Surgical bypass or angioplasty improves survival rates.

Comorbid severe renovascular hypertension, cardiac involvement, or pulmonary hypertension worsen pregnancy prognosis (Singh, 2015). Hypertension is relatively common and should be carefully controlled. Blood pressure is most accurately measured in the lower extremity. Overall, the prognosis for pregnancy is good Oohnston, 2002). A study of 58 women with Takayasu arteritis found an elevated risk of pregnancyrelated hypertension and preeclampsia but overall favorable maternal and fetal outcomes (Gudbrandsson, 2017). A study of 52 patients comparing obstetrical outcomes before and ater diagnosis reported higher rates of obstetrical complications after diagnosis. These included preeclampsia, preterm birth, and fetal-growth restriction or death (Comarmond, 2015). Involvement of the abdominal aorta portends worse perinatal outcome (Sharma, 2000). Vaginal delivery is preferred, and epidural analgesia has been advocated for labor and delivery.

Henoch-Schonlein purpura is uncommon after childhood. T ayabali and associates (2012) reviewed 20 pregnancies complicated by this vasculitis and described cutaneous lesions in three fourths. Approximately half had arthralgias. For Beh;et disease, Gungor and colleagues (2014) described 298 pregnancies in 94 women and found higher miscarriage rates and smaller babies compared with healthy controls. Formerly Churg-Strauss vasculitis, eosinophilic granulomatosis with polyangiitis is rare in pregnancy Oennette, 2013). Hot and associates (2007) described a pregnant woman who responded to IVIG therapy. Corradi and associates (2009) described an afected 35-yearold woman at term whose necrotizing vasculitis involved the heart, and she subsequently underwent cardiac transplantation. Edwards (2015) described one woman who developed postpartum relapses of this vasculitis in each of two pregnancies.

These are acquired and potentially treatable causes of skeletal muscle weakness with a prevalence of 1 in 100,000 persons (Dalakas, 2012). There are three major groups: polymyositis, dermatomyositis, and inclusion-body myositis, which all present with progressive asymmetrical muscle weakness. They have a variable association with connective tissue diseases, malignancy, drugs, systemic autoimmune disease such as Crohn disease, and viral, bacterial, and parasitic infections.

Poymyositis is a subacute inflammatory myopathy that is frequently associated with one of the autoimmune connective tissue disorders. Dermatomyositis manifests as a characteristic rash accompanying or preceding weakness. Laboratory findings include elevated muscle enzyme levels in serum and an abnormal electromyogram. Conirmation is by biopsy, which shows perivascular and perimysial inlammatory infiltrates, vasculitis, and muscle iber degeneration. It usually develops alone but can overlap with systemic sclerosis or mixed connective tissue disease.

Prevailing theories suggest that the syndromes are caused by viral infections, autoimmune disorders, or both. Importantly, approximatey 15 percent of adults who develop dermatomyositis have an associated malignant tumor. The timing of myositis and tumor appearance may be separated by several years. he most common sites of associated cancer are breast, lung, stomach, and ovary. The disease usually responds to high-dose corticosteroid therapy, immunosuppressive drugs such as azathioprine or methotrexate, or IVIG (Dalakas, 2012; Linardaki, 2011).

Experiences in pregnancy are garnered mostly from case series and reviews. Chen and colleagues (2015) found 17 women with polymyositis/ dermatomyositis in an Australian population-based cohort of births. These women had higher rates of hypertension (23 percent), antepartum hemorrhage (11 percent), cesarean delivery (88 percent), and preterm birth (35 percent). Another series of 60 women with dermatomyositis and 38 with polymyositis found that in 80 percent, pregnancy had no adverse efect on their disease. Similar results have been reported by others (Missumi, 2015; Pinal-Fernandez, 2014). Rosenzweig and colleagues (1989) reviewed 24 pregnancy outcomes in 18 women with primary disease. Of these, a fourth had an exacerbation in the second or third trimester. In 12 in whom disease became manifest first during pregnancy, half of the eight pregnancies resulted in perinatal death, and one woman died postpartum.

From their review, Doria and associates (2004) concluded that pregnancy outcome was related to dermatomyositis activity and that new-onset disease was particularly aggressive.

Numerous inherited mutations involve genes that encode for structural proteins of bone, skin, cartilage, blood vessels, and basement membranes. Although connective tissues contain many complex macromolecules such as elastin and more than 30 proteoglycans, the most common constituents are ibrillar collagen types I, II, and III. Various mutations, some recessively and some dominantly inherited, result in clinical syndromes that include Marfan and Ehlers-Danlos syndromes, osteogenesis imperfecta, chondrodysplasias, and epidermolysis bulla. Of concern during pregnancy is the predilection for these disorders to result in aortic aneurysms (Schoenhof, 2013).

This is an autosomal dominant connective tissue disorder that has a population prevalence of 1 in 3000 to 5000 (Prockop, 2015). Marfan syndrome afects both sexes equally. The syndrome is due to abnormal fibrillin-a constituent of elastincaused by any of several diferent mutations in the FENI gene (Biggin, 2004). Located on chromosome 15q21, the FENI gene has a high mutation rate, and there are many mild, subclinical cases. A 50-percent risk of disease transmission to the ofspring exists, however, the ability to predict disease severity in progeny is limited by the lack of distinct genotype-phenotype correlation and large clinical variability. Currently, preimplantation and prenatal diagnoses are limited to the 80 percent of cases in which the mutation in the FBNI gene is known (Smok, 2014).

In severe disease, there is degeneration of the elastic lamina in the media of the aorta. his weakness predisposes to aortic dilation or dissecting aneurysm, which appears more commonly during pregnancy (Curry, 2014; Roman, 2016). Marfan syndrome complicating pregnancy is discussed in more detail in Chapter 49 (p. 967).

This disease is characterized by various connective tissue changes, including skin hyperelasticity. In the more severe types, rupture of any of several arteries can cause either stroke or bleeding. There are several disease types based on skin, joint, or other tissue involvement. Some are autosomal dominant, some recessive, and some X-linked (Solomons, 2013). Their aggregate prevalence approximates 1 in 5000 births (Prockop, 2015). Types I, II, and III are autosomally dominant, and each accounts for approximately 30 percent of cases. Type IV is uncommon but is known to predispose to preterm delivery, maternal great-vessel rupture, postpartum bleeding, and uterine rupture (Pepin, 2000). In most, the underlying molecular defect afects collagen or procollagen.

In general, women with Ehlers-Danlos syndrome reportedly have a higher frequency of preterm rupture of membranes, preterm delivery, and antepartum and postpartum hemorrhage (Volkov, 2006). That said, a recent cohort study of314 women reported no greater risk of adverse pregnancy outcome, including preterm birth (Sundelin, 2017). Several cases of spontaneous uterine rupture have been described (Rudd, 1983). Tissue fragility makes episiotomy repair and cesarean delivery diicult. Hurst and colleagues (2014) surveyed 1769 respondents of the Ehlers-Danlos National Foundation and found a preterm birth rate of 25 percent and infertility rate of 44 percent. A maternal and fetal death from spontaneous rupture of the right iliac artery has been reported (Esaka, 2009). Bar-Yosef and associates (2008) described a newborn with multiple congenital skull fractures and intracranial hemorrhage caused by Ehlers-Danlos type VIIC.

This disorder has a prevalence of 1 in 20,000 births for type I and 1 in 60,000 for type II. It is characterized by brittle bones and afected patients often have blue sclerae, hearing loss, multiple prior bone fractures, and dental abnormalities. There are up to 15 subtypes based on the causative gene and clinical picture, which ranges from mild to severe (Van Dijk, 2010). Genetic inheritance includes autosomal dominant, autosomal recessive, and sporadic patterns. Type I is the mildest form, and the typical mutation afects the COLIAI gene (Sykes, 1990). Type II is typically lethal in utero (Prockop, 2015).

Women with osteogenesis imperfecta, most commonly type I, may have successful pregnancies. hat said, several risks in pregnancy include fractures, complications related to scoliosis with restrictive lung disease, micrognathia, brittle teeth, an unstable cervical spine, uterine rupture, and cephalopelvic disproportion. A retrospective cohort of 295. women with osteogenesis imperfecta found greater risks of antepartum hemorrhage, abruption, fetal-growth restriction, congenital malformations, and preterm birth (Ruiter-Ligeti, 2016). It is not unusual for afected women to enter pregnancy having had 20 to 30 prior fractures. Most require minimal treatment other than management of the fractures and consideration of bisphosphonates to decrease bone loss.

Depending on the type of osteogenesis imperfecta, the fetus may be afected and may also sufer fractures in utero or during delivery (Chap. 10, p. 210). Prenatal diagnosis is available in many situations, if desired, and in utero stem cell therapy is being evaluated (Couzin-Frankel, 2016).

Abisror N, Mekinian A, Lachassinne E, et al: Autism spectrum disorders in babies born to mothers with antiphospholipid syndrome. Semin Arthritis

Rheum 43(3):348, 2013 Adams K, Bombardier C, van der Heijde OM: Safety of pain therapy during pregnancy and lactation in patients with inflammatory arthritis: a systematic literature review. J Rheumatol Suppl 90:59, 2012 Adams KM, Nelson JL: Microchimerism: an investigative frontier in autoim munity and transplantation. JAMA 29t1: 1127, 2004 Adams M: Measurement oflupus anticoagulants: an update on quality in labo ratory testing. Semin Thromb Hemost 39(3):267,t2013 hmed K, Darakhshan A, Au E, et al: Postpartum spontaneous colonic perforation due to antiphospholipid syndrome. WorldJ GastroenteroIs15(4):502, 2009 letaha 0, Neogi T, Silman AJ, et al: 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 69(9):1580, 2010

Alijotas-Reig J: Treatment of refractory obstetric antiphospholipid syndrome: the state of the art and new trends in the therapeutic management. Lupus 22(1):6,s2013

Almarzouqi M, Scarsbrook 0, Klinkhof A: Gold therapy in women planning pregnancy: outcomes in one center. J RheumatoIs34:1827, 2007

Amengual 0, Atsumi T, Khamashta vA: Tissue factor in antiphospholipid syndrome: shifting the focus from coagulation to endothelium. Rheumatology 42: 1029, 2003

Amengual 0, Fujita 0, Otta E, et al: Primary prophylaxis to prevent obstetric complications in asymptomatic women with anti phospholipid antibodies: a systematic review. Lupus 24(11):1135, 2015

American College of Obstetricians and Gynecologists: Antiphospholipid syndrome. Practice Bulletin No. 132, December 2012, Reairmed 2017 American College of Obstetricians and Gynecologists: Antepartum fetal surveillance. Practice Bulletin No. 145, July 2014, Reairmed 2016a

American College of Obstetricians and Gynecologists: Practice Advisory on low-dose aspirin and prevention of preeclampsia: updated recommendations. July 11, 2016b

Andreoli M, Nalli Fe, Reggia R, et al: Pregnancy implications for systemic lupus erythematosus and the anti phospholipid syndrome. J Autoimmun 38:]197,s2012

Arbuckle MF, McClain MT, Ruberstone MV, et al: Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 349: 1526, 2003

Ardett CM, Smith B, Jimenez SA: Identification of fetal DNA and cells in skin lesions from women with systemic sclerosis. N Engl J Med 338: 1186, 1998

Avalos I, Tsokos GC: The role of complement in the anti phospholipid syndrome-associated pathology. Clin Rev Allergy Immunol 34(2-3):141, 2009 Bar-Yosef0, Polak-Charcon S, Hofman C, et al: Multiple congenital skull fractures as a presentation of Ehlers-Dan los syndrome type VIle. Am J Med Genet A 146A:3054, 2008

Barrett ]H, Brennan P, Fiddler M, et al: Breast-feeding and postpartum relapse in women with rheumatoid and inflammatory arthritis. Arthritis Rheum 43:010,s2000a Barrett JH, Brennan P, Fiddler M, et al: Does rheumatoid arthritis remit during pregnancy and relapse postpartum? Results from a nationwide study in the United Kingdom performed prospectively from late pregnancy. Arthritis Rheum 42:1219, 2000b Bates SM, Greer A, Middledorp S, et al: VTE, thrombophilia, antithrombotic therapy, and pregnancy. Chest 141(2 Suppl):e691S, 2012 Bernatsky S, Hudson M, Pope J, et al: Assessment of reproductive history in systemic sclerosis. Arthritis Rheum 59:1661, 2008 Berthelot JM, De Bandt M, Goupille P, et al: Exposition to anti-TNF drugs during pregnancy: outcome of 15 cases and review of the literature. Joint Bone Spine 76(1):28, 2009 Bertsias G, Ionnidis JPA, Boletis J, et al: EULAR recommendations for the management of systemic lupus erythematosus (SLE). Ann Rheum Dis 67(2): 195, 2008 Bharti B, Lindsay SP, Wingard DL, et al: Disease severity and pregnancy outcomes in women with rheumatoid arthritis: results from the Organization of Teratology Information Specialists Autoimmune Diseases in Pregnancy Project. J RheumatoIs42:1376, 2015 Biggin A, Holman K, Brett M, et al: Detection of thirty novel FBN 1 mutations in patients with Marfan syndrome or a related fibrillinopathy. Hum Mutat 23:99, 2004 BinderD, TraumZ, Makar RS, et al: Case 37-2010: a 16-year-old girl with confusion, anemia, and thrombocytopenia. N Engl J Med 363(24):2352,2010 Borden M, Parke A: Antimalarial drugs in systemic lupus erythematosus. Drug Saf24:1055,s2001 Bramham K, Soh Me, Nelson-Piercy C: Pregnancy and renal outcomes in lupus nephritis: anupdate and guide to management. Lupus 21(12):1271,s2012 Branch OW, Gibson M, Silver ,1: Recurrent miscarriage. N Engl J Med 363:18,s2010 Branch OW, Khamashta M: Antiphospholipid syndrome: obstetric diagnosis, management, and controversies. Obstet Gynecol 101: 1333, 2003 Briggs GG, Freeman RK: Drugs in Pregnancy and Lactation. 10th ed. Philadelphia, Wolters Kluwer, 2015 Burmester GR, Landewe R, Genovese Me, et al: Adalimumab long-term safety: infections, vaccination response and pregnancy outcomes in patients with rheumatoid arthritis. Ann Rheum Dis 76(2):414, 2017

Buyon JP, Kim MY, Guerra MM, et al: Predictors of pregnancy outcomes in patients with lupus: a cohort study. Ann Intern Med 163(3): 153, 2015

Buyon JP, Winchester RJ, Slade SG, et al: Identification of mothers at risk for congenital heart block and other neonatal lupus syndromes in their children. Comparison of enzyme-linked immunoabsorbent assay and immunoblot for measurement of anti SSA/Ro and anti SSB/La antibodies. Arthritis Rheum 36: 1263, 1993

Cabiddu G, Castelli no S, Gernone G, et al: A best practice position statement on pregnancy in chronic idney disease: the Italian Study Group on Kidney and Pregnancy. J NephroIs29(3)277, 2016

Carbone J, Orera M, Rodriguez-Mahou M, et al: Immunological abnormalities in primary APS evolving into SLE: 6 years' follow-up in women with repeated pregnancy loss. Lupus 8:274, 1999

Cervera R, CAPS Registry Project Group: Catastrophic antiphospholipid syndrome (CAPS): update from the "CAPS Registry." Lupus 19(4):412, 2010

Chakravarty EF, Khanna 0, Chung L: Pregnancy outcomes in systemic sclerosis, primary pulmonary hypertension, and sickle cell disease. Obstet Gynecol 111(4):927,s2008

Chen ]S, Roberts CL, Simpson JM, et al: Pregnancy outcomes in women with rare autoimmune diseases. Arthritis RheumatoIs67(12):3314, 2015

Chiou AS, Sun G, Kim J, et al: Cutaneous neonatal lupus arising in an infant conceived from an oocyte donation pregnancy. JAMA Dermatol 152(7):846,s2016

Chung L, Flyckt L, Colon I, et al: Outcome of pregnancies complicated by systemic sclerosis and mixed connective tissue disease. Lupus 15:595, 2006

Clark CA, Spitzer A, Crowther A, et al: Incidence of postpartum thrombosis and preterm delivery in women with antiphospholipid antibodies and recurrent pregnancy loss. J Rheumatol 34:992, 200

Clowse ME, Jamison M, Myers E, et al: A national study of the complications oflupus in pregnancy. Am J Obstet GynecoIs199:127.e1, 2008

Cohen 0, Buurma A, Goemaere NN, et al: Classical complement activation as a footprint for murine and human antiphospholipid antibody-induced fetal loss. J Pathol 225(4):502, 2011

Comarmond C, Mirault T, Baird L, et al: Takayasu arteritis and pregnancy. Arthritis RheumatoIs67(12):3262, 2015

Corradi 0, Maestri R, Facchetti F: Postpartum Churg-Strauss syndrome with severe cardiac involvement: description of a case and review of the literature. Clin Rheumatol 28(6):739, 2009

Couzin-Frankel]: The savior cells? Science 352(6283):284,s2016

Cruz Gl, Shao X, Quach H, et al: A child's HLA-DRBI genotype increases maternal risk of systemic lupus erythematosus.s] Autoimmun 74:201, 2016 Curry R, Gelson E, Swan L, et al: Marfan syndrome and pregnancy: maternal and neonatal outcomes. B]OG 121(5):610,s2014

Cutolo M, Capelli no S, Sulli A, et al: Estrogens and autoimmune diseases. Ann NY Acad Sci 1089:538,2006

D'Cruz 0: Renal manifestations of the anti phospholipid syndrome. Curr Rheumatol Rep 11(1):52,2009 da Silva Florim GM, Caldas He, Pavarino EC, et al: Variables associated to fetal microchimerism in systemic lupus erythematosus patients. Clin RheumatoIs35(1):107,s2016 Dalakas MC: Polymyositis, dermatomyositis, and inclusion body myositis. In Longo DL, Fauci AS, Kasper DL, et al (eds): Harrison's Principles ofInternal Medicine, 18th ed. New York, McGraw-Hill, 2012 de Jesus GR, Rodrigues G, de Jesus NR, et al: Pregnancy morbidity in antiphospholipid syndrome: what is the impact of treatment? Curr Rheumatol Rep 16:403,s2014 de Jesus GR, Rodrigues Be, Lacerda Ml, et al: Gestational outcomes in patients with neuropsychiatric systemic lupus erythematosus. Lupus 26:537, 2017 de Man YA, Dolhain RJ, van de Geijn FE, et al: Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study. Arthritis Rheum 59:1241, 2008 Dizon-Townson 0, Branch OW: Anticoagulant treatment during pregnancy: an update. Semin Thromb Hemost 24:55S, 1998

Doria A, Iaccarino L, Ghirardello A, et al: Pregnancy in rare autoimmune rheumatic diseases: UCTD, MCTD, myositis, systemic vasculitis and Behyet disease. Lupus 13:690, 2004 Edwards MH, Curtis EM, Ledingham ]M: Postpartum onset and subsequent relapse of eosinophilic granulomatosis with polyangiitis. BM] Case Rep 2015:pii: bcr2015210373, 2015 Egerman RS, Ramsey D, Kao L W, et al: Hypertensive disease in pregnancies complicated by systemic lupus erythematosus. Am ] Obstet Gynecol 193:1676,s2005

Empson M, Lassere M, Craig], et al: Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev 2:CD002859, 2005

Engel NM, Gramke HF, Peeters L, et al: Combined spinal-epidural anaesthesia for a woman with Wegener's granulomatosis with subglottic stenosis. Int J Obstet Anesth 20(1):94, 2011

Ernest JM, Marshburn PB, Kutteh H: Obstetric antiphospholipid syndrome: an update on pathophysiology and management. Semin Reprod Med 29:522,t2011

Esaka E], Golde SH, Stever MR, et al: A maternal and perinatal mortality in pregnancy complicated by the kyphoscoliotic form of Ehlers-Danlos syndrome. Obstet GynecoItI13(2):515, 2009

Farr SL, Folger SG, Paul en ME, et al: Safety of contraceptive methods for women with rheumatoid arthritis: a systematic review. Contraception 82(1):64,t2010

Fischer-Betz R, Specker C, Brinks R, et al: Low risk of renal lares and negative outcomes in women with lupus nephritis conceiving after switching from mycophenolate mofetil to azathioprine. Rheumatology (Oxford) 52(6):1070, 2013

Forger F, Marcoli N, Gadola S, et al: Pregnancy induces numerical and functional changes of CD4+CD25 high regulatory T cells in patients with rheumatoid arthritis. Ann Rheum Dis 67(7):984,t2008

Gayed M, Gordon C: Pregnancy and rheumatic diseases. Rheumatology 46: 1634, 2007

Giannakopoulos B, Krilis SA: The pathogenesis of the anti phospholipid syndrome. N Englt] Med 368:1033, 2013

Goodman R, Dellaripa PF, Miller AL, et al: An unusual case of abdominal pain. N Engl J Med 370:70, 2014

Gotestam Skorpen C, Hoeltzenbein M, Tincani A, et al: he EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis 5(5):795,t2016

Gudbrandsson B, Wallenius M, Garen T, et l: Takayasu arteritis and pregnancy-a population based study on outcome and mother-child related concerns. Arthritis Care Res (Hoboken) 69(9):1384, 2017

Gungor AN, Kalkan G, Oguz S, et al: Beh:et disease and pregnancy. Clin Exp Obstet GynecoIt41(6):617, 2014

Guthrie A, Dugowson CE, Voigt LF, et l:Does pregnancy provide vaccine-like protection against rheumatoid arthritis? Arthritis Rheum 62(7): 1842, 2010

Hadar E, Zafrir-Danieli H, Blickstein 0, et al: Antiphospholipid antibodies characteristics and adverse pregnancy outcomes. Abstract No. 748, Am J Obstet GynecoIt216:S434, 201

Haddow JE, Rote NS, Dostaljohnson D, et al: Lack of an association between late fetal death and antiphospholipid antibody measurements in the 2nd trimester. Am] Obstet GynecoIt165:1308, 1991

Hahn BH: Systemic lupus erythematosus. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles ofInternal Medicine, 19th ed. New York, McGraw-Hill,t2015

Hamed HO, Ahmed SR, Alzolibani A, et al: Does cutaneous lupus erythematosus have more favorable pregnancy outcomes than systemic disease? A two-center study. Acta Obstet Gynecol Scand 92(8):934,t2013

Hanly JG, Gladman DD, Rose TH, et al: Lupus pregnancy: a prospective study of placental changes. Arthritis Rheum 31 :358, 1988

Harris EN, Spinnato JA: Should anticardiolipin tests be performed in otherwise healthy pregnant women? Am] Obstet Gynecol 165: 2, 1991

Haupl T, 0stensen M, Griitzkau A, et al: Interaction between rheumatoid arthritis and pregnancy: correlation of molecular data with clinical disease activity measures. Rheumatology (Oxford) 47(Suppll): 19, 2008a

Haupl T, 0stensen M, Griitzkau A, et al: Reactivation of rheumatoid arthritis after pregnancy: increased phagocyte and recurring lymphocyte gene activity. Arthritis Rheum 58(10):2981, 2008b

Hochberg MC: Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725,t1997

Holers VM, Girardi G, Mo L, et al: Complement C3 activation is required for antiphospholipid antibody-induced fetal loss. J Exp Med 195:211, 2002

Hot A, Perard L, Coppere B, et al: Marked improvement of Churg-Strauss vasculitis with intravenous gamma globulins during pregnancy. Clin Rheumatol 26(12):2149, 2007

Hoxha A, Calligaro A, Di Poi E, et al: Pregnancy and foetal outcomes following anti-tumor-necrosis factor alpha therapy: a prospective multicentre study. Joint Bone Spine 84(2):169, 2017

Hurst BS, Lange SS, Kullstam SM, et al: Obstetric and gynecologic challenges in women with Ehlers-Danlos syndrome. Obstet Gynecol 123(3):506, 2014

Imbasciati E, Tincani A, Gregorini G, et al: Pregnancy in women with preexisting lupus nephritis: predictors of fetal and maternal outcome. Nephrol Dial Transplant 24(2):519, 2009

Ince-Askan H, Hazes JM, Dolhain R]: IdentiYing clinical factors associated with low disease activity and remission of rheumatoid arthritis during pregnancy. Arthritis Care Res 69(9): 1297, 2017

Iwasawa Y, Kawana K, Fujii T, et al: A possible coagulation-independent mechanism for pregnancy loss involving beta(2) glycoprotein I-dependent antiphospholipid antibodies and COld. Am] Reprod Immunol 67(1):54, 2012

Izmirly PM, Costedoat-Chalumeau N, Pisoni CN, et al: Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-SSN Ro-antibody-associated cardiac manifestations of neonatal lupus. Circulation 126(1):76,t2012

Izmirly PM, Saxena AM, Kim MY, et al: Maternal and fetal factors associated with mortality and morbidity in a multi-racial/ethnic registry of anti-SSN Ro-associated cardiac neonatal lupus. Circulation 124: 1927, 2011

Jennette JC, Falk Rj, Bacon PA, et al: 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 65(1):1,t2013

Jimenez SA, Arden CM: Microchimerism and systemic sclerosis. Curr Opin Rheumatol 17:86,t2005

Johnston SL, Lock RJ, Gompels Mvf: Takayasu arteritis: a review. ] Clin Pathol 55:481, 2002

Joven BE, Almodovar R, Carmona L, et al: Survival, causes of death, and risk factors associated with mortality in Spanish systemic sclerosis patients: results from a single university hospital. Semin Arthritis heum 39(4):285, 20t10

Julkunen H, Kurki P, Kaaja R, et al: Isolated congenital heart block. Long-term outcome of mothers and characterization of the immune response to SS-AI Ro and to SS-B/La. Arthritis Rheum 36(11):1588, 1993

Keeling SO, Oswald AE: Pregnancy and rheumatic disease: "By the book" or "by the doc." Clin RheumatoIt28(1):1, 2009

Khamashta MA, Ruiz-Irastorza G, Hughes GR: Systemic lupus erythematosus lares during pregnancy. heum Dis Clin North Am 23:15, 1997

Kitwan JR, The Arthritis and Rheumatism Council Low-Dose Glucocorticoid Study Group: The efect of glucocorticoids on joint destruction in rheumatoid arthritis. N Englt] Med 333(3):142,t1995

Koukoura 0, Mantas N, Linardakis H, et al: Successful term pregnancy in a patient with Wegener's granulomatosis: case report and literature review. Ferril Steril 89:457.el, 2008

Kozora E, Arciniegas DB, Filley CM, et al: Cognitive and neurologic status in patients with systemic lupus erythematosus without major neuropsychiatric syndromes. Arthritis Rheum 59: 1639, 2008

Kuriya B, Hernandez-Dfaz S, Liu J, et al: Patterns of medication use during pregnancy in rheumatoid arthritis. Arthritis Care Res (Hoboken) 63(5):721, 2011

Kurka], Besenyei T, Laki], et al: Genetics of rheumatoid arthritis-a comprehensive review. Clin Rev Allergy ImmunoI45(2):170, 2013

Kwak-Kim J, Agcaoili MSL, Aleta L, et al: Management of women with recurrent pregnancy losses and anti phospholipid antibody syndrome. Am J Reprod Immunol 69(6):596, 2013

Lambe M, Bjornadal L, Neregard P, et al: Childbearing and the risk of scleroderma: a population-based study in Sweden. Am J Epidemiol 159: 162, 2004 Lambert NC: Microchimerism in scleroderma: ten years later. Rev Med Interne 31(7):523,t2010

Langford CA, Fauci AS: he vasculitis syndromes. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill, 20t15

Lateef A, Petri M: Management of pregnancy in systemic lupus erythematosus.

10,t2012

Laurinaviciene R, Sandholt LH, Bygum A: Drug-induced cutaneous lupus erythematosus: 88 new cases. Eur J Dermatol 27(1):28, 2017

Lazzaroni MG, Dall'Ara F, Fredi M, et al: A comprehensive review of the clinical approach to pregnancy and systemic lupus elythematosus. J Autoimmun 74:106,t2016

Lee ES, Bou-Gharios G, Seppanen E, et al: Fetal stem cell microchimerism: natural-born healers or killers? Mol Hum Reprod 16(11):869,t2010

Lefkou E, Mamopoulos A, Dagklis T, et al: Pravastatin improves pregnancy outcomes in obstetric antiphospholipid syndrome refractory to antithrombotic therapy.t] Clin Invest 126(8):2933, 2016

Linardaki G, Cherouvim E, Goni G, et al: Intravenous immunoglobulin treatment for pregnancy-associated dermatomyositis. Rheumatol Int 31(1):113, 201t1

Liu L, Xiao ], Zhu F: Anti-beta2 glycoprotein I antibodies and pregnancy outcome in antiphospholipid syndrome. Acta Obstet Gynecol Scand 92(2):234,t2013

Lockshin M, Sammaritano L: Lupus pregnancy. Autoimmunity 36:33, 2003 Lockshin MD: Pregnancy does not cause systemic lupus erythematosus to worsen. Arthritis Rheum 32:665, 1989

Lockshin MD, Bonfa E, Elkon K, et al: Neonatal lupus risk to newborns of mothers with systemic lupus erythematosus. Arthritis Rheum 31 :69 , 1988 Lockshin MD, Druzin ML: Rheumatic disease. In Barron WM, Lindheimer JD (eds): Medical Disorders During Pregnancy, 2nd ed. St. Louis, Mosby, 1995

Lockshin MD, Sammaritano LR: Rheumatic disease. In Barron WM, Lindheimer MD (eds): Medical Disorders During Pregnancy, 3rd ed. St. Louis, Mosby, 2000

Lockwood CJ, Romero R, Feinberg RF, et al: The prevalence and biologic signiicance of lupus anticoagulant and anticardiolipin antibodies in a general obstetric population. Am J Obstet Gynecol 161 :369, 1989

Madazli R, Yuksel MA, Oncul M, et al: Obstetric outcomes and prognostic factors of lupus pregnancies. Arch Gynecol Obstet 289:49, 2014

Makol A, Wright K, Amin S: Rheumatoid arthritis and pregnancy: safety considerations in pharmacological management. Drugs 71(1t5):1973,t20t11

McInnes IB, Scherr G: The pathogenesis of rheumatoid arthritis. N Engl J Med 365(23):2205,t2011

Meier FM, Frommer W, Dinser R, et al: Update on the proile of the EUSTAR cohort: an analysis of the EULAR Scleroderma Trials and Research group database. Ann Rheum Dis 71(8):1355,t2012

Mekinian A, Bourrienne Me, Carbillon L, et al: Non-conventional antiphos pholipid antibodies in patients with clinical obstetrical APS: prevalence and treatment eicacy in pregnancies. Semin Arthritis Rheum 46(2):232, 2016 Mekinian A, Lazzaroni MG, Kuzenko A, et al: The eicacy of hydroxychloroquine for obstetrical outcome in anti-phospholipid syndrome: data from a European multicenter retrospective study. Autoimmun Rev 14(6):498, 2015 Meroni PL, Borghi MO, Raschi E, et al: Pathogenesis of anti phospholipid syn drome: understanding the antibodies. Nat Rev Rheumatol 7(6):330, 201t1 Missumi LS, Souza FH, Andrade JQ, et al: Pregnancy outcomes in dermatomyositis and polymyositis patients. Rev Bras Reumatol 55(2):95, 2015

Miyakis S, Lockshin MD, Atsumi T, et al: International consensus statement on an update of the classiication criteria for deinite antiphospholipid syndrome (APS). J hromb Haemost 4:295, 2006

Mohamed MA, Goldman C, EI-Dib M, et al: Maternal juvenile rheumatoid arthritis may be associated with preterm birth but not poor fetal growth. J Perinatol 36(4):268, 2016

Moroni G, Doria A, Giglio E, et al: Fetal outcome and recommendations of pregnancies in lupus nephritis in the 21st centuly. A prospective multicenter study. J Autoimmun 74:6, 2016a

Moroni G, Doria A, Giglio E, et al: Maternal outcome in pregnant women with lupus nephritis. A prospective multicenter study. J Autoimmun 74:194,t2016b

Moroni G, Ponticelli e Pregnancy after lupus nephritis. Lupus 14:89,t2005 Moroni G, Quaglini S, Bani G, et al: Pregnancy in lupus nephritis. Am J Kidney Dis 40:713,t2002

Moroni G, Ventura D, Riva P, et al: Antiphospholipid antibodies are associated with an increased risk for chronic renal insuiciency in patients with lupus nephritis. Am J Kidney Dis 43:28, 2004

Morra M, Bofa MC, Tincani A, et al: Follow-up of babies born to mothers with anti phospholipid syndrome: preliminary data from the European neonatal registry. Lupus 21(7):761, 2012

Moutsopoulos HM, Vlachoyiannopoulos PG: Antiphospholipid syndrome In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hili, 2015

Munoz-Suano A, Kallikourdis M, Sarris M, e al: Regulatory T cells protect from autoimmune arthritis during pregnancy. J Autoimmun 38(2-3):J103, 2012 Musiej-Nowakowska E, Ploski R: Pregnancy and early onset pauciarticular juvenile chronic arthritis. Ann Rheum Dis 58:475, 1999 Nalli e, Iodice A, Andreoli L, et al: Long-term neurodevelopmental outcome of children born to prospectively followed pregnancies of women with systemic lupus erythematosus and/or antiphospholipid syndrome. Lupus 26:552,t2017 Nelson JL, Hughes A, Smith AG, et al: Maternal-fetal disparity in HLA class II alloantigens and the pregnancy-induced amelioration of rheumatoid arthritis. N Engl J Med 329:466, 1993

Nelson JL, 0stensen M: Pregnancy and rheumatoid arthritis. Rheum Dis C1in North Am 23:195,t1997

Nodler J, Moolamalla SR, Ledger EM, et al: Elevated antiphospholipid antibody titers and adverse pregnancy outcomes: analysis of a population-based hospital dataset. BMC Pregnancy Childbirth 9(1):11, 2009

Ojeda-Uribe M, AfifN, Dahan E, et al: Exposure to abatacept or rituximab in the irst trimester of pregnancy in three women with autoimmune diseases. Clin Rheumatol 32(5):695, 2013 Oshiro BT, Silver M, Scorr JR, et al: Antiphospholipid antibodies and fetal death. Obstet Gynecol 87:489, 1996 0stensen M: Pregnancy in patients with a history of juvenile rheumatoid arthritis. Arthritis Rheum 34:881, 1991 0stensen M, Villiger PM: he remission of rheumatoid arthritis during pregnancy. Semin Immunopathol 29:185, 2007 Owen J, Hauth Je Polyarteritis nodosa in pregnancy: a case report and brief literature review. Am J Obstet Gynecol 160:606, 1989

Pagnoux e Updates in ANCA-associated vasculitis. Eur J Rheumatol 3(3): 122, 2016

Pagnoux C, Le Guern V, Goinet F, et al: Pregnancies in systemic necrotizing vasculitides: report on 12 women and their 20 pregnancies. Rheumatology (Oxford) 50(5):953,t2011

Papadopoulos NG, A1amanos Y, Voulgari PV, et al: Does cigarerre smoking influence disease expression, activity and severity in early rheumatoid arthritis patients? Clin Exp Rheumatol 23(6):861, 2005

Parderr R, Roussou E: he treatment of rheumatoid arthritis during pregnancy.

Rheumatol Int 31(4):445,t2011

Patrono e Cardiovascular efects of nonsteroidal anti-inlammatory drugs.

Curr Cardiol Rep 18(3):25,t2016

Peart E, Clowse ME: Systemic lupus erythematosus and pregnancy outcomes: an update and review of the literature. Curr Opin Rheumatol 26(2): 118,2014

Pepin M, Schwarze U, Superti-Furga A, et al: Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med 342:673, 2000

Petri M: Pregnancy in SLE. Baillieres Clin Rheumatol 12:449, 1998

Petri M, Kim MY, Kalunian Ke, et al: Combined oral contraceptives in women with systemic lupus erythematosus. N Engl J Med 353:2550, 2005 Petri M, he Hopkins Lupus Pregnancy Center: Ten key issues in manage ment. Rheum Dis Clin North Am 33:227, 2007

Phansenee S, Sekararithi R, Jatavan P, et al: Pregnancy outcomes among women with systemic lupus erythematosus: a retrospective cohort study from Thailand. Lupus January 1, 2017 [Epub ahead of print]

Pierro E, Cirino G, Bucci MR, et al: Antiphospholipid antibodies inhibit prostaglandin release by decidual cells of early pregnancy: possible involvement of extracellular secretory phospholipase 2. Fertil Steril 71 :342, 1999

Pikwer M, Bergstrom U, Nilsson JA, et al: Breast feeding, but not use of oral contraceptives, is associated with a reduced risk of rheumatoid arthritis. Ann Rheum Dis 68(4):526, 2009

Pinal-Fernandez I, Selva-O'Callaghan A, Fernandez-Codina A, et al: Pregnancy in adult-onset idiopathic inlammatory myopathy: report from a cohort of myositis patients from a single center. Semin Arthritis Rheum 44(2):234, 2014

Prockop OJ, Bateman JF: Heritable disorders of connective tissue. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles ofInternal Medicine, 19th ed. New York, McGraw-Hili, 2015

Putterman C, Wu A, Reiner-Benaim A, et al: SLE-key rule-out serologic test for excluding the diagnosis of systemic lupus erythematosus: developing the ImmunArray iCHIP. J Immunol Methods 429:1,t2016

Rai RS, Cliford K, Cohen H, et al: High prospective fetal loss rate in untreated pregnancies of women with recurrent miscarriage and anti phospholipid antibodies. Hum Reprod 10:3301,t1995

Rak JM, Maesrroni L, Balandraud C, et al: Transfer of the shared epitope through microchimerism in women with rheumatoid arthritis. Arthritis Rheum 60(1):73, 2009a

RakJM, Pagni PP, Tiev K, et al: Male microchimerism and HLA compatibility in French women with scleroderma: a diferent proile in limited and difuse subset. Rheumatology 48(4):363, 2009b

Ramaeus K, Johansson K, Askling J, et al: Juvenile onset arthritis and pregnancy outcome: a population-based cohort study. Ann Rheum Dis 76: 1809, 2017

Rand JH, Wu X, Andree HA, et al: Antiphospholipid antibodies accelerate plasma coagulation by inhibiting annexin-V binding to phospholipids: a "lupus procoagulant" phenomenon. Blood 92:1652, 1998

Rand JH, Wu X, Andree HA, et al: Pregnancy loss in the anti phospholipid antibody syndrome-a possible thrombogenic mechanism. N Engl J Med 337: 154, 1997

Ritchie J, Smyth A, Tower C, et al: Maternal deaths in women with lupus nephritis: a review of published evidence. Lupus 21 (5):534, 2012 Robertson B, Greaves M: Antiphospholipid syndrome: an evolving stoty.

Blood Reviews 20:201, 2006

Robinson DP, Klein SL: Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis. Horm Behav 62(3):263, 2012

Rom AL, Wu CS, Olsen J, et al: Fetal growth and preterm birth in children exposed to maternal or paternal rheumatoid arthritis. A nationwide cohort study. Arthritis Rheumatol 66:3265, 2014

Roman MJ, Pugh NL, Hendershot TP, et al: Aortic complications associated with pregnancy in Marfan syndrome: the NHLBI National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC). J m Heart Assoc 5(8), 2016

Roque H, Paidas M, Funai E, et al: Maternal thrombophilias are not associated with early pregnancy loss. hromb Haemost 91t(2):290,t2004

Rosenzweig BA, Rotmensch S, Binette SP, et al: Primary idiopathic polymyositis and dermatomyositis complicating pregnancy: diagnosis and manageme1t. Obstet Gynecol Surv 44: 162, 1989

Rudd NL, Nimrod C, Holbrook A, et al: Pregnancy complications in type IV Ehlers-Danlos syndrome. Lancet 1(8314-5):50,t1983

Rufatti A, Tonello M, Visentin MS, et al: Risk factors for pregnancy failure in patients with anti-phospholipid syndrome treated with conventional therapies: a multicentre, case-control study. Rheumatology 50(9):1684, 2011

Ruiter-Ligeti J, Czuzoj-Shulman N, Spence AR, et al: Pregnancy outcomes in women with osteogenesis imperfecta: a retrospective cohort study. J PerinatoIt36(10):828,t2016

Saccone G, Maruotti GM, Berghella V, et al: Obstetric outcomes in pregnant women with primary anti phospholipid syndrome according to the antibody proile: the PREGNANTS study. Abstract No. 62, Am J Obstet Gynecol 21t6:S45,t20t17

Sammaritano LR: Contraception in patients with systemic lupus erythematosus and antiphospholipid syndrome. Lupus 23(12):1242, 2014

Sanchez-Guerrero J, Uribe AG, Jimenez-Santana L, et al: A trial of cotraceptive methods in women with systemic lupus erythematosus. N Engl J Med 353:2539, 2005

SchoenhofF, Schmidli J, Czerny M, et al: Management of aortic aneurysms in patients with connective tissue disease. J Cardiovasc Surg 54(1 suppl 1): 125, 2013

Schreiber K, Hunt BJ: Pregnancy and antiphospholipid syndrome. Semin Thromb Hemost 42(7):780,t2016

Sciascia S, Hunt BJ, Talavera-Garcia E, et al: The impact of hydroxychloroquine treatment on pregnancy outcome in women with anti phospholipid antibodies. Am J Obstet GynecoI214(2):273.e1, 2016

Shah A, St. Clair EW: Rheumatoid arthritis. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles ofInternal Medicine, 19th ed. New York, McGraw-Hill, 2015

Sharma BK, Jain S, Vasishta K: Outcome of pregnancy in Takayasu arteritis. Int J Cardiol 75:S159, 2000

Sherer Y, Gorstein A, Fritzler MJ, et al: Autoantibody explosion in systemic lupus erythematosus: more than 100 diferent antibodies found in SLE patients. Semin Arthritis Rheum 34(2):501,t2004

Shinohara K, Miyagawa S, Fujita T, et al: Neonatal lupus erythematosus: results of maternal corticosteroid therapy. Obstet Gynecol 93:952, 1999 Silman A, Kay A, Brennan P: Timing of pregnancy in relation to the onset of rheumatoid arthritis. Arthritis Rheum 35: 152, 1992

Silver M, Parker CB, Reddy UM, et al: Antiphospholipid antibodies in stillbirth. Obstet Gynecol 122(3):641,2013

Silverman E, Jaeggi E: Non-cardiac manifestations of neonatal lupus erythematosus. Scand J Immunol 72:223, 2010

Simchen MJ, Goldstein G, Lubetsky A, et al: Factor V Leiden and anti ph ospholipid antibodies in either mothers or infants increase the risk for perinatal arterial ischemic stroke. Stroke 40(1):65, 2009

Simpson JL: Cell-free fetal DNA and maternal serum analytes for monitoring embryonic and fetal status. Fertil Steril 99(4):1124, 2013

Singh JA, Saag KG, Bridges SL] r, et aI: 2015 American College of Rheumatology Guideline for the management of rheumatoid arthritis. Arthritis Care Res (Hoboken) 68(1):1, 2016

Singh N, Tyagi S, Tripathi R, et al: Maternal and fetal outcomes in pregnant women with Takayasu aortoarteritis: does optimally timed intervention in women with renal artery involvement improve pregnancy outcome? Taiwan ] Obstet Gynecol 54(5):597, 2015

Sitar G, Brambati B, Baldi M, et al: he use of non-physiological conditions to isolate fetal cells from maternal blood. Exp Cell Res 302: 153, 2005

Smok DA: Aortopathy in pregnancy. Semin Perinatol 38(5):295, 2014

Sneller MC: Wegener's granulomatosis.]AMA 273:1288, 1995

Sobanski V, Launay D, Depret S, et al: Special considerations in pregnant systemic sclerosis patients. Expert Rev Clin Immunol 12(11):1161, 2016

Solomons ], Coucke P, Symoens S, et al: Dermatosparaxis (Ehlers-Danlos type VIIC): prenatal diagnosis following a previous pregnancy with unexpected skull fractures at delivery. Am ] Med Genet A 161 (5): 1122, 2013

Spinillo A, Beneventi F, Epis OM, et al: he efect of newly diagnosed undif ferentiated connective tissue disease on pregnancy outcome. Am ] Obstet

GynecoIt199(6):632.e1,t2008

Spinillo A, Beneventi F, Locatelli E, et al: The impact of unrecognized autoimmune rheumatic diseases on the incidence of preeclampsia and fetal growth restriction: a longitudinal cohort study. BMC Pregnancy Childbirth 16(1):313,t2016

Srivatsa B, Srivatsa S, Johnson K, et al: Microchimerism of presumed fetal origin in thyroid specimens from women: a case-control study. Lancet 358:2034,t2001

Steen VD: Pregnancy in women with systemic sclerosis. Obstet Gynecol 94: 15, 1999

Steen VD, Conte C, Day N, et al: Pregnancy in women with systemic sclerosis.

Arthritis Rheum 32: 15t1, 1989

Stevens M. Maternal microchimerism in health and disease. Best Pract Res Clin Obstet GynecoIt31:121, 2016

Stojan G, Baer AN: Flares of systemic lupus erythematosus during pregnancy and the puerperium: prevention, diagnosis and management. Expert Rev Clin Immunol 8(5):439, 2012

Sukara G, Baresic M, Sen tic M, et al: Catastrophic antiphospholipid syndrome associated with systemic lupus erythematosus treated with rituximab: case report and a review of the literature. Acta Reumatol Port 40(2):169,t2015

Sundelin HE, Stephansson 0, Johansson K, et al: Pregnancy outcome in joint hypermobility syndrome and Ehlers-Danlos syndrome. Acta Obstet Gynecol Scand 96(1):1t14, 2017

Sykes B, Ogilvie D, Wordsworth P, et al: Consistent linkage of dominantly inherited osteogenesis imperfecta to the type I collagen loci: COLIAI and COUA2. Am] Hum Genet 46(2):293, 1990

T araborelli M, Ramoni V, Brucato A, et al: Brief report: successful pregnancies but a higher risk of preterm births in patients with systemic sclerosis: an Italian multicenter study. Arthritis Rheum 64(6):1970, 2012

Tayabali S, Andersen K, Yoong W: Diagnosis and management of HenochSch6nlein purpura in pregnancy: a review of the literature. Arch Gynecol Obstet 286(4):825,t2012

Tenti S, Cheleschi S, Guidelli GM, et al: Intravenous immunoglobulins and antiphospholipid syndrome: how, when and why? A review of the literature. Autoimmun Rev 15(3):226,t2016

Tincani A, Rebaioli CB, Andreoli L, et al: Neonatal efects of maternal anti phospholipid syndrome. Curr Rheumatol Rep 11 (1):70, 2009

Toglia MR, Weg ]G: Venous thromboembolism during pregnancy. N Englt] Med 335:108, 1996

Tower C, Mathen S, Crocker I, et al: Regulatory T cells in systemic lupus ery thematosus and pregnancy. Am J Reprod Immunol 69(6):588, 2013 Tsokos GC: Systemic lupus erythematosus. N Engl] Med 365(22):21t10, 2011 Unger A, Kay A, Griin A], et al: Disease activity and pregnancy associated beta2-glycoprotein in rheumatoid arthritis. BM] 286:750, 1983

Van Dijk FS, Pals G, Van Rijn RR, et al: Classification of osteogenesis imperfecta revisited. Eur] Med Genet 53(1):1, 2010

Varga]: Systemic sclerosis (scleroderma) and related disorders. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles ofInternal Medicine, 19th ed. New York, McGraw-Hill, 2015

Varner MW, Meehan RT, Syrop CH, et al: Pregnancy in patients with systemic lupus erythematosus. Amt] Obstet Gynecol 145:1025, 1983

Volkov N, Nisenblat V, Ohel G, et al: Ehlers-Danlos syndrome: insight on obstetric aspects. Obstet Gynecol Surv 62:51, 2006

Wagner S, Craici I, Reed 0, et al: Maternal and foetal outcomes in pregnant patients with active lupus nephritis. Lupus 18(4)342, 2009

Waldorf M, Nelson ]L: Autoimmune disease during pregnancy and the microchimerism legacy of pregnancy. Immunol Invest 37:63t1,t2008

Wallenius M, Salvesen A, Daltveit AK, et al: Rheumatoid arthritis and outcomes in first and subsequent births based on data from a national birth registry. Acta Obstet Gynecol Scand 93(3):302, 2014

Wei S, Lai K, Yang Z, et al: Systemic lupus erythematosus and risk of preterm birth: a systematic review and meta-analysis of observational studies. Lupus 26: 563, 2017

Wong LF, Porter TF, Scott ]R: Immunotherapy for recurrent miscarriage.

Cochrane Database Syst Rev 1 O:CDOOO 112, 2014

Wu H, Birmingham OJ, Rovin B, et al: D-dimer level and the risk for thrombosis in systemic lupus erythematosus. Clint] Am Soc Nephrol 3:1628, 2008

Yang H, Liu H, Xu D, et al: Pregnancy-related systemic lupus erythematosus: clinical features, outcome and risk factors of disease flares-a case control study. PLoS One 9(8):el04375, 2014

Yang W, Tang H, Zhang Y, et al: Meta-analysis followed by replication identiies loci in or near CDKNIB, TET3, CD80, DRAMl, and ARID5B as associated with systemic lupus erythematosus in Asians. Am ] Hum Genet 92(1):41,t2013

Yasuda M, Takakuwa K, Tokunaga A, et al: Prospective studies of the association between anticardiolipin antibody and outcome of pregnancy. Obstet Gynecol 86:555, 1995

Ye Y, van Zyl B, Varsani H, et al: Maternal microchimerism in muscle biopsies from children with juvenile dermatomyositis. Rheumatology (Oxford) 51(6):987,t2012

Zangari M, Lockwood CJ, Scher J, et al: Prothrombin activation fragment (F1.2) is increased in pregnant patients with antiphospholipid antibodies. Thromb Res 85:177, 1997

Zhao C, Zhao J, Huang Y, et al: New-onset systemic lupus erythematosus during pregnancy. Clin Rheumatol 32(6):815, 2013

Zuppa A, Riccardi R, Frezza A, et al: Neonatal lupus: follow-up in infants with anti SSA/Ro antibodies and review of the literature. Autoimmun Rev ,2017

CENTRAL NERVOUS SYSTEM IMAGING.. . . . . . . . . . .. 1156

HEADACHE ................................... 1157

SEIZURE DISORDERS.. . . . . . . . . . . . . . . . . . . . . . . . . .. 1158 CEREBROVASCULAR DISEASES . . . . . . . . . . . . . . . . .. 1160

DEMYELINATING OR DEGENERATIVE DISEASES ..... 1164

NEUROPATHIES ............................... 1166

SPINAL CORD INJURY.. . . . . . . . . . . . . . . . . . . . . . . . .. 1167

IDIOPATHIC INTRACRANIAL HYPERTENSION ....... 1168

MATERNAL VENTRICULAR SHUNTS ............... 1168

MATERNAL BRAIN DEATH ....................... 1168

Epilepsy appears to have no fect on pregnancy, though at the time of labour it may be mistaken or eclampsia by inexperienced observers. f the attacks are requent the patient should be put upon large doses of potassium bromide and treated just as at other times.

-J. Whitridge Williams (1903)

Although several neurological diseases are relatively common in women of childbearing age, less than two pages were devoted to Diseases of the Nervous System in this textbook's first edition. In the past, some may have precluded pregnancy, however, few do so now. Most encountered during pregnancy are the same as for nonpregnant women, however a few neurological disorders may be seen more frequently in pregnant women. Examples are Bell palsy, specific types of strokes, and benign intracranial hypertension or pseudotumor cerebri. Neurovascular disorders are an important cause of maternal mortality and accounted for nearly 7 percent of maternal deaths in the United States from 2011 through 2013 (Creanga, 2017).

Many neurological disorders frequently precede pregnancy. fost women with chronic neurological disease who become pregnant will have successful outcomes, but some disorders have speciic risks. Conversely, other women will have newonset neurological symptoms during pregnancy, and these often must be distinguished from pregnancy complications. Psychiatric disorders can also manifest with cognitive and neuromuscular abnormalities and should be considered in the evaluation.

Computed tomography (CT) and magnetic resonance (MR) imaging assist in the diagnosis, classification, and management of many neurological and psychiatric disorders. As discussed in Chapter 46 (p. 907), these imaging methods can be used safely during pregnancy. CT scanning is often used when rapid diagnosis is necessary and is excellent for detecting recent hemorrhage. Because it does not use radiation, MR imaging is oten preferred and is particularly helpful to diagnose demyelinating diseases, arteriovenous malformations, congenital and developmental nervous system abnormalities, posterior fossa lesions, and spinal cord diseases. Whenever either test is done, the woman with advanced pregnancy should be positioned in a left lateral tilt with a wedge under one hip to prevent hypotension and to diminish aortic pulsations, which may degrade the image.

Cerebral angiography with contrast injection, usually via the femoral artery, is a valuable adjunct to the diagnosis and treatment of some cerebrovascular diseases. Fluoroscopy delivers more radiation but can be performed with abdominal shielding. Positron emission tomography (PET) and functional MR imaging (fMI) have not been evaluated for use in pregnant patients (Chiapparini, 2010).

In one national survey in the United States in 2012, 17 percent ofthose aged 18 to 44 years reported a severe headache or migraine within the past 3 months (Blackwell, 2014). Burch and coworkers (2015) reported that 24 percent ofnonpregnant women in this age group were similarly afected. Of pregnant women presenting with headache who received a neurological consultation, two thirds were due to primary disorders, with over 90 percent due to migraine. Of the other third due to secondary conditions, over half were due to hypertensive disorders (Robbins, 2015). Interestingly, Aegidius and associates (2009) reported a decline in the rate of all headache types during pregnancy in nulliparas, especially during the third trimester.

The classification by the International Headache Society (20l3) is shown in Table

In pregnant women, primary headaches are more common than those stemming from secondary causes (Digre, 2013; Sperling, 2015). Migraine headaches are those most likely to be afected by the hormonal changes of pregnancy (Pavlovic, 2017). The incidences ofsevere headache causes in pregnancy are shown in Figure 60-1 .

These are the most frequent cause of all headaches. Characteristic features include muscle tightness and mild-to-moderate pain in the back ofthe neck and head that can persist for hours. Neurological disturbances or nausea are typically absent. The pain usually responds to rest, massage, application of heat or ice, antiinlammatory medications, or mild tranquilizers. Hospital admission is seldom necessary.

The term migraine describes a periodic, sometimes incapacitating neurological disorder with episodic attacks ofsevere headache and autonomic nervous system dysfunction (Goadsby, 2015). The International Headache Society (20l3) classifies

TABLE 60-1. Headache Classification

Disorders of homeostasis

Data from International Headache Society, 2013.

Pituitary, 3.6%

Infection, 2.1% Stroke, 2.8% Other headache, 6% (tension 3%) Migraine, 59% With aura, 37% Without aura, 24••• Chronic, 6%

FIGURE 60-1 Incidences of headache causes in 140 consecutive pregnant women for whom in-hospital neurology consultation was requested. (Data from Robbins, 201o5.) three migraine types based on chronicity and on the presence or absence ofan aura.

1.

Migrainewithoutaura-formerlytermedcommon migraineis characterized by a unilateral throbbing headache, nausea and vomiting, or photophobia.

2.

Migraine with aura-formerly termed classic migraine-has similar symptoms preceded by premonitory neurological phenomena such as visual scotoma or hallucinations. A third of patients have this type of migraine, which sometimes can be averted ifmedication is taken at the first premonitory sign.

3.

Chronic migraine is defined by a migraine headache occurring at least 15 days each month for more than 3 months.

These are the most common reason for admission for headache evaluation and management. Migraines may begin in childhood, peak in adolescence, and tend to diminish in both frequency and severity with advancing years. According to Lipton and associates (2007), their annual prevalence is 17 percent in women and 6 percent in men. Another 5 percent ofwomen have probable migraine, that is, they have all criteria but one (Silberstein, 2007). Speciic polymorphisms have been identified that modulate the risk of migraines (Chen, 2015; Schiirks, 2010). hese headaches are especially common in young women and have been linked to hormone levels (Charles, 2017; Pavlovic, 2017). They are frequently encountered during pregnancy.

Sensory sensitivity with migraines is likely caused by monoaminergic sensory control systems in the brainstem and hypothalamus (Goadsby, 2015). his exact pathophysiology is uncertain, but they occur when neuronal dysfunction leads to decreased cortical blood How, activation ofvascular and meningeal nociceptors, and stimulation oftrigeminal sensory neurons (Brandes, 2007; D'Andrea, 2010). A predilection for the posterior circulation has been described (Kruit, 2004). Migrainesespecially those with aura in young women-are associated with increased risk for ischemic strokes. The risk is greater in those who smoke or use combination oral contraceptives.

The prevalence of migraine headaches in the first trimester is 2 percent (Chen, 1994). Most migraineurs have improvement during pregnancy (Kvisvik, 2011). Still, migraines-usually those with an aura-occasionally appear for the first time during pregnancy. Pregnant women with preexisting migraine symptoms may have other symptoms suggestive of a more serious disorder, and new neurological symptoms should prompt a complete evaluation (Detsky, 2006; Heaney, 2010).

Although conventional thinking has been that migraine headaches do not pose increased maternal or fetal risks, several recent studies have refuted this (Allais, 2010). In these, rates of preeclampsia, gestational hypertension, preterm birth, and other cardiovascular morbidities, including ischemic stroke, were increased (Grossman, 2017; Wabnitz, 2015). Bushnell and coworkers (2009) identiied an incidence of migraines during pregnancy of 185 per 100,000 deliveries. Of diagnoses associated in these gravid migraineurs, risks were signiicantly higher for stroke, 16-fold; myocardial infarction, ivefold; heart disease, twofold; venous thromboembolism, twofold; and preeclampsia/gestational hypertension, twofold.

Data are limited regarding non pharmacological management in pregnancy such as biofeedback techniques, acupuncture, and transcranial magnetic stimulation (Airola, 2010; Dodick, 2010). Efective medications include nonsteroidal antiinlammatory drugs (NSAIDs), and most migraine headaches respond to simple analgesics such as ibuprofen, acetaminophen, or Midrin, especially if given early.

Severe migraines are vexing for the patient and her caregivers. Multitargeted drug therapy is necessary in most cases for migraine relief (Gonzalez-Hernandez, 2014). Headaches are treated aggressively with intravenous hydration and parenteral antiemetics and opioids for immediate pain relie. Although a 2-g infusion of magnesium sulfate has gained favor in the past few years, a metaanalysis reported no beneits (Choi, 2014). Ergotamine derivatives are potent vasoconstrictors and are avoided in pregnancy because of their uterotonic efects (Briggs, 2015).

Triptans are serotonin 5-HT I Bl20-receptor agonists that efectively relieve headaches by causing intracranial vasoconstriction (Contag, 2010). They also relieve nausea and vomiting and greatly reduce the need for analgesics. Triptans can be given as an oral tablet, injection, rectal suppository, or intranasal spray. hey are best used in combination with NSAIDs (Goadsby, 2015). The greatest experience is with sumatriptan (Imitrex), and although not studied extensively in pregnancy, it appears to be safe (Briggs, 2015; Nezvalova-Henriksen, 2010). However, in one follow-up study at 36 months of children exposed to triptans in pregnancy, Wood and colleagues (2016) found neurodevelopment diferences, including emotionality and activity problems.

Some women will beneit from peripheral nerve blocks, and Govindappagari and coworkers (2014) described their experiences with 13 pregnant women. For women with frequent migraine headaches, oral prophylactic therapy is warranted. Amitriptyline (Elavil), 10 to 175 mg daily; propranolol (Inderal), 40 to 120 mg daily; or metoprolol (Lopressor, Toprol), 25 to 100 mg daily, have been used with success (Contag, 2010; Goadsby, 2015; Lucas, 2009).

This rare primary headache disorder is characterized by severe unilateral lancinating pain radiating to the face and orbit, lasting 15 to 180 minutes, and occurring with autonomic symptoms and agitation. Pregnancy does not afect symptom severity. Afected women should avoid tobacco and lcohol. Acute mnagement includes 100-percent oxygen therapy and sumatriptan given as a 6-mg dose subcutaneously (VanderPluym, 2016). If recurrent, prophylaxis is administered using a calcium-channel blocking agent.

The Centers for Disease Control and Prevention reported that the prevalence of epilepsy in adults in 2005 was 1.65 percentthus over 1 million American women of childbearing age are afected (Kobau, 2008). After headaches, seizures are the next most prevalent neurological condition encountered in pregnancy, and they complicate 1 in 200 births (Brodie, 1996; Yerby, 1994). Importantly, epilepsy accounted for 5 percent of maternal deaths in the United Kingdom for the 2011 to 2013 triennium (Knight, 2015).

A seizure is deined as a paroxysmal disorder of the central nervous system characterized by an abnormal neuronal discharge with or without loss of consciousness. Some identiiable causes of convulsive disorders in young adults include head trauma, alcohol-and other drug-induced withdrawals, cerebral infections, brain tumors, biochemical abnormalities, and arteriovenous malformations. A search for these is prudent with a new-onset seizure disorder in a pregnant woman. he diagnosis of idiopathic epilepsy is one of exclusion.

Epilepsy encompasses diferent syndromes whose cardinal feature is a predisposition to recurrent unprovoked seizures. he International League Against Epilepsy Commission on Classiication and Terminology recently updated the following deinitions (Fisher, 2014).

These originate in one localized brain area and afect a correspondingly localized area of neurological unction. They are believed to result from trauma, abscess, tumor, or perinatal factors, although a speciic lesion is rarely demonstrated. Focal seizures without dyscognitive eatures start in one region of the body and progress toward other ipsilateral areas of the body, producing tonic and then clonic movements. Simple seizures can afect sensory unction or produce autonomic dysfunction or psychological changes. Cognitive function is not impaired, and recovery is rapid. Focal seizures with dyscognitive eatures are oten preceded by an aura and followed by impaired awareness manifested by sudden behavioral arrest or motionless stare. Involuntary movements such as picking motions or lip smacking are common.

These involve both brain hemispheres and may be preceded by an aura before an abrupt loss of consciousness. There is a strong hereditary component. In generalized tonic-clonic seizures, loss of consciousness is followed by tonic contraction of the muscles and rigid posturing, and then by clonic contractions of all extremities while the muscles gradually relax. Return to consciousness is gradual, and the patient may remain confused and disoriented for several hours. Absence seizures-also called petit mal seizures-are a form of generalized epilepsy that involve a brief loss of consciousness without muscle activity and are characterized by immediate recovery of consciousness and orientation.

Women with epilepsy ideally are counseled before pregnancy and relevant points are presented also in Chapter 8 (p. 148). Folic acid supplementation with 0.4 mg per day is begun at least 1 month before conception. The dose is increased to 4 mg when the woman taking antiepileptic medication becomes pregnant. hese medications are assessed and adjusted with a goal of mono therapy using the least teratogenic medication. If this is not feasible, then attempts are made to reduce the number of medications used and to use them at the lowest efective dose (Patel, 2016). Medication withdrawal should be considered if a woman is seizure free for 2 years or more.

The major pregnancy-related risks to women with epilepsy are fetal malformations and increased seizure rates. Seizure control is the main priority to avoid its attendant morbidity and mortality risks. Early studies described worsening seizure activity during pregnancy, however, this is less so now because of more efective drugs. Contemporary studies cite higher rates of seizure activity in only 20 to 30 percent of pregnant women (Mawer, 2010; Vajda, 2008). Women who are seizure free for at least 9 months before conception will likely remain so during pregnancy (Harden, 2009b).

Greater seizure frequency is often associated with decreased and thus subtherapeutic anticonvulsant serum levels, a lower seizure threshold, or both. An impressive number of pregnancyassociated alterations can result in sub therapeutic serum levels. These include nausea and vomiting, slower gastrointestinal motility, antacid use that diminishes drug absorption, pregnancy hypervolemia ofset by protein binding, induction of hepatic enzymes such as cytochrome oxidases, placental enzymes that metabolize drugs, and increased glomerular iltration that hastens drug clearance. Importantly, some women discontinue medication because of teratogenicity concerns. Finally, the seizure threshold can be afected by pregnancyrelated sleep deprivation and by hyperventilation and pain during labor.

Women with epilepsy have a small increased risk of pregnancy complications that include spontaneous abortion, hemorrhage, hypertensive disorders, preterm birth, fetal-growth restriction, and cesarean delivery (Harden, 2009b; Viale, 2015). Importantly, MacDonald (2015) also reports a tenfold higher maternal death rate, and, as mentioned earlier, epilepsy accounted for 5 percent of maternal deaths in the United Kingdom.

Postpartum depression rates are also reportedly higher in epileptic women (Turner, 2009). Finally, children of epileptic mothers have a 10-percent risk of developing a seizure disorder.

For years, it was diicult to separate efects of epilepsy from those of its therapy as the primary cause of fetal malforma tions. As discussed in Chapter 8 (p. 148), it is now believed that untreated epilepsy is not associated with an elevated fetal malformation rate (Thomas, 2008). That said, the fetus of an has an indisputably greater risk for congenital malformations.

Moreover, mono therapy is associated with a lower birth defect rate compared with multiagent therapy. hus, if necessary, increasing monotherapy dosage is at least initially preferable to adding another agent (Buhimschi, 2009).

Specific drugs, when given alone, increase the malformation rate (Chap. 12, p. 240). Some of these are listed in Table 60-2.

Phenytoin and phenobarbital increase the major malformation rate two-to threefold above baseline (Perucca, 2005; Thomas, 2008). Valproate is a particularly potent teratogen, which has a dose-dependent efect and raises the malformation risk four-to eightfold (Eadie, 2008; lein, 2014; Wyszynski, 2005). Val proate is also associated with lower cognitive performance (Kas radze, 2017). In general, with poly therapy, the risk rises with each drug added. A metaanalysis of 31 studies found lamotrig ine and levetiracetam to carry the lowest risk of malformations (Weston, 2016).

The American Academy of Neurology and the American Epilepsy Society have guidelines regarding treatment in pregnant women (Harden, 2009a-c). The major goal is seizure prevention. To accomplish this, treatment for nausea and vomiting is provided, seizure-provoking stimuli are avoided, and medication compliance is emphasized. The fewest necessary anticonvulsants are given at the lowest dosage efective for seizure control. Although some providers routinely monitor serum drug levels, these concentrations may be unreliable because of altered protein binding. Free or unbound drug levels, although perhaps more accurate, are not widely available. Importantly, there is no evidence that such monitoring improves seizure control (Adab, 2006). For these reasons, drug levels may be most informative if measured following seizures or if noncompliance is suspected.

For women taking anticonvulsant drugs, a targeted so nographic examination at midpregnancy is recommended by some to search for anomalies. Testing to assess fetal well-being is generally not indicated for women with uncomplicated epilepsy.

For women desiring to breastfeed, data regarding the safety of the various anticonvulsant medications are limited. That said, no obvious deleterious efects, such as long-term cognitive issues, have been reported (Briggs, 2015; Harden, 2009c). Of birth control methods, oral contraceptive pill failure rates are higher with some of the anticonvulsant agents, especially lamotrigine. Thus, other more reliable methods should be considered (Chap. 38, p. 680).

TABLE 60-2. Teratogenic Effects of Common Anticonvulsant Medications

Neural-tube defects, clefts, cardiac anomalies; associated developmental delay

Fetal hydantoin syndrome-craniofacial anomalies, fingernail hypoplasia, growth deficiency, developmental delay, cardiac anomalies, clefts

Fetal hydantoin syndrome, as above; spina bifida

Clefts, cardiac anomalies, urinary tract malformations aRisk categories from Briggs, 2015; Food and Drug Administration, 2011; Harden, 2009b; Holmes, 2008; Hunt, 2008.

Abnormalities of the cerebrovascular circulation include strokes-both ischemic and hemorrhagic, as well as anatomical anomalies, such as arteriovenous malformations and aneurysms. Cerebral ischemia is caused by reduction in blood low that lasts longer than several seconds. Early, neurological symptoms may manifest. Ater a few minutes, however, infarction often follows. Hemorrhagic stroke is caused by bleeding directly into or around the brain. It produces symptoms by its mass efect, by toxic efects of blood, or by increasing intracranial pressure. Of strokes in pregnant women, roughly half are ischemic and the other half hemorrhagic (Zofkie, 2018).

he current obesity endemic in this country, along with concomitant increases in rates of heart disease, hypertension, and diabetes, has increased the prevalence of strokes (Centers for Disease Control and Prevention, 2012). Women have higher lifetime risk of stroke than men and greater associated mortality rates (Martinez-Sanchez, 2011; Roger, 2012). Moreover, pregnancy increases the immediate and lifetime risk of both ischemic and hemorrhagic stroke (Jamieson, 2010; lung, 2010).

Stroke is relatively uncommon in pregnant women, occurring in 10 to 40 per 100,000 births, but it contributes disparately to maternal mortality rates (Lefert, 2016; Miller, 20 16; Yoshida, 2017). he incidence is rising as measured by pregnancy-related hospitalizations for stroke (Callaghan, 2008; Kukiina, 2011). Importantly, most are associated with hypertensive disorders or heart disease. Of the pregnancy-related mortality rate in the United States, 6.6 percent is due to cerebrovascular accidents, and 7.4 percent is associated with preeclampsia (Creanga, 2017). Of maternal deaths after 42 days postpartum, 9.8 percent were attributable to cerebrovascular accidents.

Most strokes in pregnancy manifest either during labor and delivery or in the puerperium. In a study of 2850 pregnancyrelated strokes, approximately 10 percent developed antepartum, 40 percent intrapartum, and almost 50 percent postpartum (James, 2005). In contrast, Lefert (2016) reports a timing of 45 percent antepartum, 3 percent intrapartum, and 53 percent postpartum in 145 women. Several risk factorsunrelated and related to pregnancy-have been reported from studies that included more than 10 million pregnancies. These include age; migraines, hypertension, obesity, and diabetes; cardiac disorders such as endocarditis, valvular prostheses, and patent foramen ovale; and smoking. hose related to pregnancy include hypertensive disorders, gestational diabetes, obstetrical hemorrhage, and cesarean delivery. By ar, the most common risk actors are pregnancy-associated hypertensive disorders. A third of strokes are associated with gestational hypertension, and hypertensive women compared with normotensive counterparts have a three-to eightfold greater risk of stroke (Scott, 2012; Wang, 2011). Women with preeclampsia undergoing general anesthesia may be at higher risk of stroke compared with those given neuraxial anesthesia (Huang, 2010). Another risk factor for peripartum stroke is cesarean delivery, which raises the risk 1.5-fold compared with vaginal delivery (Lin, 2008).

Pregnancy-induced efects on cerebrovascular hemodynamics include enhanced autoregulation that maintains blood low despite changes in systemic blood pressure (van Teen, 2016). Although cerebral blood low decreases by 20 percent from midpregnancy until term, it increases signiicantly with gestational hypertension (Zeeman, 2003, 2004b). Such hyperperfusion at least intuitively would be dangerous for women with certain vascular anomalies.

FIGURE 60-2 Illustrations of a brain showing various types of strokes seen in pregnancy: (1) subcortical infarction (preeclampsia), (2) hypertensive hemorrhage/ (3) aneurysm, (4) embolism or thrombosis in middle cerebral artery, (5) arteriovenous malformation, and (6) cortical vein thrombosis.

Cocaine, amphetamines

From Smith, 2015; Yager, 2012. Neurological Disorders 1161

Acute occlusion or embolization of an intracranial blood vessel causes cerebral ischemia, which may result in death of brain tissue (Fig. 60-2). he more common associated conditions and etiologies of ischemic stroke are shown in Table 60-3. A transient ischemic attack (TIA) is caused by reversible ischemia, and symptoms usually last less than 24 hours. Approximately 10 percent of these patients have a stroke by 1 year (Amarenco, 2016). Patients with a stroke usually have a sudden onset of severe headache, hemiplegia or other neurological deicits, or occasionally seizures. In contrast, focal neurological symptoms accompanied by an aura usually signiy a irst-episode migraine (Liberman, 2008).

Evaluation of an ischemic stroke includes echocardiography and cranial imaging with CT, MR, or angiography. Serum lipids are measured with the caveat that their values are distorted by normal pregnancy (Appendix, p. 1259). Tests to detect antiphospholipid antibodies and lupus anticoagulant are performed. These underlie up to a third of ischemic strokes in otherwise healthy young women (Chap. 59, p. 1143). Also, sickle-cell syndromes are evaluated when indicated (Buonanno, 2016).

With a thorough evaluation, most causes of embolism can be identified, although treatment is not always available. Some of these include cardiacassociated embolism, vasculitis, or vasculopathy such as Moyamoya disease (Ishimori, 2006; Miyakoshi, 2009; Simolke, 1991). Outcomes of embolic strokes were reported to be favorable and similar to those of nonpregnant women (Lefert, 2016). hrombolysis for ischemic stroke during pregnancy has been reported (Tversky, 2016).

In reproductive-age women, a significant proportion of pregnancyrelated ischemic strokes are caused by gestational hypertension and preeclampsia (Jeng, 2004; Miller, 2016). s shown in Figure 60-2, areas of subcortical perivascular edema and petechial hemorrhage may progress to cerebral infarction (Aukes, 2007, 2009; Zeeman, 2004a). Although these are usually clinically manifest by an eclamptic convulsion, a few women will sufer a symptomatic stroke from a larger cortical infarction (Chap. 40, p. 734).

Other conditions with findings similar to preeclampsia include thrombotic microangiopathies (Chap. 56, p. 1088) and the reversible cerebral vasoconstriction syndrome (Chap. 40, p. 744). The latter, also termed pospartum angiopathy, can cause extensive cerebral edema with necrosis and widespread infarction with areas of hemorrhage (Edlow, 2013; Katz, 2014; Miller, 2016).

These strokes usually involve the middle cerebral artery (see Fig. 60-2). he diagnosis can be made with conidence only after thrombosis and hemorrhage have been excluded and is more certain if an embolic source is identified. Hemorrhage may be more diicult to exclude because embolization and thrombosis are both followed by hemorrhagic infarction. Paradoxical embolism is an uncommon cause, even considering that more than a fourth of adults have a patent foramen ovale through which right-sided venous thromboemboli are deported (Scott, 2012). Foraminal closure may not improve outcomes in these patients, however, this procedure has been performed during pregnancy (Dark, 2011). Assorted cardioembolic causes of stroke include arrhythmias-especially atrial ibrillation, valvular lesions, mitral valve prolapse, mural thrombus, infective endocarditis, and peripartum cardiomyopathy.

Management of embolic stroke in pregnancy consists of supportive measures and antiplatelet therapy. Thrombolytic therapy and anticoagulation in pregnancy are controversial issues (U,r2012).

Most thrombotic strokes afect older individuals and are caused by atherosclerosis, especially of the internal carotid artery. Many are preceded by one or more TIAs. hrombolytic therapy with a recombinant tissue plasminogen activator (rt-PAj is recommended. Alteplase is one of these and given within the irst 3-hour window if there is measurable neurological deficit and if neuroimaging has excluded hemorrhage. his recombinant enzyme can be used in pregnancy. A principal risk is hemorrhagic transformation of an ischemic stroke in 3 to 5 percent of treated patients (Smith, 2015; van der Worp, 2007).

In one study in the United States, 7 percent of cerebral venous thromboses were associated with pregnancy (Wasay, 2008). But, in the Nationwide Inpatient Sample of more than 8 million deliveries, James and associates (2005) reported that venous thrombosis caused only 2 percent of pregnancy-related strokes (Saposnik, 2011). here are numerous predisposing causes, and for gravidas, late pregnancy and the puerperium are times of greatest risk.

Thrombosis of the lateral or superior sagittal venous sinus usually occurs in the puerperium and often in association with preeclampsia, sepsis, or thrombophilia (see Fig. 60-2). It is more common in patients with inherited thrombophilias or antiphospholipid antibodies (Chaps. 52, p. 1006 and 59, p. 1143). Headache is the most frequent presenting symptom, neurological deficits are common, and up to a third of patients have convulsions (Wasay, 2008). he diagnosis is made using MR venography (Saposnik, 2011).

Management includes anticonvulsants for seizures, and although heparinization is recommended by most, its eicacy is controversial (Saposnik, 2011; Smith, 2015). Antimicrobials are given if there is septic thrombophlebitis, and fibrinolytic therapy is reserved for those women failing systemic anticoagulation. The acute prognosis for venous thrombosis in pregnant women is better than in nonpregnant subjects, and mortality rates are less than 10 percent (McCaulley, 2011).

In women with a prior cerebral venous thrombosis, one systematic review found only one recurrence in 217 pregnancies and five noncerebral venous thrombotic events in 186 pregnancies (Aguiar de Sousa, 2016). In a study of 52 women on prophylactic anticoagulation with prior cerebral venous thrombosis, there were no cases of recurrent thrombosis or bleeding, however 24 percent had late obstetrical complications (Martinelli, 2016).

Recurrence Risk of Ischemic Stroke

Women with prior ischemic stroke have a low risk for recurrence during a subsequent pregnancy unless a specific, persistent cause is identiied. During a 5-year follow-up of 373 women with arterial ischemic strokes, there were 187 pregnancies in 125 women. Thirteen women had a recurrent ischemic stroke, and of these, only two were associated with pregnancy. The authors concluded that the risk of stroke recurrence is low and a previous ischemic stroke is not a contraindication to pregnancy (Lamy, 2000). In one study of 1770 nonpregnant women with anti phospholipid-related ischemic stroke, investigators reported no diference in the recurrence risk as long as preventative treatment was given with warfarin or aspirin (Levine, 2004).

Currently, no irm guidelines define prophylaxis in pregnant women with a stroke history (Helms, 2009). The American Heart Association stresses the importance of controlling risk factors such as hypertension and diabetes (Furie, 201l). Women with anti phospholipid syndrome or certain cardiac conditions should be considered for prophylactic anticoagulation as discussed in Chapter 49 (p. 954) and 52 (p. 1008).

The two distinct categories of spontaneous intracranial bleeding are intracerebral and subarachnoid hemorrhage. The symptoms of a hemorrhagic stroke are similar to those of an ischemic stroke, and their diferentiation is only possible with CT or MR imaging (Morgenstern, 2010; Smith, 2015).

Bleeding into the brain parenchyma most often is caused by spontaneous rupture of small vessels previously damaged by chronic hypertension (see Fig. 60-2). Thus, pregnancy-associated hemorrhagic strokes such as the one shown in Figure 60-3 are

FIGURE 60-3 A 37-year-old gravida with intrapartum eclampsia at term. A noncontrast computed tomography axial head image demonstrates a large intraparenchymal hemorrhage.

oten associated with chronic hypertension and superimposed preeclampsia (Cunningham, 2005; Martin, 2005). Because of its location, this type of hemorrhage has much higher morbidity and mortality rates than does subarachnoid hemorrhage (Smith, 2015). Pressure-induced rupture causes bleeding into the putamen, thalamus, adjacent white matter, pons, and cerebellum. In the 28 women described by Martin and associates (2005), half died and most survivors had permanent disabilities. his cautions for the importance of proper management for gestational hypertension-especially systolic hypertension-to prevent cerebrovascular pathology (Chap. 40, p. 738).

In a study of 639 cases of pregnancy-related subarachnoid hemorrhage from the Nationwide Inpatient Sample, the incidence was 5.8 per 100,000 pregnancies, with half occurring postpartum (Bateman, 2012). A remarkably similar incidence was reported in Japanese women (Yoshida, 2017). hese bleeds are more likely caused by an underlying cerebrovascular malformation in an otherwise norml patient (see Fig. 60-2). Ruptured saccular or "berry" aneurysms cause 80 percent of all subarachnoid hemorrhages. The remaining cases are caused by a ruptured arteriovenous malformation, coagulopathy, angiopathy, venous thrombosis, infection, drug abuse, tumors, or trauma. Such cases are uncommon, and a ruptured aneurysm or angioma or bleeding from a vascular mlformation has an incidence of 1 in 75,000 pregnancies. Although this frequency is not diferent from that in the general population, the mortality rate during pregnancy is reported to be as high as 35 percent (Yoshida, 2017).

Intracranial Aneurysm. Approximately 1 to 2 percent of adults have this lesion (Lawton, 2017). Fortunately, only a small percentage rupture. he rate approximates 0.1 percent for aneurysms <10 mm and 1 percent for those >10 mm (Smith, 2015). Most aneurysms identified during pregnancy arise from the circle of Willis, and in 20 percent of case, there are multiple lesions. Pregnancy does not raise the risk for aneurysmal rupture. However, because of their high prevalence, they are more likely to cause subarachnoid bleeding than other etiologies (Hirsch, 2009; Tiel Groenestege, 2009). A systematic review of 44 women with 50 aneurysms in pregnancy reported that 72 percent ruptured during pregnancy, and 78 percent of these did so during the third trimester (Barbarite, 2016). his proclivity for rupture late in pregnancy was also reported by Yoshida and colleagues (2017).

The cardinal symptom of a subarachnoid hemorrhage from an aneurysm rupture is sudden severe headache that is accompanied by visual changes, cranial nerve abnormalities, focal neurological deicits, and altered consciousness. Patients typically have signs of meningeal irritation, nausea and vomiting, tachycardia, transient hypertension, low-grade fever, leukocytosis, and proteinuria. Prompt diagnosis and treatment may prevent potentially lethal complications. The American Heart Association recommends noncontrast cranial CT imaging as the irst diagnostic test, although MR imaging may be superior (Connolly, 2012; Smith, 2015).

Treatment of subarachnoid hemorrhage includes bed rest, analgesia, and sedation, with neurological monitoring and strict blood pressure control. Repair of a potentially accessible aneurysm during pregnancy depends in part on the risk of recurrent hem orrhage versus the surgical risks. At least in nonpregnant patients, the risk of subsequent bleeding with conservative treatment is 20 to 30 percent for the irst month and then 3 percent per year.

The risk of rebleeding is highest within the irst 24 hours, and recurrent hemorrhage leads to death in 70 percent.

Early repair after the sentinel hemorrhage is done by surgi cal clipping of the aneurysm. Also, an endovascular coil can be placed using luoroscopic angiography, while attempting to limit fetal radiation exposure. Barbarite and colleagues (2016) report lower complication rates with coil embolization than clipping. For unruptured aneurysms, surgical management resulted in a third fewer complications than no treatment. For gravidas remote from term, repair without hypotensive anes thesia seems optimal. For women near term, cesarean delivery followed by aneurysm repair is a consideration, and we have successfully done this in several cases.

For aneurysms repaired either before or during pregnancy, mal repair. Problems arise in defining "remote," and although some recommend 2 months, the time for complete healing is unknown. For women who survive subarachnoid hemor rhage, but in whom surgical repair is not done, we agree with another way, we favor cesarean delivery.

Arteriovenous Malformations. hese are congenital focal abnormal conglomerations of dilated arteries and veins with sub arteriolar disorganization (see Fig. 60-2). hey lack capillaries and have resultant arteriovenous shunting. Although unclear, the risk of bleeding may rise with gestational age. When arteriovenous malformations (A VMs) bleed, half do so into the subarachnoid space, whereas half are intraparenchymal with subarachnoid extension (Smith, 2015). hey are uncommon and are estimated to occur in 0.01 percent of the general population. Of 65 identiied cases of A VM in pregnancy, 83 percent ruptured during pregnancy or postpartum, and more than 80 percent of these ruptured in the second or third trimester. Hemorrhage upon presentation is associated with poor maternal outcome (Lu, 2016).

Bleeding does not appear to be more likely during pregnancy. lthough these malformations are correspondingly rare during pregnancy, A VM bleeding accounted for 17 percent of hemorrhagic strokes in one study (Yoshida, 2017). At Parkland Hospital in a 33-year period during which there were about 466,000 births, 57 women had a CVA, and five of these strokes were due to a bleeding A M (Simolkie, 1991; Zokie, 2018).

Treatment of AVMs in nonpregnant patients is largely individualized. No consensus guides whether all accessible lesions should be resected. Factors include AVM symptoms; its anatomy and size; presence of an associated aneurysm, which is found in up to 60 percent of cases; and especially, prior A VM bleeding. Mter hemorrhage, the risk of recurrent bleeding in unrepaired lesions is 6 to 20 percent within the first year, and 2 to 4 percent per year thereater (Friedlander, 2007; Smith, 2015). The mortality rate with a bleeding AVM is 10 to 20 percent. In pregnancy, the decision to operate is usually based on neurosurgical considerations, and Friedlander (2007) recommends strong consideration for treatment if bleeding occurs. Because of the high risk of recurrent hemorrhage from an unresected or inoperable lesion, we favor cesarean delivery.

The demyelinating diseases are neurological disorders characterized by immune-mediated focal or patchy destruction of myelin sheaths accompanied by an inflammatory response. The degenerative diseases are multifactorial and are characterized by progressive neuronal death.

In the United States, multiple sclerosis (MS) is second only to trauma as a cause of neurological disability in middle adulthood (Hauser, 2015b). The disease afects women twice as often as men, and it usually begins in the 20s and 30s. he familial recurrence rate of MS is 15 percent, and the incidence in ofspring is increased IS-fold. Studying California deliveries, Fong and colleagues (2018) reported that 0.03 percent of deliveries were complicated by MS between 2001 and 2009.

The demyelinating characteristic of this disorder results predominately from T cell-mediated autoimmune destruction of oligodendrocytes that synthesize myelin. here is a genetic susceptibility and likely an environmental trigger such as exposure to certain bacteria and viruses. Of these, Chlamydophila pneumoniae, human herpesvirus 6, or Epstein-Barr virus are implicated (Frohman, 2006; Goodin, 2009).

There are four clinical types of MS: 1. Relapsing-remitting MS accounts for initial presentation in 85 percent of afected individuals. With it, unpredictable recurrent episodes of focal or multifocal neurological dysfunction usually are followed by full recovery. Over time, however, relapses lead to persistent deficits.

2.

Secondary progressive MS disease is relapsing-remitting disease that begins to pursue a progressive downhill course after each relapse. All patients likely develop this type eventually.

3.

Primary progressive MS accounts for 15 percent of cases.

With it, disability gradually progresses from the time of initial diagnosis.

4.

Progressive-relapsing MS refers to primary progressive vIS with apparent relapses.

Classic findings of MS include sensory loss, visual symptoms from optic neuritis, weakness, paresthesias, and a host of other neurological symptoms. Almost 75 percent of women with isolated optic neuritis develop MS within 15 years. Clinical diagnosis is confirmed by MR imaging and cerebrospinal fluid analysis. In greater than 95 percent of cases, MR imaging shows characteristic multifocal white matter plaques that represent discrete areas of demyelination (Fig. 60-4). Their appearance and extent are less helpful for predicting treatment response. Similarly, identification of serum antibodies against myelin oligodendrocyte glycoprotein and myelin basic protein is not predictive of recurrent disease activity (Kuhle, 2007).

Efects of Pregnancy

The PRegnancy In Multiple Sclerosis-PlMS-study was a European prospective multicenter study in which 254 pregnancies were described (Vukusic, 2006). Relapse risk was reduced 70 percent during pregnancy, but with a significantly greater relapse rate postpartum. This may be related to higher pregnancy-induced numbers of T-helper lymphocytes and an increased T2/Tl ratio (Airas, 2008). In a metaanalysis of women with more than 1200 pregnancies complicated by lvIS, their relapse rate was 0.4 per year before pregnancy; 0.26 per year during pregnancy; and this increased to 0.7 per year

FIGURE 60-4 Magnetic resonance cranial images from a woman with mUltiple sclerosis. A.T2-weighted axial image shows bright signal abnormalities in white matter, typical for multiple sclerosis. B. Sagittal T2-FLAIR image shows hyperintense areas within the corpus callosum that are representative of demyelination in multiple sclerosis. (Reproduced with permission from Hauser SL, Goodin DS: Multiple Sclerosis and other demyelinating diseases. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. McGraw-Hili,

New York, 201o5b.) after delivery (Finkelsztejn, 2011). Bove and associates (2014) reached similar conclusions after a systematic review. Factors associated with postpartum relapse include a high relapse rate before pregnancy, relapses during pregnancy, and a high MS disability score (Portaccio, 2014; Vukusic, 2006). Breastfeeding has no apparent efect on postpartum relapses (Hellwig, 2015; Portaccio, 2011).

Efects of Multiple Sclerosis on Pregnancy

With uncomplicated disease, there are usually no adverse efects on pregnancy ourcome (Bove, 2014). Some women may become fatigued more easily, those with bladder dysfunction are predisposed to urinary infection, and women with spinal lesions at or above T 6 are at risk for autonomic dysrelexia. In one study of 449 pregnancies in afected women, the labor induction rate was higher, and second-stage labor was longer (Dahl, 2006). he greater induction rate and elective operations contributed to the overall higher cesarean delivery rate. In an analysis of 649 afected women, the mean birthweight was lower but the perinatal mortality rate was similar compared with that of controls (Dahl, 2005). Other studies have corroborated that MS does not significantly afect obstetrical and neonatal outcomes (Finkelsztejn, 2011; Fong, 2018).

Goals are to arrest acute or initial attacks, employ diseasemodiying agents, and provide symptomatic relief. Some treatments may need to be modiied during pregnancy. Acute or initial attacks are treated with high-dose intravenous methylprednisolone-500 to 1000 mg daily for 3 to 5 days, followed by oral prednisone for 2 weeks. Plasma exchange may be considered. Symptomatic relief can be provided by analgesics; carbamazepine, phenytoin, or amitriptyline for neurogenic pain; baclofen for spasticity; :Tadrenergic blockade for bladder neck relaxation; and cholinergic and anticholinergic drugs to stimulate or inhibit bladder contractions.

Several disease-modiying therapies can be used for relapsing MS or for exacerbations. Examples include in terferons 31 a (Rebi), 31 b (Betaseron), and glatiramer acetate (Copaxone), which lower relapse rates by a third (Rudick, 201l). Data concerning safety in pregnancy are limited but overall reassuring (Amato, 2010; Salminen, 2010). In clinical trials, natalizumab (Tysabri), an :4-integrin antagonist, especially when combined with interferon 31a, significantly reduced MS clinical relapse rates (Polman, 2006; Rudick, 2006). In a review of 35 pregnancies, irst-trimester drug exposure did not worsen outcomes (Hellwig, 2011). If these drugs are used in pregnancy, the neonate should be monitored for thrombocytopenia and anemia (Alroughani, 2016).

Fetal exposure in 89 pregnancies to ingolimod (Gilenya), another immune-modulating drug, was associated with six fetal malformations and nine spontaneous losses. Because of this and associated animal teratogenicity, its use in pregnancy is not recommended. Due to its prolonged persistence, contraception is recommended for 2 months ater drug cessation (Alroughani, 2016; Karlsson, 2014).

Prevention of relapses postpartum is aforded by treatment with intravenous immunoglobulin (I I G) , given in a dose of 0.4 g/kg daily for 5 days during weeks 1, 6, and 12 (Argyriou, 2008).

his adult-onset neurodegenerative disease stems from an autosomal dominant expanded CAG trinucleotide repeat within the Huntington gene on chromosome 4. It is characterized by choreoathetotic movements, progressive dementia, and psychiatric manifestations. Because the mean age of onset is 40 years, Huntington disease rarely complicates pregnancy. Prenatal diagnosis is discussed in Chapter 14 (p. 288). Prenatal screening is controversial, and because this usually is a late-onset adult disease, extensive counseling is important (Schulman, 2015).

approximately 1 in 7500 persons. It is more common in women, and its incidence peaks in their 20s and 30s. he eti ology is unknown, but genetic factors likely playra role. Most patients demonstrate antibodies to the acetylcholine receptor, although 10 to 20 percent are seronegative (Drachman, 2015).

he latter often have antibodies to muscle-specific tyrosine kinase (MuSK), which regulates assembly of the acetylcholine receptor subunits at the neuromuscular junction (Pal, 201l).

Cardinal features of myasthenia are weakness and easy fatigability of facial, oropharyngeal, extraocular, and limb muscles. Deep tendon reflexes are preserved. Cranial muscles are involved early and disparately, and diplopia and ptosis are common. Facial muscle weakness causes diiculty in smiling, chewing, and speaking. In 85 percent of patients, the weakness becomes generalized. Other autoimmune diseases may coexist, and hypothyroidism should be excluded. The clinical course is marked by exacerbations and remissions, especially when it first becomes clinically apparent. Remissions are not always complete and are seldom permanent. Systemic diseases, concurrent infections, and even emotional upset may precipitate exacerbations, of which there are three types: 1.

Myasthenic crises-characterized by severe muscle weakness, inability to swallow, and respiratory muscle paralysis.

2.

Rtactory crises-characterized by the same symptoms but unresponsive to the usual therapy.

3.

Cholinergic crisesexcessive cholinergic medication leads to nausea, vomiting, muscle weakness, abdominal pain, and diarrhea.

All three of these can be life threatening, but a refractory crisis is a medical emergency. Those with bulbar myasthenia are at particular risk because they may be unable to swallow or even ask for help.

Myasthenia is manageable but not curable. Oral pyridostigmine is the first-line treatment. Thymectomy is recommended but postponed until ater pregnancy (Sanders, 2016). Anticholinesterase medications improve symptoms by impeding acetylcholine degradation but seldom produce normal muscle function. Ironically, overdose is manifest by increased weness-cholinergic crisisthat may be diicult to diferentiate from myasthenic symptoms. Most of those refractory to anticholinesterase therapy respond to immunosuppressive therapy with glucocorticoids, azathioprine, or cyclosporine in pregnancy. When short-term, rapid clinical improvement is needed-such as for a surgical procedure or a myasthenic crisis-high-dose IVIG or plasma exchange is usually efective (Barth, 2011; Cortese, 2011; Sanders, 2016).

Because the greatest period of risk is within the first year following diagnosis, postponing pregnancy until there is sustained improvement is reasonable. Antepartum management of myasthenia includes close observation with liberal rest and prompt treatment of infections (Heaney, 2010; Kalidindi, 2007). Women in remission who become pregnant while taking corticosteroids or azathioprine should continue these. hymectomy has been successfully performed during pregnancy in refractory cases (Ip, 1986). Acute onset of myasthenia or its exacerbation demands prompt hospitalization and supportive care. Plasmapheresis and high-dose IVIG are options for emergency situations (Drachman, 2015).

Although pregnancy does not appear to afect the overall course of myasthenia, fatigue common to most pregnancies may be exacerbated, and the expanding uterus may compromise respiration. Maternal hypotension or hypovolemia are ideally avoided as they can trigger crises. he clinical course of myasthenia during pregnancy is unpredictable, and frequent hospitalizations are the norm. Up to a third of women have worsening myasthenia during pregnancy, and exacerbations occur equally in all three trimesters (Djelmis, 2002; Podciechowski, 2005). In women with stable disease, most will remain stable throughout pregnancy but likely worsen in the first few months postpartum (Sanders, 2016).

Myasthenia gravis has no significant adverse efects on pregnancy outcomes (Wen, 2009). Preeclampsia is a concern because magnesium sulfate may precipitate a severe myasthenic crisis (Hamaoui, 2009; Heaney, 2010). Although phenytoin use is also problematic in this regard, its adverse efects are less troublesome. hus, many choose it for neuroprophylaxis in women with severe preeclampsia.

Because smooth muscle is unafected, most women have normal labor. Oxytocin is given for the usual indications, and cesarean delivery is reserved for obstetrical indications. Narcotics may cause respiratory depression, and close observation and respiratory support are essential during labor and delivery. Curariform drugs are avoided-examples include magnesium sulfate discussed above, muscle relaxants used with general anesthesia, and aminoglycosides. Neuraxial analgesia is accomplished with amide-type local agents. Regional analgesia is preferred unless there is signiicant bulbar involvement or respiratory compromise (Almeida, 2010; Blichfeldt-Lauridsen, 2012). During second-stage labor, some women may have impaired voluntary expulsive eforts that may warrant operative vaginal delivery.

As discussed above, 80 percent of mothers with myasthenia gravis have anti-acetylcholine-receptor immunoglobulin G (IgG) antibodies. These and anti-MuSK antibodies cross transplacentally, and the fetus can be afected. Poor fetal swallowing may yield hydramnios (Heaney, 2010). Similarly, 10 to 20 percent of neonates manifest myasthenia symptoms (Jovandaric, 2016). Transient symptoms usually include a feeble cry, poor suckling, and respiratory distress. Symptoms usually respond to cholinesterase inhibitors and resolve within a few weeks as maternal IgG antibodies clear.

Peripheral neuropathy is a general term used to describe disorders of peripheral nerve(s) from various sources. Poyneuropathies can be axonal or demyelinating as well as acute, subacute, or chronic (Amato, 2015). hese are often associated with systemic diseases such as diabetes, with drug or environmental toxin exposure, or with genetic disease.

Mononeuropathies are relatively common in pregnancy and signiY focal involvement of a single nerve trunk. These imply local causation such as trauma, compression, or entrapment. Traumatic pudendal, obturator, femoral, and common fibular mononeuropathies are usually caused by childbirth and are discussed in Chapter 36 (p. 661).

In 75 percent of cases, this acute demyelinating polyradiculoneuropathy has clinical or serological evidence for an acute infection. Commonly associated are infections with Campylobacter jjuni, cytomegalovirus, Zika virus, and Epstein-Barr virus; surgical procedures; and immunizations (Haber, 2009; Hauser, 2015a; Pacheco, 2016). Guillain-Barre syndrome is thought to be immune-mediated from antibodies formed against nonself antigens. Demyelination causes sensory and motor conduction blockade, and remyelination yields recovery in most cases.

Clinical features include areflexic paralysis-usually ascending-with or without sensory disturbances. Autonomic dysfunction is common. The full syndrome develops over 1 to 3 weeks. Some manifest as chronic inlammatoy demyelinating poyneuropathy, and our experiences indicate that this may be relatively common in these young women.

Guillain-Barre syndrome is not more common in pregnancy, and its clinical course mirrors that for nonpregnant individuals. After an insidious onset, paresis and paralysis most oten continue to ascend to cause ventilatory weakness. Management is supportive and incorporates venous thromboembolism prophylaxis, pressure ulcer prevention, and enteral nutrition. In the worsening phase, patients are hospitalized, and a fourth requires ventilatory assistance. IVIG or plasmapheresis is beneficial if begun within 1 to 2 weeks of motor symptoms, however, neither decreases mortality rates (Cortese, 2011; Gwathmey, 2011; Pritchard, 2016). Up to 10 percent of patients deteriorate after initial improvement on therapy, and retreatment with 2 g/kg IVIG over 5 days is recommended. Although most patients recover fully within several months to a year, the mortality rate is 5 percent, mainly due to pulmonary complications and arrhythmias (Hauser, 20 15a; Pacheco, 2016).

FIGURE 60-5 Bell facial nerve palsy developing on the day of cesarean delivery for dichorionic twins. This woman was treated with prednisone and antiviral medication, and the palsy had almost resolved 3 weeks postpartum.

his disfiguring palsy is usually a mononeuropathic acute facial paralysis that is relatively common in reproductive-aged women (Fig. 60-5). It has a female predominance, and pregnant women carry a fourfold risk compared with nonpregnant women (Cohen, 2000; Heaney, 2010). The disease is characterized by facial nerve inlammation and often is associated with reactivation of herpes simplex virus or herpes zoster virus.

Bell palsy usually has an abrupt and painful onset with maximum weakness by 48 hours. In some cases, hyperacusis and loss of taste accompany paralysis (Beal, 2015). Management includes supportive care with facial muscle massage and eye protection against corneal lacerations from drying. here is general consensus that prednisone, 1 mg/kg given orally daily for 5 days, will improve outcomes and shorten the recovery period (Salinas, 2016; Sullivan, 2007). It is controversial whether addition of an antiviral medication will add benefits (de Almeida, 2009; Gagyor, 2015; Quant, 2009).

It is unclear if pregnancy alters the prognosis for spontaneous facial palsy recovery. Gillman and associates (2002) found that only half of pregnant women recovered to a satisfactory level after 1 year, compared with approximately 80 percent of nonpregnant women and men. Some prognostic markers for incomplete recovery are bilateral palsy, recurrence in a subsequent pregnancy, greater percentage of nerve function loss, and a faster rate of loss (Cohen, 2000; Gilden, 2004). Other than a ivefold greater rate for gestational hypertension or preeclampsia, women with Bell palsy do not have increased adverse pregnancy outcomes rates (Katz, 2011; Shmorgun, 2002).

This syndrome results from compression of the median nerve and is the most frequent mononeuropathy in pregnancy (Padua, 2010). Symptoms include burning, numbness, or tingling along the inner half of one or both hands. Others are wrist pain and numbness extending into the forearm and sometimes into the shoulder (Katz, 2002). Symptoms are bilateral in 80 percent of gravidas, and 10 percent have evidence for severe denervation (Seror, 1998). Diferential diagnosis includes cer vical radiculopathy of C6-C7 and de Quervain tendonitis. he latter is caused by swelling of the conjoined tendons and their sheaths near the distal radius. Nerve conduction studies may be helpful for clariication (Alfonso, 2010).

In pregnancy, the reported incidence of carpal tunnel syn drome is 7 to 43 percent and varies greatly because the range of symptoms is marked (Meems, 2015; Padua, 2010). Symp tomatic treatment with a splint applied to a slightly lexed wrist during sleep lightens pressure and usually provides relief.

Although symptoms typically are self-limited, occasionally sur gical decompression and corticosteroid injections are necessary (Keith, 2009; Shi, 2011). Symptoms may persist in more than half of patients at 1 year and in a third at 3 years (Padua, 2010).

According to the National Spinal Cord Injury Statistical Center (2017), there are approximately 17,000 new spinal cord injuries each year. he average age is 42 years, and males account for 80 percent of new cases. Cord injury severity determines the short-and long-term prognosis as well as that for pregnancy. For women, many have altered sexual function and transient hypothalamic pituitary hypogonadism. hat said, pregnancy is not uncommon if menstruation resumes (Bughi, 2008). In a review of nearly 2000 women in the National Spinal Cord Injury Database, 2 percent reported pregnancy in the prior 12 months (Iezzoni, 2015).

Gravidas with spinal cord injury have an increased frequency of pregnancy complications that include preterm and low-birth weight neonates. Recent observations in nonpregnant women note that the vaginal microbiota is altered in these women (Pires, 2016). Perhaps related, most have asymptomatic bacteriuria with sporadic symptomatic urinary infections. Bowel dysfunction causes constipation in more than half, and anemia and pressure-necrosis skin lesions are also common.

Two serious and life-threatening events can complicate spinal cord injuries. First, if the cord is transected above T 10' the cough reflex is impaired, respiratory function may be compromised, and pneumonitis from covert aspiration can be serious. Pulmonary function tests are considered to assess this risk, and some women may need ventilatory support in late pregnancy or in labor.

Second, women with lesions above T 5-T6 are at risk for autonomic dysrlexia. With this, stimuli from structures innervated below the level of the spinal lesion lead to massive, disordered sympathetic stimulation. Abrupt catecholamine release can cause vasoconstriction with severe hypertension and symptoms that include throbbing headaches, facial flushing, sweating, bradycardia, tachycardia, arrhythmias, and respiratory distress . Dysrelexia can be precipitated by various stimuli. hese include urethral catheterization, bladder distention from urinary retention, rectal or cervical stretch during digital examinations, uterine contractions and cervical dilation, or any manipulation of other pelvic structures (American College of Obstetricians and Gynecologists, 2016; Krassioukov, 2009). In one report, 12 of 15 women at risk for autonomic dysreflexia sufered at least one episode during pregnancy (Westgren, 1993).

Because uterine contractions are not afected by spinal cord lesions, labor is usually easy-even precipitous, and comparatively painless. If the lesion is below T12' uterine contractions are felt normally. For lesions above T 2, the risk of out-of 1rhospital delivery is substantial and can be minimized by teaching women to palpate for uterine contractions. This is especially important because up to 20 percent of women deliver preterm (Westgren, 1993). Some recommend tocodynamometry and weekly cervical examinations beginning at 28 to 30 weeks. Another reasonable option that we frequently employ at Park land Hospital is elective hospitalization after 36 to 37 weeks' gestation (Hughes, 1991).

Spinal or epidural analgesia extending to TIO prevents autonomic dysrelexia and should be instituted at the start of labor. If there are severe symptoms before epidural placement, steps are taken to abolish the provoking stimulus. A parenteral antihypertensive agent such as hydralazine or labetalol is given. Labor and vaginal delivery with epidural or spinal analgesia is preferable and will minimize autonomic dysrelexia (Kuczkowski, 2006). Operative vaginal delivery is frequently necessary.

Also known as pseudotumor cerebri, this disorder is typified by increased intracranial pressure without hydrocephalus. The cause is unknown, but it may result from overproduction or under absorption of cerebrospinal luid (CSF). Symptoms include headache in at least 90 percent of cases, visual disturbances such as loss of a visual field or central visual acuity in 70 percent, and commonly occurring papilledema that may be sight-threatening (Evans, 2000; Heaney, 2010). Other complaints are stif neck, back pain, pulsatile tinnitus, and cranial nerve palsies.

he syndrome is oten found in young women and is prevalent in those who are obese, who recently gained weight, or both (Fraser, 201r1). Along with symptoms, other criteria for diagnosis include elevated intracranial pressurer> 25 em H20, normal CSF composition, normal cranial CT or MR imaging indings, papilledema, and no evidence for systemic disease. If papilledema is not present, other criteria are required (Friedman, 2013).

Idiopathic intracranial hypertension is usually self-limited.

Visual defects can be prevented by lowering the CSF pressure, and agents include acetazolamide to reduce fluid production, furosemide, or topiramate. Corticosteroids are now rarely used. Surgical intervention is occasionally necessary and is accomplished by either lumboperitoneal shunting of spinal fluid or optic nerve sheath fenestration.

It is controversial if pregnancy is a risk factor for idiopathic intracranial hypertension. Certainly, symptoms may first appear in pregnancy, and women previously diagnosed may become symptomatic. Symptoms usually develop by midpregnancy, tend to be self-limited, and usually resolve postpartum.

Pregnancy does not alter management. Some recommend serial visual field testing to forestall permanent vision loss. In a report of 16 pregnant women, visual ield loss developed in four, and it became permanent in one (Huna-Baron, 2002). Visual ield loss is often coincident with the development of papilledema, for which acetazolamide is given. Lee and associates (2005) reported successful treatment of 12 pregnant women. Although outmoded for treatment of nonpregnant individuals, repeated lumbar punctures are generally successful in providing temporary relief throughout pregnancy. In some pregnant women, surgical therapy becomes necessary, and we and others have had promising results with optic nerve sheath fenestration (hambisetty, 2007).

Pregnancy complications are likely due to associated obesity and not to intracranial hypertension. In a review of 54 pregnancies, rates of adverse perinatal outcomes were not elevated (Katz, 1989). he route of delivery depends on obstetrical indications, and conduction analgesia is safe (Aly, 2007; Karmaniolou, 2011).

Pregnancies in women with previously placed ventricular shunts for obstructive hydrocephalus usually have satisfactory outcomes (Landwehr, 1994). Shunts may be ventriculoperitoneal, ventriculoatrial, or ventriculopleural. Partial obstruction of a shunt is common, especially late in pregnancy (Schiza, 2012). In one report of 17 such pregnancies, neurological complications were reported in 13 (Wisof, 1991). Findings included headaches in 60 percent, nausea and vomiting in 35 percent, lethargy in 30 percent, and ataxia or gaze paresis, each in 20 percent. Most symptoms respond to conservative management. However, if CT scanning during symptom evaluation discloses acute hydrocephaly, then the shunt is tapped or pumped several times daily. In some cases, surgical revision is necessary and may be emergently indicated (Murakami, 2010).

Another shunting procedure is placement of an endoscopic third ventriculostomy for hydrocephalus (de Ribaupierre, 2007). With this, a small hole is created in the loor of the third ventricle to allow CSF to low directly into lower cisterns. One report described successful results in ive pregnant women who underwent endoscopic ventriculostomy (Rifaud, 2006). In a review, however, reproductive function and miscarriage rates were found to significantly worsen in these women (Bedaiwy, 2008).

Vaginal delivery is preferred in women with shunts, and unless there is a meningomyelocele, conduction analgesia is permitted. Antimicrobial prophylaxis is indicated if the peritoneal cavity is entered for cesarean delivery or tubal sterilization.

Brain death is rare in obstetrics. Life-support systems and parenteral alimentation for up to 15 weeks while awaiting delivery have been described (Hussein, 2006; Powner, 2003; Souza, 2006). Some women were treated with aggressive tocolysis and antimicrobial therapy. In one review of 17 women with persistent vegetative state who were given various levels of support, five women died after delivery, and most of the others remained in their vegetative state (Chiossi, 2006).

With a diagnosis of brain death using the uniform Determination of Death Act definition, there are no published reports of neurological recovery (Wijdicks, 2010). Few institutional brain-death policies address pregnancy (Lewis, 2016). The ethical, inancial, and legal implications, both civil and criminal, that arise from attempting or not attempting such care are profound (Farragher, 2005; Feldman, 2000). In some women, perimortem cesarean delivery is performed as discussed in Chapter 47 (p. 931).

Adab N: Therapeutic monitoring of antiepileptic drugs during pregnancy and in the postpartum period: is it useful? CNS Drugs 20:791, 2006

Aegidius K, Anker-Zwartt], Hagen K, et al: he efect of pregnancy and parity on headache prevalence: the head-HUNT study. Headache 49:851,t2009 Aguiar de Sousa 0, Canhao P, Ferro ]M: Safety of pregnancy after cerebral venous thrombosis: a systematic review. Stroke 47(3):713,t2016

Airas L, Saraste M, Rinta S, et al: Immunoregulatory factors in multiple sclerosis patients during and after pregnancy: relevance of natural killer cells. Clin Exp Immunol 151 :235, 2008

Airola G, Allais G, Castagno Ii I, et al: Non-pharmacological management of migraine during pregnancy. Neurol Sci 31(1):S63, 2010

Alfonso C, ]ann S, Massa R, et al: Diagnosis, treatment and follow-up of the carpal tunnel syndrome: a review. Neurol Sci 31 :243, 20t10

Allais G, Castagnoli Gabellari 1, Borgogno P, et al: The risks of women with migraine during pregnancy. Neurol Sci 31(Supplt1):S59, 2010 lmeida C, Coutinho E, Moreira 0, et al: Myasthenia gravis and pregnancy: anaesthetic management-a series of cases. Eur] AnaesthesioI27:985, 2010

Alroughani R, Altintas A, Al ] umah M, et al: Pregnancy and the use of diseasemodiying therapies in patients with multiple sclerosis: beneits versus risks. Mult Scler Int 2016:1034912,t2016

Aly EE, Lawther BK: Anaesthetic management of uncontrolled idiopathic intracranial hypertension during labour and delivery using an intrathecal catheter. Anaesthesia 62: 178, 2007

Amarenco P, Lavallee PC, Labreuche], et al: One-year risk of stroke after transient ischemic attack or minor stroke. N Engl] Med 374(16):1533, 2016

Amato A, Barohn R]: Peripheral neuropathy. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. McGraw-Hill Education, New York, 2015

Amato MP, Portaccio E, Ghezzi A, et al: Pregnancy and fetal outcomes after interferon-beta exposure in multiple sclerosis. Neurology 75: 1794, 2010

American College of Obstetricians and Gynecologists: Obstetric management of patients with spinal cord injuries. Committee Opinion No. 275, September 2002, Reairmed 2016

Argyriou A, Makris N: Multiple sclerosis and reproductive risks in women.

Reprod Sci 15(8):755,t2008

Aukes AM, de Groot ]C, Aarnoudse ]G, et al: Brain lesions several years after eclampsia. Am] Obstet GynecoI200(5):504.e1, 2009

Aukes A, Wessel I, Dubois M, et al: Self-reported cognitive functioning in formerly eclamptic women. Amt] Obstet Gynecol 197:365.e1, 2007

Barbarite E, Hussain S, Dellarole A, et al: he management of intracranial aneurysms during pregnancy: a systematic review. Turk Neurosurg 26(4):465,t2016

Barth 0, Nouri M, Ng E, et al: Comparison of IVIG and PLEX in patients with myasthenia gravis. Neurology 76:2017, 2011 Bateman BT, Olbrecht VA, Berman MF, et al: Peripartum subarachnoid hemorrhage. Anesthesiology 116:242, 2012

Beal MF, Hauser SL: Trigeminal neuralgia, Bell's palsy, and other cranial nerve disorders. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles ofInternai Medicine, 19th ed. McGraw-Hill Education, New York, 2015

Bedaiwy MA, Fathalla MM, Shaaban OM, et al: Reproductive implications of endoscopic third ventriculostomy for the treatment of hydrocephalus. Eur ] Obstet Gynecol Reprod BioI 140(1):55,t2008

Blackwell DL, Lucas ]W, Clarke TC: Summary health statistics for U.S. adults:

National Health Interview Survey, 2012. Vital Health Stat (260):1, 2014 Blichfeldt-Lauridsen L, Hansen BD: Anesthesia and myasthenia gravis. Acta Anaesthesiol Scand 56(1):17, 2012

Bove R, Alwan S, Friedman ]M, et al: Management of multiple sclerosis during pregnancy and the reproductive years: a systematic review. Obstet Gynecol 124(6):1157,t2014

Brandes ]L, Kudrow 0, Stark SR, et al: Sumatriptan-naproxen for acute treatment of migraine.t]AMA 297:t1443,t2007

Briggs GG, Freeman RK: Drugs in Pregnancy and Lactation, 10th ed. Philadelphia, Lippincott Williams & Wilkins, 2015

Brodie M], Dichter MA: Antiepileptic drugs. N Engl] Med 334:168,t1996

Bughi S, Shaw S], Mahmood G, et al: menorrhea, pregnancy, and pregnancy outcomes in women following spinal cord injury: a retrospective crosssectional study. Endocr Pract 14(4):437,t2008

Buhimschi CS, Weiner CP: Medication in pregnancy and lactation: part 1.

Teratology. Obstet GynecoIt113:166, 2009

Buonanno FS, Schmahmann ]0, Romero ]M, et al: Case 10-2016: a 22-yearold man with sickle cell disease, headache, and diiculty speaking. N Engl ] Med 374(13):1265, 2016

Burch RC, Loder S, Loder E, et al: he prevalence and burden of migraine and severe headache in the United States: updated statistics from government health surveillance studies. Headache 55 (1) :21, 2015

Bushnell CD, Jamison M, James AH: Migraines during pregnancy linked to stroke and vascular diseases: US population based case-control study. BM] 338:b664, 2009

Callaghan WM, MacKay AP, Berg q: Identiication of severe maternal morbidity during delivery hospitalizations, United States, 1991-2003. Am ] Obstet GynecoIt199:133.e1, 2008

Cartlidge NE: Neurologic disorders. In Barron M, Lindheimer MD (eds):

Medical Disorders During Pregnancy, 3rd ed. St. Louis, Mosby, 2000 Centers for Disease Control and Prevention: Prevalence of stroke-United States, 2006-2010, MMWR 61:379,t2012

Chen M, Tang W, Hou L, et al: Tumor necrosis factor (TNF) -308G>A, nitric oxide synthase 3 (NOS 3) +894G>T polymorphisms and migraine risk: a meta-analysis. PLoS One 10(6): e0129372, 2015

Chen TC, Leviton A: Headache recurrence in pregnant women with migraine.

Headache 34: 1 07, 1994

Charles A: Migraine. N Englt] Med 7(6):553,t2017

Chiapparini L, Ferraro S, Grazzi L: Neuroimaging in chronic migraine. Neurol Sci 31(Supplt1):S19, 2010

Chiossi G, Novic K, Celebrezze ]U, et al: Successful neonatal outcome in 2 cases of maternal persistent vegetative state treated in a labor and delivery suite. Amt] Obstet Gynecol 195:316,t2006

Choi H, Parman N: The use of intravenous magnesium sulphate for acute migraine: meta-analysis of randomized controlled trials. Eur ] Emerg Med 21:2,t2014

Cohen Y, Lavie 0, Granoxsky-Grisaru S, et al: Bell palsy complicating pregnancy: a review. Obstet Gynecol Surv 55:184, 2000

Connolly ES ]R, Rabinstein A, Carhuapoma ]R: Guidelines for the management of aneurismal subarachnoid hemorrhage: a guideline for health care professionals from the American Heart Association/American Stroke Association. Stroke 43: 1711, 2012

Contag SA, Bushnell C: Contemporary management of migraine disorders in pregnancy. Cure Opin Obstet GynecoIt22:437, 2010

Cortese 1, Chaudhry V, So T, et al: Evidence-based guideline update: plasmapheresis in neurologic disorders. Neurology 76:294,t20t11

Creanga A, Syverson C, Seed K, et al: Pregnancy-related mortality in the United States, 2011-2013. Obstet GynecoIt130(2):366, 2017 Cunningham FG: Severe preeclampsia and eclampsia: systolic hypertension is also important. Obstet Gynecol 105:237,t2005

Dahl J, Myhr M, Daltveit AK, et al: Planned vaginal births in women with multiple sclerosis: delivery and birth outcome. Acta Neurol Scand Suppl 183:51,t2006

Dahl J, Myhr M' Daltveit AK, et al: Pregnancy, delivery, and birth outcome in women with multiple sclerosis. Neurology 65:1961,t2005

D'Andrea G, Leon A: Pathogenesis of migraine: from neurotransmitters to neuromodulators and beyond. Neurol Sci 31(Suppl l):SI, 2010

Dark L, Loiselle A, Hatton R, et al: Stroke during pregnancy: therapeutic options and role of percutaneous device closure. Heart Lung Circ 20:538,t201t1 de Almeida JR, Khabori >A, Guyatt GH, et al: Combined corticosteroid and antiviral treatment for Bell palsy. JAMA 302(9):985, 2009 de Ribaupierre S, Rilliet B, Vernet 0, et al: Third ventriculostomy vs ventriculoperitoneal shunt in pediatric obstructive hydrocephalus: results from a Swiss series and literature review. Childs Nerv Syst 23:527, 2007

Detsky ME, McDonald DR, Baerlocher MO: Does this patient with headache have a migraine or need neuroimaging? JAMA 296(10):1274,t2006

Digre KB: Headaches during pregnancy. Clin Obstet Gynecol 56:317, 2013 Djelmist], Sostarko M, Mayer 0, et al: Myasthenia gravis in pregnancy: report on 69 cases. Eur J Obstet Gynecol Reprod Bioi 104:21,t2002

Dodick OW, Schembri CT, Helmuth M, et al: Transcranial magnetic stimulation for migraine: a safery review. Headache 50: 1153, 2010

Drachman DB, Amato A: Myasthenia gravis and other diseases of the neuromuscular junction. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. McGraw-Hill Education, New York, 2015

Eadie MJ: Antiepileptic drugs as human teratogens. Expert Opin Drug Saf 7:195,t2008

Edlow JA, Caplan LR, O'Brien K, et al: Diagnosis of acute neurological emergencies in pregnant and post-partum women. Lancet Neurol 12: 175, 2013 Evans RW, Friedman DI: Expert opinion: the management of pseudotumor cerebri during pregnancy. Headache 40:495, 2000

Farragher A, Lafey JG: Maternal brain death and somatic support. Neurocrit Care 3:99, 2005

Feldman DM, Borgida AF, Rodis JF, et al: Irreversible maternal brain injury during pregnancy: a case report and review of the literature. Obstet Gynecol Surv 55:708, 2000

Finkelsztejn A, Brooks JB, Paschoal FM Jr, et al: What can we really tell women with multiple sclerosis regarding pregnancy? A systematic review and meta-analysis of the literature. BJOG 11t8:790,t2011

Fisher RS, Acevedo C, Arzimanoglou A, et al: A practical clinical definition of epilepsy. Epilepsia 55(4):475, 2014

Fong A, Chau CT, Quant C, et al: Multiple sclerosis in pregnancy: prevalence, sociodemographic features and obstetrical outcomes. J Matern Fetal Neonatal Med 31(3):382,2018

Food and Drug Administration: FDA drug safety communication: risk of oral clefts in children born to mothers taking Topamax (topiramate). 2011. Available at: http://www.fda.gov/drugs/drugsafety/ucm245085.htm. Accessed June 10,t2017

Fraser C, Plant GT: The syndrome of pseudotumour cerebri and idiopathic intracranial hypertension. Curr Opin Neurol 24:12, 2011

Friedlander M: Arteriovenous malformations of the brain. N Engl J Med 356(26):2704, 2007

Friedman DI, Lie GT. Digre KB: Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children. Neurology 81(13):1159, 2013 Frohman EM, Racke MK, Raine CS: Multiple sclerosis-the plaque and its pathogenesis. N Engl J Med 354:942, 2006

Furie KL, Kasner SE, Adams RJ, et al: Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42:227,t2011

Gagyor 1, Madhok VB, Daly F, et al: Antiviral treatment for Bell's palsy (idiopathic facial paralysis). Cochrane Database of Systematic Reviews Issue 1l:CD001869,t2015

Gilden DH: Bell's palsy. N Engl J Med 351:1323,t2004

Gillman GS, Schaitkin BM, May M, et al: Bell's palsy in pregnancy: a study of recovery outcomes. Otolaryngol Head Neck Surg 126:26, 2002

Goadsby PJ, Raskin NH: Migraine and other primary headache disorders. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles ofInternal Medicine, 19th ed. McGraw-Hill Education, New York, 2015

Gonzalez-Hernandez A, Condes-Lara M: he multitarget drug approach in migraine treatment: the new challenge to conquer. Headache 64: 197,t2014 Goodin DS: The causal cascade to multiple sclerosis: a model for MS pathogenesis. PLoS One 4(2):e4565, 2009

Govindappagari S, Grossman TB, Ashlesha K, et al: Peripheral nerve blocks in the treatment of migraine in pregnancy. Obstet GynecoIt124(6): 1169,2014

Grossman TB, Robbins MS, Govindappagari S, et al: Delivery outcomes of patients with acute migraine in pregnancy: a retrospective study. Headache 57(4):605,t2017.

Gwathmey K, Balogun A, Burns T: Neurologic indications for therapeutic plasma exchange: an update. J Clin Apheresis 26:261, 2011

Haber P, Sejvar J, Mikaelof Y, et al: Vaccines and Guillain-Barre syndrome.

Drug Saf 32(4):309,t2009

Hamaoui A, Mercado R: Association of preeclampsia and myasthenia: a case report. J Reprod Med 54(9):587, 2009

Harden CL, Hopp J, Ting Y, et al: Practice parameter update: management issues for women with epilepsy-focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency. Neurol 3(2): 126, 2009a

Harden CL, Meador KJ, Pennell PB, et al: Practice parameter update: management issues for women with epilepsy-focus on pregnancy (an evidencebased review): teratogenesis and perinatal outcomes. Neurology 73(2):133, 2009b

Harden CL, Pennell PB, Koppel BS, et al: Practice parameter update: management issues for women with epilepsy-focus on pregnancy (an evidence-based review): vitamin K, folic acid, blood levels, and breastfeeding. Neurology 73(2): 142, 2009c

Hauser SL, Amato A: Guillain-Barre and other immune-mediated neuropathies. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles ofInternal Medicine, 19th ed. McGraw-Hill Education, New York, 2015a

Hauser SL, Goodin DS: Multiple sclerosis and other demyelinating diseases.

In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. McGraw-Hill Education, New York, 2015b

Heaney DC, Williams DJ, O'Brien PO: Neurology. In Powrie R, Greene M, Camann W (eds): de Swiet's Medical Disorders in Obstetric Practice, 5th ed. Wiley-Blackwell, Oxford, 2010

Hellwig K, Haghikia A, Gold R. Pregnancy and natalizumab: results of an observational study in 35 accidental pregnancies during natalizumab treatment. Mult Scler 17:958,t2011

Hellwig K, Rockhof M, Herbstritt S, et al: Exclusive breastfeeding and the efect on postpartum multiple sclerosis relapses. JAMA Neurol 72(10): 1132, 2015

Helms AK, Drogan 0, Kittner SJ: First trimester stroke prophylaxis in pregnant women with a history of stroke. Stroke 40(4):1158,t2009

Hirsch KG, Froehler MT, Huang J, et al: Occurrence of perimesencephalic subarachnoid hemorrhage during pregnancy. Neurocrit Care 10(3):339, 2009

Holmes LB, Baldwin EJ, Smith CR, et al: Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy. Neurology 70(22 Pt 2):2152, 2008

Huang CJ, Fan YC, Tsai PS: Diferential impacts of modes of anaesthesia on the risk of stroke among preeclamptic women who undergo Caesarean delivery: a population-based study. BJA 105(6):818, 2010

Hughes SJ, Short DJ, Usherwood MM, et al: Management of the pregnant women with spinal cord injuries. BJOG 98:513, 1991

Huna-Baron R, Kupersmith MJ: Idiopathic intracranial hypertension in pregnancy. J NeuroIt249(8):1078, 2002

Hunt S, Russell A, Smithson WH, et al: Topiramate in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register. Neurology 71(4):272,t2008

Hussein IY, Govenden V, Grant JM, et al: Prolongation of pregnancy in a woman who sustained brain death at 26 weeks of gestation. B JOG 113: 120, 2006

Iezzoni LI, Chen Y, McLain AB: Current pregnancy among women with spinl cord injury: findings from the US national spinal cord injury database. Spinal Cord 53(11):821, 2015 International Headache Society: he Intenational Classification of Headache Disorders, 3rd ed. (beta version) Cephalalgia 33(9):629,t2013

Ip MSM, So SY, Lam WK, et al: Thymectomy in myasthenia gravis during pregnancy. Postgrad Med J 62:473, 1986

Ishimori ML, Cohen SN, Hallegue DS, et al: Ischemic stroke in a postpartum patient: understanding the epidemiology, pathogenesis, and outcome of Moyamoya disease. Semin Arthritis Rheum 35:250, 2006

James AH, Bushnell CD, Jamison MG, et al: Incidence and risk factors for stroke in pregnancy and the puerperium. Obstet Gynecol 106:509,t2005 Jamieson DG, Sliut M: Stroke in women: what is diferent? Curr Atheroscler

Rep 12:236,t2010

Jeng JS, Tang Sc, Yip PK: Stroke in women of reproductive age: comparison between stroke related and untelated to pregnancy. J Neurol Sci 22t1t:25, 2004

Jovandaric MZ, Despotovic DJ, Jesic MM, et al: Neonatal outcome in pregnancies with auto-immune myasthenia gravis. Fetal Pediatr Pathol 35(3):167,t2016

Jung SY, Bae HJ, Park BJ, et al: Parity and risk of hemorrhagic strokes. Neurology 74:1424,t2010 Kalidindi M, Ganpot S, Tahmesebi F, et al: Myasthenia gravis and pregnancy. J Obstet GynaecoIt27:30, 2007 Karlsson G, Francis G, Koren G, et al: Pregnancy outcomes in the clinical development program of ingolimod in multiple sclerosis. Neurology 82(8):674,t2014 Karmaniolou 1, Petropoulos G, Theodoraki K: Management of idiopathic intracranial hypertension in parturients: anesthetic considerations. Can J Anesth 58:650, 201t1 Kasradze S, Gogatishvili N, Lomidze G, et al: Cognitive functions in children exposed to antiepileptic drugs in utero-study in Georgia. Epilepsy Behav 66:105,t2017 Katz A, Sergienko R, Dior U, et al: Bell's palsy during pregnancy: is it associated with adverse perinatal outcome? Laryngoscope 121: 1395, 2011 Katz BS, Fugate JE, Ameriso SF, et al: Clinical worsening in reversible vasoconstriction syndrome. ]AMA Neurol 71:68, 2014 Katz ]N, Simmons BP: Carpal tunnel syndrome. N Engl ] Med 346:1807, 2002 Katz L, Peterson R, Cefalo RC: Pseudotumor cerebri and pregnancy. Am ] Perinatol 6:442, 1989 Keith MW, Masear V, Amadio PC, et a1: Treatment of carpal tunnel syndrome. ] Am Acad Orthop Surg 17:397, 2009 Klein P, Mathews GC: Antiepileptic drugs and neurocognitive development. Neurology 82(3):194, 2014 Knight M, Tufnell D, Kenyon S, et al (eds): Saving lives, improving mothers; care surveillance of maternal deaths in the UK 2011-13 and lessons learned to inform maternity care from the UK and Ireland Conidential Enquiries into Maternal Deaths and Morbidity 2009-13. Oxford, National Perinatal Epidemiology Unit, 20t15 Kobau R, Zahran H, Thurman D], et al: Epilepsy surveillance among adults-19 states, behavioral risk factor surveillance system, 2005. MMWR 57:1,t2008

Krassioukov A, Warburton DE, Teasell R, et al: A systematic review of the management of autonomic dysreflexia after spinal cord injury. Arch Phys Med Rehabil 90:682, 2009

Kruit MC, van Buchem MA, Hofman PA, et al: Migraine as a risk factor for subclinical brain lesions.t]AMA 291:427,t2004

Kuczkowski M: Labor analgesia for the parturient with spinal cord injury: what does an obstetrician need to know? Arch Gynecol Obstet 274: 108, 2006

Kuhlet], Po hi C, Mehling M, et al: Lack of association berween antimyelin antibodies and progression to multiple sclerosis. N Engl ] Med 356:371, 200

Kuklina EV, Tong X, Bansil P, et al: Trends in pregnancy hospitalizations that included a stroke in the United States from 1994 to 2007. Stroke 42:2564,2011 Kvisvik EV, Stovner L], Helde G, et al: Headache and migraine during pregnancy and puerperium: the MIGRA-study.t] Headache Pain 12: 443, 2011 Lamy C, Hamon ]B, Costet], et al: Ischemic stroke in young women. Neurol ogy 55:269, 2000

Landwehr ]B, Isada NB, Pryde PG, et al: Maternal neurosurgical shunts and pregnancy outcome. Obstet Gynecol 83:134, 1994

Lawton MT, Yates GE: Subarachnoid hemorrhage. N Engl ] Med 377:257, 201

Lee AG, Pless M, Falardeau], et al: he use of acetazolamide in idiopathic intracranial hypertension during pregnancy. Amt] Ophthalmol 139:855, 2005

Lefert LR, Clancy CR, Bateman BT, et al: Treatment patterns and shortterm outcomes in ischemic stroke in pregnancy or postpartum period. Am ] Obstet 23.e1,t2016

Levine SR, Brey L, Tilley BC, et al: Antiphospholipid antibodies and subsequent thrombo-occlusive events in patients with ischemic stroke. ]AMA 291:576,t2004

Lewis A, Varelas P, Greer 0: Pregnancy and brain death: lack of guidance in

U.S. hospital policies. Am] Perinatol 33(14):1382, 2016 Li Y, Margraf], Kluck B, et al: Thrombolytic therapy for ischemic Stroke secondary to paradoxical embolism in pregnancy. Neurologist 18:44, 2012

Liberman A, Karussis D, Ben-Hur T, et al: Natural course and pathogenesis of transient focal neurologic symptoms during pregnancy. Arch Neurol 65:218,t2008

Lin SY, Hu C], Lin HC: Increased risk of stroke in patients who undergo cesarean section delivery: a nationwide population-based srudy. Amt] Obstet GynecoIt198:391.e1,t2008

Lipton RB, Bigal ME, Diamond M, et al: Migraine prevalence, disease burden, and the need for preventive therapy. Neurology 68:343, 2007

Lu X, Liu P, Li Y: Pre-existing, incidental and hemorrhagic AVMs in pregnancy and postpartum: gestational age, morbidity and mortality, management and risk to the fetus. Interv NeuroradioIt22(2):206, 2016

Lucas S: Medication use in the treatment of migraine during pregnancy and lactation. Curr Pain Headache Rep 13:392,t2009

MacDonald Sc, Bateman BT, McElrath TF, et al: Mortality and morbidity during delivery hospitalization among pregnant women with epilepsy in the United States.t]AMA Neurol 72(9):981, 2015

Madhok VB, Gagyor I,Daly F, et al: Corticosteroids for Bell's palsy (idiopathic facial paralysis). Cochrane Database Syst Rev 7:CDOOtI942, 20t16

Martin ]N ]r, Thigpen BD, Moore RC, et al: Stroke and severe preeclampsia and eclampsia: a paradigm shift focusing on systolic blood pressure. Obstet Gynecol 105:246,t2005

Martinelli I, Passamonri SM, Maino A, et al: Pregnancy outcome after a irst episode of cerebral vein thrombosis.] hromb Haemost 14(12):2386, 20t16

Martinez-Sanchez P, Fuetes B, Fernandez-Dominguezt], et al: Young women have poorer outcomes than men after stroke. Cerebrovasc Dis 31:455,t2011 Mawer G, Briggs M, Baker GA, et al: Pregnancy with epilepsy: obstetric and neonatal outcome of a controlled study. Seizure 19(2): 112,t2010 McCaulley ]A, Pates ]A: Postpartum cerebral venous thrombosis. Obstet Gynecol 118:423,t201]

Meems M, Truijens S, Spek \ , et al: Prevalence, course and determinants of carpal tunnel syndrome symptoms during pregnancy: a prospective study. B]OG 122(8):1112,t2015

Miller EC, Gatollari H], Too G, et al: Risk of pregnancy-associated stroke across age groups in New York state.t]AMA Neurol 73(12):1461, 2016 Miyakoshi K, Matsuoka M, Yasutomi 0, et a1: Moyamoya-disease-related isch emic stroke in the postpartum period.t] Obstet Gynaecol Res 35(5):974, 2009

Morgenstern LB, Hemphillt]C 3rd, Anderson C, et a1: Guidelines for the management of spontaneous itracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 41:2108,t2010

Murakami M, Morine M, lwasa T, et al: Management of maternal hydrocephalus requires replacement of ventriculoperitoneal shunt with ventriculoatrial shunt: a case report. Arch Gynecol Obstet 282:339,t20]0

National Spinal Cord Injury Statistical Center: Spinal cord injuty facts and igures at a glance. 2012. Available at: https://ww.nscisc.uab.edu. Accessed March 6, 2017

Nezvalova-Henriksen K, Spigset 0, Nordeng H: Triptan exposure during pregnancy and the risk of major congenital malformations and adverse pregnancy outcomes: results from the Norwegian Mother and Child Cohort Study. Headache 50:563, 2010

Pacheco LD, Saad AF, Hankins GD, et al: Guillain-Barre Syndrome in pregnancy. Obstet GynecoIt128(5):1105, 2016

Padua L, Di Pasquale A, Pazzaglia C, et al: Systematic review of pregnancyrelated carpal tunnel syndrome. Muscle Nerve 42:697,t2010

Pal], Rozsa C, Komoly S, et al: Clinical and biological heterogeneity of autoimmune myasthenia gravis.t] Neuroimmunol 23t1t:43,t20t1t1

Patel SI, Pennell PB: Management of epilepsy during pregnancy: an update.

Ther Adv Neurol Disord 9(2):118, 2016

Pavlovic ]M, Akcali D, Bolay H, et al: Sex-related inluences in migraine. ] Neurosci Res 95(1-2):587, 2017

Perucca E: Birth defects after prenatal exposure to antiepileptic drugs. Lancet NeuroIt4:78t1,t2005

Pires CVG, Linhares 1M, Serzedello F, et al: Alterations in the genital microbiota in women with spinal cord injury. Obstet GynecoIt127(2):273, 2016

Podciechowski L, Brocka-Nitecka U, Dabrowska K, et al: Pregnancy complicated by myasthenia gravis-twelve years' experience. Neuro Endocrinol Lett 26:603, 2005

Polman CH, O'Connor PW, Havrdova E, et al: A randomized, placebocontrolled trial of natalizumab for relapsing multiple sclerosis. N Engl ] Med 354:899, 2006

Portaccio E, Ghezzi A, Hakiki B, et al: Breastfeeding is not related to postpartum relapses in multiple sclerosis. Neurology 77:145,t2011

Portaccio E, Ghezzi A, Hakiki B, et al: Postpartum relapses increase the disability progression in multiple sclerosis: the role of disease modiying drugs. ] Neurol Neurosurg Psychiatry 85(8):845,t2014

Powner D], Bernstein 1M: Extended somatic support in pregnant women after brain death. Crit Care Med 31:1241,t2003

Pritchardt], Hughes RA, Hadden RD: Pharmacological treatment other than corticosteroids, intravenous immunoglobulin and plasma exchange for Guillain-Barre syndrome. Cochrane Database Syst Rev 11:CD008630, 2016

Quant EC, ]este SS, Muni RH, et al: he beneits of steroids versus steroids plus antivirals for treatment of Bell's palsy: a meta-analysis. BM] 339:b3354, 2009

Rifaud L, Ferre ]C, Carsin-Nicol B, et al: Endoscopic third ventriculostomy for the treatment of obstructive hydrocephalus during pregnancy. Obstet Gynecolt108:801,t2006

Robbins MS, Farmakidis C, Dayal AK, et al: Acute headache diagnosis in pregnant women: a hospital-based study. Neurology 85(12):1024,2015

Roger VL, Go AS, L1oyd-]ones DM, et al: Heart disease and stroke statistics20t12 update: a report from the American Heart Association. Circulation 125:e2,t2012

Rudick RA, Goelz SE: Beta-interferon for multiple sclerosis. Exp Cell Res 317: 1301, 2011

Rudick RA, Stuart H,Calabresi PA, et al: Natalizumab plus interferon betala for relapsing multiple sclerosis. N Engl] Med 354:911, 2006

Salminen H], Leggett H, Boggild M: Glatiramer acetate exposure in pregnancy: preliminary safety and birth outcomes. ] Neurol :2020, 2010

Sanders DB, Wolde GI, Benatar M, et al: International consensus guidance for management of myasthenia gravis: executive summary. Neurology 87(4): 419, 2016

Saposnik G, Barinagarrementeria F, Brown RD, et al: Diagnosis and management of cerebral venous thrombosis: a statement for health care professionals from the American Heart Association/American Stroke Association. Stroke 42:1158,t2011

Schiza S, Starnatakis E, Panagopoulou A, et al: Management of pregnancy and delivery of a patient with malfunctioning ventriculoperitoneal shunt. ] Obstet Gynaecol 32(1):6, 2012

Schulman ]D, Stern H]: Low utilization of prenatal and pre-implantation genetic diagnosis in Huntington disease-risk discounting in preventive genetics. Clin Genet 88(3):220, 2015

Schurks M, Rist PM, Kurth T: STin2 VNTR polymorphism in the serotonin transporter gene and migraine: pooled and meta-analyses. ] Headache Pain 11(4): 317, 2010

Scott CA, Bewley S, Rudd A: Incidence, risk factors, management, and outcomes of stroke in pregnancy. Obstet Gynecol 120:318,t2012 Seror P: Pregnancy-related carpal tunnel syndrome. ] Hand Surg Br 23:98, 1998

Shi Q, MacDermid ]C: Is surgical itervention more efective than nonsurgical treatment for carpal tunnel syndrome? A systemic review. ] Orthop Surg 6:17,t201t1

Shmorgun D, Chan WS, Ray ]G: Association between Bell's palsy in pregnancy and pre-eclampsia. 1M 95:359, 2002

Silberstein S, Loder E, Diamond S, et al: Probable migraine in the United States: results of the American Migraine Prevalence and Prevention (AMPP) Study. Cephalalgia 27(3):220, 2007

Simolke GA, Cox SM, Cunningham FG: Cerebrovascular accident complicating pregnancy and the puerperium. Obstet Gynecol 78:37, 1991

Smith WS, Johnston C, Hemphill ]C: Cerebrovascular diseases. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles ofInternal Medicine, 19th ed. McGraw-Hill Education, New York, 2015

Souza ]P, Oliveira-Neto A, Surita FG, et al: he prolongation of somatic support in a pregnant woman with brain-death: a case report. Reprod Health 27:3, 2006

Sperling ]D, Dahlke ]D, Huber l, et al: The role of headache in the classification and management of hypertensive disorders in pregnancy. Obstet GynecoI 126(2):297, 2015

Sullivan FM, Swan IR, Donnan PT, et al: Early treatment with prednisolone or acyclovir in Bell's palsy. N Engl] Med 357:1598, 2007 hambisetry M, Lavin P], Newman N], et al: Fulminant idiopathic intracranial hypertension. Neurology 68:229, 2007 homas SV, Ajaykumar B, Sindhu K, et al: Cardiac malformations are increased in infants of mothers with epilepsy. Pediatr Cardiol 29:604, 2008

Tiel Groenestege AT, Rinkel G], van der Bon ]G, et al: The risk of aneurysmal subarachnoid hemorrhage during pregnancy, delivery, and the puerperium in the Utrecht population: case-crossover study and standardized incidence ratio estimation. Stroke 40(4):1148, 2009

Turner K, Piazzini A, Franza A, et al: Epilepsy and postpartum depression.

Epilepsia 50(1):24, 2009

Tversky S, Libman RB, Reppucci ML, et al: Thrombolysis for ischemic stroke during pregnancy: a case report and review of the literature. ] Stroke Cerebrovasc Dis 25(10):e167, 2016

Vajda F], Hitchcock A, Graham ], et al: Seizure control in antiepileptic drugtreated pregnancy. Epilepsia 49(1): 172, 2008

VanderPluym ]: Cluster headache: Special considerations for treatment of female patients of reproductive age and pediatric patients. Curr Neurol Neurosci Rep 16(1):5, 2016 van der Worp HB, van Gijn ]: Acute ischemic stroke. N Engl ] Med 357(6):572, 2007

Van Teen TR, Panerai RB, Haeri S, et al: Changes in cerebral autoregulation in the second half of pregnancy and compared to non-pregnant controls. Pregnancy Hypertens 6(4):380, 2016

Viale L, Allotey ], Cheong-See F, et al: Epilepsy in pregnancy and reproductive outcomes: a systematic review and meta-analysis. Lancet 386: 1845, 2015 Vukusic S, Confavreux C: Pregnancy and multiple sclerosis: the children of

PRIMS. Clin Neurol Neurosurg 108:266, 2006

Wabnitz A, Bushnell C: Migraine, cardiovascular disease, and stroke during pregnancy: systematic review of the literature. Cephalalgia 35(2): 132, 2015

Wang IK, Chang SN, Liao CC, et al: Hypertensive disorders in pregnancy and preterm delivery and subsequent stroke in Asian women: a retrospective cohort study. Stroke 42:716, 2011

Wasay M, Bakshi R, Bobustuc G, et al: Cerebral venous thrombosis: analysis of a multicenter cohort from the United States. ] Stroke Cerebrovasc Dis 17:49, 2008

Wen ]C, Liu TC, Chen H, et al: No increased risk of adverse pregnancy outcomes for women with myasthenia gravis: a nationwide population-based study. Eur] NeuroI 16:889, 2009

Westgren N, Hultling C, Levi R, et al: Pregnancy and delivery in women with a trauma spinal cord injury in Sweden, 1980-1991. Obstet Gynecol 81:926, 1993

Weston ], Bromley R, Jackson CF, et al: Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database Syst Rev II:CDOI0224, 2016

Wijdicks EFM, Varelas PN, Gronseth GS, et al: Evidence-based guideline update: determining brain death in adults. Neurology 74:1911, 2010

Wisof ]H, Kratzert K], Handwerker SM, et al: Pregnancy in patients with cerebrospinal fluid shunts: report of a series and review of the literature. Neurosurgery 29:827, 1991

Wood ME, Frazier ]A, Nordeng HM, et al: Longitudinal changes in neurodevelopmental outcomes between 18 and 36 months in children with prenatal trip tan exposure: findings from the Norwegian Mother and Child Cohort Study. BM] Open 6(9):eOI1971, 2016

Wyszynski DF, Nambisan M, Surve T, et al: Increased rate of major malformations in ofspring exposed to valproate during pregnancy. Neurology 64:961, 2005

Yager PH, SinghalAV, Nogueira RG: Case 31-2012: an 18-year-old man with blurred vision, dysarthria, and ataxia. N Engl] Med 367: 1450, 2012

Yerby MS: Pregnancy, teratogenesis, and epilepsy. Neurol Clin 12:749, 1994

Yoshida K, Takahashi ]C, Takenobu Y, et al: Strokes associated with pregnancy and puerperium. A nationwide study by the Japan Stroke Society. Stroke 48:276, 2017 Zeeman GG, Fleckenstein ]L, Twickler DM, et al: Cerebral infarction in eclampsia. Am] Obstet Gynecol 190:714, 2004a

Zeeman GG, Hatab M, Twickler DM: Increased cerebral blood low in preeclampsia with magnetic resonance imaging. Am ] Obstet Gynecol 191:1425, 2004b

Zeeman GG, Hatab M, Twickler DM: Maternal cerebral blood low changes in pregnancy. Am] Obstet Gynecol 189:968, 2003

Zofkie A, Cunningham FG: A 33-year single-center experience with pregnancy-associated strokes. Abstract. Presented at the 38th Annual Meeting of the Society for Maternal-Fetal Medicine. February 1-3, 2018

CHAPTER 61 .

PSYCHOLOGICAL ADJUSTMENTS TO PREGNANCY .. 1173

MAJOR DEPRESSION.. . . . . . . . . . . . . . . . . . . . . . . . . .. 1175

BIPOLAR AND RELATED DISORDERS .............. 1178

ANXIETY DISORDERS. . . . . . . . . . . . . . . . . . . . . . . . . .. 1179 SCHIZOPHRENIA SPECTRUM DISORDERS.. . . . . . . . .. 1180 EATING DISORDERS. . . . . . . . . . . . . . . . . . . . . . . . . . .. 1180 PERSONALITY DISORDERS.. . . . . . . . . . . . . . . . . . . . .. 1181 he insaniy ofpregnancy is usualy a manestation of autointoxication, and may be accompanied by melancholic or maniacal symptoms. It usualy persists throughout gestation, but disappears shorty ater labour, unless the patient has an hereditary tendency to mental derangement.

-]. Whitridge Williams (1903)

The subject of mental illness was only briely addressed by Williams in 1903, when it appears that acute puerperal psychoses were manifestations of eclampsia or sepsis. More than 100 years later, we have learned that pregnancy and the puerperium are at times suiciently stressful to provoke mental illness. Such illness may represent recurrence or exacerbation of a preexisting psychiatric disorder, or it may signal the onset of a new condition. his 25th edition of Williams Obstetrics marks only the second edition with a focused chapter dedicated to psychiatric illnesses. To emphasize the rising national interest, American College of 0bstetricians and Gynecologists President Dr. Gerald F. Joseph Jr. declared postpartum depression as an initiative in 2009.

Psychiatric disorders during pregnancy are associated with less prenatal care, substance use, poor obstetrical and neonatal outcomes, and higher rates of postpartum psychiatric illness (Frieder, 2008). Despite these known risks, obstetrical providers often are reluctant to confront or fail to identiy some of these mental health issues during pregnancy. For example, Lyell and colleagues (2012) found that the diagnosis of depression was not documented in nearly half of the records of depressed women. Yet, perinatal mood disorders can have far-reaching consequences beyond the immediate efect on maternal mental health and social function by adversely afecting the motherchild relationship (Weinberg, 1998).

lso, suicide is a primary cause of death among women during the perinatal period in the United States, and major depression is among the strongest predictors of suicidal ideation (Melville, 2010). Between 2004 and 2012, self-harm, suicide, or drug overdose was the leading cause of maternal death in Colorado (Metz, 2016). In a 10-year analysis of Washington state hospitalizations, Comtois and associates (2008) studied 355 women with a postpartum suicide attempt. Substance abuse was linked with a sixfold higher and prior psychiatric hospitalization with a 27 -fold greater risk for suicide. These rates rose further if there were multiple hospitalizations. Also of note, 54 percent of pregnancy-associated suicides involve intimatepartner conlict (Palladino, 201r1).

Biochemical factors and life stressors can markedly inluence mental health and mental illness during the perinatal period. Intuitively, pregnancy exacerbates some coexisting psychological disorders. Namely, an increased risk for mood disorders is linked with pregnancy-related shifts in sex steroid and monoamine neurotransmitter levels, dysfunction of the hypothalamicpituitary-adrenal axis, thyroid dysfunction, and alterations in immune response (Yonkers, 2011). These changes, coupled with familial clustering of depression cases, suggest that there may be a subgroup of women at risk for developing a unipolar major depressive disorder during pregnancy.

Women respond in various ways to stressors of pregnancy, and some express persistent concerns regarding fetal health, child care, lifestyle changes, or fear of childbirth pain. Anxiety, sleep disorders, and unctional impairment are common (Romero, 2014; Vythilingum, 200S). However, according to Littleton and coworkers (2007), anxiety symptoms in pregnancy are associated with psychosocial variables similar to those for nonpregnant women. he level of perceived stress is significantly higher for women whose fetus is at high risk for a malformation, for those with preterm labor or delivery, and for those with other medical complications (Alder, 2007; Ross, 2006). Hippman and colleagues (2009) screened for depression in Sl women who had an increased risk for a fetus with aneuploidy. Half of these women had a positive depression screening score, whereas only 2.4 percent of those with a normal pregnancy did so.

Several steps can be taken to diminish psychological stress in the event of a poor obstetrical outcome. For example, following a stillbirth, Gold (2007) encouraged parental contact with the newborn and provision of photographs and other infant memorabilia. Addressing associated sleep disorders also seems reasonable Quulia Paavonen, 2017; Romero, 2014).

• The Puerperium

This is a particularly stressful time for women, and risks for mental illness are increased. Up to 15 percent of women develop a nonpsychotic postpartum depressive disorder within 6 months of delivery (Tam, 2007; Yonkers, 201r1). A few have a psychotic illness following delivery, and half of these manifest a bipolar disorder. Depressive disorders are more likely in women with obstetrical complications such as severe preeclampsia or fetal-growth restriction, especially if associated with early delivery. Houston and coworkers (2015) found that expectations at delivery also increased the risk for postpartum depression.

Importantly, stressors beyond those directly related to the pregnancy can raise perinatal depression rates. T arney and colleagues (2015) identified spouse deployment as a factor for postpartum depression in a study at Womack Army Medical Center. But, among women with a history of bipolar disorder, these elements playra lesser role in the development of mania or depression (Yonkers, 2011).

Also called pospartum blues, this is a time-limited period of heightened emotional reactivity experienced by half of women within the irst week after parturition. Prevalence estimates for the blues range from 26 to S4 percent depending on diagnostic criteria (O'Hara, 2014). his emotional state generally peaks on the fourth or ifth postpartum day and normalizes by day 10 (O'Keane, 2011).

he predominant mood is happiness, but afected mothers are more emotionally labile. hey also may have insomnia, weepiness, depression, anxiety, poor concentration, and irritability. Mothers may be transiently tearful for several hours and then recover completely, only to be tearful again the next day. Supportive treatment is indicated, and afected women are reassured that the dysphoria is transient and most likely due to biochemical changes. They should be monitored for development of depression and other severe psychiatric disturbances.

Both the American College of Obstetricians and Gynecologists (2016a) and the United States Preventative Services Task Force now recommend screening at least once during the perinatal period for depression and anxiety (Siu, 2016). Identiication of psychiatric disorders in pregnancy can be challenging because changes in behavior and mood are often attributed to pregnancy. To diferentiate these, Yonkers (2011) recommends assessment of cognitive symptoms-for example, loss of concentration. Excessive symptoms of anxiety and insomnia-even during periods of infant sleep-can also suggest postpartum depression. Speciic factors for depression are reviewed and include a prior personal or family history of depression.

Universal-screening programs for depression continue to evolve (Venkatesh, 2016). At Parkland Hospital, mental illness screening is generally done at the irst prenatal visit using a brief risk-based query and again postpartum using a universalapplied screening tool for postpartum depression. Questions search for psychiatric disorders, related therapy, prior or current use of psychoactive medications, and current symptoms. Women with a history of sexual, physical, or verbal abuse; substance abuse; and personality disorders are also at greater risk for depression (man, 2007; Janssen, 2012). History of neglect and abuse are especially powerful antecedents of depression in adolescent pregnancy (Meltzer-Brody, 2014). Smoking and nicotine dependence and obesity also raise rates of all mental disorders in pregnancy (Goodwin, 2007; Molyneaux, 2014). Finally, because eating disorders may be exacerbated by pregnancy, afected women are followed closely (p. l1S0).

Several screening instruments shown in Table 61-1 are available and have been validated for use during pregnany and the puerperium. Use of one of these screening tools is encouraged because symptom-or risk-based screening alone may be insuficient (American College of Obstetricians and Gynecologists, 2016a). Cerimele and colleagues (2013) found that obstetricians and gynecologists failed to identiY 60 percent of depressed women in clinical practice. As mentioned earlier, at Parkland Hospital, all women are screened during their irst postpartum visit using the Edinburgh Postnatal Depression Scale (EPDS). In an analysis of more than 17,000 women, 6 percent had scores that indicated either minor or major depressive symptoms, and 12 women had thoughts of self-harm (Nelson, 2013). Similarly, Kim and coworkers (2015) assessed suicidal ideation in more than 22,000 women screened using the EPDS both during pregnancy and postpartum. They found rates of depression as high as 3.4 percent during the puerperium. A small fraction of those with thoughts of self-harm had a credible plan, intent, and means for attempted suicide. Obviously, suicidal ideation warrants prompt psychiatric consultation for evaluation and management.

Screening for perinatal depression without appropriate subsequent treatment is insuicient (American College of Obstetricians and Gynecologists, 20 16a). hat said, mechanisms to ensure adequate ensuing care can be problematic. In

TABLE 61 -1 . Depression Screening Toolsa

Time to Complete

Edinburgh Postnatal 10 <5 http://www.fresno.ucsf.ed u/ped iatricsl down loadsl edi nbu rg hsca Ie. pdf

Patient Health 9 <5 http://www.integration.samhsa.gov/images/res/PHQ%20-%20Questions.pdf

Center for Epidemiologic 20 5-10 http://www.perinatalweb.org/assets/cms/uploads/files/CES-D.pdf aAIl depression screening tools are also available in Spanish. bAvailable free online.

the study by Nelson and associates (2013) more than three fourths of the 1106 women with abnormally elevated EPDS scores did not keep their later appointment, which ofered more formal psychiatric evaluation. Barriers include diiculties with access to care, personal perception of depression, and societal stigmata (Flynn, 2010; Smith, 2008). Women referred to a behavioral health provider located at the same site as their obstetrical care are four times more likely to access treatment than those referred elsewhere (Smith, 2009). To take advantage of this, at Parkland Hospital, mental health counselors also practice at postpartum clinic sites. Other promising interventions for puerperal depression include home visits, telephonebased peer support, and interpersonal psychotherapy (Dennis, 2013; Lavender, 2013; Yonemoto, 2017). A report from Kaiser Permanente, which describes the benefits and hurdles to system-based perinatal mental health care, provides a glimpse into the possible future of universal perinatal screening and treatment (Avalos, 2016; Flanagan, 2016).

Many psychiatric disorders can be improved with counseling and psychotherapies. In some instances, psychotropic medications are needed. Treatment decisions are ideally shared between patients and their health-care providers. In particular, women taking psychotropic medication are informed of likely side efects. Many of these drugs are discussed in Chapter 12 and by the American College of Obstetricians and Gynecologists (2016b) in their Practice Bulletin No. 92. Some of these drugs are discussed subsequently.

Emerging information on psychiatric disorders and pregnancy outcomes suggest a link between maternal psychiatric illness and untoward outcomes such as preterm birth, low birthweight, and perinatal mortality (Grigoriadis, 2013; Steinberg, 2014; Straub, 2012; Yonkers, 2009). In a study of 16,334 deliveries, Shaw and coworkers (2014) identiied a signiicant association between posttraumatic stress disorder and spontaneous pre term delivery. Domestic abuse-another aforementioned risk factor for perinatal mood disorder-is also linked with adverse perinatal outcomes (Yost, 2005). Finally, Littleton and associates (2007) reviewed 50 studies and concluded that anxiety symptoms, which are commonly comorbid with depression, had no adverse efect on perinatal outcomes.

is the most recent version by the American Psychiatric Associa tion (2013). It assists in classiying mental disorders and speci fies criteria for each diagnosis.

Of categories, depressive disorders are common. According to the National Institute of Mental Health (2010), the life time prevalence of depressive disorders in the United States is 21 percent. Historically, depressive disorders include major bipolar disorder with both manic and depressive episodes. It also includes dysthymia, which is chronic, mild depression.

This is the most common depressive disorder, and the 12-month prevalence of major depressive episodes among U.S. women is 8.2 percent (Center for Behavioral Health Statistics and Quality, 2015). In 2011 to 2014, 16 percent of U.S. women had used an antidepressant in the prior month (Pratt, 2017). The diagnosis is made by identiying symptoms listed in Table 61-2, but very few patients manifest all of these.

Major depression is multifactorial and prompted by genetic and environmental factors. Families of afected individuals often also have members sufering with alcohol abuse and anxiety disorders. Provocative conditions leading to depression include life events that prompt grief reactions, substance abuse, use of certain medications, and other medical disorders. Although life events can trigger depression, genes influence the response to these events and render the distinction between genetic and environmental factors diicult. One genome-wide linkage analysis of more than 1200 mothers suggests that variation in chromosomes 1 and 9 raises susceptibility to postpartum mood symptoms (Mahon, 2009).

It is unquestionable that pregnancy is a major life stressor that can precipitate or exacerbate depressive tendencies. In

TABLE 61-2. Symptoms of Depressive IIlnessa

Persistent sad, anxious, or "empty" feelings worthlessness, and/or helplessness

Irritabi Iity, restlessness

Loss of interest in activities once pleasurable, including sex Fatigue and decreased energy

Difficulty concentrating, remembering details, and making decisions Insomnia, early-morning wakefulness, or excessive sleeping Overeating or appetite loss

Thoughts of suicide, suicide attempts

Persistent aches or pains, headaches, cramps or digestive problems that do not ease with treatment aNot all patients experience the same symptoms.

Modified with permission from National Institute of Mental Health, 2010.

addition, various pregnancy-induced efects are implicated. Hormones certainly afect mood, as evidenced by premenstrual Major or minor depression develops postpartum in 10 to 20 syndrome and menopausal depression. Estrogen has been percent of women (Mental Health America, 2016). Available linked to increased serotonin synthesis, decreased serotonin data indicate that unipolar major depression may be slightly breakdown, and serotonin-receptor modulation (Deecher, more prevalent during the puerperium than among women in 2008). Concordantly, women who experience postpartum the general population (Yonkers, 2011). Postpartum depressive depression often have higher predelivery serum estrogen and symptoms are associated with young maternal age, antenatal progesterone levels and experience a greater decline postpardepression, unmarried status, smoking, newborns requiring tum (Ahokas, 1999). intensive care, and those with a history of stressors during preg

Dennis and associates (2007) queried the Cochrane Datanancy (Ko, 2017; Silverman, 2017). Speciically, physical or base and reported that the prevalence of antenatal depression verbal abuse during pregnancy is a potent risk for postpartum averaged 11 percent. Melville and coworkers (2010) found it depression (McFarlane, 2014). Finally, serious adverse obstetriin nearly 10 percent of more than 1800 women enrolled for cal events, especially those involving the neonate, are strongly prenatal care at a single university clinic. Others have reported linked to postpartum depression (Nelson, 2013, 2015). the incidence to be much higher depending on the population Depression is frequently recurrent. Up to 70 percent of studied (Gavin, 2005; Hayes, 2012; Lee, 2007). women with previous postpartum depression have a subsequent aChapter 12 (p. 245). bChapter 60 (p. 11r60).

SSRI = Selective serotonin-reuptake inhibitor.

Data from Briggs, 2015; Huybrechts, 2015; Koren, 2012.

Immediate referral to psychiatrist if no response, consider antidepressant Rx; antidepressant psychotherapy beneficial for pregnant women with mood disorders.

episode. Women with both prior puerperal depression and a current episode of "maternity blues" carry an inordinately high risk for major depression. Indeed, 2 to 9 months postpartum, assistance with postpartum depression was the fourth most common challenge identiied in women in the Pregnancy Risk Assessment Monitoring System-PRAMS (Kanotra, 2007).

Postpartum depression is generally underrecognized and undertreated. Major depression during pregnancy or after delivery can have devastating consequences for afected women, their children, and families. One of the most significant contributions to the mortality rate among new mothers is suicide, which is most frequent among women with mental illness (Koren, 2012; Palladino, 2011). If left untreated, up to 25 percent of women with postpartum depression will be depressed 1 year later. As the duration of depression increases, so too does the number of sequelae and their severity. Maternal depression during the first weeks and months after delivery can lead to insecure attachment and later behavioral problems in the child.

Therapy for mood disorders during pregnancy and postpartum has undergone a significant evolution during the past decade. Babbitt (2014) and Pozzi (2014) and their associates have reviewed principles of antenatal and intrapartum care of women with major mental disorders. In general, for mild and mild-moderate depression, psychological treatment options, such as cognitive behavioral therapy, are considered irst (Yonkers, 2011). Antidepressant medications together with some form of psychotherapy are indicated for moderate to severe depression during pregnancy or the puerperium (American College of Obstetricians and Gynecologists, 2016b).

Shown in Figure 61-1 is one algorithm regarding treatment of mood disorders. Some of these medications are listed in 1 able 61-3. For women with severe depression, a selective sero tonin-reuptake inhibitor (SSRI) is selected initially. In contrast, tricyclic antidepressants and monoamine oxidase inhibitors are infrequently selected in contemporary practice. If depressive symptoms improve during a 6-week trial, the medication is continued for a minimum of 6 months to prevent relapse (Wisner, 2002). At least 60 percent of women taking antidepressant medication before pregnancy have symptoms during pregnancy. According to Hayes and colleagues (2012), approximately three fourths of women taking antidepressants before pregnancy stopped taking them before or during early pregnancy. For those who discontinue treatment, almost 70 percent have a relapse compared with approximately 25 percent who continue therapy. If the response is suboptimal or a relapse occurs, another SSRI is substituted, or psychiatric referral is considered.

Various dietary deiciencies have suggested links to perinatal depression (Yonkers, 2011). Supplements that include omega-3 fatty acids, iron, folate, ribolavin, vitamin D, calcium, and docosahexaenoic acid (DHA) have been studied (Keenan, 2014; Miller, 2013). However, evidence currently is insuicient to support use of these dietary supplements for this purpose.

Importantly, in a metaanalysis by Huang and coworkers (2014), women using antidepressants during pregnancy have higher rates of preterm birth and low-birthweight neonates. Nevertheless, in their review, Ray and Stowe (2014) concluded that the relative reproductive safety data are reassuring and that antidepressants remain a viable treatment option. Furthermore, recurrence sometime after medication is discontinued develops in 50 to 85 percent of women with an initial postpartum depressive episode. Women with a history of more than one depressive episode carry greater risk (American Psychiatric Association, 2000). Surveillance includes monitoring for thoughts of suicide or infanticide, emergence of psychosis, and response to therapy. For some women, the course of illness is severe enough to warrant hospitalization.

Fetal and Neonatal Efects of Therapy. Some known and possible fetal and neonatal efects of treatment are listed in Table 61-3. Some studies suggest that SSRIs pose an elevated teratogenic risk for fetal cardiac defects, and these have mainly focused on paroxetine (Paxil). Associations were most consistent for ventricular septal defects. The estimated risk is no greater than 1 in 200 exposed newborns (Koren, 2012). Nevertheless, the American College of Obstetricians and Gynecologists (20 16b) recommends that paroxetine be avoided in women who are either pregnant or planning pregnancy. In women exposed to paroxetine in the irst trimester, fetal echocardiography is considered. Jimenez-Solem and coworkers (2013) in their analysis of SSRIs found no association between exposure to SSRIs during pregnancy and perinatal mortality. Andersen and associates (2014) found that women discontinuing SSRI treatment in early pregnancy had a small increased risk of miscarriage, but that this was similar to the risk in women discontinuing SSRI treatment months before pregnancy. Taken together, these investigators concluded that treatment with SSRIs during pregnancy should not be discontinued for fear of miscarriage.

Of other potential efects, the risk of persistent pulmonary hypertension of the newborn rose sixfold in neonates exposed to SSRIs after 20 weeks' gestation (Chambers, 2006). his translates to an overall risk of pulmonary hypertension that would be less than 1 in 100 exposed newborns (Koren, 2012). In contrast, a population-based cohort study of 1.6 million pregnancies identiied a twofold greater rate in exposed neonates. his yields an estimated attributable risk of 2 cases per 1000 births (Kieler, 2012). In a study of more than 120,000 gravidas prescribed antidepressants, Huybrechts and coworkers (2015) found an attributed risk of 1 case per 1000 births.

In sum, the maternal risk associated with discontinuing or tapering SSRI use during pregnancy must be weighed against marginally increased neonatal risks (Ornoy, 2017). Women who abruptly discontinue either serotonin-or norepinephrinereuptake inhibitor therapy typically experience some form of withdrawal.

Not surprisingly, up to 30 percent of exposed neonates may also exhibit withdrawal symptoms. Symptoms are similar to opioid withdrawal, but typically are less severe. Neonatal SSRI withdrawal is usually self-limited, and the newborn rarely remains in the nursery more than 5 days (Koren, 2009). Currently, convincing evidence of long-term neurobehavioral efects of fetal exposure to these medications is lacking (Koren, 2012). Grzeskowiak and coworkers (2016) found no increased risk of behavioral problems in 7 -year-old children exposed to antidepressants prior to their birth.

Some psychotropic medications pass into breast milk. In most cases, however, levels are very low or undetectable. Efects may be transient irritability, sleep disturbances, and colic.

Electroconvulsive Therapy. This form of depression treatment is occasionally necessary during pregnancy for women with major mood disorders unresponsive to pharmacotherapy. Women undergoing electroconvulsive therapy (ECT) should be fasting for at least 6 hours. hey are given a rapid-acting antacid before the procedure, and their airway is protected to decrease the likelihood of aspiration. Ater midpregnancy, a wedge is placed under the right hip to prevent sudden maternal hypotension from aortocaval compression. Other important preparatory steps include assessment of the cervix, discontinuation of nonessential anticholinergic medication, uterine and fetal heart rate monitoring, and intravenous hydration. During the procedure, excessive hyperventilation is avoided. In most cases, maternal and fetal heart rate and maternal blood pressure and oxygen saturation remain normal throughout the procedure.

With proper preparation, the risks to both mother and fetus appear to be reasonable (Pinette, 2007). hat said, adverse maternal and perinatal outcomes have followed ECT. Balki and associates (2006) reported a pregnancy in which fetal brain damage likely was caused by sustained maternal hypotension associated with treatment of status epilepticus stimulated by ECT.

At least two extensive reviews have evaluated ECT outcomes in pregnancy. In the earlier one, Miller (1994) found 300 cases and reported complications in 10 percent. These included fetal arrhythmias, vaginal bleeding, abdominal pain, and self-limited contractions. Women not adequately prepared had increased risks for aspiration, aortocaval compression, and respiratory alkalosis. In the more recent review, Andersen and Ryan (2009) described 339 cases, undoubtedly with some homology with the earlier study. In most cases, ECT therapy was done to treat depression, and it was 78-percent efective. hey reported a 5-percent maternal ECT -related complication rate. here was a 3-percent associated perinatal complication rate, which included two fetal deaths. For all of these reasons, we agree with Richards (2007) that ECT in pregnancy is not "low risk" and that it should be reserved for women whose severe depression is resistant to intensive pharmacotherapy.

According to the National Institute of Mental Health (2010), the lifetime prevalence for manic-depression illness is 3.9 percent. he prevalence of bipolar disorder does not vary between gravidas and nonpregnant reproductive-aged women (Yonkers, 2011). It has a strong genetic component and has been linked to possible mutations on chromosomes 16 and 8 (Jones, 2007). The risk that monozygotic twins are both afected is 40 to 70 percent, and the risk for first-degree relatives is 5 to 10 percent (Muller-Oerlinghausen, 2002).

Periods of depression last at least 2 weeks. At other times, patients are manic, in which mood is abnormally raised, expan sive, or irritable. Potential organic causes of mania include substance abuse, hyperthyroidism, and central nervous system (CNS) tumors. hese are all excluded during an acute event.

Importantly, pregnancy frequently prompts medication dis continuation, which poses a twofold increased risk for relapse (Viguera, 2007). Afected women are considered high risk, and as many as 20 percent of patients with manic-depression illness commit suicide.

his has also been associated with adverse perinatal outcomes, for example, preterm birth (Mei-Dan, 2015). Di Florio and associates (2013) found that those women who experience pregnancy complications are more likely to exhibit periods of mania or depression. Women who tend to be manic present with exacerbations earlier in the postpartum period.

Typical therapy for bipolar disorder includes mood stabilizers such as lithium, valproic acid, and carbamazepine, as well as antipsychotic medications (see Table 61-3). Treatment of bipolar disorder in pregnancy is complex and is ideally managed concurrently with a psychiatrist. Decisions include risks versus benefits of using mood stabilizers, some of which are teratogenic. For example, lithium has been linked to Ebstein anomaly in exposed fetuses. More recent data, however, suggest a lower risk of cardiac malformations than previously indicated (Micromedex, 2016; Patomo, 2017) . Nevertheless, many recommend fetal echocardiography for lithium-exposed fetuses. Some limited evidence suggests that lithium in breast milk, when its elimination is impaired as in dehydration or immaturity, can adversely afect the infant (Davanzo, 2011). However, lithium use in mothers with a healthy, term fetus is considered moderately safe. A more detailed discussion of other mood stabilizers and antipsychotic medications side efects can be found in Chapter 12 (p. 244).

This severe mental disorder is usually a bipolar disorder, but it may be due to major depression (American Psychiatric Association, 2013). Its incidence is estimated to be 1 in every 1000 deliveries, and it is more common in nulliparas, especially those with obstetrical complications (Bergink, 2011; Blackmore, 2006). In most cases, illness manifests within 2 weeks of delivery. In one study of postpartum women with their first lifetime episode of psychosis, the median onset of psychiatric symptoms was 8 days after delivery, and the median duration of the episode was 40 days (Bergink, 2011). Because those with underlying psychiatric disease have a 10-to 15-fold risk for recurrence postpartum, close monitoring is imperative.

The most important risk for postpartum psychosis is a history of bipolar disease. These women typically exhibit symptoms within 1 to 2 days after delivery (Heron, 2007, 2008). Manic symptoms include feeling excited or elated, being active or energetic, feeling "chatty," and sufering insomnia. Afected women have signs of confusion and disorientation but may also have lucid episodes.

Postpartum psychosis has a 50-percent recurrence risk in the next pregnancy. As a result, Bergink and associates (2012) rec in women with a history of postpartum psychosis.

The clinical course of bipolar illness with postpartum psycho sis is comparable with that for nonpregnant women. Patients usually require hospitalization, pharmacological treatment, and long-term psychiatric care. Psychotic women may have delu sions leading to thoughts of self-harm or harm to their infants.

Unlike women with nonpsychotic depression, these women commit infanticide, albeit uncommonly (Kim, 2008). In most instances, women with postpartum psychosis ultimately develop relapsing, chronic psychotic manic-depression.

These relatively common disorders-18 percent prevalence overall-include panic attack, panic disorder, social anxiety disorder, specific phobia, separation anxiety disorder, and generalized anxiety disorder. All are characterized by irrational fear, tension, and worry, which are accompanied by physiological changes such as trembling, nausea, hot or cold lashes, dizziness, dyspnea, insomnia, and frequent urination (Schneier, 2006). They are treated with psychotherapy and medication, including SSRIs, tricyclic antidepressants, monoamine oxide inhibitors, or others.

Despite the relative high prevalence in childbearing-aged women, little speciic attention has been directed to anxiety disorders in pregnancy. Most reports conclude that rates between pregnant and nonpregnant women do not difer. One recent analysis of 268 gravidas with generalized anxiety disorder demonstrated that both symptoms and severity of anxiety decline across pregnancy (Buist, 2011).

From their review, Ross and McLean (2006) concluded that some of the anxiety disorders may have important matemalfetal implications. Some have been linked to preterm birth, fetal-growth restriction, and poor neurobehavioral development (Van den Bergh, 2005). Children with a history of in utero exposure to maternal anxiety are felt to be at increased risk for various neuropsychiatric conditions such as attention-deicit/ hyperactivity disorder (ADHD). Hunter and coworkers (2012) analyzed infants of 60 mothers with an anxiety disorder and found that auditory sensory gating-a relection of inhibitory neurotransmission-was impaired, particularly in ofspring of untreated women. Conversely, Littleton and associates (2007) found no excessive adverse pregnancy outcomes with "anxiety symptoms." One important exception is their link with postpartum depression (Vythilingum, 2008).

Anxiety disorders can be efectively treated during pregnancy with psychotherapy, cognitive-behavioral therapy, or medications. vlood and anxiety disorders coexist in more than half of women identified with either diagnosis (Frieder, 2008). hus, antidepressants listed in Table 61-3 are often the first line of pharmacotherapy.

Benzodiazepines are also commonly used to treat anxiety or panic disorders before and during pregnancy. Earlier casecontrol studies linked use of these CNS depressants to a possible increased risk for cleft lip and palate. A metaanalysis of more than 1 million exposed pregnancies, however, did not identiY a teratogenic risk (Enato, 2011). Benzodiazepines, especially when taken during the third trimester, can cause neonatal withdrawal syndrome, which persists for days to weeks after delivery.

his major form of mental illness afects 1.1 percent of adults (National Institute of Mental Health, 2016). Schizophrenia spectrum disorders are defined by abnormalities in one or more of the following domains: delusions, hallucinations, disorganized thinking, grossly disorganized or abnormal motor behavior, and negative symptoms. Brain-scanning techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (MRI) show that schizophrenia is a degenerative brain disorder. Subtle anatomical abnormalities are present early in life and worsen with time.

Schizophrenia has a major genetic component, and there is a 50-percent concordance in monozygotic twins. If one parent has schizophrenia, the risk to ofspring is 5 to 10 percent. Some data, including a strong association between schizophrenia and the velocardiofacial syndrome, suggest that associated genes are located on chromosome 22q 11 (Murphy, 2002). But sophisticated gene mapping studies clearly show that schizophrenia is not related to a single gene or mutation. Instead, multiple DNA variants likely interact to lead to schizophrenia (Kukshal, 2012). Other putative risks for subsequent schizophrenia in an exposed fetus include maternal iron-deiciency anemia, diabetes, and acute maternal stress (Insel, 2008; Malaspina, 2008; Van Lieshout, 2008). hese remain unproven, as does the association with maternal inluenza A infection.

Signs of illness begin approximately at age 20 years, and commonly, work and psychosocial functioning deteriorate over time. Women have a slightly later onset than men and are less susceptible to autism and other neurodevelopmental abnormalities. hus, many investigators theorize that estrogen is protective. Afected women may become pregnant before symptoms manifest. With appropriate treatment, patients can experience a decrease or cessation of symptoms. Within 5 years from the irst signs of illness, 60 percent have social recovery, 50 percent are employed, 30 percent are mentally handicapped, and 10 percent require continued hospitalization (American Psychiatric Association, 2013).

vlost studies have not found adverse maternal outcomes, although researchers in a Swedish study noted increased rates of low birthweight, fetal-growth restriction, and preterm delivery (Bennedsen, 1999). In a study of more than 3000 pregnancies in schizophrenic women, Jablensky and coworkers (2005) reported that placental abruption was increased threefold and "fetal distress" -vaguely deined-was increased l.4-fold.

Because schizophrenia has a high recurrence if medications are discontinued, continued therapy during pregnancy is advised. Ater 40 years of use, no evidence links the conventional or "typical" antipsychotic drugs listed in Table 61-3 and adverse fetal or maternal sequelae (McKenna, 2005; Robinson, 2012; Yaeger, 2006). Because less is known about "atypical" antipsychotics, the American College of Obstetricians and Gynecologists (2016b) recommends against their routine use in pregnant and breastfeeding women. In response to adverse event reports, the Food and Drug Administration (2011) issued a safety communication alerting health-care providers concerning some antipsychotic medications. hese have been associated with neonatal extrapyramidal and withdrawal symptoms similar to the neonatal behavioral syndrome seen in those exposed to SSRIs.

hese include anorexia nervosa, in which the patient refuses to maintain minimally normal body weight, and bulimia nervosa, in which binge eating is usually followed by purging or excessive fasting to maintain normal body weight (Zerbe, 2008). Eating behavior disturbances largely afect adolescent females and young adults. With anorexia and bulimia, the lifetime prevalence for each is 2 to 3 percent (National Institute of Mental Health, 2016).

Bulik and coworkers (2009) studied pregnancy outcomes in almost 36,000 Norwegian women screened for eating disorders. Approximately 0.1 percent had anorexia nervosa, 0.85 percent had bulimia nervosa, and 5.1 percent reported a binge-eating disorder. This 6-percent pregnancy prevalence is similar to the 6-month prevalence for nonpregnant individuals (National Institute of Mental Health, 2016). he last subtype had a higher risk for large-for-gestational age neonates with a concomitantly increased cesarean delivery rate. All eating disorders begin with the desire to be slim, and women with chronic eating disorders may migrate between subtypes (Andersen, 2009).

Early pregnancy complication rates are increased with both eating disorders, but especially in women with bulimia nervosa (Andersen, 2009; Hofman, 2011). Generally, eating disorder symptoms improve during pregnancy, and remission rates may reach 75 percent. In contrast, typical cases of hyperemesis gravidarum may actually be a new or relapsing case of bulimia nervosa or of binge-purge type anorexia nervosa (Torgerson, 2008). As perhaps expected, anorexia is associated with low-birthweight neonates (Micali, 2007). Additional risks associated with eating disorders include poor wound healing and diiculties with breastfeeding (Andersen, 2009). At a minimum, closely monitoring gestational weight gain in women with a suspected history of an eating disorder seems prudent.

Care for these women involves a multidisciplinary team that includes an obstetrician, mental health provider, and either dietician or nutritionist (American Dietetic Association, 2006).

Psychological treatment is the cornerstone for treatment in women with eating disorders and frequently includes cognitivebehavioral therapy. Anorexia nervosa oten responds to motivational interactions with meal planning (Cardwell, 2013). After delivery, women with eating disorders are more prone to postpartum depression. Women with bulimia are at particular risk for disease rebound ater delivery because of body image concerns.

hese disorders are characterized by the chronic use of certain coping mechanisms in an inappropriate, stereotyped, and maladaptive manner. hey are rigid and unyielding personality traits. The American Psychiatric Association (2013) recognizes three clusters of personality disorders: 1.

Paranoid, schizoid, and schizotypal personality disorders, which are characterized by oddness or eccentricity.

2.

Histrionic, narcissistic, antisocial, and borderline disorders, which are all characterized by dramatic presentations along with self-centeredness and erratic behavior.

3.

Avoidant, dependent, compulsive, and passive-aggressive personalities, which are characterized by underlying fear and anxiety.

Genetic and environmental factors are important in the genesis of these disorders, whose prevalence may be as high as 20 percent. lthough management is through psychotherapy, most afected individuals do not recognize their problem, and thus only 20 percent seek help. In an observational study of 202 women with borderline personality disorder, De Genna during the most severe trajectory of their illness. hey are at increased risk for teen and unintended pregnancies.

Personality disorders during pregnancy are probably no diferent than in nonpregnant women. Akman and colleagues (2007) reported that avoidant, dependent, and obsessive-compulsive disorders are associated with an excessive prevalence of postpartum major depression. Magnusson and associates (2007) found a link between some personaliy traits-not disordersand excessive alcohol consumption, but not necessarily addiction or dependence. Conroy and coworkers (2010) found that a mother's ability to care for her newborn was impaired only when a personality disorder was coupled with depression.

Ahokas A, Kaukorantat], Aito M: Efect of oestradiol on postpartum depres sion. Psychopharmacology 146: 108, 1999 Akman C, Uguz F, Kaya N: Postpartum-onset major depression is associated with personality disorders. Compr Psychiatry 48:343, 2007

Alder ], Fink N, Bitzer ], et al: Depression and anxiety during pregnancy: a risk factor for obstetric, fetal and neonatal outcome? A critical review of the literature. ] Matern Fetal Neonatal Med 20: 189, 2007 American College of Obstetricians and Gynecologists: Screening for perinatal depression. Committee Opinion No. 630. May 2015, Reairmed 2016a American College of Obstetricians and Gynecologists: Use of psychiatric medication during pregnancy and lactation. Practice Bulletin No. 92. April 2008, Reairmed 2016b American Dietetic Association: Position of the American Dietetic Association: nutritional intervention in the treatment of anorexia nervosa, bulimia ner vosa, and other eating disorder. ] Am Diet Assoc 106:2073Y2082, 2006

American Psychiatric Association: Guidelines for the treatment of patients with major depressive disorder (revision). Am] Psychiatry 157:1,2000

American Psychiatric Association: The Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5). rlington, American Psychiatric Publishing, 2013 Andersen E, Ryan GL: Eating disorders in the obstetric and gynecologic patient population. Obstet Gynecol 114: 1353, 2009

Andersen ]T, Andersen NL, Horwitz H, et al: Exposure to selective serotonin reuptake inhibitors in early pregnancy and the risk of miscarriage. Obstet Gynecol 124(4):655,t2014

Avalos A, Raine-Bennett T, Chen H, et al: Improved perinatal depression screening, treatment, and outcomes with a universal obstetric program. Obstet GynecoIt127(5):917, 2016

Babbitt E, Bailey K], Coverdale ]H, et al: Professionally responsible intrapartum management of patients with major mental disorders. Am ] Obstet Gynecol 210:27, 2014

Balki M, Castro C, Ananthanarayan C: Status epilepticus after electroconvulsive therapy in a pregnant patient. Int] Obstet Anest 15:325,2006

Bennedsen BE, Mortensen PB, Olesen Av, et al: Preterm birth and intra-uterine growth retardation among children of women with schizophrenia. Br] Psychiatry 175:239, 1999

Bergink V, Bouvy PF, Vervoort ]S, et al: Prevention of postpartum psychosis and mania in women at high risk. Amt] Psychiatry 169:609, 2012

Bergink V, van den Berg L, Koorengevel KM, et al: First-onset psychosis occurring in the postpartum period: a prospective cohort study. ] Clin Psychiatry 72(1t1):1531,t2011

Blackmore ER, Jones I, Doshi M, et al: Obstetric variables associated with bipolar afective puerperal psychosis. Br] Psychiatry 188:32, 2006

Briggs GG, Freeman RK: Drugs in Pregnancy and Lactation, 10th ed. Philadelphia, Wolters Kluwer, 2015

Buist A, Gotman N, Yonkers A: Generalized anxiety disorder: course and risk factors in pregnancy.] Afective Dis 131(1-3):277,t2011

Bulik CM, Von Holle A, Siega-Riz AM, et al: Birth outcomes in women with eating disorders in the Norwegian mother and child cohort (MoBa). Int ] Eat Disord 42(1):9, 2009

Cardwell MS: Eating disorder during pregnancy. Obstet Gynecol Surv 68(4):312,t2013

Center for Behavioral Health Statistics and Quality: Behavioral health trends in the United States: results from the 2014 National Survey on Drug Use and Health. HHS Publication No. SMA 15-4927, NSDUH Series H-50, 2015

Cerimele ]M, Vanderlip ER, Croicu CA, et al: Presenting symptoms of women with depression in an obstetrics and gynecology setting. Obstet Gynecol 122(2 Pt 1):313,t2013

Chambers CD, Hernandez-Diaz S, Van Martin L], et al: Selective serotoninreuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl ] Med 354(6):579, 2006

Comtois A, SchifMA, Grossman DC: Psychiatric risk factors associated with postpartum suicide attempt in Washington state, 1992-2001. Amt] Obstet Gynecol 199:120.e1, 2008

Conroy S, Marks MN, Schacht R, et al: The impact of maternal depression and personality disorder on early infant care. Soc Psychiatry Epidemiol 45(3):285,t2010

Davanzo R, Copertino M, De Cunto A, et al: Antidepressant drugs and breastfeeding: a review of the literature. Breastfeeding Med 6(2):89, 2011

Deecher D, Andree TH, Sloan D, et al: From menarche to menopause: exploring the underlying biology of depression in women experiencing hormonal changes. Psychoneuroendocrinology 33:3, 2008

De Genna NM, Feske U, Larkby C, et al: Pregnancies, abortions, and births among women with and without borderline personality disorder. Women's Health Issues 22(4):e371, 2012

Dennis CL, Dowswell T: Psychological interventions for preventing postpartum depression. Cochrane Database Syst Rev 2:CD001134, 2013

Dennis CL, Ross LE, Grigoriadis S: Psychosocial and psychological interventions for treating antenatal depression. Cochrane Database Syst Rev 3:CD006309,t2007

Di Florio A, Forty L, Gordon-Smith K, et al: Perinatal episodes across the mood disorder spectrum.t]AMA Psychiatry 70(2):168,t2013

Enato E: he fetal safety of benzodiazepines: an updated meta-analysis. ] Obstet Gynaecol Can 33(4):319,t2011

Flnagan T, Avalos A: Perinatal obstetric oice depression screening and treatment: implementation in a health care system. Obstet GynecoIt127(5):911, 2016

Flynn A, Henshaw E, O'Mahen H, et al: Patient perspectives on improving the depression referral processes in obstetrics settings: a qualitative study. Gen Hosp Psychiatry 32:9,t2010

Food and Drug Administration: Antipsychotic drug labels updated on use during pregnancy and risk of abnormal muscle movements and withdrawal symptoms in newborns, 201t1. Available at: http://www.fda.gov/Drugs/ DrugSafety/ucm243903.htm. Accessed July 12,t2016

Frieder A, Dunlop AI, Culpepper L, et al: The clinical content of preconception care: women with psychiatric conditions. Am ] Obstet Gynecol 199:S328,t2008

Gavin NI, Gaynes BN, Lohr N, et al: Perinatal depression: a systematic review of prevalence and incidence. Obstet Gynecolt106:1071, 2005

Gold K], Dalton VK, Schwenk TL: Hospital care for parents after perinatal death. Obstet Gynecol 109: 1156, 2007

Goodwin RD, Keyes K, Simuro N: Mental disorders and nicotine dependence among pregnant women in the United States. Obstet Gynecolt1 09:875, 2007

Grigoriadis S, VonderPorten EH, Mamisashvili L, et al: he impact of maternal depression during pregnancy on perinatal outcomes: a systematic review and meta-analysis.] Clin Psychiatry 74(4):e321, 2013

Grzeskowiak LE, Morrison ]L, Henriksen TB, et al: Prenatal antidepressant exposure and child behavioural outcomes at years of age: a study within the Danish National Birth Cohort. B]OG 123(12):1919,t2016

Hayes RM, Wu P, Shelton RC, et al: Maternal antidepressant use and adverse outcomes: a cohort study of 228,876 pregnancies. Am ] Obstet Gynecol 207:49.e1,t2012

Heron], Blackmore ER, McGuinnes M, et al: No "latent period" in the onset of bipolar afective puerperal psychosis. Arch Womens Ment Health 10:79, 2007

Heront], McGuinness M, Blackmore ER, et al: Early postpartum symptoms in puerperal psychosis. B]OG 115(3):348,2008

Hippman C, Oberlander TG, Honer WG, et al: Depression during pregnancy: the potential impact of increased risk for fetal aneuploidy on maternal mood. Clin Genet 75(1):30, 2009

Hofman ER, Zerwas SC, Bulik CM: Reproductive issues in anorexia nervosa.

Obstet Gynecol 6:403, 2011

Houston A, Kaimal A], Nakagawa S, et al: Mode of delivery and postpartum depression: the role of patient preferences. Am ] Obstet Gynecol 212(2):229.e1,2015

Huang H, Coleman S, Bridge ]A, et al: A meta-analysis of the relationship berween antidepressant use in pregnancy and the risk of preterm birth and low birth weight. Gen Hosp Psychiatry 36(1):13,t2014

Hunter SK, Mendoza], D'Anna K: Antidepressants may mitigate the efects of prenatal maternal anxiety on infant auditory sensory gating. Amt] Psychiatry 169:616,t2012

Huybrechts F, Bateman BT, Palmsten K, et al: Antidepressant use late in pregnancy and risk of persistent pulmonary hypertension of the newborn. ]AMA 313(21):2142,t2015

Insel B], Schaefer CA, McKeague IW, et al: Maternal iron deficiency and the risk of schizophrenia in ofspring. Arch Gen Psychiatry 65(10):1136,t2008 ] ablensky A V, vlorgan V, Zubrick SR, et al: Pregnancy, delivery, and neonatal complications in a population cohort of women with schizophrenia and major afective disorders. Amt] Psychiatry 162:79,t2005

Janssen PA, Heaman MI, Urquia ML, et al: Risk factors for postpartum depression among abused and nonabused women. Am] Obstet GynecoI207:489.e1, 2012

Jimenez-Solem E, Andersen ]T, Petersen M, et al: SSRI use during pregnancy and risk of stillbirth and neonatl mortality. Am] Psychiatry 170(3):299, 2013

Jones I, Hamshere M, Nangle ]M, et al: Bipolar afective puerperal psychosis: genome-wide significant evidence for linkage to chromosome 16. Amt] Psychiatry 164:999, 2007 ]uulia Paavonen E, Saarenpaa-Heikkila 0, Polkki P, et al: Maternal and paternal sleep during pregnancy in the Child-sleep birth cohort. Sleep Med , 2017

Kanotra S, D'Angelo 0, Phares TM, et al: Challenges faced by new mothers in the early postpartum period: an analysis of comment data from the 2000 Pregnancy Risk Assessment Monitoring System (PMS) Survey. Matern Child Health] 11(6):549,t2007

Keenan K, Hipwell E, Bortner ], et al: Association berween fatty acid supplementation and prenatal stress in African Americans: a randomized controlled trial. Obstet Gynecol 124(6):1080,2014

Kieler H, Artama M, Engeland A, et al: Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population based cohort study from the ive Nordic countries. BM] 344:d8012, 2012

Kim ]H, Choi SS, Ha K: A closer look at depression in mothers who kill their children: is it unipolar or bipolar depression? ] Clin Psychiatry 69(10):1625, 2008

Kim J], La Porte LM, Saleh MP, et al: Suicide risk among perinatal women who report thoughts of self-harm on depression screens. Obstet Gynecol 125(4):885,t2015

Ko ]Y, Rockhill KM, Tong T, et al: Trends in Postpartum Depressive Symptoms-27 States, 2004, 2008, and 2012. MMx'R 66(6):153,t2017

Koren G, Finkelstein Y, Matsui 0, et al: Diagnosis and management of poor neonatal adaptation syndrome in newborns exposed in utero to selective serotonin/norepinephrine reuptake inhibitors. ] Obstet Gynaecol Can 31(4):348,2009

Koren G, Nordeng H:

Antidepressant use during pregnancy: the beneit-risk ratio. Amt] Obstet ,t2012

Kukshal P, Thelma BK, Nimgaonkar VL, et al: Genetics of schizophrenia from a clinical perspective. Int Rev Psychiatry 24(5):393, 2012

Lavender T, Richens Y, Milan S], et al: Telephone support for women during pregnancy and the irst six weeks postpartum. Cochrane Database Syst Rev 7:CD009338,t2013

Lee M, Lam SK, Lau SM, et al: Prevalence, course, and risk factors for antenatal anxiety and depression. Obstet Gynecol 110: 11 02, 200

Littleton HL, Breitkopf CR, Berenson AB: Correlates of anxiety symptoms during pregnancy and association with perinatal outcomes: a meta-analysis. Am] Obstet Gynecol 196(5):424,t200

Lyell 0], Chambers AS, Steidtmann 0, et al: Antenatal identiication of major depressive disorder: a cohort study. Am] Obstet GynecoI207(6):506.e1, 2012 Magnusson A, Goransson M, Heilig M: Hazardous alcohol users during pregnancy: psychiatric health and personality traits. Drug Alcohol Depend 89:275, 200 Mahon P, Payne ]L, MacKinnon OF, et al: Genome-wide linkage and follow-up association study of postpartum mood symptoms. Am ] Psychiatry 166:1229,t2009

Malaspina 0, Corcoran C, Kleinhaus KR, et al: Acute maternal stress in pregnancy and schizophrenia in ofspring: a cohort prospective. BMC Psychiatry 8:71,t2008

McFarlane ], Maddoux ], Cesario S, et al: Efect of abuse during pregnancy on maternal and child safety and functioning for 24 months after delivery. Obstet GynecoIt123(4):839, 2014

McKenna K, Koren G, Tetelbaum M, et al: Pregnancy outcome of women using atypical antipsychotic drugs: a prospective comparative study. ] Clin Psychiatry 66:444, 2005 Mei-Dan E, Ray ]G, Vigod SN, et al: Perinatal outcomes among women with bipolar disorder: a population-based cohort study. Am ] Obstet Gynecol 212(3):367.el,t2015

Meltzer-Brody S: Treating perinatal depression: risks and stigma. Obstet Gynecol 124(4):653,t2014

Melville ]L, Gavin A, Guo Y, et al: Depressive disorders during pregnancy.

Obstet GynecoIt116:1064, 2010

Mental Health America: Postpartum disorders. 2016. Available at: http:// ww.mentalhealthamerica.net/conditions/postpartum-disorders. Accessed July 12, 2016

Metz TO, Rovner P, Allshouse A, et al: Maternal deaths from suicide and drug overdose in Colorado. Am] Obstet Gynecol 214(1):S126, 2016 Micali N, Simonof E, Treasure]: Risk of major adverse perinatal outcomes in women with eating disorders. Brt] Psychiatry 190:255, 2007

Micromedex: Lithium. Available at: http://ww.micromedexsolutions.com/ micromedex2/li brarian/PF Defaul tActionld/ evidencexpert. Doln tegratedSearch. Accessed June 29, 2016

Miller B], Murray L, Beckman MM, et al: Dietary supplements for preventing postnatal depression. Cochrane Database Syst Rev 10:CD009104, 2013 Miller L]: Use of electroconvulsive therapy during pregnancy. Hosp Community Psychiatry 45:444, 1994

Molyneaux E, Poston L, Ashurst-Williams S, et al: Obesity and mental disorders during pregnancy and postpartum: a systematic review and metaanalysis. Obstet GynecoIt123(4):857, 2014

Muller-Oerlinghausen B, Berghofer A, Bauer JvI: Bipolar disorder. Lancet 359:241, 2002

Murphy KC: Schizophrenia and velocardiofacial syndrome. Lancet 359(9304): 426, 2002 National Institute of Mental Health: Spotlight on postpartum depression. 2010. Available at: http://ww.nimh.nih.gov/about/directorl20 1 0/ spotlight-on-postpartum-depression.shtml. Accessed] uly 12, 2016

National Institute of Mental Health: he numbers count: mental disorders in America. NIH Publication No. 06-4584, 2016

Nelson DB, Doty M, McIntire DO, et al: Rates and precipitating factors for postpartum depression following screening in consecutive births. ] Matern Fetal Neonatal Med 11:1,t2015

Nelson DB, Freeman MP, Johnson NL, et al: A prospective study of postpartum depression in 17648 parturients. ] Matern Fetal Neonatal Med 26(12):1156,t2013

O'Hara MW, Wisner L: Perinatal mental illness: definition, description and aetiology. Best Pract Res Clin Obstet Gynaecol 28(1):3, 2014

O'Keane V, Lightman S, Patrick K, et al: Changes in the maternal hypothalamicpituitary-adrenal axis during the early puerperium may be related to the postpartum blues. ] Neuroendocrinol 23(11): 1149, 2011

Ornoy A, Koren G: Selective serotonin reuptake inhibitors during pregnancy: do we have now more definite answers related to prenatal exposure. Birth Defects Res 109(12):898, 2017

Palladino CL, Singh V, Campbell H, et al: Homicide and suicide during the perinatal period: indings from the National Violent Death Reporting System. Obstet Gynecol 118(5):1056,t2011

Patorno E, Huybrechts KF, Bateman BT, et al: Lithium use in pregnancy and the risk of cardiac malformations. N Engl J Med 376(23):2245, 2017 Pinette MG, Santarpio C, Wax JR, et al: Electroconvulsive therapy in pregnancy. Obstet Gynecol 110:465, 2007

Pozzi A, Yee LM, Brown K, et al: Pregnancy in the severely mentally ill patient as an opportuniry for global coordination of care. Am J Obstet Gynecol 210:32, 2014

Pratt LA, Brody OJ, Gu Q: antidepressant use among persons aged 12 and over: United States, 2011-2014. NCHS Data Brief 283: 1,2017

Ray 5, Stowe ZN: he use of antidepressant medication in pregnancy. Best Pract Res Clin Obstet GynaecoIt28(l):71, 2014

Richards OS: Is electroconvulsive therapy in pregnancy safe? Obstet Gynecol 11t0:45t1,t2007

Robinson GE: Treatment of schizophrenia in pregnancy and postpartum.

J Popul her Clin PharmacoIt19(3):e380, 2012

Romero R, Badr MS: A role for sleep disorders in pregnancy complications: challenges and opportunities. Am J Obstet Gynecol 210:3, 2014

Ross LE, McLean LM: Anxiery disorders during pregnancy and the postpartum period: a systematic review. J Clin Psychiatry 67:1285,t2006

Schneier FR: Clinical practice. Social anxiery disorder. N Engl J Med 355(10): 1029,t2006

Shaw JG, Asch SM, Kimerling R, et al: Posttraumatic stress disorder and risk of spontaneous preterm birth. Obstet Gynecol 124(6): 1111, 2014

Silverman ME, Reichenberg A, Savitz DA, et al: The risk factors for postpartum depression: a population-based study. Depress Anxiery 34(2): 178, 2017

Siu AL, US Preventive Services Task Force (USPSTF), Bibbins-Domingo K, et al: Screening for depression in adults: US Preventive Services Task Force recommendation statement. JAMA 315(4):380,t2016

Smith MV, Busser 0, Ganann R, et al: Women's care-seeking experiences after referral for postpartum depression. Qual Health Res 18: 1161, 2008

Smith MV, Howell H, Wang H, et al: Success of mental health referral among pregnant and postpartum women with psychiatric distress. Gen Hosp Psychiatry 31(2):155,t2009

Steinberg JR, McCulloch CE, Adler NE: Abortion and mental health: findings from the National Comorbidiry Survey Replication. Obstet Gynecol 123:263,t2014

Straub H, Adams M, Kim JJ, et al: Antenatal depressive symptoms increase the likelihood of pre term birth. Am J Obstet GynecoIt207:329.el, 2012

Tam H, Chung T: Psychosomatic disorders in pregnancy. CUlT Opin Obstet Gynecol 19: 126, 2007

Tarney CM, Berry-Caban C, Jain RB, et al: Association of spouse deployment on pregnancy outcomes in a U.S. military population. Obstet Gynecol 126(3):569,t2015

Torgerson L, Von Holle A, Reichborn-Kjennerud T, et al: Nausea and vomiting of pregnancy in women with bulimia nervosa and eating disorders not otherwise specified. Int J Eat Disord 41t:722, 2008

Van den Bergh BR, Mulder EJ, Mennes M, et al: Antenatal maternal anxiery and stress and the neurobehavioural development of the fetus and child: links and possible mechanisms. A review. Neurosci Biobehav Rev 29(2):237, 2005

Van Lieshout RJ, Voruganti LP: Diabetes mellitus during pregnancy and increased risk of schizophrenia in ofspring: a review of the evidence and putative mechanisms. J Psychiatry Neurosci 33(5):395, 2008

Venkatesh KK, Kaimal A, Nadel H, et al: Implementation of universal screening for depression during pregnancy: feasibiliry and impact on obstetric care. 215(4):517.e1,t2016

Viguera AC, Whitfield T, Baldessarini RJ, et al: Risk of recurrence in women with bipolar disorder during pregnancy: prospective study of mood stabilizer discontinuation. Am J Psychiatry 164(12): 1817,t2007

Vythilingum B: Anxiery disorders in pregnancy. Curr Psychiatry Rep 10(4): 331,t2008

Weinberg MK, Tronick EZ: The impact of maternal illness on infant development. J Clin Psychiatry 59:53, 1998

Wisner KL, Parry BL, Piontek CM: Postpartum depression. N Engl J Med 347:t194,t2002

Yaeger 0, Smith HG, Altshuler LL: Arypical antipsychotics in the treatment of schizophrenia during pregnancy and the postpartum. Am J Psychiatry 163:2064,t2006

Yonemoto N, Dowswell T, Nagai 5, et al: Schedules for home visits in early postpartum period. Cochrane Database Syst Rev 8:CD009326, 2017

Yonkers A, Vigod 5, Ross LE: Diagnosis, pathophysiology, and management of mood disorders in pregnant and postpartum women. Obstet Gynecol 117:961,201t1

Yonkers A, Wisner KL, Stewart DE, et al: he management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Obstet Gynecol 114:703,t2009

Yost NP, Bloom SL, McIntire DD, et al: A prospective observational study of domestic violence during pregnancy. Obstet Gynecol 106(1):61, 2005

Zerbe KJ, Rosenberg J: Eating disorders. Clinical Updates in Women's Health Care. American College of Obstetricians and Gynecologists, Vol VU, No.t1, January 2008

PREGNANCY-SPECIFIC DERMATOSES .i...i.....i....i... 1184

SPECIFIC TO PREGNANCY.. . . . . . . . . . . . . . . . . . . . . .. 1186

DERMATOLOGICAL TREATMENT.. . . . . . . . . . . . . . . .. 1188

Herpes Gestationis-This disease, more requenty known as dermatitis herpetormis is an inlammatory supeicialy seated multorm herpetiorm eruption, which is characterized by erythematous, vesicular, pustular, and bulous lesions.

-J. Whitridge Williams (1903)

Four dermatoses considered unique to pregnancy include intrahepatic cholestasis of pregnancy, pruritic urticarial papules and plaques of pregnancy (PUPPP), atopic eruption of pregnancy (AEP), and pemphigoid gestationis (PG). Descriptions of these are given in Table 62-1. As a group, these are diagnosed in up to 5 percent of pregnancies (Chander, 2011). Their gross appearance may be similar to each other or to other skin disorders, and pruritus is a common feature of all four. Only intrahepatic cholestasis and pemphigoid gestationis have been linked with adverse fetal outcomes.

• Intrahepatic Cholestasis of Pregnancy

Previously termed pruritus gravidarum, this condition is found in 0.5 percent of pregnancies (Wikstrom Shemer, 2013). In contrast to the other pregnancy-speciic dermatoses, intrahepatic cholestasis of pregnancy generally has no primary skin lesions. Rarely, a rash precedes pruritus, which is usually associated with abnormally elevated serum bile acid levels and mildly increased hepatic aminotransferase levels (Chao, 2011). Adverse fetal efects have been linked to this condition, and it is discussed in detail in Chapter 55 (p. 1059).

his rare autoimmune bullous disease is notable for its maternal and fetal efects. Initially, pruritic papules and urticarial plaques form and are then followed in most cases after 1 to 2 weeks by vesicles or bullae. Lesions are frequently distributed periumbilically, often develop on other skin surfaces, but spare mucous membranes, scalp, and face (Fig. 62-1).

Previously termed hepes gestationis, pemphigoid gestationis is not related to the herpesvirus. Instead, maternal immunoglobulin G (IgG) antibodies target collagen VII found in the basement membrane of skin and amnionic epithelium (Kelly, 1988; Shimanovich, 2002). Collagen VII is also termed bullous pemphigoid 180 (BP 180). Autoantibody binding to collagen VII activates complement to promote eosinophil chemotaxis to the antigenantibody complexes. Eosinophilic degranulation damages the dermal-epidermal junction and leads to blistering (Engineer, 2000).

In most cases, PG develops during a irst pregnancy. It may rarely be associated with gestational trophoblastic disease (Matsumoto, 2013; Takatsuka, 2012). Most subsequent pregnancies are also afected, usually earlier and more severely (Tani, 2015). Whites have a higher incidence, and other autoimmune diseases are frequent in afected women (Shornick, 1984, 1992).

PG usually begins during the second or third trimester, but postpartum onset or exacerbation is common (Lawley, 1978). The disease course is often marked by antepartum flares and remissions. And, especially in cases with early-onset and blistering, PG has an association with preterm birth and fetalgrowth restriction (Al-Saif, 2016; Chi, 2009). One theory for

TABLE 62-1 . Pregnancy-specific Dermatoses

Cholestasis of Common No primary lesions, secondary Increased perinatal Anti pru ritics, pregnancy excoriations from scratching morbidity cholestyramine, plaques of on abdomen, thighs, buttocks, pregnancy (PUPPP) especially within striae, but

Atopic eruptions of None

Anti pru ritics, Eczema of pregnancy Common Dry, red scaly patches on emollients, topicalextremity flexures, neck, face corticosteroids, oral Prurigo of pregnancy Common 1-5 mm pruritic red papules on steroids if severe extensor surfaces, trunk

Pruritic folliculitis of Rare Small red papules, sterile

Pemphigoid Rare Erythematous pruritic papules, Preterm birth, fetal gestationis plaques, vesicles, and bullae; growth restriction, abdomen often with umbilical transient neonatal involvement, extremities lesions this is mild placental insuiciency that stems from IgG and resolution is protracted, and disease may be exacerbated during complement deposition along the amnionic basement memmenses or by oral contraceptives (Semkova, 2009). brane (Huilaja, 2013). Accordingly, antepartum surveillance of afected pregnancies is reasonable.

In 5 to 10 percent of cases, IgG antibodies passively transfer Before bullae form, these lesions may resemble pruritic urtifrom the mother to cause similar skin lesions in the newborn carial papules and plaques of pregnancy. Other diagnoses (Erickson, 2002). hese eruptions in the neonate require only include pustular psoriasis, dermatitis herpetiformis, erythema wound care and clear spontaneously within a few weeks as the multiforme, linear 19A bullous dermatosis, urticaria, allergic passively acquired IgG levels decline. Slowly following contact dermatitis, bullous pemphigoid, and atopic eruption maternal lesions resolve without scarring, and most women are of pregnancy (LipozenCic, 2012). Drug-induced blistering disease-free after 6 months (Jenkins, 1999). In some, however, syndromes must also be excluded as some are life-threatening,

FIGURE 62-1 Pemphigoid gestation is. A. Abdominal plaques classically involve the umbilicus. B. Blistered lesions on the wrist and forearm. (Used with permission from Dr. Kara Ehlers.) for example, Stevens-Johnson syndrome and toxic epidermal necrolysis (Stern, 2012).

Skin biopsy and serum antibody assays are informative.

Immunofluorescent staining of a skin punch biopsy sample is the gold standard, and C3 complement and sometimes IgC are seen deposited along the basement membrane between the epidermis and the dermis (Katz, 1976). Also, in many cases, circulating IgC antibodies against collagen V1I can be detected in maternal serum (Powell, 2005; Sitaru, 2004).

Pruritus can be severe. Early in its course, topical highpotency corticosteroids and oral antihistamines may be efective. Oral prednisone, 0.5 to 1 mg/kg daily gradually tapered to a maintenance dose, may be needed for relief and also for inhibition of new lesions. Plasmapheresis, high-dose intravenous immunoglobulin (IVIC) therapy, or cyclosporine has been used in intractable cases (Huilaja, 2015; Ko, 2014; Van de Wiel, 1980).

Plaques of Pregnancy his relatively common pregnancy-speciic dermatosis is characterized by its benign efects on pregnancy and by intensely pruritic 1-to 2-mm erythematous papules that coalesce to form urticarial plaques. Also known as poymorphic eruption of pregnancy, PUPPP usually appears late in pregnancy (Rudolph, 2005). Rarely, postpartum onset has been described (Park, 2013). he rash afects the abdomen and proximal thighs in 97 percent of women (Fig. 62-2). Lesions often initially form within striae but show periumbilical sparing. The face, palms, and soles also are rarely involved (High, 2005). It is more frequent in white and nulliparous women, those with multifetal gestation, and those carrying a male fetus (Regnier, 2008). PUPPP seldom recurs in subsequent pregnancies (Ahmadi, 2005). Its cause is unknown, but an autoimmune basis is not implicated (Lawley, 1979).

PUPPP may be compared with several skin eruptions. Some include contact dermatitis, drug eruption, viral exanthem, insect bites, scabies infestation, pityriasis rosea, and the other pregnancy-speciic dermatoses. It also may appear similar to early PC that has not yet blistered. In unclear cases, skin biopsy and negative serum collagen V1I antibody levels help to differentiate the two. Pruritus will usually respond to treatment with oral antihistamines, skin emollients, and topical corticosteroids. A few women will need systemic corticosteroids to relieve severe itching (Scheinfeld, 2008).

FIGURE 62-2 Pruritic urticarial papules and plaques of pregnancy (PUPPP) shows sma" papules on the buttock and proximal thigh and within abdominal striae.

PUPPP usually resolves within several days following delivery and leaves no scarring. In 15 to 20 percent of women, however, symptoms persist for 2 to 4 weeks postpartum (Vaughan Jones, 1999).

• Atopic Eruption of Pregnancy his umbrella term encompasses three conditions previously considered separate: eczema in pregnancy, prurigo of pregnancy, and pruritic folliculitis of pregnancy (Ambros-Rudolph, 2006). Two thirds of women with atopic eruption have widespread eczematous changes, whereas the other third have papular lesions (American Academy of Dermatology, 201r1). As a group, these pose no risk to the fetus. Diagnosis is greatly aided by a history of atopy and by rash characteristics.

Eczema in pregnany has the appearance of traditional eczema but with a pregnancy onset. It is the most common pregnancy-specific dermatosis, and afected skin shows dry, thickened, scaly, red patches involving extremity lexures, nipples, neck, and face. In contrast, prurigo of pregnancy, also known as prurigo gestationis) is characterized by 5-to 10-mm, itchy, erythematous papules or nodules commonly found on the extensor surfaces and trunk. Last, pruritic olliculitis of pregnancy is rare and notable for small, erythematous follicular papules and sterile pustules predominantly on the trunk. Onset for all is during the second or third trimester, although eczema in pregnancy may develop earlier than the other two. All lesions commonly resolve with delivery, but may persist for up to 3 months postpartum. Recurrence with subsequent pregnancies is variable but common.

Diagnosis is one of exclusion. Serum bile acid levels are elevated but not greater than concentrations expected for normal pregnancy, and aminotransferase levels are normal. Serology specific for PC is negative. Many women with eczema of pregnancy have elevated serum IgE levels, which are not seen with the two other AEP dermatoses (Ambros-Rudolph, 201r1).

For all three manifestations, skin lesions and pruritus are usually controlled with low-or moderate-potency topical corticosteroids and oral antihistamines. For severe eczema, second-line agents include short-course ultrapotent topical corticosteroids. In some cases, however, an oral corticosteroid, narrow-band ultraviolet B, or cyclosporine is required (Lehrhof, 2013).

pregnancy. Some of those chronic conditions are considered here.

his common chronic dermatosis is unpredictably afected by pregnancy and, if necessary, is treated with benzoyl peroxide alone or coupled with either topical erythromycin or topical clindamycin (Zaenglein, 2016). In these combinations, benzoyl peroxide minimizes Propionibacterium acnes drug resistance. Azelaic acid is another comedolytic agent, which is category B. Topical salicylic acid is category C, but amounts in over-the-counter products are considered safe (Murase, 2014). Topical retinoids, which include tretinoin and adapalene, also appear safe, are category C drugs, but are probably best avoided during pregnancy, especially during the irst trimester (Kaplan, 2015; Panchaud, 2012). Topical tazarotene is contraindicated. For more severe cases, oral antibiotics that include erythromycin, azithromycin, cephalexin, or amoxicillin may be coupled with benzoyl peroxide. Systemic antibiotics are ideally delayed until the second trimester, and therapy duration limited to 4 to 6 weeks (Chien, 2016).

his chronic dermatosis also has a variable course during pregnancy, however, postpartum lares are common (Oumeish, 2006). Emollients alone are given initially, and low-or moderate-potency topical corticosteroids can be added. In resistant cases, restrained use of high-potency or ultrapotent corticosteroids appears safe in the second and third trimesters. Ultraviolet B phototherapy can be used as a second-line option. Last, cyclosporine, systemic corticosteroids, or tumor necrosis factor (TNF)-a antagonists that include adalimumab, etanercept, and inliximab are third-tier agents for pregnancy (Bae, 2012). Overall, data do not support an increased risk of adverse pregnancy outcomes with psoriasis (Bobotsis, 2016). With severe disease, a small increased risk for low-birthweight neonates was found by some (Lima, 2012; Yang, 2011). Also, in general, psoriatic patients have higher associated rates of depression (Bandoli, 2017; Cohen, 2016).

Psoriasis is most commonly of the chronic plaque variety. In contrast, with generalized pustuar psoriasis of pregnancy, severe systemic symptoms may develop. Formerly called impetigo herpetiformis, this rare pustular form has erythematous, sometimes pruritic plaques ringed by sterile pustules that enlarge and then crust (Fig. 62-3). Lesions initially involve intertriginous areas but may spread to the torso, extremities, and oral mucosa. Comorbid constitutional symptoms are common. Laboratory testing may reveal hypocalcemia, elevated erythrocte sedimentation rate, leukocytosis, and hypoalbuminemia (Lehrhof, 2013). Extensive lesions can lead to sepsis from secondary infection and to massive fluid loss with hypovolemia and placental insuiciency. First-line treatment is with oral prednisone, cyclosporine, infliximab, topical corticosteroids, or topical calcipotriene (Robinson, 2012). Phototherapy is a second-line option. For secondary infections, intravenous antibiotics are added (Huang, 2011). Pustular psoriasis typically resolves quickly in the puerperium, but recurrences have been reported in subsequent pregnancies and with menstruation or oral contraceptive use (Roth, 2011).

his skin condition represents inflammation of subcutaneous fat associated with numerous disorders, including pregnancy. Other triggers are infections, sarcoidosis, drugs, Beh:et syndrome, inlammatory bowel disease, or a malignancy (Mert, 2007; Papagrigoraki, 2010). Characteristically, 1-to 6-cm tender, red, warm nodules and plaques develop rapidly on the extensor surface of the legs and arms. Within a few days, lesions flatten and undergo the color evolution of a bruise-from dark red and purple to yellow green. Constitutional symptoms may also be present. Initial evaluation and treatment focuses on the underlying etiology. Symptoms spontaneously resolve in 1 to 6 weeks without scarring but may leave residual hyperpigmentation (Acosta, 2013).

his lesion is frequently seen in pregnancy (Fig. 62-4). Poorly named, pyogenic granuloma is actually a lobular capillary hemangioma commonly forming on the mouth or hand in response to low-grade local irritation or traumatic injury. hey grow

FIGURE 62-3 Generalized pustular psoriasis of pregnancy displays FIGURE 62-4 Pyogenic granuloma is characterized grossly by a erythematous, sometimes pruritic plaques ringed by sterile pustules lobulated red growth on a pedunculated or sessile base. With minithat enlarge and then form a scaling crust. (Used with permission mal trauma, these vascular lesions bleed easily. (Used with permisfrom Dr. Paul Slocum.) sion from Dr. Abel Moron.) quickly and bleed with minimal provocation. Active bleeding can be controlled with pressure and application of a silver nitrate stick or Monsel paste (ferric subsulfate). These growths often resolve within months postpartum. But with a symptomatic antepartum growth, a persistent postpartum lesion, or with an unclear diagnosis, excision can be done using suture and scalpel, electrosurgical curettage, laser photocoagulation, or cryotherapy. Oral lesions are best referred to oral health-care specialists.

These lesions are typiied by benign cutaneous neuroibromas, cafe-au-lait spots, axillary and inguinal freckling, benign nodules of the iris (Lisch nodules), and optic nerve gliomas. Neuroibromas may increase in size and number during pregnancy (Cesaretti, 2013; Dugof, 1996). With the more common neuroibromatosis type 1, higher rates of preclampsia and preterm birth complicate pregnancy (Leppavirta, 2017; Terry, 2013). With neurofibromatosis type 2, some evidence suggests a risk for preeclampsia (Terry, 2015). Prenatal genetic diagnosis is available for both types (Merker, 2015; Spits, 2007).

Rosacea ulminans is also known as pyoderma aciale. It is rare and characterized by facial pustules and coalescing draining sinuses. Topical or oral antimicrobials are primary treatment, although surgical drainage and corticosteroids have also been used (F uentelsaz, 2011; Jarrett, 2010).

Hidradenitis suppurativa is said to improve with pregnancy, but in our experiences, it is not appreciably changed. Twice daily topically applied I-percent clindamycin gel for 12 weeks aims to prevent new lesions. This can be supplemented by 7-to 10-day courses of oral amoxicillin plus clavulanic acid or oral clindamycin to reduce lesion progression (Margesson, 2014). Other options are reviewed by Perng and coworkers (2017).

Other skin conditions that are discussed elsewhere in this book include hirsutism and melanoma (Chap. 63, p. 1203), cutaneous lupus (Chap. 59, p. 1140), hyperpigmentation (Chap. 4, p. 53), and skin lesions seen with infections (Chaps. 64 and 65).

Local skin care, oral antihistamines, and topical corticosteroids are commonly used for many dermatoses. Oral antihistamines are given for pruritus. Suitable options include irst-generation agents such s diphenhydramine (Benadryl), 25 to 50 mg every 6 hours, or chlorpheniramine (Chlor-Trimeton), 4 mg every 6 hours. Second-generation agents-Ioratadine (Claritin) 10 mg daily or cetirizine (Zyrtec) 5 or 10 mg daily-may produce less sedation and are also pregnancy category B.

Hundreds of topical corticosteroid preparations are available, and in the United States, these are categorized by potency into seven groups. For initial treatment of dermatological disorders, low-or moderate-potency agents are preferred. Low-potency agents include those in groups 6 and 7, such as I-percent hydrocortisone or 0.05-percent desonide (DesOwen). Moderate-potency drugs are in groups 5, 4, and 3-such as O.I-percent triamcinolone acetonide (Aristocort) or O.I-percent mometasone furoate (Elocon). High-potency medications are in group 2, such as 0.05-percent betamethasone dipropionate (Diprolene). Ultrapotent agents in group 1, such as 0.05-percent clobetasol propionate (Temovate), are best reserved for refractory disorders and used for only 2 to 4 weeks on small surface areas.

Mild and moderate strengths are not associated with adverse pregnancy outcomes, whereas high-and ultrapotent agents pose a small risk for fetal-growth restriction with large cumulative doses (Chi, 2013, 2015). Even then, this risk is less than that with systemic corticosteroids. Importantly, with any topical agent, factors that increase systemic absorption include a large surface area treated, compromised epidermal barrier, occlusive dressings, prolonged treatment duration, and coadministration of topical agents that increase absorption.

The list of other agents used for dermatological conditions is extensive. For use in pregnancy and lactation, Murase (2014) and Butler (2014) have compiled tables and evidencebased descriptions of most. Notable therapeutic agents to avoid during pregnancy include methotrexate, psoralen plus ultraviolet A, mycophenolate mofetil, podophyllin, and systemic retinoids. hese are discussed in more detail in Chapter 12. Bacterial infections are a potential secondary complication of skin disorders and are treated promptly with oral antimicrobial agents with gram-positive coverage.

Acosta A, Haver MC, Kelly B: Etiology and therapeutic management of erythema nodosum during pregnancy: an update. Am J Clin Dermatol 14(3):215,t2013

Ahmadi S, Powell FC: Pruritic urticarial papules and plaques of pregnancy: current status. Australas J Dermatol 46(2):53, 2005

Al-Saif F, Elisa A, Al-Homidy A, et al: Retrospective analysis of pemphigoid gestationis in 32 Saudi patients-clinicopathological features and a literature review. J Reprod Immunol 11t6:42,t20t16

Ambros-Rudolph CM: Dermatoses of pregnancy-clues to diagnosis, fetal risk and therapy. Ann Dermatol23(3):265, 2011

Ambros-Rudolph CM, Mullegger R, Vaughan-Jones SA, et al: The specific dermatoses of pregnancy revisited and reclassified: results of a retrospective two-center study on 505 pregnant patients. J Am Acad Dermatol 54:395, 2006

American Academy of Dermatology: Learning module: dermatoses in pregnancy. 2011t. Available at: https://www.aad.org/education/basic-dermcurricul um/ suggested -order-of-modules/ dermatoses-in -p regnancy. Accessed May 17, 2016

Bae YS, Van Voorhees AS, Hsu S, et al: Review of treatment options for psoriasis in pregnant or lactating women: from the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol67(3):459, 2012

Bandoli G, Chambers CD: Autoimmune conditions and comorbid depression in pregnancy: examining the risk of preterm birth and preeclampsia. J Perinatolt37(lO):1082,t2017

Bobotsis R, Gulliver P, Monaghan K, et al: Psoriasis and adverse pregnancy outcomes: a systematic review of observational studies. Br J Dermatol 175(3):464,t2016

Butler DC, Heller MM, Murase JE: Safety of dermatologic medications in pregnancy and lactation: Part II. Lactation. J Am Acad Dermatol 70(3):417.e1, 2014

Cesaretti C, Melloni G, Quagliarini D: Neuroibromatosis type 1 and pregnancy: maternal complications and attitudes about prenatal diagnosis. m J Med Genet A 161A (2):386, 2013

Chander R, Garg T, Kakkar S, et al: Speciic pregnancy dermatoses in 1430 females from Northern India. J Dermatol Case Rep 5(4):69, 201t1

Chao TT, Sheield JS: Primary dermatologic indings with early-onset intrahepatic cholestasis of pregnancy. Obstet Gynecol 117:456, 2011

Chi CC, Wang SH, Charles-Holmes R, et al: Pemphigoid gestationis: early onset and blister formations are associated with adverse pregnancy outcomes. Br] DermatoIt160(6):1222, 2009

Chi CC, Wang SH, Mayon-White R: Pregnancy outcomes after maternal exposure to topical corticosteroids: a UK population-based cohort study. ]AMA DermatoIt149(11):1274, 2013

Chi CC, Wang SH, Wojnarowska F, et al: Safety of topical corticosteroids in pregnancy. Cochrane Database Syst Rev 10:CD007346, 2015

Chien AL, Qi], Rainer B, et al: Treatment of acne in pregnancy.] Am Board Fam Med 29(2):254,t2016

Cohen BE, Martires K], Ho RS: Psoriasis and the risk of depression in the US population: national health and nutrition examination survey 2009-2012. ]AMA Dermatol 3,t2016

Dugof L, Sujansky E: Neuroibromatosis type 1 and pregnancy. Am ] Med Genet 66(1):7, 1996

Engineer L, Bhol K, Ahmed AR: Pemphigoid gestationis: a review. Am ] Obstet GynecoIt183(2):483, 2000

Erickson NI, Ellis L: Neonatal rash due to herpes gestation is. N Englt] Med 347(9):660, 2002 Fuentelsaz V, Ara M, Corredera C, et al: Rosacea fulminans in pregnancy: successful treatment with azithromycin. Clin Exp DermaroI36(6):674, 2011

High WA, Hoang MP, Miller MD: Pruritic urticarial papules and plaques of pregnancy with unusual and extensive palmoplantar involvement. Obstet Gynecol 105:1261,t2005

Huang H, Chen P, Liang CC, et al: Impetigo herpetiform is with gestational hypertension: a case report and literature review. Dermatology 222(3):221, 2011

Huilaja L, Makikallio K, Hannula-]ouppi K, et al: Cyclosporine treatment in severe gestational pemphigoid. Acta Derm Venereol 95(5):593, 2015 Huilaja L, Makikallio K, Sormunen R, et al: Gestational pemphigoid: placental morphology and function. Acta Derm Venereol 93(1):33, 2013

Jarrett R, Gonsalves R, Anstey AV: Difering obstetric outcomes of rosacea fulminans in pregnancy: report of three cases with review of pathogenesis and management. Clin Exp Dermatol 35(8):888, 2010

Jenkins E, Hern S, Black MM: Clinical features and management of 87 patients with pemphigoid gestationis. Clin Exp DermatoI24(4):255, 1999

Kaplan YC, Ozsarfati ], Etwel F, et al: Pregnancy outcomes following irsttrimester exposure to topical retinoids: a systematic review and meta-analysis. Br] DermatoIt173(5):1132, 2015

Katz SI, Hertz KC, Yaoita H: Herpes gestationis. Immunopathology and characterization of the HG factor.t] Clin Invest 57(6):1434,t1976

Kelly SE, Bhogal BS, Wojnarowska F, et al: Expression of a pemphigoid gestationisrelated antigen by human placenta. Br] DermatoIt118:605, 1988

Ko B], Whang KU: Intravenous immunoglobulin therapy for persistent pemphigoid gestationis with steroid induced iatrogenic Cushing's syndrome. Ann DermatoIt26(5):661, 2014

Lawley T], Hertz KC, Wade TR, et al: Pruritic urticarial papules and plaques of pregnancy. ]AMA 241 (16): 1696, 1979

Lawley T], Stingl G, Katz SI: Fetal and maternal risk factors in herpes gestationis. Arch DermatoIt114(4):552, 1978

Lehrhof S, Pomeranz MK: Specific dermatoses of pregnancy and their treatment. Dermatol her 26(4):274,t2013

Leppavirtat], Kallionpaa A, Uusitalo E, et al: he pregnancy in neuroibromatosis 1: A retrospective register-based total population study. Amt] Med Genet A 173(10):2641,t2017

Lima XT, ]anakiraman V, Hughes MD, et al: The impact of psoriasis on pregnancy outcomes.t] Invest Dermatol 132(1):85,t2012

Lipozencic ], Ljubojevic S, Bukvic-Mokos Z: Pemphigoid gestationis. Clin DermatoIt30(1):51,t2012

Margesson L], Danby FW: Hidradenitis suppurativa. Best Pract Res Clin Obstet GynaecoIt28(7):1013, 2014

Matsumoto N, Osada M, Kaneko K, et al: Pemphigoid gestation is after sponta neous expulsion of a massive complete hydatidiform mole. Case Rep Obstet 268,t2013

Merker VL, Murphy TP, Hughes ]B, et al: Outcomes of preimplantation genetic diagnosis in neuroibromatosis type 1. Ferti! Steriltl03(3):76t1, 20t15 Men A, Kumbasar H, Ozaras R, et al: Erythema nodosum: an evaluation of 100 cases. Clin Exp Rheumatol 25(4):563, 200

Murase ]E, Heller MM, Buder DC: Safety of dermatologic medications in pregnancy and lactation: part r. Pregnancy.] Am Acad Dermatol 70(3):40 l.e1, 2014

Oumeish OY, AI-Fouzan A W: Miscellaneous diseases afected by pregnancy.

Clin Dermatol 24: 113, 2006

Panchaud A, Csajka C, Merlob P, et al: Pregnancy outcome following exposure to topical retinoids: a multicenter prospective study. ] Clin Pharmacol 52(12):1844,t2012

Papagrigoraki A, Gisondi P, Rosina P, et al: Erythema nodosum: etiological factors and relapses in a retrospective cohort study. Eur ] Dermatol 3,t2010

Park SY, Kim ]H, Lee WS: Pruritic urticarial papules and plaques of pregnancy with unique distribution developing in postpartum period. Ann Dermatol 25(4):506,t2013

Perng P, Zampella]G, Okoye GA: Management of hidradenitis suppurativa in pregnancy.] Am Acad Dermatol 76(5):979, 2017

Powell M, Sakuma-Oyama Y, Oyama N, et al: Usefulness of BP180 NC16a enzyme-linked immunosorbent assay in the serodiagnosis of pemphigoid gestationis and in diferentiating between pemphigoid gestationis and pruritic urticarial papules and plaques of pregnancy. Arch Dermatol 141(6): 705, 2005

Regnier S, Fermand V, Levy P, et al: A case-control study of polymorphic eruption of pregnancy. ] Am Acad Dermatol 58 (1):63, 2008

Robinson A, Van Voorhees AS, Hsu S, et al: Treatment of pustular psoriasis: from the Medical Board of the National Psoriasis Foundation. ] Am Acad Dermatol 67(2):279, 2012

Roth MM: Pregnancy dermatoses: diagnosis, management, and controversies.

Amt] Clin Dermatol 12(1):25,t2011

Rudolph CM, AI-Fares S, Vaughan-Jones SA, et al: Polymorphic eruption of pregnancy: clinicopathology and potential trigger factors in 181 patients. Br ] Dermatol 154:54,t2005

Scheinfeld N: Pruritic urticarial papules and plaques of pregnancy wholly abated with one week twice daily application of fluticasone propionate lotion: a case report and review of the literature. Dermatol Online 14(11):4,2008

Segal 0, Holcberg G, Sapir 0, et al: Neuroibromatosis in pregnancy. Maternal and perinatal outcome. Eur] Obstet Gynecol Reprod Bioi 84(1):59, 1999 Semkova K, Black M: Pemphigoid gestationis: current insights into pathogenesis and treatment. Eur] Obstet Gynecol Reprod Bioi 145(2):138, 2009

Shimanovich 1, Skrobek C, Rose C, et al: Pemphigoid gestationis with predominant involvement of oral mucous membranes and IgA autoantibodies targeting the C-terminus ofBP180.] Am Acad DermaroI47:780, 2002

Shornick]K, Black MM: Fetal risks in herpes gestationis. ] Am Acad Dermatol 26:63, 1992

Shornick ]K, Meek T], Nesbitt LT, et al: Herpes gestationis in blacks. Arch DermatoIt120(4):511,t1984

Sitaru C, Powell], Messer G, et al: Immunoblotting and enzyme-linked immunosorbent assay for the diagnosis of pemphigoid gestationis. Obstet Gynecol 103(4):757,t2004

Spits C, De Rycke M, Van Ranst N, et al: Preimplantation genetic diagnosis for cancer predisposition syndromes. Prenat Diagn 27(5):44 ,t2007

Stern RS: Exanthematous drug eruptions. N Engl] Med 366:2492, 2012 Takatsuka Y, Komine \1, Ohtsuki M: Pemphigoid gestation is with a complete hydatidiform mole.] DermatoI39(5):474, 2012

Tani N, Kimura Y, Koga H, et al: Clinical and immunological proiles of 25 patients with pemphigoid gestationis. Br] DermatoIt172(1):120, 2015

Terry AR, Barker FG 2nd, Lefert L, et al: Neuroibromatosis type 1 and pregnancy complications: a population-based study. Am ] Obstet Gynecol 209(1) :46.e1, 2013

Terry AR, Merker L, Barker FG 2nd, et al: Pregnancy complications in women with rare tumor suppressor syndromes afecting central and peripheral nervous system. Amt] Obstet GynecoIt213(1):108, 2015

Van de Wiel A, Hart HC, Flinterman], et al: Plasma exchange in herpes gestationis. BM] 281: 1041, 1980

Vaughan Jones SA, Hern S, Nelson-Piercy C, et al: A prospective study of 200 women with dermatoses of pregnancy correlating clinical indings with hormonal and immunopathological proiles. Br J

Dermatol 1, 1999 iksrr:im Shemer E, Marschall HU, Ludvigsson ]F, et al: Intrahepatic cholestasis of pregnancy and associated adverse pregnancy and fetal outcomes: a 12-year population-based cohort study. B]OG ,t2012

Yang YW, Chen CS, Chen H, et al: Psoriasis and pregnancy outcomes: a nationwide population-based study.t] Am Acad Dermatol 64(1):71, 201t1 Zaenglein AL, Pathy AL, Schlosser B], et al: Guidelines of care for the manage ment of acne vulgaris.] Am Acad Dermatol 74(5):945, 2016

CANCER THERAPY IN PREGNANCY .i........i....... 1191

REPRODUCTIVE TRACT NEOPLASMS.. . . . . . . . . . . . .. 1192

BREAST CARCINOMA. . . . . . . . . . . . . . . . . . . . . . . . . .. 1200 THYROID CANCER.. . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1201 LYMPHOMAS.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1202 MALIGNANT MELANOMA. . . . . . . . . . . . . . . . . . . . . .. 1203

GASTROINTESTINAL TRACT . . . . . . . . . . . .. 1204 MISCELLANEOUS TUMORS. . . . . . . . . . . . . . . . . . . . .. 1204 of the more frequent ones are shown in Figure 63-1. Breast cancer is found in 1 in 5000 pregnancies, thyroid-1 in 7000, and cervical-1 in 8500 (Smith, 2003). These, along with lymphoma and melanoma, account for 65 percent of malignancy cases in pregnancy (Eibye, 2013). For some cancers-ovary, endometrium, and breast-evidence suggests that high parity is protective (Hognas, 2014).

During pregnancy, cancer management poses unique problems related to fetal concerns, and treatment must be individualized. Considerations include the type and stage of malignancy, the desire for pregnancy continuation, and inherent risks associated with modiying or delaying cancer treatment.

Any excessive enlargement of the abdomen or the appearance of pressure symptoms should always lead one to make a carul examination, and in not a ew cases a tumour will be ound occupying the pelvic caviy. In rare instances malignant tumours of the rectum may so obstruct the pelvic canal as to render caesarean section imperative.

-J. Whitridge Williams (1903)

Any neoplasm can complicate pregnancy, and as written by Williams, physical examination often suggests the diagnosis. Current imaging also allows a greater number of these to be identiied antepartum. Most encountered neoplasms are benign, and uterine leiomyomas and ovarian cysts are the most frequent.

Cancer has an incidence approximating 1 per 1000 pregnancies (Parazzini, 2017; Salani, 2014). One third are diagnosed prenatally, and the others within 12 months of delivery. Some

FIGURE 63-1 Proportion of malignancies during pregnancy and within 12 months of delivery in 4.85 million women from the California Cancer Registry. GI = gastrointestinal. (Data from Smith, 2003.) diagnosis, staging, or therapy. Fortunately, most procedures that do not interfere with the reproductive tract are well toler ated by both mother and fetus (Chap. 46, p. 901). Although many operations have classically been deferred until after 12 to 14 weeks' gestation to minimize miscarriage risks, this probably is not necessary. We are of the opinion that surgery should be performed regardless of gestational age if maternal well-being is imperiled.

Both pregnancy and malignancy are risk factors for venous thromboembolism (VTE). In one study, Bleau and coworkers (2016) reported a higher risk ofVTE in gravidas with myeloid leukemia, Hodgkin disease, cervical cancer, and ovarian cancer compared with that in pregnant women without a malignancy.

The risk was not increased in those with brain or thyroid cancer, melanoma, or lymphoid leukemia. That said, current guidelines ing surgeries for cancer. hus, depending on the complexity of the planned procedure, it seems reasonable to use prophylactic low-molecular-weight heparin combined with elastic stockings and/or intermittent pneumatic compression as described in

Chapter 52 (p. 1019).

Sonography is a preferred imaging tool during pregnancy. Even so, according to the American College of Obstetricians and Gynecologists (2017a), most diagnostic radiographic procedures deliver very low x-ray doses and should not be delayed if they would directly afect therapy (Chap. 46, p. 906). Magnetic resonance (MR) imaging can safely be performed in any trimester, but delay until after the irst trimester may lower potential risks. Gadolinium should not be used in the irst trimester and should be used later in pregnancy only when the beneits overwhelmingly outweigh the risks (American College of Radiology, 2016; Kanal, 2013). Computed tomography (CT) is less often selected due to ionizing radiation, and procedure-related doses are listed in Chapter 46 (p. 907). Accordingly, CT is used in pregnancy most often to evaluate acute concerns that include pulmonary embolism, bowel or renal obstruction, and acute neurological events. To enhance CT, oral and intravenous contrasts may be added. hese lack known fetal harm, and postpartum breastfeeding need not be interrupted. Last, some radioisotopes are relatively safe in pregnancy and are listed in Table 46-8 (p. 909).

herapeutic radiation often results in signiicant fetal exposure depending on the dose, tumor location, field size, and gestational age. Potential adverse efects include fetal malformation, intellectual disability, growth restriction, sterility, and carcinogenesis (Brent, 1999; Stovall, 1995). In the 2 weeks following fertilization, exposure typically leads to chromosomal damage and embryonic death. he next most susceptible period is during organogenesis in weeks 2 through 8, and exposure can cause malformation. These might develop above a threshold dose of 0.1 to 0.2 Gy. During weeks 8 through 25, the fetal central nervous system is especially vulnerable. The threshold dose for intellectual disability at 8 to 15 weeks' gestation approximates 0.06 Gy, and at 16 to 25 weeks it is about 0.25 Gy (Kal, 2005; Otake, 1996). After 25 weeks' gestation, susceptibility is less, although no gestational age is considered safe for therapeutic radiation exposure. hus, radiotherapy to the maternal abdomen is contraindicated. With some head and neck cancers, however, radiotherapy to supradiaphragmatic areas can be used relatively safely with abdominal shielding of the fetus (Amant, 2015a).

Various antineoplastic drugs may be given for primary treatment or for adjunctive therapy. Although chemotherapy often improves long-term maternal outcomes, many are reluctant to employ it during pregnancy. Concerns for the fetus include malformations, growth restriction, intellectual disability, and the risk of future childhood malignancies. Risks are dependent primarily on fetal age at exposure, and most agents are potentially detrimental in the irst trimester during organogenesis. Indeed, in one review, 14 percent of major malformations were attributable to irst-trimester exposure to cytotoxic drugs (National Toxicology Program, 2013).

Ater the first trimester, most antineoplastic drugs are without immediate obvious adverse fetal sequelae (Abdel-Hady, 2012; Vercruysse, 2016). Similarly, late mutagenic efects appear limited (Amant, 2015b; Cardonick, 2015). Although not always practicable, some recommend that chemotherapy be withheld in the 3 weeks before expected delivery because neutropenia or pancytopenia might cause undue risk for maternal infection or hemorrhage. Another concern is that neonatal hepatic and renal clearance of chemotherapy metabolites is limited (Ko, 2011). For these reasons, most cytotoxic chemotherapy agents are contraindicated with breastfeeding (Pistilli, 2013).

Drugs designed to stimulate hemopoiesis are commonly used with cancer treatments. Some of these include the granulocyte colony-stimulating factors filgrastim (Neupogen) and pegilgrastim (Neulasta). If required in pregnancy, limited data support the safety of these agents (Boxer, 2015). Red blood cells can be stimulated by erythropoietin alfa (Procrit), which from case reports also appears safe in pregnancy (Sienas, 2013). However, maternal hypertension is a known potential risk.

he two main types of targeted therapy are monoclonal antibodies and small molecule inhibitors. Both block the actions of specific enzymes, proteins, or other molecules involved in cancer cell growth. hese drugs are designed to treat an everexpanding list of cancers, and some are described in later discussions of specific tumors. Most of these compounds are labeled by the Food and Drug Administration (FDA) as class

D, and data are limited regarding their pregnancy or breastfeeding efects.

Many of these drugs target tyrosine kinase, an important enzyme that regulates signaling pathways involved with cell division, diferentiation, and apoptosis. With irst-trimester use, embryo toxicity or teratogenicity has been attributed to these. Thus, this speciic group of targeted agents is considered for use in pregnancy only if the potential beneit to the pregnant woman justifies the potential risk to the fetus (Lodish, 2013).

Of other agents, the monoclonal antibody trastuzumab (Herceptin) inhibits the human epidermal growth factor receptor type 2 (HER2), which some breast cancers express. Although not teratogenic, its use in the second and third trimesters is associated with oligohydramnios, which appears to be reversible upon stopping the drug (Sarno, 2013; Zagouri, 2013b). Because of sparse available data, other HER2 inhibitors are best avoided in pregnancy (Lambertini, 2015).

Fertility may be diminished after chemotherapy or radiotherapy. Counseling ideally takes place before cancer treatment, and guidelines for this have been developed (American Society for Reproductive Medicine, 2013a; Lambertini, 2016; Loren, 2013; Peccatori, 2013). Prior to therapy, cryopreservation of embryos or of oocytes is a recognized fertility-preserving option (American Society for Reproductive Medicine, 2013b,c). Surgical transposition of the ovaries can be considered if pelvic radiation is planned. For this, ovaries and their intact primary blood supply are carried out of the pelvis and ixed to the lateral abdominal wall at a site 3 to 4 cm above the level of the umbilicus. In one review, functional preservation was reported in 65 to 94 percent, depending on radiotherapy type (Gubbala, 2014). Also, such transposition requires transabdominal egg retrieval if later in vitro fertilization is planned (American Society for Reproductive Medicine, 20 13a).

Ovarian suppression with gonadotropin-releasing hormone agonists is not beneficial, according to a recent review (Elgindy, 2015). At this time, cryopreservation of ovarian tissue is considered investigational. These methods currently are limited to referral centers.

In counseling cancer survivors, evidence suggests that exposure to most radiotherapy or chemotherapy agents in childhood or adulthood does not signiicantly increase the risk of congenital anomalies or genetic disease in their ofspring (Haggar, 2014; Signorello, 2012; Stensheim, 2013; Winther, 2012). In those treated as children with chemotherapy, studies also do not show a consistent link to adverse obstetrical outcomes (Melin, 2015; Reulen, 2009). Data are limited regarding those with cancer treated as an adult, and some studies have shown slightly higher rates of preterm birth and cesarean delivery (Haggar, 2014; Stensheim, 2013).

Notably, prior abdominopelvic radiation more convincingly afects neonatal outcomes. Adverse efects include elevated rates of abortion, low birthweight, stillbirth, and preterm birth (Signorello, 2006, 2010; Winther, 2008). Radiation may lower reproductive potential by creating reduced uterine volume, a thinned endometrium, and impaired uterine blood flow (Critchley, 1992; Larsen, 2004). Greater efects are seen with direct uterine radiation and with radiotherapy at younger ages (Teh,r2014).

Importantly, many cancer survivors conceive by assisted reproductive technology, which by itself has associated obstetrical risks. his is discussed in Chapter 8 (p. 151).

Tumors infrequently metastasize to the placenta. As described in Chapter 6 (p. 116), the most common types are malignant melanomas, leukemias, lymphomas, and breast cancer (AlAdnani, 2007). Placentas from pregnancies in these and all other women with a malignancy should be sent for histological evaluation. Because tumor cells are usually confined within the intervillous spaces, fetal metastases are infrequent.

Benign neoplasms are common and include leiomyomas, ovarian neoplasms, and endocervical polyps. Cancer in these organs may also complicate pregnancy, and of these, cervical neoplasia makes up the majority (Fig. 63-2).

These are overgrowths of endocervical stroma covered by epithelium. hey typically appear as single, red, elongated leshy masses of variable size that extend outward from the endocervical canal. Usually benign, they can bleed and can be a source of Pap test results describing aypical glandular cels of undetermined signiicance-AGUS. With removal and histological

Ovary 23% Uterus, vulva,

FIGURE 63-2 Frequency of reproductive-tract malignancies in 844 pregnant women. (Data from Haas, 1984; Lutz, 1977; Smith, 2003.) evaluation of these polyps, dysplasia is diagnosed in up to 0.5 percent, and there is malignant transformation in up to 0.1 percent (Esim Buyukbayrak, 2011; Long, 2013).

Few formal data guide management in pregnancy. Small asymptomatic lesions may be left alone to slough during delivery or puerperal remodeling. Removal and histological evaluation is reasonable if malignancy is suspected or if bleeding is trouble some. For those with a slender stalk, the polyp is grasped with ring forceps and twisted repeatedly about its base to strangulate feeding vessels. With repeated twisting, the base narrows and avulses. Monsel paste, which is ferric subsulfate, can be applied with pressure to the stalk stub for hemostasis. A thick-pedicle polyp may sometimes warrant surgical ligation and excision.

Pregnancy provides an opportune time to screen for cervical intraepithelial neoplasia (CIN), especially in women without regular access to health care. With Pap test screening, preg nancy status is noted on the requisition form because interpre changes. Some of these changes include presence of decidual cells and less often, Arias-Stella reaction. he latter gives an appearance of endocervical gland hyperplasia, which can make diferentiating this from truly atypical glandular cells diicult.

Screening guidelines also applicable in pregnant women were updated in 2012 by the American Society for Colposcopy and Cervical Pathology (ASCCP). hese include: (1) no screening until age 21, (2) cytology alone every 3 years in those aged 21 to 29 years, and (3) in those older than 30, human papillomavirus (HPV) and cytology co-testing every 5 years, or cytology alone every 3 years (Massad, 2013). High-risk conditions for cervical neoplasia include human immunodeficiency virus (HIV) infection, other immunocompromised states, and in utero diethylstilbestrol (DES) exposure. For women with HIV infection, initiation of cervical cancer screening with cytology alone begins within the first year after HIV diagnosis (American College of Obstetricians and Gynecologists, 20 16b).

Human Papillomaviru5. This virus infects cervical epithelia. In most instances, the infection clears, but in a smaller number, the virus may promote benign, premalignant, or cancerous neoplastic growth. he prevalence of HPV infection in pregnant women approximates 15 percent (Hong, 2013; Liu, 2014). here are more than 100 serotypes, and several are associated with high-grade intraepithelial lesions and invasive cancer. he most prominent of these are serotypes 16 and 18. Cervical cancer screening that combines both cytology and testing for high-risk HPV serotypes is termed co-testing and is suitable for women 30 years and older. Notably, as a new paradigm for screening, primary HPV testing alone can be considered an appropriate sole method for women older than 25 years (Huh, 2015). With this, identiication of serotypes 16 or 18 prompts colposcopic evaluation.

Serotypes HPV 6 and 11 are linked with benign maternal genital warts. Congenital HPV infection from vertical transmission-mother to fetus or newborn-beyond transient skin colonization is rare. Still, conjunctival, laryngeal, vulvar, or perianal warts present at birth in the neonate or that develop within 1 to 3 years of birth are most likely due to perinatal exposure to these maternal HPV serotypes. his is described further in Chapter 65 (p. 1245). Importantly, cesarean delivery does not lower the risk of neonatal laryngeal papillomatosis.

has prompted development of three approved vaccines. These are not administered during pregnancy, are compatible with breastfeeding, and are discussed in Chapter 65 (p. 1245).

Abnormal Cytology and Histology. The incidence of abnor mal cervical cytology during pregnancy is at least as high as that reported for nonpregnant women. Abnormal cytological indings and their suggested management according to consen sus guidelines are summarized in Table 63-1. Many of these cytological abnormalities should prompt colposcopy, and the main goal during pregnancy is exclusion of invasive cancer.

Accordingly, lesions suspicious for high-grade disease or cancer should undergo biopsy. Unsatisfactory colposcopic evaluation is less common during pregnancy because the transformation zone is better exposed due to cervical eversion. With insui cient visualization of the zone, colposcopy is repeated in 6 to 8 weeks. During this time, the squamocolumnar junction usually will further evert to permit satisfactory examination.

Women with histologically confirmed CIN during pregnancy may be allowed to deliver vaginally, with further evaluation planned after delivery. For those with CIN 1, the recommended management is reevaluation postpartum. For those with CIN 2 or 3 in which invasive disease has been excluded, deferring reevaluation until at least 6 weeks postpartum is acceptable. Alternatively, repeat colposcopic and cytological evaluations are performed at intervals no more frequent than 12 weeks. Repeat biopsy is recommended only if appearance of the lesion worsens or if cytology suggests invasive cancer (Massad,r2013).

Regression of a CIN lesion is common during pregnancy or postpartum. In a study of 1079 pregnant women with cervical dysplasia in which biopsy correlated with colposcopic findings, 61 percent of lesions reverted to normal postpartum (Fader, 2010). In another study, Yost and colleagues (1999) reported postpartum lesion regression in 70 percent of women with CIN 2 or 3. And, although 7 percent of women had CIN 2 lesions that progressed to CIN 3, no lesion progressed to invasive carcinoma. In another study of 77 women with carcinoma in situ (CIS) diagnosed during pregnancy, a third had postpartum regression of their lesion, two thirds had persistent CIS, and only two women had microinvasive cancer on cone biopsy after delivery (Ackermann, 2006).

Adenocarcinoma in situ (AIS) is managed similarly to CIN 3 (Dunton, 2008). hus, unless invasive cancer is identified, treatment of AIS is not recommended until 6 weeks postpartum.

Cervical Conization. If invasive epithelial lesions are suspected, conization is indicated and may be done with loop electrosurgical excisional procedure (LEEP) or by cold-knife conization. However, the epithelium and underlying stroma within the endocervical canal cannot be extensively excised without the risk of membrane rupture. Logically, residual disease is common. Of 376 cone biopsies during pregnancy, Hacker and aWomen aged 30+ years.

bEndocervical curettage and endometrial sampling are contraindicated in pregnancy.

adenoCA = adenocarcinoma; AGC = atypical glandular cells; AIS = adenocarcinoma in situ; ASC-H = atypical squamous cells, cannot exclude high-grade squamous intraepithelialrlesion; ASC-US = atypical squamous cells of undetermined significance; HPV = human papillomavirus;

HSIL = high-grade squamous intraepithelialrlesion; LSIL = low7grade squamous intraepithelial lesion; NILM = negative for intraepithelialrlesion or malignancy; SCCA = squamous cell carcinoma. Adapted from American Society for Colposcopy and Cervical Pathology (ASCCP) 2012 Consensus Guidelines; Massad, 20lr3.

Table summarized and used with permission from Dr. Claudia L. Werner.

associates (1982) found residual neoplasia in 43 percent of subsequent specimens. In addition, nearly 10 percent of 180 pregnant women required transfusion after conization (Averette, 1970). hus, if possible, conization is avoided in pregnancy because of its higher risks for abortion, membrane rupture, hemorrhage, and preterm delivery.

Women with CIN treated bore pregnancy may also encounter pregnancy complications. First, cicatricial cervical stenosis is uncommon but may follow conization, LEEP, or laser surgery. Cervical stenosis almost always yields during labor. A so-called conglutinated cervix may undergo almost complete intrapartum efacement without dilation, and the presenting part is separated from the vagina by only a thin layer of cervical tissue. Spontaneous dilation usually promptly follows firm pressure with a ingertip, although instrumented dilation or cruciate incisions may be required.

Second, preconceptional cold-knife conization is associated with cervical insuiciency and preterm birth. That said, the relationship between preterm birth and LEEP continues to be debated (Castanon, 2012; Conner, 2014; Stout, 2015; Werner, 2010). he size of tissue excised seems to be directly related to adverse outcomes (Weinmann, 2017).

he incidence of invasive cervical carcinoma has dramatically declined in the United States as a result of PAP testing (American College of Obstetricians and Gynecologists, 2016b). This cancer is found in approximately 1 in 8500 pregnancies (Bigelow, 2017; Pettersson, 2010). The diagnosis is conirmed with biopsies taken during colposcopy, with conization, or from a grossly abnormal lesion. Of the histological types, squamous cell carcinomas account for 75 percent of all cervical cancers, whereas adenocarcinomas compose the remainder. Cancers may appear as exophytic or endophytic growth; as a polypoid mass, papillary tissue, or barrel-shaped cervix; or as focal ulceration or necrosis. A watery, purulent, foul, or bloody discharge may also be present. Biopsy with Tischler forceps is warranted for suspicious lesions. Abnormal tumor vessels may cause heavier than expected biopsy-site bleeding, which is usually controlled by Monsel paste and pressure.

Cervical cancer is staged clinically, and 70 to 75 percent of cases that are diagnosed in pregnancy are stage I (Bigelow, 2017; Morice, 2012). Physiological pregnancy changes may impede accurate staging, and the extent of cancer is more likely to be underestimated in pregnant women. Specifically, induration of the broad ligament base, which characterizes tumor spread beyond the cervix, may be less prominent due to cervical, paracervical, and parametrial pregnancy-induced softening. Staging in pregnancy typically incorporates indings from pelvic examination and from renal sonography, chest radiography, cystoscopy, proctoscopy, and perhaps cone biopsy. Although MR imaging is not formally considered for clinical staging, it can be used without gadolinium contrast to ascertain involvement of the urinaty tract and lymph nodes (Fig. 63-3).

FIGURE 63-3 Sagittal T2-weighted magnetic resonance image of a gravid uterus at 32 weeks' gestation with a large cervical carcinoma (arrows).

Management and Prognosis. Cervical cancer treatment in pregnant women is individualized, and factors include the clinical stage, fetal age, and individual desire to continue pregnancy. Stage IA1 is termed microinvasive disease and describes lesions with deepest invasion ;3 mm and widest lateral extension ;7 mm (FIGO Committee on Gynecologic Oncology, 2009). If diagnosed by cone biopsy, then treatment follows guidelines similar to those for intraepithelial disease. In general, continuation of pregnancy and vaginal delivery are considered safe, and definitive therapy is reserved until 6 weeks postpartum.

In contrast, invasive cancer demands relatively prompt therapy. During the first half of pregnancy, immediate treatment is advised by most, but this depends on the decision whether to continue pregnancy. During the latter half of pregnancy, most agree that pregnancy can safely be continued until fetal lung maturity is attained (Greer, 1989). In two studies with a total of 40 women past 20 weeks' gestation with either stage I or stage IIA carcinoma, delayed treatment was considered reasonable in women without bulky lesions (Takushi, 2002; van Vliet, 1998). Another option is to complete staging using laparoscopic lymphadenectomy and to delay treatment if metastases are excluded (louini, 2008; Favero, 2010). In a metaanalysis, neoadj uvant chemotherapy, that is, prior to surgery, with platinum derivatives was found to be promising for treatment in pregnancy (Zagouri, 2013a).

Although surgical therapy and radiation are equally efective, radical hysterectomy plus pelvic lymphadenectomy is the preferred treatment for invasive cervical cancer in most young women with stage I and early stage IIA lesions. Disadvantageously, radiotherapy for cervical cancer destroys ovarian and possibly sexual function, and frequently causes intestinal and urinary tract injury. In 49 women with pregnancy-associated stage

IB cancer, a 30-percent severe complication rate accompanied radiotherapy compared with that of only 7 percent with radical surgery (Nisker, 1983). With surgery before 20 weeks' gestation, radical hysterectomy is usually performed with the fetus in situ.

In later pregnancy, however, hysterotomy is oten performed first.

Although less commonly selected during pregnancy, other cers. U ngGr and colleagues (2006) performed abdominal radical in five pregnant women. Yahata and associates (2008) treated four women at 16 to 23 weeks for stage IA1 adenocarcinoma with laser conization, and all delivered at term. Van Calsteren and coworkers (2008) reported similar success.

For more advanced-stage cancer, radiotherapy is given.

External beam radiation in early in pregnancy typically leads to spontaneous abortion. If miscarriage does not ensue, curettage is performed. During the second trimester, spontaneous abortion up to a fourth of cases. his is selected because labor induction or dilation and evacuation may pose serious hemorrhage risks.

Pregnancy does not have a negative efect on the prognosis of cervical cancer, and survival outcomes are similar for preg nant and nonpregnant women (Amant, 2014; Mogos, 2013).

In a case-control study of 44 women with pregnancy-associated cervical cancer, the overall 5-year survival rate approximated (van de' Vange, 1995).

Delivery. Any adverse prognostic efects that vaginal delivery through a cancerous cervix might have are unknown. For this reason, the mode of delivery is controversial, especially for small, early-stage lesions. In some cases of bulky or friable tumors, significant hemorrhage from the cancer may complicate vaginal delivery. Also, recurrences have been reported in the episiotomy scar, which result from tumor cells apparently "seeding" the episiotomy (Goldman, 2003). Thus, most favor cesarean delivery.

Pregnancy ater Radical Trachelectomy. There is growing experience with pregnancy in women who have undergone fertility-sparing radical trachelectomy for stage IB 1 and IB2 cervical cancer before conception. During the typically vaginal procedure, the cervix is amputated at the level of the internal os, and a permanent-suture cerclage is placed around the isthmus for support in future pregnancies. The uterine isthmus is then reconstructed to the vagina. Because of the permanent cerclage, a classical cesarean incision is required for delivery.

Shepherd and colleagues (2006) presented outcomes for 123 such women cared for at their institution. Of 63 women who attempted pregnancy, 19 had 28 live births. All underwent classical cesarean delivery, and one fourth delivered before 32 weeks. Similar findings were reported by Kim (2012) and Park (2014) and their coworkers.

Also known as myomas and somewhat erroneously called ibrois, uterine leiomyomas are common benign smooth-muscle tumors.

heir incidence during pregnancy approximates 2 percent, and the cited range depends on the frequency of routine sonography and population characteristics (Qidwai, 2006; Stout, 2010). In one study of 4271 women, the irst-trimester leiomyoma prevalence was highest in black women-18 percent-and lowest in whites-8 percent (Laughlin, 2009).

Leiomyomas vary in location and may develop as submucous, subserosal, or intramural growths. Less often, these develop in the cervix or broad ligament. Some become parasitic and their blood supply is derived from adjacent structures such as the highly vascularized omentum. In one rare manifestation-leiomyomatosis peritonealis disseminata-numerous, small, benign subperitoneal smooth-muscle tumors appear similar to carcinomatosis. The tumors are likely caused by estrogen stimulation of multicentric subcoelomic mesenchymal cells to become smooth-muscle cells (Bulun, 2015). hese growths often regress after pregnancy.

he stimulatory efects of pregnancy progesterone on myoma growth are unpredictable and can be impressive. hese tumors respond diferently in individual women and may grow, regress, or remain unchanged in size during pregnancy (Laughlin, 2009; Neiger, 2006).

Especially during pregnancy, myomas can be conused with other adnexal masses, and sonographic imaging is indispensable (Fig. 63-4). In women in whom sonographic indings are unclear, MR imaging performed ater the first trimester may be necessary. Once diagnosed, leiomyomas do not require surveillance with serial sonography unless associated complications are anticipated.

Symptoms. Most leiomyomas are asymptomatic, but acute or chronic pain or pressure may develop. Large myomas more oten require admission for pain (Dogan, 2016). For chronic pain secondary to large tumor size, nonnarcotic analgesic drugs usually suice. More acutely, some myomas can outgrow their blood supply and hemorrhagic infarction follows, which is termed red

FIGURE 63-4 Sonogram of a pregnant uterus with a large uterine leiomyoma. The heterogeneous mass (arrows) lies beside the fetus (seen in cross section) and has the classic appearance of a leiomyoma in pregnancy. The placenta is located anteriorly, and the mass originates from the posterior lower uterine segment and occupies more than half of the total uterine volume.

or carneous degeneration. Clinically, there is acute focal abdominal pain and tenderness, and sometimes a low-grade fever and leukocytosis. As such, tumor degeneration may be diicult to diferentiate from appendicitis, placental abruption, ureteral stone, or pyelonephritis. Sonographic imaging can be helpful, but close observation is requisite because an infarcted myoma is essentially a diagnosis of exclusion. In some women, preterm labor is stimulated by associated inlammation.

Treatment of a degenerated myoma is analgesic medications, and symptoms usually abate within a few days. In severe cases, close observation may be needed to exclude a septic cause. Although surgery is rarely necessary during pregnancy, myomectomy in highly selected cases has resulted in good outcomes. Of 23 reported cases, women were 14 to 20 weeks' gestation, and in almost half, surgery was performed because of pain (Celik, 2002; De Carolis, 2001). In some, an intramural leiomyoma was in contact with the implantation site. Except for one loss immediately following surgery at 19 weeks, most underwent cesarean delivery later, at term.

Occasionlly, a pedunculated subserosal myoma will undergo torsion with subsequent painul necrosis. Laparoscopy or laparotomy can be used to ligate the stalk and resect the necrotic tumor. That said, we believe that surgery should be limited to tumors with a discrete pedicle that can be easily clamped and ligated.

Pregnancy Complications. Myomas are associated with several complications that include preterm labor, placental abruption, fetal malpresentation, obstructed labor, cesarean delivery, and postpartum hemorrhage. In a review of pregnancy outcomes in 2065 women with leiomyomas, Coronado and colleagues (2000) reported that placental abruption and breech presentation were each increased fourfold; irst-trimester bleeding and dysfunctional labor, twofold; and cesarean delivery, sixfold. Salvador and associates (2002) reported an eightfold higher second-trimester abortion risk in these women.

Factors most important in determining morbidity in pregnancy are leiomyoma number, size, and location (Ciavattini, 2015; Jenabi, 2018; Lam, 2014). If the placenta is adjacent to or implanted over a leiomyoma, rates of abortion, preterm labor, placental abruption, and postpartum hemorrhage are all increased. Retroplacental myomas are also associated with fetal-growth restriction (Knight, 2016) . Tumors in the cervix or lower uterine segment may obstruct labor, as did the one shown in Figure 63-5. Despite these complications, Qidwai and associates (2006) reported a 70-percent vaginal delivery rate in women in whom myomas measured : 10 cm. hese data argue against empirical cesarean delivery for leiomyomas, and we allow a trial of labor unless myomas clearly obstruct the birth canal. If cesarean delivery is indicated, uterine malrotation should be excluded prior to hysterotomy. Myomas are generally let alone unless they cause recalcitrant bleeding. n important caveat is that cesarean hysterectomy may be technically diicult because of lateral ureteral displacement by the masses.

Bleeding due to myomas may develop during pregnancy from any of several factors. Especially common is bleeding with miscarriage, preterm labor, placenta previa, and placental abruption. Much less often, bleeding may result from a submucous myoma that has prolapsed from the uterus and into the cervix or vagina. In this unusual circumstance, although heavy or persistent bleeding may require earlier intervention, the stalk, if accessible, can be ligated vaginally near term to avoid tumor avulsion during delivery.

FIGURE 63-5 Cesarean delivery performed because of a large leiomyoma in the lower uterine segment. A classical vertical uterine incision, seen to the left of the myoma, was required for delivery of the fetus.

Fortunately, myomas rarely become infected (Genta, 2001).

When infection develops, it usually is postpartum, especially if the tumor is located immediately adjacent to the implantation site (Lin, 2002). hey also may become infected with an associated septic abortion and myoma perforation by a sound, dilator, or curette.

Fertility Considerations. Despite the relatively high prevalence of myomas in young women, it is not clear whether they diminish fertility, other than by possibly causing miscarriage. In a review of 11 studies, Pritts (2001) concluded that submucous myomas did signiicantly afect fertility. He also found that hysteroscopic myomectomy improved infertility and early miscarriage rates in these women. If truly implicated in infertility, myomas in other locations may require laparoscopy or laparotomy for excision.

Some of these methods of treatment for infertility may afect subsequent pregnancies. For example, after myomectomy, the gravid uterus can rupture either before or during labor (American College of Obstetricians and Gynecologists, 20 16a). Management is individualized, and review of the prior operative report is prudent. If resection resulted in a defect into or immediately adjacent to the endometrial cavity, then cesarean delivery is usually done before labor begins.

Although less efective than surgery, uterine artery embolization of myomas has also been used to treat infertility or symptoms (Mara, 2008). Women so treated have higher rates of miscarriage, cesarean delivery, and postpartum hemorrhage (Homer, 2010). he Society of Interventional Radiology considers myoma embolization relatively contraindicated in women who plan future pregnancies (Stokes, 2010).

Finally, outside the United States, ulipristal-a selective progesterone-receptor modulator-can be used for myoma regression. Successful subsequent pregnancies without tumor regrowth have been reported (Luycx, 2014).

Occasionally, endometriosis can develop after delivery from otomy scars (Bumpers, 2002). Here, they form a palpable mass and can cause cyclic localized pain. Endometriomas within an ovary are discussed in the next section.

Adenomyosis is traditionally found in late reproductive life and beyond. Its acquisition may be at least partially related to disruption of the endometrial-myometrial border during sharp curettage for abortion (Curtis, 2002). In a case-control study, associated rates of second-trimester abortion, preeclampsia, fetal malposition, and preterm delivery.

Endometrial carcinoma is an estrogen-dependent neoplasia also usually found in women older than 40 years. hus, it is seen only rarely with pregnancy. Of 27 cases that were identi fied during pregnancy or within the irst 4 months postpartum, nuna, 2009). These are usually early-stage, well-diferentiated adenocarcinomas for which treatment consists primarily of tomy. Much less commonly, to preserve future fertility, curet tage with or without postprocedural progestational therapy has been used for the rare patient with cancer identified in a miscar riage curettage specimen (Schammel, 1998).

Many more studies describe a conservative approach for well-selected nonpregnant women diagnosed with endometrial cancer who wish to preserve fertility. One study followed 13 women treated with progestins for early-stage, well-diferentiated adenocarcinoma who then later conceived after apparent remission (Godieb, 2003). Nine had liveborn neonates, and four of six women with a recurrence responded to another course of therapy. Similar outcomes were described in 12 women by Niwa (2005) and in 21 women by Signorelli (2009), each with their coworkers. Despite these acceptable pregnancy rates, recurrences and death have been reported, and conservative management is not considered standard (Erkanli, 2010).

Ovarian masses found during pregnancy are relatively common. Among studies, incidences vary depending on the frequency of prenatal sonography, the ovarian size threshold used to define a clinically signiicant "mass," and whether the study site is tertiary or primary care. Thus, the incidence of ovarian masses not surprisingly ranges from 1 in 100 to 2000 pregnancies (Whitecar, 1999; Zan etta, 2003). Of ovarian malignancies, the absolute incidence in the California Cancer Registry was 1 in 19,000 pregnancies (Smith, 2003).

The most frequent types of ovarian masses are corpus luteum cysts, endometriomas, benign cystadenomas, and mature cystic teratomas. Because pregnant women are usually young, malignant tumors and those of low malignant potential are proportionately uncommon. Our experiences from Parkland Hospital are similar to those of Leiserowitz and associates (2006), who

FIGURE 63-6 Sonographic characteristics of common adnexal masses in pregnancy. A. A simple anechoic cyst with smooth walls is characteristic of a physiological corpus luteum cyst or benign cystadenoma. B. Cystic structure with difuse internal low-level echoes sug gestive of an endometrioma or hemorrhagic corpus luteum. C. Mature cystic teratoma appears as an adnexal cyst (marked by calipers) with accentuated lines and dots that represent hair in both longitudinal and transverse planes. At the central inferior aspect of this cyst, a mural nodule-Rokitansky protuberance-is seen. These typically rounded protuberances range in size from 1 to 4 cm, they are predominantly hyperechoic, and they create an acute angle with the cyst wall. Although not seen here, fat-fluid levels are often identified with cystic teratomas. (Used with permission from Dr. Elysia Moschos.) found that 1 percent of9375 ovarian masses were frankly malignant and that another 1 percent were of low malignant potential. In surgically excised masses, rates of malignancy are higher, vary from 4 to 13 percent, and probably reRect a greater preoperative concern for cancer (Hofman, 2007; Sherard, 2003).

Most ovarian masses are asymptomatic in pregnant women.

Some cause pressure or chronic pain, and acute abdominal pain may be due to torsion, rupture, or hemorrhage. Seldom is blood loss signiicant enough to cause hypovolemia.

Many ovarian masses are detected during routine prenatal sonography or during imaging done for other indications, including evaluation of symptoms. The typical sonographic appearance of these masses is shown in Figure 63-6. In some instances, MR imaging can be used to evaluate complicated anatomy.

Cancer antigen 125 (CA125) serves as a tumor marker, and levels are frequently elevated with ovarian malignancy. Importantly, concentrations of CA125 in early pregnancy and early puerperium are normally elevated, possibly from the decidua (slam , 2000; Spitzer, 1998). As shown in the Appendix (p. 1257), from the second trimester until term, levels are not normally higher than those in the nonpregnant woman (Szecsi, 2014). With severe preeclampsia, however, levels are abnormally elevated (Karaman, 2014). Other tumor markers that are not useul for diagnosis or posttreatment surveillance in pregnancy include human chorionic gonadotropin (hCG) , alpha-fetoprotein, inhibins A and B, and the multimarker OVAl test (Liu, 2011).

The two most common are torsion and hemorrhage. Torsion usually causes acute constant or episodic lower abdominal pain that frequently is accompanied by nausea and vomiting. Sonography often aids the diagnosis. With color Doppler, presence of an ovarian mass with absent Row strongly correlates with torsion. However, minimal or early twisting may compromise only venous Row, thus leaving the arterial supply intact. If torsion is suspected, laparoscopy or laparotomy is warranted. Contrary to prior teaching, adnexectomy is generally unnecessary to avoid clot release, thus, most recommend attempts at untwlstmg (McGovern, 1999; Zweizig, 1993). With a salvageable ovary, within minutes, congestion is relieved, and ovarian volume and cyanosis diminish. If cyanosis persists, however, then removal of the infarcted adnexum is typically indicated.

If the adnexum is healthy, there are options. First, neoplasms are resected. However, ovarian cystectomy in an ischemic, edematous ovary may be technically diicult, and adnexectomy may be necessary. Second, unilateral or bilateral oophoropexy has been described to minimize the risk of repeated torsion (Djavadian, 2004; Germain, 1996). Techniques described include shortening of the utero ovarian ligament or fixing the utero ovarian ligament to the posterior uterus, the lateral pelvic wall, or the round ligament (Fuchs, 2010; Weitzman, 2008).

he most common cause of ovarian hemorrhage follows rupture of a corpus luteum cyst. If the diagnosis is certain and symptoms abate, then observation and surveillance is usually suicient. Concern for ongoing bleeding will typically prompt surgical evaluation. If the corpus luteum is removed before 10 weeks' gestation, progestational support is recommended to maintain the pregnancy. Suitable regimens include: (1) micronized progesterone (Prometrium) 200 or 300 mg orally once daily; (2) 8-percent progesterone vaginal gel (Crinone), one premeasured applicator vaginally daily plus micronized progesterone 100 or 200 mg orally once daily; or (3) intramuscular 17 -hydroxyprogesterone caproate, 150 mg. The first two regimens are given until 10 completed weeks. For the last, if given between 8 and 10 weeks' gestation, only one injection is required immediately after surgery. If the corpus luteum is excised between 6 and 8 weeks' gestation, then two additional doses should be given 1 and 2 weeks after the irst.

Because most of these are incidental findings, management considerations include whether resection is necessary and its timing. A cystic benign-appearing mass that is <5 cm often requires no additional antepartum surveillance. Early in pregnancy, this is likely a corpus luteum cyst, which typically resolves by the early second trimester. For cysts ::10 cm, because of the substan tial risk of malignancy, torsion, or labor obstruction, surgical removal is reasonable. Tumors between 5 and 10 cm should be carefully evaluated by sonography along with color Doppler and possibly MR imaging. If they have a simple cystic appear ance, these cysts can be managed expectantly with sonographic surveillance (Schmeler, 2005; Zan etta, 2003). Resection is done if cysts grow, begin to display malignant qualities, or become symptomatic. hose with classic indings of endometrioma or cesarean for obstetrical indications.

On the other hand, if sonographic characteristics suggest cancer-thick septa, nodules, papillary excrescences, or solid components-immediate resection is indicated (Caspi, 2000).

In one review of 563 masses, approximately half were simple, and the other half complex (Webb, 2015). Among simple masses, 1 percent were malignant, and of complex masses, 9 percent were cancerous.

Approximately 1 in 1000 pregnant women undergoes surgical exploration for an adnexal mass (Boulay, 1998). In general, we plan resection at 14 to 20 weeks' gestation because most masses that will regress will have done so by this time. As outlined in Chapter 46 (p. 901), laparoscopic removal is ideal (Naqvi, 2015; Sisodia, 2015). Importantly, in any instance in which cancer is strongly suspected, the American College of Obstetricians and Gynecologists (2017b) recommends consultation with a gynecologic oncologist.

Pregnancy Luteoma. One group of ovarian masses results directly from the stimulating efects of various pregnancy hormones on ovarian stroma. These include pregnancy luteoma, hyperreactio luteinalis, and ovarian hyperstimulation syndrome.

Of these, pregnancy luteoma is a rare, benign ovarian neoplasm that arises from luteinized stromal cells and classically causes elevated testosterone levels (Hakim, 2016; Irving, 2011). Up to 25 percent of afected women will be virilized, and of these afected women, nearly half of their female fetuses will have some degree of virilization. However, most mothers and their fetuses are unafected because the placenta rapidly converts testosterone to estrogen (KanovG, 2011).

In typical cases, an adnexal mass along with maternal virilization will prompt sonography and measurement of testosterone and CA125 levels. Luteomas range in size from microscopic to >20 cm. hey appear as solid tumors, may be multiple or bilateral, and may be complex because of internal hemorrhage (Choi, 2000). Concerns for malignancy may be further investigated with MR imaging (Kao, 2005; Tannus, 2009).

Total testosterone levels are increased, but notably, levels in normal pregnancy can be substantially elevated (Appendix, p. 1259). Diferential diagnoses include granulosa cell tumors, thecomas, Sertoli-Leydig cell tumors, Leydig cell tumors, stromal hyperthecosis, and hyperreactio luteinalis.

Generally, luteomas do not require surgical intervention unless there is torsion, rupture, or hemorrhage (Masarie, 2010). hese tumors spontaneously regress during the irst few months postpartum, and androgen levels drop precipitously during the irst 2 weeks following delivery (Wang, 2005). Lactation may be delayed a week or so by hyperandrogenemia (Dahl, 2008). Recurrence in subsequent pregnancies is rare.

Hyperreactio Luteinalis. In this condition, one or both ovaries develop multiple, large theca-lutein cysts, typically after the first trimester. Cysts are caused by luteinization of the follicular theca interna layer, and most are in response to stimulation by excep tionally high hCG levels (Russell, 2009). For this reason, they are more common with gestational trophoblastic disease, twins, fetal hydrops, and other conditions with increased placental mass. Maternal virilization may develop, but fetal virilization has not been reported (KanovG, 2011; Malinowski, 2015).

s reported by Baxi and coworkers (2014), these ovarian tumors appear sonographically to have a "spoke wheel" pattern (Fig. 20-3, p. 391). If the diagnosis is confident, and unless com plicated by torsion or hemorrhage, surgical intervention is not required. hese masses resolve ater delivery. Few data allow pre diction of risk in a subsequent pregnancy, but in one case report, a woman had hyperreactio with three pregnancies (Bishop, 2016).

Ovarian Hyperstimulation Syndrome. This is typified by multiple ovarian follicular cysts accompanied by increased capillary permeability. It most often is a complication of ovulationinduction therapy for infertility, although it rarely may develop in an otherwise normal pregnancy. It has also been reported with a partial molar pregnancy (Suzuki, 2014). Its etiopathogenesis is thought to involve hCG stimulation of vascular endothelial growth factor (VEGF) expression in granulosa-lutein cells (Soares, 2008). This causes greater that can lead to ascites, pleural or pericardial efusion, hypovolemia with acute kidney injury, and hypercoagulability. Serious complications are renal dysfunction, adult respiratory distress syndrome, ovarian rupture with hemorrhage, and VTE. Unlike hyperreactio lutealis, virilization is absent (Suzuki, 2004).

Detailed guidelines for management are outlined by the American Society for Reproductive Medicine (2016). Treatment is primarily supportive with attention to maintaining vascular volume and thromboprophylaxis. In severe cases, paracentesis can be helpful.

Malignancies of the ovary are the leading cause of death from genital-tract cancers in all women (American Cancer Society, 2017). Still, it is uncommon in young women, and the incidence of ovarian malignancy ranges from 1 in 20,000 to 1 in 50,000 births (Eibye, 2013; Palmer, 2009). Fortunately, 75 percent of these found in pregnancy are early-stage cancers that carry a 5-year survival rate between 70 and 90 percent (Brewer, 2011). The types of malignancy are also markedly diferent in pregnant women compared with those in older women. In gravidas, these are, in decreasing order of frequency, germ cell and sex cord-stromal tumors, low-malignant-potential tumors, and epithelial tumors (Morice, 2012).

Pregnancy apparently does not alter the prognosis of most ovarian malignancies. Management is similar to that for nonpregnant women, with the usual proviso that it may be modiied depending on gestational age. Thus, if frozen section histopathological analysis veriies malignancy, surgical staging is done with careful inspection of all accessible peritoneal and visceral surfaces (Giuntoli, 2006). Peritoneal washings are taken for cytology, biopsies are obtained from the diaphragmatic surface and peritoneum, omentectomy is completed, and pelvic and infrarenal paraaortic lymph nodes are sampled, if accessible.

If there is advanced disease, bilateral adnexectomy and omentectomy will decrease most tumor burden. In early pregnancy, hysterectomy and aggressive surgical debulking procedures may be elected. In other cases, minimal debulking as described in the previous paragraph is done and the operation terminated. In some cases of aggressive or large-volume disease, chemotherapy can be given during pregnancy while awaiting pulmonary maturation. Monitoring maternal CA125 serum levels during chemotherapy is not accurate in pregnancy (Aslam, 2000; Morice, 2012).

Paratubal and paroovarian cysts are either distended remnants of the paramesonephric ducts or are mesothelil inclusion cysts. Although most measure 53 cm, they occasionally attain worrisome dimensions. Their reported incidence is inluenced by size, but one autopsy series in nonpregnant women cited this to be 5 percent (Dorum, 2005). The most common parmesonephric cyst is the hydatid of Morgagni, which is pedunculated and typically dangles from one of the imbria. hese cysts infrequently cause complications and are most oten identiied at the time of cesarean delivery or puerperal sterilization. In these instances, they can simply be excised or drained by creating a large window in the cyst wll. Neoplastic paraovarian cysts are rare, sonographically and histologically resemble tumors of ovarian origin, and rarely are of borderline potential or frankly malignant (Korbin, 1998).

Preinvasive disease in young women-vulvar intraepithelial neoplasia (YIN) and vaginal intraepithelial neoplasia (VAIN)are seen more often than invasive disease and are commonly associated with HPV infection. As with cervical neoplasia, these premalignant conditions are treated after delivery.

Cancer of the vulva or vagina is generally a malignancy of older women, and thus, these are rarely associated with pregnancy. Even so, any suspicious lesions should be biopsied. Treatment is individualized according to the clinical stage and depth of invasion. In a review of 23 cases, investigators concluded that radical surgery for stage I disease was feasible during pregnancy-including in the last trimester (Heller, 2000).

We and others question the necessity of resection in late pregnany because deinitive therapy can oten be delayed due to these cancers' typically slow progression (Anderson, 2001). It appears that vaginal delivery is not contraindicated if vulvar and inguinal incisions are well healed. Vulvar sarcoma, vulvar melanoma, and vaginal malignancies are rare in pregnancy and are the subjects of case reports (lexander, 2004; Kuller, 1990; Matsuo, 2009).

Breast cancer rates rise most acutely between ages 40 and 80 years. However, because of its overall high frequency, breast cancer is relatively common even in younger women and is the most frequent cancer found in gravidas. From the Nationwide Inpatient Sample of 11.8 million births, the incidence approximated 1 in 15,000 (Maor, 2017). And, as more women choose to delay childbearing, the frequency of associated breast cancer is certain to grow. Postponed childbearing was considered partially responsible for the increase in pregnancy-associated breast cancer in Sweden and Denmark (Andersson, 2015; Eibye, 2013).

Some studies suggest that women with a family history of breast cancer-especially those with BRCAl and BRC2 breast cancer gene mutations-are more likely to develop breast malignancy during pregnancy (Wohlfahrt, 2002). However, it may be that it is parity that modiies this risk. Namely, parous women older than 40 years with these mutations have a signiicantly lower cancer risk than nulliparas with these mutated genes (Andrieu, 2006; Antoniou, 2006). Women with BRAl and BRC2 gene mutations who undergo induced abortion or those who breastfeed do not have an increased breast cancer risk (Friedman, 2006). Moreover, Jernstrom and associates (2004) found that breastfeeding conveyed a protective efect against this cancer in those with BRCAl gene mutation, but not in those with BRCA2 mutations. Of other congenital factors, it is controversial whether DES exposure raises breast cancer risks (Hoover, 2011; Titus-Ernstof, 2006).

More than 90 percent of gravidas with breast cancer have a palpable mass, and greater than 80 percent of cases are selfreported (Brewer, 2011). In pregnancy, clinical assessment, diagnostic procedures, and treatment of women with breast tumors are often slightly delayed (Berry, 1999). his can be partially attributed to pregnancy-induced breast tissue that obscures masses.

The evaluation of pregnant women with a breast mass does not difer from that for nonpregnant women (Loibl, 2015). hus, any suspicious breast mass should be pursued to diagnosis. Pragmatically, a palpable discrete mass can be biopsied or excised. If imaging is desirable to distinguish between a solid mass and a cystic lesion, sonography has high sensitivity and specificity (Navrozoglou, 2008). Mammography is appropriate if indicated, and the fetal radiation risk is negligible-0.04 mGywith appropriate shielding (rishna, 2013). But, because breast tissue is denser in pregnancy, mammography has a false-negative rate of 35 to 40 percent (Woo, 2003). If the decision to biopsy is uncertain, then MR imaging may be used. With such techniques, masses can usually be described as either solid or cystic.

Cystic breast lesions are simple, complicated, or complex (Berg, 2003). Simple cysts do not require special management or monitoring, but they may be aspirated if symptomatic. Complicated cysts show internal echoes during sonography, and they sometimes are indistinguishable from solid masses. These are typically aspirated, and if the sonographic abnormality does not resolve completely, a core-needle biopsy is usually performed. Complex cysts have septa or intracystic masses seen sonographically. Because some breast cancer may form complex cysts, excision is usually recommended.

For solid breast masses, evaluation is with the triple test, that is, clinical examination, imaging, and core needle biopsy. If all three suggest a benign lesion or if all three suggest a breast cancer, the test is said to be concordant. A concordant benign triple test is �99-percent accurate, and breast lumps in this category can be followed by clinical examination alone. Fortunately, most masses in pregnancy have these three reassuring features. In contrast, if any of the three assessments suggests malignancy, the mass should be excised.

Once breast cancer is diagnosed, a limited search of the most common metastatic sites is completed. For most women, this includes a chest radiograph, liver sonography, and skeletal MR imaging (Becker, 2016; Krishna, 2013).

Treatment of breast cancer is multidisciplinary and includes an obstetrician, breast surgeon, and medical oncologist. Ini tially, desires for pregnancy continuation are addressed, and data indicate that pregnancy interruption does not influence the course or prognosis of breast cancer (Cardonick, 2010). With pregnancy continuation, treatment in general mirrors that for nonpregnant women. Important caveats are that chemotherapy and surgery are postponed to the second trimester, and adjuvant radiotherapy is withheld until after delivery (Brewer, 2011).

Surgical treatment may be definitive. In the absence of metastatic disease, either a wide excision or a modified or total mastectomy-each with axillary node staging-can be performed (Rosenkranz, 2006). Staging by sentinel lymph node biopsy and lymphoscintigraphy with technetium-99m is safe. Breast reconstruction, if desired, is typically delayed until after delivery (Viswanathan, 2011). hat said, Caragacianu and coworkers (2016) described good results in 10 pregnant women who underwent immediate reconstruction after mastectomy.

Chemotherapy is usually given with both positive-and negative-node breast cancers. In premenopausal women, survival rates with this approach are improved, even if lymph nodes are cancer free. For node-positive disease, multiagent chemotherapy is begun if delivery is not anticipated within several weeks. Cyclophosphamide, doxorubicin, and cisplatin are currently used (Euhus, 2016). If an anthracycline-based agent such as doxorubicin is used, pretherapy maternal echocardiography is performed because of associated cardiotoxicity (Brewer, 2011). Good maternal and perinatal results have been reported (Berry, 1999; Hahn, 2006).

Immunotherapy for breast cancers is now commonplace.

T rastuzumab (Herceptin) is a monoclonal antibody to the HER2/neu receptor, which is found in approximately a third of invasive breast cancers (Hudis, 2007). The drug is not recommended in pregnancy. This is because HER21 neu is strongly expressed in fetal renal epithelium, and trastuzumab has been linked with miscarriage, fetal renal failure and related oligohydramnios, and preterm birth (Amant, 2010; Azim, 2010).

he efects of pregnancy on the course of breast cancer and its prognosis are complex. Breast cancer is more aggressive in younger women, but whether it is more aggressive during pregnancy in these same women is debatable (Azim, 2014). Clinically, most studies indicate little diference in overall survival rates with pregnancy-associated breast cancer compared with similarly aged and staged nonpregnant women (Beadle, 2009).

Other reports note worse overall survival rates with pregnancy associated breast cancer (Rodriguez, 2008). hese investigators do conclude, however, that later disease stages are more preva lent in pregnant women.

Indeed, breast cancer is usually found at a more advanced stage in pregnant women, and thus overall prognosis is dimin ished (Andersson, 2015). The aggregate of studies published after 1990 indicate that up to 60 percent of pregnant women have concomitant axillary node involvement at diagnosis. And although, stage for stage, the 5-year survival rate is compara ble in pregnant and nonpregnant women, the more advanced stages that are typical of pregnant women worsen their progno sis (Kuo, 2017; Zemlickis, 1992).

After breast cancer treatment, chemotherapy will render some women infertile, and options for childbearing are limited (Kim, 2011). For those who become pregnant, long-term maternal survival rates are not adversely afected (Averette, 1999; Velentgas, 1999). One metaanalysis of 10 studies found that for women with early breast cancer, pregnancy that occurs 10 months after diagnosis may, in fact, confer a survival benefit (Valachis, 2010). Data do not indicate that breastfeeding adversely the course.

In women successfully treated for breast cancer, recurrence is a concern. Because recurrences are more common soon after treatment, it seems reasonable to delay conception for 2 to 3 years. Hormonal contraceptive methods are contraindicated, and a copper-containing intrauterine device is an excellent long-acting reversible method for many. That said, women who conceive do not appear to have diminished survival rates (Ives, 2006). Notably, women treated with tamoxifen are at risk for several months after its discontinuation to have a newborn with congenital anomalies. This drug has an extremely long half-life, and thus delaying conception is recommended for at least 2 months after tamoxifen completion (Braems, 2011).

Palpable thyroid nodules are detected in 4 to 7 percent of the population, and approximately 10 percent are malignant (Burman, 2015). Clinical nodules are typically evaluated with sonography and measurement of serum thyroid-stimulating hormone (TSH) and free thyroxine levels. Fine-needle aspiration is indicated for a suspicious nodule (lexander, 2017; Gharib, 2016).

With a diagnosis of thyroid malignancy, pregnancy termination is not necessary. Primary therapy is thyroidectomy performed ideally during the second trimester. Postoperatively, replacement thyroxine is given. Most thyroid cancers are well diferentiated and follow an indolent course. Thus, delayed surgical treatment does not usually alter outcome (Yazbeck, 2012; Yu, 2016).

In some types of thyroid cancer, radioiodine is used for primary or postoperative treatment. This is contraindicated in both pregnancy and lactation for several reasons. First, transplacental 1311 is avidly trapped by the fetal thyroid gland to cause hypothyroidism. Second, during lactation, the breast also concentrates a substantial amount of iodide. This may pose neonatal risk due to radioiodine-contaminated milk ingestion and maternal risk from significant breast irradiation. To limit maternal exposure, a delay of 3 months between lactation and thyroid ablation will more reliably ensure complete breast involution (Sisson, 2011). In women with thyroid cancer who ultimately receive 131 I doses, pregnancy should be avoided for 6 months to 1 year. This time ensures thyroid function stability and permits confirmation of cancer remission (Abalovich, 2007).

This lymphoma is probably B-cell derived and is cytologically distinguished from other lymphomas by Reed-Sternberg cells. Of cancers in pregnancy, lymphomas are common, and gestational rates are rising because of delayed childbearing (Horowitz, 2016). In pregnant women, Hodgkin lymphomas are more frequent than non-Hodgkin lymphomas. In one populationbased review of 7.9 million births from the Nationwide Inpatient Sample, El-Messidi and colleagues (2015) reported its incidence to be 1 in 12,400.

In more than 70 percent of Hodgkin disease cases, lymph nodes painlessly enlarge at sites above the diaphragm, that is, in the axillary, cervical, or submandibular chains. Approximately one third of patients have symptoms such as fever, night sweats, malaise, weight loss, and pruritus. Diagnosis is by histological examination of involved nodes (Longo, 2015).

The Ann Arbor staging system, shown in Table 63-2, is applied to Hodgkin and other lymphomas. For staging, pregnancy limits the use of some radiographic studies, but at minimum, chest radiography, abdominal imaging with sonography or MR imaging, and bone marrow biopsy are completed (Williams, 2001). MR imaging is excellent for evaluating thoracic and abdominal paraaortic lymph nodes (Brenner, 2012). Staging laparotomy is seldom done today (Longo, 2015).

The current trend for nonpregnant individuals is to administer chemotherapy for all stages of Hodgkin disease. In pregnancy, for early-stage disease in the first trimester, options include observation until after 12 weeks' gestation, single-agent vinblastine until the second trimester, pregnancy termination followed by multiagent chemotherapy, or radiotherapy alone for isolated neck or axillary sites (EI-Hemaidi, 2012; Eyre, 2015).

For advanced-stage disease, chemotherapy is recommended regardless of gestational age. Before 20 weeks, therapeutic abortion is a consideration, but if termination is unacceptable, then treatment with vinblastine followed by multi agent therapy in the second trimester can be used (Eyre, 2015). For most advancedstage disease after the irst trimester, cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine are given, and radiotherapy can be added postpartum (Cohen, 2011). In general, postponement of therapy until fetal maturity is achieved seems justiiable only when the diagnosis is made late in pregnancy.

Women with Hodgkin lymphoma have a higher incidence of VTE (El-Messidi, 2015; Horowitz, 2016). lso, in our experiences, pregnant women with Hodgkin disease-even after they arer" cured" -are inordinately susceptible to infection and sepsis. Active antineoplastic therapy only increases this vulnerability.

The overall prognosis with Hodgkin lymphoma is good, and survival rates exceed 70 percent. Pregnancy does not adversely afect the cancer course or pregnancy outcomes in women with this lymphoma. Speciically, neither chemotherapy after the first trimester nor mediastinal and neck irradiation has adverse fetal efects (Brenner, 2012; El-v1essidi, 2015; Pinnix, 2016). For women with disease in remission, pregnancy does not stimulate a relapse (Weibull, 2016).

lthough usually B-cell tumors, non-Hodgkin lymphomas can also be T-cell or natural-killer-cell neoplasms. heir biology, classification, and treatment are complex (Longo, 2015; O'Gara, 2009). hey are associated with viral infections, and indeed, their incidence has risen sharply at least pardy because 5 to 10 percent of HIV-infected persons develop lymphoma. Other associated viruses include Epstein-Barr virus, hepatitis C virus, and human herpes virus 8. Some of these lymphomas are aggressive, and survival rates vary with the type of cell line involved (Longo, 2015).

Non-Hodgkin lymphomas are infrequent during pregnancy (Brenner, 2012; Pinnix, 2016). They are also staged according to the Ann Arbor system. If diagnosed in the irst trimester, pregnancy termination followed by multiagent chemotherapy is recommended for all but indolent or very early disease. These less aggressive forms may either be observed or be temporized with focal supradiaphragmatic radiotherapy and then full treatment in the second trimester. If one of these lymphomas is diagnosed after the irst trimester, chemotherapy and immunotherapy

TABLE 63-2. Ann Arbor Staging System for Hodgkin and Other Lymphomas

I Involvement in a single lymph node region or lymphoid site-e.g., spleen or thymus

II Involvement of two or more lymph node groups on the same side of the diaphragm-the mediastinum is a single site

III Involvement of lymph nodes on both sides of the diaphragm 1.

Limited to spleen or splenic hilar, celiac, or portal nodes 2.

Includes paraaortic, iliac, or nodes plus those in III

IV Extralymphatic involvement-e.g., liver or bone marrow

Substage A = no symptoms; substage B = fever, sweats, or weight loss; substage E = extralymphatic involvement excluding liver and bone marrow.

with rituximab are given (Cohen, 2011; Rizack, 2009). In one follow-up of 55 individuals at 6 to 29 years after exposure to chemotherapy in utero during maternal lymphoma treatment, no congenital, neurological, or psychological abnormalities were noted (Aviles, 2001).

Burkitt lymphoma is an aggressive B-cell tumor associ ated with Epstein-Barr virus infection. Prognosis is poor, and treatment is given with multiagent chemotherapy. In a review of 19 women whose pregnancies were complicated by this lymphoma, 17 died within a year of diagnosis (Barnes, 1998).

In general, these malignancies arise either from lymphoid tissues-lymphoblastic or lymphocytic leukemias, or from bone marrow-myeloid leukemias. hey can be acute or chronic. Although adult leukemias are more prevalent after age 40, they still are among the most common malignancies of young women (see Fig. 63-1). Leukemia was diagnosed in 1 in 40,000 pregnancies reported to the California Cancer Registry (Smith, 2003). In a review of 72 pregnancies complicated by leukemia from 1975 until 1988, 44 had acute myelogenous leukemia; 20 had acute lymphocytic leukemia; and eight had one of the chronic leukemias (Caligiuri, 1989).

Acute leukemias almost always cause marked peripheral blood count abnormalities, and often the white blood cell count is elevated with readily recognizable circulating blast cells. The diagnosis is made from bone marrow biopsy.

With current multiagent chemotherapy, remission during pregnancy is common, compared with an almost 100-percent mortality rate before 1970. Pregnancy termination does not further improve the prognosis, however, abortion is a consideration in early pregnancy to avoid potential chemotherapy teratogenesis. One example of the latter is treatment of acute promyelocytic leukemia with all-trans-retinoic acid, also known as tretinoin (Carradice, 2002; Sanz, 2015). This potent teratogen causes retinoic acid syndrome (Chap. 12, p. 245). In another example, acute myeloid leukemia is treated with tyrosine kinase inhibitors, another teratogen group (Palani, 2015). In other cases, pregnancy termination before viability may simpliY management of an acutely ill woman.

Other than these caveats, treatment of gravidas with leukemia is similar to that for nonpregnant women. Acute myeloid leukemia is treated without delay (Ali, 2015). After induction chemotherapy, postremission maintenance therapy is mandatory to prevent a relapse, which is then usually treated with stem-cell transplantation. If allogeneic stem-cell transplantation is indicated, early delivery is considered. With some chronic leukemias, it may be possible to delay therapy until after delivery (Fey, 2008). As with lymphoma, infection and hemorrhage are signiicant complications that should be anticipated in women with active disease.

Most descriptions of leukemia treatment in pregnancy are single cases or small series (Routledge, 2016; Sanz, 2015). In an earlier review of 58 cases, 75 percent were diagnosed after the irst trimester (Reynoso, 1987). Half were acute myelogenous leukemia, which had a remission rate of 75 percent with chemotherapy. Only 40 percent of these pregnancies resulted in liveborn neonates (Caligiuri, 1989).

and its pigment-producing melanocytes. Melanomas should be suspected in pigmented lesions that show changes in contour, surface elevation, discoloration, bleeding, or ulceration, which should prompt biopsy (Richtig, 2017). They are most com in women of childbearing age.

In some population studies, melanoma is the most frequent malignancy complicating pregnancy (Andersson, 2015; Ban nister-Tyrrell, 2015). Still, the reported incidence ranges widely from 0.03 to 2.8 per 1000 live births (Eibye, 2013; Smith, 2003). One explanation is that many are treated as outpatients and thus are not entered into tumor registries. As noted earlier (p. 1192), malignant melanoma is one of the tumors that is known to metastasize to the placenta and fetus. Placental evaluation for metastases should be performed after delivery.

Staging is clinical. Stage I is a melanoma with no palpable lymph nodes; in stage II, lymph nodes are palpable; and in stage III, there are distant metastases. For patients with stage

I, tumor thickness is the single most important predictor of survival. he Clark classiication includes ive levels of involve ment by depth into the epidermis, dermis, and subcutaneous fat. he Breslow scale measures tumor thickness and size, in addition to depth of invasion.

Primary surgical treatment for melanoma is determined by the stage and includes wide local resection, sometimes with extensive regional lymph node dissection. Schwartz and associates (2003) recommend sentinel lymph node mapping and biopsy using 99mT c-sulfur colloid, which has a calculated fetal dose of 0.014 mSv or 0.014 mGy. Routine regional node dissection reportedly improves survival rates in nonpregnant patients with microscopic metastases (Cascinelli, 1998). For pregnant patients, an algorithm has been proposed that begins with resection of the primary tumor under local anesthesia but postpones sentinel lymph node biopsy until after delivery (Broer, 2012). lthough prophylactic chemotherapy or immunotherapy is usually avoided during pregnancy, it may be given if indicated by tumor stage and maternal prognosis. In most cases of distant metastatic melanoma, treatment is at best palliative. Currently, the role of estrogen receptor-� in melanoma progression is under investigation, and it may be a target for future therapeutic intervention (de Giorgi, 2011).

Stage-for-stage, survival is equivalent between pregnant and nonpregnant women (Driscoll, 2016; Johansson, 2014). In one study, half of pregnant women had stage III or IV lesions (de Haan, 2017). Therapeutic abortion does not improve maternal survival rates. Clinical stage is the strongest determinant of survival, and women with deep cutaneous invasion or regional node involvement have the worst prognosis. Approximately 60 percent of recurrences will manifest within 2 years, and 90 percent by 5 years. Thus, most recommend that pregnancy be avoided for 3 to 5 years after surgical resection. Interim contraception can include combination oral contraceptives, as they do not appear to have adverse cancer efects (Gandini, 2011). Related, subsequent pregnancies in women with localized melanoma do not lower cancer survival rates (Driscoll, 2009).

Carcinomas of the colon and rectum are the third most frequent in women of all age groups in the United States (American Cancer Society, 2016). heir incidence in pregnancy is rising because of delayed childbearing (Rogers, 2016) . Even so, colorectal tumors are uncommon before age 40. Smith and colleagues (2003) reported an approximate incidence of 1 per 150,000 deliveries in the California Cancer Registry. he incidence approximated 1 per 35,000 births in a Danish Registry (Eibye, 2013). Most-80 percent-of colorectal carcinomas in pregnant women arise from the rectum. In one review, only 41 cases in pregnancy were colon cancers above the peritoneal reflection (Chan, 1999).

he most frequent symptoms of colorectal cancer are abdominal pain, distention, nausea, constipation, and rectal bleeding. If symptoms of colon disease persist, digital rectal examination, stool tests for occult blood, and lexible sigmoidoscopy or colonoscopy are done. Some malignancies of the gastrointestinal tract are discovered because of metastases to the ovary. Kruckenberg tumors are tumor-laden ovaries from another primary, often gastrointestinal, and have a bleak prognosis (GliSic, 2006; Kodama, 2016).

Treatment of colon cancer in pregnant women mirrors the same general guidelines as for nonpregnant women. Without evidence of metastatic disease, surgical resection is preferred, but most gravidas have advanced lesions (AI-Ibrahim, 2014). During the first half of pregnancy, hysterectomy is not necessary to perform colon or rectal resection, and thus, therapeutic abortion is not mandated. During later pregnancy, therapy may be delayed until fetal maturation, however, bowel hemorrhage, obstruction, or perforation may force surgical intervention (Minter, 2005).

Gastric cancer is rarely associated with pregnancy, and most reported cases are from Japan. Hirabayashi and coworkers (1987) reviewed outcomes in 60 pregnant women during a 70-year period from 1916 to 1985. Delayed diagnosis during pregnancy is common, and the prognosis is consistently poor (Lee, 2009). Esophageal cancer has similar symptoms, but it is rare (Sahin, 2015). It is axiomatic that persistent unexplained upper gastrointestinal symptoms should be evaluated by endoscopy.

Various other neoplasms have been reported in pregnancy and are usually the subject of case reports. Examples include carcinoid tumors, which are usually of gastrointestinal origin (Durkin, 1983). Both pancreatic and hepatocellular cancer are rare during pregnancy (Kakoza, 2009; Marinoni, 2006; Papoutsis, 2012; Perera, 2011). Another report described a massive intrahepatic cholangiocarcinoma masquerading as HELLP syndrome (Bladerston, 1998). Except for thyroid cancer, malignant tumors of the head and neck are rare (Cheng, 2015). Lung cancer is also uncommon (Boussios, 2013). Central nervous system neoplasms had a reported frequency of 1 in 10,000 to 28,000 births (Eibye, 2013; Smith, 2003). Bladder and urachal duct carcinoma are rarely coincident with pregnancy (McNally, 2013; Yeaton-Massey, 2013). Last, bone tumors have been described (Kathiresan, 2011).

Abalovich M, Amino N, Barbour A, et al: 2007 management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 92:S 1, 2007

Abdel-Hady ES, Hemida A, Gamal A, et al: Cancer during pregnancy: perinatal outcome after in utero exposure to chemotherapy. Arch Gynecol Obstet 286(2):283,t2012

Ackermann S, Gehrsitz C, Mehihorn G, et al: Management and course of histologically verified cervical carcinoma in situ during pregnancy. Acta Obstet Gynecol Scand 85: 1134,t2006

AI-Adnani M, Kiho L, Scheimberg 1: Maternal pancreatic carcinoma metastatic to the placenta: a case report and literature review. Pediatr Dev Pathol 10:61,t2007

AI-Ibrahim A, Parrish J, Dunn E, et al: Pregnancy and maternal outcomes in women with prior or current gastrointestinal malignancies. J Obstet Gynaecol Can 36(1):34, 2014

Alexander A, Harris M, Grossman D, et al: Vulvar melanoma: difuse melanosis and metastases to the placenta. J Am Acad Dermatol 50(20):293, 2004

Alexander EK, Pearce EN, Brent GA, et al: 20t16 guidelines of the American hyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid 27(3):315,t2017

Ali S, Jones GL, Culligan DJ, et al: Guidelines for the diagnosis and management of acute myeloid leukaemia in pregnancy. Br J HaematoIt170(4):487, 20t15 Alouini S, Rida K, Mathevet P: Cervical cancer complicating pregnancy: impli cations oflaparoscopic lymphadenectomy. Gynecol Oncolt108(3):472, 2008

Amant F, Deckers S, Van Calsteren K, et al: Breast cancer in pregnancy: recommendations of an international consensus meeting. Eur J Cancer 46(18):3158,t2010

Amant F, Han SN, Gziri MM, et al: Management of cancer in pregnancy. Best Pract Res Clin Obstet GynaecoIt29(5):741, 2015a Amant F, Uzan C, Han SN, et al: Matched cohort study on patients with cervical cancer diagnosed during pregnancy. Ann OncoI25(suppI4):iv320, 2014 Amant F, Vandenbroucke T, Verheecke M, et al: Pediatric outcome ater maternal cancer diagnosed during pregnancy. N Engl J Med 373: 1824, 20t15b American Cancer Society: Leading sites of new cancer cases and deaths-20t16 estimates. 2016. Available at: https://www.cancer.org/content/dam/ cancer-org/ research/ cancer-facts-and -statistics/ ann ual-cancer-facts-andfigures/20 1t6/leading-sites-of-new-cancer-cases-and-deaths-20 1t6-estimate. Accessed June 11, 2017 American Cancer Society: What are the key statistics about ovarian cancer? 2017. Available at: https://www.cancer.org/cancerlovarian-cancerlabout/ key-statistics.html. Accessed June 11, 2017 American College of Obstetricians and Gynecologists: Alternatives to hysterectomy in the management of leiomyomas. Practice Bulletin No. 96, August 2008, Reairmed 2016a American College of Obstetricians and Gynecologists: Cervical cancer screening and prevention. Practice Bulletin No. 168, October 2016b American College of Obstetricians and Gynecologists: Guidelines for diagnostic imaging during pregnancy and lactation. Committee Opinion No. 723, October 2017a American College of Obstetricians and Gynecologists: he role of the obstetrician-gynecologist in the early detection of epithelial ovarian cancer in women at average risk. Committee Opinion No. 716, September 2017b American College of Radiology: ACR manual on contrast media. Version 10.2. Reston, American College of Radiology, 20t16 American Society for Reproductive Medicine: Fertility preservation and reproduction in patients facing gonadotoxic therapies: a committee opinion. Fertil Sterilt100(5):1224, 2013a American Society for Reproductive Medicine: Prevention and treatment of moderate and severe ovarian hyperstimulation syndrome: a guideline. Fertil Steril 106(7):1634,t2016 American Society for Reproductive Medicine, Society for Assisted Reproductive Technology: Mature oocyte cryopreservation: a guideline. Fertil Steril ,2013b merican Society for Reproductive Medicine, Society for Assisted Reproductive Technology: Recommendations for gamete and embryo donation: a committee opinion. Fertil Steril 99(1):47, 2013c

Anderson ML, Mari G, Schwartz PE: Gynecologic malignancies in pregnancy.

In Barnea ER, Jauniaux E, Schwartz PE (eds): Cancer and Pregnancy. London, Springer, 2001

Andersson TM, Johansson AL, Fredriksson 1, et al: Cancer during pregnancy and the postpartum period: a population-based study. Cancer 121 (12):20 2, 2015

Andrieu N, Goldgar DE, Easton OF, et al: Pregnancies, breast-feeding, and breast cancer risk in the International BRCA1I2 Carrier Cohort Study (IBCCS). J Natl Cancer Inst 98:535,t2006

Antoniou AC, Shenton A, Maher ER, et al: Parity and breast cancer risk among BRCA1 and BRCA2. Breast Cancer Res 2, 2006

Aslam N, Ong C, Woelfer B, et al: Serum CA125 at 11-14 weeks of gestation in women with morphologically normal ovaries. BJOG 107:689,t2000 Averette HE, Mirhashemi R, Mofat FL: Pregnancy after breast carcinoma: the ultimate medical challenge. Cancer 85:2301, 1999

Averette HE, Nasser N, Yankow SL, et al: Cervical conization in pregnancy: analysis of 180 operations. m J Obstet Gynecol 106:543, 1970

Aviles A, Neri N: Hematological malignancies and pregnancy: a inal report of 84 children who received chemotherapy in utero. Clin Lymphoma 2(3):173,t2001

Azim HA Jr, Azim H, Peccatori FA: Treatment of cancer during pregnancy with monoclonal antibodies: a real challenge. Expert Rev Clin Immunol 6(6):821,t2010 zim HA Jr, Partridge AH: Biology of breast cancer in young women. Breast Cancer Res 16(4):427,t2014

Bannister-Tyrell M, Roberts CL, Hasovits C, et al: Incidence and outcomes of pregnancy-associated melanoma in New South Wales 1994-2008. Aust N Z J Obstet Gynaecol 55(2):116, 2015

Barnes MN, Barrett JC, Kimberlin OF, et al: Burkitt lymphoma in pregnancy.

Obstet Gynecol 92:675, 1998

Baxi LV, Grossman LC, Abellar R: Hyperreactio luteinalis in pregnancy and hyperandrogenism: a case report. J Reprod Med 59(9-10):509,2014

Beadle BM, Woodward W A, vliddleton LP, et al: The impact of pregnancy on breast cancer outcomes in women < or = 35 years. Cancer 115 (6): 4, 2009

Becker S: Breast cancer in pregnancy: a brief clinical review. Best Pract Res Clin Obstet Gynaecol 33:79, 2016

Berg WA, Campassi C1, Lofe OB: Cystic lesions of the breast: sonographicpathologic correlation. Radiology 227: 183, 2003

Berry DL, heriault L, Holmes FA, et al: Management of breast cancer during pregnancy using a standardized protocol. J Clin Oncol 17:855, 1999

Bigelow CA, Horowitz NS, Goodman A, et al: Management and outcome of cervical cancer diagnosed in pregnancy. Am J Obstet Gynecol 216(3):276. el-276.e6,t2017

Bishop A, Patel S, Fries fH: A case of recurrent hyperreactio luteinalis in three spontaneous pregnancies. J Clin Ultrasound 44(8):502,t2016

Bladerston KD, Tewari K, Azizi F, et al: Intrahepatic cholangiocarcinoma masquerading as the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) in pregnancy: case report. Am J Obstet Gynecol 9:823, 1998

Bleau N, Patenaude V, Abenhaim HA: Risk of venous thromboembolic events in pregnant patients with cancer. J Matern Fetal Neonatal Med 29(3):380, 2016

Boulay R, Podczaski E: Ovarian cancer complicating pregnancy. Obstet Gynecol Clin North Am 25:3856, 1998

Boussios S, Han SN, Fruscio R, et al: Lung cancer in pregnancy: report of nine cases from an international collaborative study. Lung Cancer 82(3):499, 2013

Boxer A, Bolyard A, Kelley ML, et al: Use of granulocyte colony-stimulating factor during pregnancy in women with chronic neutropenia. Obstet Gynecol 125(1):197, 2015

Braems G, Denys H, DeWever 0, et al: Use of tamoxifen before and during pregnancy. Oncologist 16(11):1547,t2011

Brenner B, Avivi 1, Lishner M: Haematological cancers in pregnancy. Lancet 379:580,t2012

Brent L: Utilization of developmental basic science principles in the evaluation of reproductive risks from pre-and postconception environmental radiation exposures. Teratology 59:t182,t1999

Brewer M, Kueck An, Runowicz CD: Chemotherapy in pregnancy. Clin Obstet Gynecol 54:602, 2011

Broer N, Buonocore S, Goldberg C: A proposal for the timing of management of patients with melanoma presenting during pregnancy. J Surg Oncol 106(1):36,t2012

Bulun SE, Moravek MB, Yin P, et al: Uterine leiomyoma stem cells: linking progesterone to growth. Semin Reprod Med ,t2015

Bumpers HL, Butler L, Best 1M: Endometrioma of the abdominal wall. Am J Obstet Gynecol 187:t1709,t2002

Burman KD, Wartofsky L: hyroid nodules. N Engl J Med ,t2015

Caligiuri MA, .Mayer ]: Pregnancy and leukemia. Semin OncoIt16:388, 1989

Caragacianu DL, Mayer EL, Chun YS, et al: Immediate breast reconstruction following mastectomy in pregnant women with breast cancer. J Surg Oncol 114(2):140,t2016

Cardonick E, Dougherty R, Grana G et al: Breast cancer during pregnancy: maternal and fetal outcomes. Cancer 16:76, 2010

Cardonick EH, Gringlas MB, Hunter K, et al: Development of children born to mothers with cancer during pregnancy comparing in utero chemotherapy-exposed children with non exposed controls. m J Obstet Gynecol 212(5):658.e1,t2015

Carradice 0, Austin N, Bayston K, et al: Successful treatment of acute promyelocytic leukaemia during pregnancy. Clin Lab Haematol 2002

Cascinelli N, Morabito A, Santinami M, et al: Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomized trial. Lancet 351:793,t1998

Caspi B, Levi R, Appelman Z, et al: Conservative management of ovarian cystic teratoma during pregnancy and labor. Am J Obstet Gynecol 182:503, 2000

Castanon A, Brocklehurst P, Evans H, et al: Risk of preterm birth after treatment for cervical intraepithelial neoplasia among women attending colposcopy in England: retrospective-prospective cohort study. BM] 345:e5174, 2012

Celik C, Acar A, Cicek N, et al: Can myomectomy be performed during pregnancy? Gynecol Obstet Invest 53:79, 2002

Chan YM, Ngai SW, Lao TT: Colon cancer in pregnancy. A case report. ] Reprod Med 44:733, 1999

Cheng K, Zhang F, Tang LL, et al: Pregnancy associated nasopharyngeal carcinoma: a retrospective case-control analysis of maternal survival outcomes. Radiother OncoIt116(1):125, 2015

Choi JR, Levine 0, Finberg H: Luteoma of pregnancy: sonographic indings in two cases. J Ultrasound Med 19(12):877, 2000

Ciavarrini A, Clemente N, Delli Carpini G, et al: Number and size of uterine ibroids and obstetric outcomes. J Maten Fetal Neonatal Med 28(4):484, 2015 Cohen JB, Blum A: Evaluation and management of lymphoma and leukemia in pregnancy. Clin Obstet Gynecol 54:556, 2011

Conner SN, Frey A, Cahill AG, et al: Loop electrosurgical excision procedure and risk of preterm birth. A systematic review and meta-analysis. Obstet Gynecol 123:752,t2014

Coronado GO, Marshall LM, Schwartz SM: Complications in pregnancy, labor, and delivery with uterine leiomyomas: a population-based study. Obstet Gynecol 95:764, 2000

Critchley HOD, Wallace WHB, Shalet SM, et al: Abdominal irradiation in childhood: the potential for pregnancy. BJOG 99(5):392, 1992

Curtis KM, Hillis SO, Marchbanks PA, et al: Disruption of the endometrialmyometrial border during pregnancy as a risk factor for adenomyosis. Am J Obstet Gynecol 187(3):543, 2002

Dahl SK, Thomas A, Williams DB, et al: Maternal virilization due to luteoma associated with delayed lactation. Fertil Steril 90(5):2006.e1 ,t2008 De Carolis S, Fatigante G, Ferrazzani S, et al: Uterine myomectomy in preg nant women. Fetal Diagn Ther 16: 116, 2001 de Giorgi V, Gori A, Grazzini M, et al: Estrogens, estrogen receptors and melanoma. Expert Rev Anticancer her 11t:739, 2011 de Haan J, Lok CA, de Groot CJ, et al: Melanoma during pregnancy: a report of 60 pregnancies complicated by melanoma. Melanoma Res .

Djavadian 0, Braendle W, Jaenicke F: Laparoscopic oophoropexy for the treatment of recurrent torsion of the adnexa in pregnancy: case report and review. Ferril Steril 82(4):933, 2004

Dogan S, Gzyuncu G, Atak Z: Fibroids during pregnancy: efects on pregnancy and neonatal outcomes. J Reprod Med 61(1-2):52, 2016

Dorum A, Blom GP, Ekerhovd E, et al: Prevalence and histologic diagnosis of adnexal cysts in postmenopausal women: an autopsy study. Am J Obstet Gynecol 192(1):48,t2005

Driscoll MS, Grant-Kels ].1: Nevi and melanoma in the pregnant woman.

Clin Dermatol 27(1): 116, 2009

MS, Martires K, Bieber AK, et al: Pregnancy and melanoma. J m Acad 5(4):669,t2016

Dunton CJ: Management of arypical glandular cells and adenocarcinoma in situ. Obstet Gynecol Clin North Am 35(4):623, 2008

Durkin JW Jr: Carcinoid tumor and pregnancy. Am J Obstet Gynecol 145: 57, 1983

Eibye S, Kjaer SK, Mellemkjaer L: Incidence of pregnancy-associated cancer in Denmark, 1977-2006. Obstet Gynecol 122:608,t2013

Elgindy E, Sibai H, Abdelghani A, et al: Protecting ovaries during chemotherapy through gonad suppression. A systematic review and meta-analysis. Obstet GynecoIt126:187, 2015

EI-Hemaidi I, Robinson SE: Management of haematological malignancy in pregnancy. Best Pract Res Clin Obstet Gynaecol 26(1):149, 2012

EI-Messidi A, Patenaude V, Hakeem G, et al: Incidence and outcomes of women with Hodgkin's lymphoma in pregnancy: a population-based study on 7.9 million births. J Perinat vIed 43(6):683,2015

Erkanli S, Ayhan A: Fertiliry-sparing therapy in young women with endometrial cancer: 2010 update. Int J Gyn Cancer 20: 1170, 2010

Esim Buyukbayrak E, Karageyim Karsidag AY, Kars B, et al: Cervical polyps: evaluation of routine removal and need for accompanying O&C. Arch Gynecol Obstet 283(3):581,t2011

Euhus OM: Breast disease. In Hofman BL, Schorge JO, Bradshaw KO, et al (eds): Williams Gynecology, 3rd ed. McGraw-Hill Education, New York, 2016

Eyre T A, Lau IJ, Mackillop L, et al: Management and controversies of classical Hodgkin lymphoma in pregnancy. Br J Haematol 169(5):613,t2015

Fader AN, lward EK, Niederhauser A, et al: Cervical dysplasia in pregnancy: a multi-institutional evaluation. Am J Obstet Gynecol 203: 113, 2010

Favero G, Chiantera V, Oleszczuk A, et al: Invasive cervical cancer during pregnancy: laparoscopic nodal evaluation before oncologic treatment delay. Gynecol OncoIt118:123, 2010

Fey MF, Surbek 0: Leukaemia and pregnancy. Recent Results Cancer Res 178:97,t2008

FIGO Committee on Gynecologic Oncology: Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 105:103,t2009

Friedman E, Kotsopoulos J, Lubinski J, et al: Spontaneous and therapeutic abortions and the risk of breast cancer among BRCA mutation carriers. Breast Cancer Res 8:R15, 2006

Fuchs N, Smorgick N, Tovbin Y, et al: Oophoropexy to prevent adnexal torsion: how, when, and for whom? J Minim Invasive GynecoIt17(2):205, 2010

Gandini S, Iodice S, Koomen E, et al: Hormonal and reproductive factors in relation to melanoma in women: current review and meta-analysis. Eur J Cancer 47(1 ):2607,t2011

Genta PR, Oias ML, Janiszewski TA, et al: Streptococcus agalactiae endocarditis and giant pyomyoma simulating ovarian cancer. South Med J 94:508, 2001 Germain M, Rarick T, Robins E: Management of intermittent ovarian torsion by laparoscopic oophoropexy. Obstet Gynecol 88(4 Pt 2):715, 1996

Gharib H, Papini E, Garber JR, et al: American Association of Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi medical guidelines for clinical practice for diagnosis and management of thyroid nodules-2016 update. Endocr Pract 22(5):622,t2016

Giuntoli RL Jr, Yang RS, Bristow RE: Evaluation and management of adnexal masses during pregnancy. Clin Obstet Gynecol 49(3):492, 2006

Glisic A, Atanackovic J: Krukenberg tumor in pregnancy. he lethal outcome.

Pathol Oncol Res 12(2): 108, 2006

Goldman NA, Goldberg GL: Late recurrence of squamous cell cervical cancer in an episiotomy site after vaginal delivery. Obstet Gynecol 101: 1127, 2003

Got!ieb WH, Beiner ME, Shalmon B, et al: Outcome of fertiliry-sparing treatment with progestins in young patients with endometrial cancer. Obstet Gynecol 102:718,t2003

Greer BE, Easterling TR, McLennan OA, et al: Fetal and maternal considerations in the management of stage I-B cervical cancer during pregnancy. Gynecol Oncol 34:61, 1989

Gubbala K, Laios A, Gallos I, et al: Outcomes of ovarian transposition in gynaecological cancers: a systematic review and meta-analysis. J Ovarian Res 7:69,t2014

Haas JF: Pregnancy in association with newly diagnosed cancer: a populationbased epidemiologic assessment. Int J Cancer 34:229, 1984

Hacker NF, Berek JS, Lagasse LO, et al: Carcinoma of the cervix associated with pregnancy. Obstet Gynecol 59:735, 1982

Haggar FA, Pereira G, Preen 0, et al: Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population based cohort study. PLoS One 9(12):el13292, 2014

Hahn KM, Johnson PH, Gordon N, et al: Treatment of pregnant breast cancer patients and outcomes of children exposed to chemotherapy in utero. Cancer :1219,t2006

Hakim C, Padmanabhan V, Vyas AK: Gestational hyperandrogenism in developmental programming. Endocrinology 14:en20161801, 2016

Hannuna Y, Putignani L, Silvestri E, et al: Incidental endometrial adenocarcinoma in early pregnancy: a case report and review of the literature. Int J Gynecol Cancer 19(9):1580,t2009

Hashimoto A, Iriyama T, Sayama S, et al: Adenomyosis and adverse perinatal outcomes: increased risk of second trimester miscarriage, preeclampsia, and placental malposition. J Matern Fetal Neonatal Med 23: 1, 201

Heller OS, Cracchiolo B, Hameed M, et al: Pregnancy-associated invasive squa mous cell carcinoma of the vulva in a 28-year-old, HIV-negative woman: a case report. J Reprod Med 45:659, 2000

Hirabayashi M, Ueo H, Okudaira Y, et al: Early gastric cancer and a concomitant pregnancy. Am Surg 30, 198

Hofman MS, Sayer A:

A guide to management: adnexal masses in pregnancy.

OBG Management ,2007

Hognas E, KauppilatA, Pukkala E, et al: Cancer risk in women with 10 or more deliveries. Obstet GynecoIt123(4):811, 2014

Homer H, Saridogan E: Uterine artery embolization for ibroids is associated with an increased risk of miscarriage. Fertil Steril 94(1):324, 2010

Hong Y, Li SQ, Hu L, et al: Survey of human papillomavirus rypes and their vertical transmission in pregnant women. BMC Infect Dis 13:109,t2013 Hoover N, Hyer M, Pfeifer M, et al: Adverse health outcomes in women exposed in utero to diethylstilbestrol. N Engl J Med 365: 1304, 2011

Horowitz NA, Lavi N, Nadir Y, et al: Haematological malignancies in pregnancy: an overview with an emphasis on thrombotic risks. Thromb Haemost 116(4):613,t2016

Hudis CA: Trastuzumab-mechanism of action and use in clinical practice.

N Engl J Med 357:39, 2007

Huh K, Ault A, Chelmow 0, et al: Use of high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance. Obstet Gynecol 125(2):330,t2015

Irving JA, Clement PB: Nonneoplastic lesions of the ovary. In Kurman J, Ellenson LH, Ronnett BM (eds): Blaustein's Pathology of the Female Genital Tract, 6th ed. New York, Springer, 201t1

Ives A, Saunders C, Bulsara M, et al: Pregnancy after breast cancer: population based study. BMJ 334(7586): 194,t2006

Jenabi E, Khazaei S: The efect of uterine leiomyoma on the risk of malpresentation and cesarean: a meta-analysis. J Matern Fetal Neonatal Med 31 (1):87, 2018

Jernstrom H, Lubinski J, Lynch HT, et al: Breast-feeding and the risk of breast cancer in BRCAI and BRCA2 mutation carriers. J Nat! Cancer Inst 96(14):1094,t2004

Johansson AL, ndersson TM, Plym A, et al: Mortaliry in women with pregnancyassociated malignant melanoma. J Am Acad Oermatol 71(6):1093, 2014

Kakoza RM, Vollmer CM Jr, Stuart E, et al: Pancreatic adenocarcinoma in the pregnant patient: a case report and literature review. J Gastrointest Surg 13(3):535,t2009

Kal HB, Struikmans H: Radiotherapy during pregnancy: fact and iction. Lancet Oncol 6(5):328, 2005

Kanal E, Barkovich AJ, Bell C, et al: Expert panel on MR safery. ACR practice guideline for imaging pregnant or potentially pregnant adolescents and women with ionizing radiation. J Magn Reson Imaging 37:501, 2013

Kanova N, BiCikova M: Hyperandrogenic states in pregnancy. Physiol Res 60(2):243,t2011

Kao HW, Wu CJ, Chung KT, et al: MR imaging of pregnancy luteoma: a case report and correlation with the clinical features. Korean J Radiol 6(1):44, 2005

Karaman E, Karaman Y, Alkis I, et al: Maternal serum CA-125 level is elevated in severe preeclampsia. Pregnancy Hypertens 4(1):29,t2014

Kathiresan AS, Johnson IN, Hood BJ, et al: Giant cell bone tumor of the thoracic spine presenting in late pregnancy. Obstet Gynecol 118(2 Pt 2):428,2011

Kim CH, Abu-Rustum NR, Chi OS, et al: Reproductive outcomes of patients undergoing radical trachelectomy for early-stage cervical cancer. Gynecol Oncol 125(3):585,t2012

Kim SS, Klemp J, Fabian C: Breast cancer and fertiliry preservation. Fertil Steril 95(5): 1535, 2011

Knight JC, Elliott JO, Amburgey OL: Efect of maternal retroplacental leiomyomas on fetal growth. J Obstet Gynaecol Can 38(12):1100, 2016

Ko EM, Van Le L: Chemotherapy for gynecologic cancers occurring during pregnancy. Obstet Gynecol Surv 66(5):291,t2011

Kodama M, Moeini A, Machida H, et al: Feto-matenal outcomes of pregnancy complicated by Krukenberg tumor: a systematic review of literature. rch Gynecol Obstet 294(3):589,t2016

Korbin CD, Brown OL, Welch WR: Paraovarian cystadenomas and cystadenoibromas: sonographic characteristics in 14 cases. Radiology 208(2):459, 1998

Krishna I, Lindsay M: Breast cancer in pregnancy. Obstet Gynecol Clin N Am 40:559,t2013

Kuller JA, Zucker PK, Peng TC: Vulvar leiomyosarcoma in pregnancy. Am J Obstet Gynecol 162:164, 1990

Kuo K, Caughey AB: Optimal timing of delivery for women with breast cancer, according to cancer stage and hormone status: a decision-analytic model. J Matern Fetal Neonatal Med September 27,t2017 [Epub ahead of print]

Lam SJ, Best S, Kumar S: The impact of ibroid characteristics on pregnancy outcome. Am J Obstet Gynecol 211(4):395.e1, 2014

Lambertini M, Del Mastro L, Pescio MC, et al: Cancer and fertility preservation: international recommendations from an expert meeting. BMC Med 14:1,t2016

Lambertini M, Peccatori FA, Azim HAJr: Targeted agents for cancer treatment during pregnancy. Cancer Treat Rev 41(4):301,t2015

Larsen EC, Schmiegelow K, Rechnitzer C, et al: Radiotherapy at a young age reduces uterine volume of childhood cancer survivors. Acta Obstet Gynecol Scand 83:96, 2004

Laughlin SK, Baird DO, Savitz DA, et al: Prevalence of uterine leiomyomas in the first trimester of pregnancy: an ultrasound-screening study. Obstet Gynecol 113(3):630, 2009

Lee HJ, Lee IK, Kim JW, et a1: Clinical characteristics of gastric cancer associated with pregnancy. Dig Sutg 26(1):31,t2009

Leiserowitz GS, Xing G, Cress R, et al: Adnexal masses in pregnancy: how often are they malignant? Gynecol Oncol 101 :315, 2006

Lin H, Hwang JL, Huang L W, et al: Pyomyoma after a cesarean section. Acta Obstet Gynecol Scand 81:571, 2002

Liu J, Zanotti K: Management of the adnexal mass. Obstet Gynecol 117: 1413, 2011

Liu P, Xu L, Sun Y, et al: The prevalence and risk of human papillomavirus infection in pregnant women. Epidemiol Infect 142(8):1567,t2014

Lodish MB: Clinical review: kinase inhibitors: adverse efects related to the endocrine system. J Clin Endocrinol Metab 98(4):1333, 2013

Loibl S, Schmidt A, Gentillini 0, et al: Breast cancer diagnosed during pregnancy: adapting recent advances in breast cancer care for pregnant patients. JAMA Oncoltl(8):1145, 2015

Long ME, Dwarica OS, Kastner TM, et al: Comparison of dysplastic and benign endocervical polyps. J Low Genit Tract Dis 17(2):142,t2013

Longo DL: Malignancies of lymphoid cells. In: Kasper DL, Fauci AS, Hauser SL, et aI (eds): Harrison's Principles of Intenal Medicine, 19th ed. New York, McGraw-Hill Education, 20t15

Loren AW, Mangu PB, Beck LN, et al: Fertiliry preservation for patients with cancer: American Sociery of Clinical Oncology clinical practice guideline update. J Clin OncoIt31(19):2500, 2013

Lutz MH, Underwood PB Jr, Rozier JC, et al: Genital malignancy in pregnancy. Am J Obstet GynecoIt129:536, 1977

Luyckx M, Squiflet JL, Jadoul P, et al: First series of 18 pregnancies after ulipristal acetate treatment for uterine ibroids. Fertil Steril 102(5): 1404, 20t14 lalinowski AK, Sen J, Sermer M: Hyperreactio luteinalis: maternal and fetal efects. J Obstet Gynaecol Can 37(8):715, 2015

Maor GS, Czuzoj-Shulman N, Spence AR, et al: Maternal and neonatal outcomes of pregnancy associated breast cancer. Abstract No. 802, Am J Obstet GynecoIt216:S461,t2017

Mara M, Maskova J, Fucikova Z, et al: Midterm clinical and irst reproductive results of a randomized controlled trial comparing uterine ibroid embolization and myomectomy. Cardiovasc Intervent Radiol 31 (1): 73, 2008

Marinoni E, Di Netta T, Caramanico L, et al: Metastatic pancreatic cancer in late pregnancy: a case report and review of the literature. J Matern Fetal Neonatal Med 19(4):247,t2006

Masarie K, Katz V, Baldersron K: Pregnancy lureomas: clinical presentations and management strategies. Obstet Gynecol Surv 65(9):575,t2010

Massad LS, Einstein MH, Huh K, et a1: 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Obstet Gynecol 121(4):829,t2013

Matsuo K, Eno ML, 1m DO, et a1: Pregnancy and genital sarcoma: a systematic review of the literature. Am J Perinatol 26(7):507, 2009

McGovern PG, Noah R, Koenigsberg R, et al: Adnexal torsion and pulmonary embolism: case report and review of the literature. Obstet Gynecol Surv 54(9) :60 1, 1999

McNally L, Osmundson S, Barth R, et al: Urachal duct carcinoma complicating pregnancy. Obstet Gynecol 122:469,t20t13

Melin J, Heinavaara S, Malila N, et al: Adverse obstetric outcomes among early-onset cancer survivors in Finland. Obstet Gynecol 126:803, 2015 Minter A, Malik R, Ledbetter L, et al: Colon cancer in pregnancy. Cancer

Control 12(3):196,t2005

Mogos MF, Rahman S, Salihu HM, et al: Association between reproductive cancer and fetal outcomes: a systematic review. Int J Gynecol Cancer 23(7):1171,t2013

Morice P, Uzan C, Gouy S, et al: Gynaecological cancers in pregnancy. Lancet 379:558,t2012

Naqvi M, Kaimal A: Adnexal masses in pregnancy. Clin Obstet Gynecol 58(1):93,t2015

National Toxicology Program: NTP monograph: developmental efects and pregnancy outcomes associated with cancer use during pregnancy. NTP Monogr 2:1,t2013

Navrozoglou 1, Vrekoussis T, Kontostolis E et al: Breast cancer during pregnancy: a mini-review. Eur J Surg OncoIt34:837, 2008

Neiger R, Sonek JD, Croom CS, et al: Pregnancy-related changes in the size of uterine leiomyomas. J Reprod Med 1, 2006 Nisker JA, Shubat M: Stage IB cervical carcinoma and pregnancy: report of 49 cases. Am J Obstet Gynecol 145:203, 1983

Niwa K, Tagami K, Lian Z, et al: Outcome of fertiliry-preserving treatment in young women with endometrial carcinomas. BJOG 112:317,t2005

O'Gara P, Shepard J, Yared K, et al: Case 39-2009L: a 28-year-old pregnant woman with acute cardiac failure. N Engl J Med 361:2462, 2009

Otake M, Schull WJ, Lee S: Threshold for radiation-related severe mental retardation in prenatally exposed A-bomb survivors: atre-analysis. Int ] Radiat BioI 70:755-63, 1996

Palani R, Milojkovic 0, Apperley JF: Managing pregnancy in chronic myeloid leukaemia. Ann Hematolt94 SuppIt2:S167, 2015

Palmer J, Vatish M, Tidy J: Epithelial ovarian cancer in pregnancy: a review of the literature. BJOG 116:480, 2009

Papoutsis 0, Sindos M, Papantoniou N, et al: Management options and prognosis of pancreatic adenocarcinoma at 16 weeks' gestation: a case report.

:167,t2012

Parazzini F, Franchi M, Tavani A, et al: Frequency of pregnancy related cancer: a population based linkage study in Lombardy, Italy. Int J Gynecol Cancer 27(3):613,t2017

Park JY, Kim DY, Suh OS, et al: Reproductive outcomes after laparoscopic radical trachelectomy for early-stage cervical cancer. ] Gynecol Oncol 25:9, 2014

Peccatori FA, Azim HAtJr, Orecchia R, et al: Cancer, pregnancy and fertiliry:

ESMO clinical practice guidelines for diagnosis, treatment and follow-up.

Ann Oncol 24 SuppIt6:viI60, 2013

Perera 0, Kandavar R, Palacios E: Pancreatic adenocarcinoma presenting as acute pancreatitis during pregnancy: clinical and radiologic manifestations. J La State Med Soc 163: 114, 2011

Pettersson BF, Andersson S, Hellman K, et al: Invasive carcinoma of the uterine cervix associated with pregnancy: 90 years of experience. Cancer 116:2343,t2010

Pinnix CC, Osborne EM, Chihara 0, et al: Maternal and fetal outcomes after therapy for Hodgkin or non-Hodgkin lymphoma diagnosed during pregnancy. JAMA Oncol 2(8):1065, 2016

Pistilli B, Belletini G, Giovannetti E, et al: Chemotherapy, targeted agents, anti emetics and growth-factors in human milk: how should we counsel cancer patients about breastfeeding? Cancer Treat Rev 39(3):207,t2013

PrittS EA: Fibroids and infertiliry: a systematic review of the evidence. Obstet Gynecol Surv 56:483, 200t1

Qidwai II, Caughey AB, Jacoby AF: Obstetric outcomes in women with sonographically identiied uterine leiomyomata. Obstet Gynecol 107:376, 2006

Reulen RC, Zeegers MP, Wallace WH, et al: Pregnancy outcomes among adult survivors of childhood cancer in the British Childhood Cancer Survivor Study. Cancer Epidemiol Biomarkers Prev 18(8):2239,t2009

Reynoso EE, Shepherd FA, Messner HA, et 1: Acute leukemia during pregnancy: the Toronto Leukemia Study Group experience with long-term follow-up of children exposed in utero to chemotherapeutic agents. J Clin Oncol 5:1098,t1987

Richtig G, Byrom L, Kupsa R, et al: Pregnancy as driver for melanoma. Br J Dermatol 177(3):854,t2017

Rizack T, Mega A, Legare R, et al: Management of hematological malignancies during pregnancy. Am J Hematol 84(12):830, 2009

Rodriguez AO, Chew H, Cress R, et al: Evidence of poorer survival in pregnancy-associated breast cancer. Obstet Gynecol 112(1): 1, 2008

Rogers JE, Dasari A, Eng C: he treatment of colorectal cancer during pregnancy: cytotoxic chemotherapy and targeted therapy challenges. Oncologist 21(5):563,t2016

Rosenkranz KM, Lucci A: Surgical treatment of pregnancy associated breast cancer. Breast Dis 23:87, 2006

Routledge OJ, Tower C, Davies E, et al: Successful management of acute myeloid leukaemia in a twin pregnancy-a case report. Br J Haematol October 21, 2016 [Epub ahead of print]

Russell P, Robboy SJ: Ovarian cysts, tumor-like, iatrogenic and miscellaneous conditions. In Robboy SJ, Mutter GL, Prat J, et al (eds): Robboy's Pathology of the Female Reproductive Tract, 2nd ed. London, Churchill Livingstone, 2009

Sahin M, Kocaman G, Ozkan M, et al: Resection of esophageal carcinoma during pregnancy. Ann horac Surg 99(1):333,t2015 Salani R, Billingsley CC, Crafton SM: Cancer and pregnancy: an overview for obstetricians and gynecologists. Am J Obstet Gynecol 211 (1): 7, 2014

Salvador E, Bienstock J, Blakemore KJ, et al: Leiomyomata uteri, genetic amniocentesis, and the risk of second-trimester spontaneous abortion. Am J Obstet Gynecol 186:913,t2002

Sanz MA, Montesinos P, Casale MF, et al: Maternal and fetal outcomes in pregnant women with acute promyelocytic leukemia. Ann Hematol 94(8):1357,t2015

Sarno MA, Mancari R, Azim HA, et al: Are monoclonal antibodies a safe treatment for cancer during pregnancy? Immunotherapy 5(7):733, 2013

Schammel DP, Mittal KR, Kaplan K, et al: Endometrial adenocarcinoma associated with intrauterine pregnancy: a report of ive cases and a review of the literature. Int J Gynecol Pathol 17:327, 1998

Schmeler v1, Mayo-Smith W, Peipert JF, et al: Adnexal masses in pregnancy: surgery compared with observation. Obstet Gynecol 105: 1098, 2005

Schwartz JL, Mozurkewich EL, Johnson TM: Current management of patients with melanoma who are pregnant, want to get pregnant, or do not want to get pregnant. Cancer 97(9):2130,t2003

Shepherd JH, Spencer C, Herod J, et al: Radical vaginal trachelectomy as a fertiliry-sparing procedure in women with early-stage cervical cancercumulative pregnancy rate in a series of 123 women. BJOG 113:719, 2006

Sherard GB III, Hodson CA, Williams HJ, et al: Adnexal masses and pregnancy: a 12-year experience. Am J Obstet Gynecol 189:358,2003

Sienas L, Wong T, Collins R, et al: Contemporary uses of erythropoietin in pregnancy: a literature review. Obstet Gynecol Surv 68(8):594, 2013

Signorelli M, Caspani G, Bonazzi C, et al: Fertility-sparing treatment in young women with endometrial cancer or atypical complex hyperplasia: a prospective single-institution experience of21 cases. BJOG 116(1):114,t2009

Signorello LB, Cohen SS, Bosetti C, et al: Female survivors of childhood cancer: preterm birth and low birth weight among their children. J Nat! Cancer Inst 98:1453,t2006

Signorello LB, Mulvihill J], Green DM, et al: Congenital anomalies in the children of cancer survivors: a report from the childhood cancer survivor study. J Clin OncoIt30(3):239, 2012

Signorello LB, Mulvihill J], Green DM, et al: Stillbirth and neonatal death in relation to radiation exposure before conception: a retrospective cohort study. Lancet 6:624, 2010

Sisodia RM, Del Carmen MG, Boruta DM: Role of minimally invasive surgery in the management of adnexal masses. Clin Obstet Gynecol 58(1):66, 2015

Sisson Jc, Freitas J, McDougall IR, et al: Radiation safety in the treatment of patients with thyroid diseases by radioiodine 1311: practice recommendations of the American hyroid Association. Thyroid 21(4):335,t2011

Smith LH, Danielsen B, Allen ME, et al: Cancer associated with obstetric delivery: results of linkage with the California cancer registry. m J Obstet GynecoIt189:1128,t2003

Soares SR, Gomez R, Simon C, et al: Targeting the vascular endothelial growth factor system to prevent ovarian hyperstimulation syndrome. Hum Reprod Update 14(4):321,t2008

Spitzer M, Kaushal N, Benjamin F: Maternal CA-125 levels in pregnancy and the puerperium. J Reprod Med 43:387, 1998

Stensheim H, Klungs0yr K, Skjaerven R, et al: Birth outcomes among ofspring of adult cancer survivors: a population-based study. Int J Cancer 133(11):2696,t2013

Stokes LS, Wallace MJ, Godwin RB, et al: Quality improvement guidelines for uterine artery embolization for symptomatic leiomyomas. J Vasc Interv RadioIt21(8):1153,t2010

Stout MJ, Frey A, Tuuli MG, et al: Loop electro surgical excision procedure and risk of vaginal infections during pregnancy: an observation study. B JOG 122(4):545,t2015

Stout MJ, Odibo AO, GraseckAS, et al: Leiomyomas at routine second-trimester ultrasound examination and adverse obstetric outcomes. Obstet Gynecol 116(5):1056,t2010

Stovall M, Blackwell CR, Cundif J, et al: Fetal does from radiotherapy with photon beams: report of AAPM Radiation Therapy Committee Task Group No. 36. Med Phys 22(1):63, 1995

Suzuki H, Matsubara S, Uchida S, et al: Ovary hyperstimulation syndrome accompanying molar pregnancy: case report and review of the literature. Arch Gynecol Obstet 290(4):803,t2014

Suzuki S: Comparison between spontaneous ovarian hyperstimulation syndrome and hyperreactio luteinalis. Arch Gynecol Obstet 269(3):227, 2004

Szecsi PB, Anderson MR, Bj0rngaard B, et al: Cancer antigen 125 after delivery in women with a normal pregnancy: a prospective cohort study. Acta Obstet Gynecol Scand 93(12):1295,t2014

Takushi M, Moromizato H, Sakumoto K, et al: Management of invasive carcinoma of the uterine cervix associated with pregnancy: outcome of intentional delay in treatment. Gynecol OncoI87:185, 2002

Tannus JF, Hertzberg BS, Haystead CM, et al: Unilateral luteoma of pregnancy mimicking a malignant ovarian mass on magnetic resonance and ultrasound. J Magn Reson Imaging 13, 2009

Teh T, Stern C, Chander S, et al: he impact of uterine radiation on subsequent fertility and pregnancy outcomes. Biomed Res Int 2014:482968,2014 Titus-ErnstofL, Troisi R, Hatch EE, et al: Mortality in women given diethylstilbestrol during pregnancy. Br J Cancer 95:107, 2006

Ungar L, Smith JR, PaIfavli L, et al: Abdominal radical trachelectomy during pregnancy to preserve pregnancy and fertility. Obstet Gynecol 108:811, 2006

Valachis A, Tsali L, Pesce LL, et al: Safety of pregnancy after primary breast carcinoma in young women: a meta-analysis to overcome bias of healthy mother efect studies. Obstet Gynecol Surv 65:786,t2010

Van Calsteren K, Hanssens I, Moerman P, et al: Successful conservative treatment of endocervical adenocarcinoma stage Ib1 diagnosed early in pregnancy. Acta Obstet Gynecol Scand 87(2):250, 2008 van der Vange N, Weverling GJ, Ketting BW, et al: The prognosis of cervical cancer associated with pregnancy: a matched cohort study. Obstet Gynecol 85:1022,t1995 van Vliet W, van Loon AJ, ten Hoor A, et al: Cervical carcinoma during pregnancy: outcome of planned delay in treatment. Eur J Obstet Gynecol Reprod 9:153,t1998

Velentgas P, Daling JR, Malone E, et al: Pregnancy after breast carcinoma: outcomes and influence on mortality. Cancer 85:2424, 1999

Vercruysse DC, Deprez S, Sunaert S, et al: Efects of prenatal exposure to cancer treatment on neurocognitive development, a review. Neurotoxicology 54:11, 2016

Viswanathan S, Ramaswamy B: Pregnancy-associated breast cancer. Clin Obstet Gynecol 54(4):546, 2011

Wang yc, Su HY, Liu JY, et al: Maternal and female fetal virilization caused by pregnancy luteomas. Fertil Steril 84:509.e15, 2005

Webb E, Sakhel K, Chauhan SP, et al: Adnexal mass during pregnancy: a review. Am J Perinatol 32(11): 10 10, 2015

Weibull CE, Eloranta S, Smedby E,et al: Pregnancy and the risk of relapse in patients diagnosed with Hodgkin lymphoma. J Clin OncoIt34(4):337, 2016

Weinmann S, Naleway A, Swamy G, et al: Pregnancy outcomes after treatment for cervical cancer precursor lesions: an observational study. PLoS One 12(1):e0165276,t2017

Weitzman VN, DiLuigi AJ, Maier DB, et al: Prevention of recurrent adnexal torsion. Fertil Steril 90(5):2018.e1, 2008

Werner CL, Lo JY, Hefernan, et al: Loop electrosurgical excision procedure and risk of preterm birth. Obstet Gynecol 115:605,t2010

Whitecar MP, Turner S, Higby MK: Adnexal masses in pregnancy: a review of 130 cases undergoing surgical management. Am J Obstet Gynecol 181: 19, 1999

Williams SF, Schilsky L: Neoplastic disorders. In Barron WI, Lindheimer MD (eds): Medical Disorders During Pregnancy, 3rd ed. St. Louis, Mosby, 2001

Winther JF, Boice JD Jr, Svendsen L, et al: Spontaneous abortion in a Danish population-based cohort of childhood cancer survivors. J Clin Oncol 26(26):4340, 2008

Winther JF, Olsen JH, Wu H, et al: Genetic disease in the children of Danish survivors of childhood and adolescent cancer. J Clin OncoIt30(1):27, 2012 Wohlfahrt J, Olsen JH, Melby M: Breast cancer risk after childbirth in young women with family history. Cancer Causes Control 13:169, 2002

WOO JC, Yu T, Hurd TC: Breast cancer in pregnancy. Arch Surg 138:91,t2003

Yahata T, Numata M, Kashima K, et al: Conservative treatment of stage IA1 adenocarcinoma of the cervix during pregnancy. Gynecol Oncol 109(1):49, 2008 Yazbeck CF, Sullivan SD. hyroid disorders during pregnancy. Med Clin No America 96:235,t2012 Yeaton-Massey A, Brooield F, Aziz N, et al: Maternal bladder cancer diagnosed at routine first-trimester obstetric ultrasound examination. Obstet Gynecol 122:464,t2013 Yost NP, Santoso JT, McIntire DD, et al: Postpartum regression rates of antepartum cervical intraepithelial neoplasia II and III lesions. Obstet Gynecol 93:359, 1999 Yu 5S, Bischof A: hyroid cancer in pregnancy. Semin Reprod Med 34(6):351,t2016 Zagouri F, Sergentanis TN, Chrysikos D, et al: Platinum derivatives during pregnancy in cervical cancer: a systematic review and meta-analysis. Obstet GynecoIt121:337,t2013a Zagouri F, Sergentanis TN, Chrysikos D, et al: Trastuzumab administration during pregnancy: a systematic review and meta-analysis. Breast Cancer Res Treat (2):349,t2013b Zanetta G, Mariani E, Lissoni A, et al: A prospective study of the role of ultrasound in the management of adnexal masses in pregnancy. BJOG 110:578, 2003 Zemlickis D, Lishner M, Degendorfer P, et al: Maternal and fetal outcome after breast cancer in pregnancy. Am J Obstet Gynecol 166:781, 1992 Zweizig S, Perron J, Gtubb 0, et al: Conservative management of adnexal torsion. Am J Obstet Gynecolt168(6 Pt 1):1791,t1993

MATERNAL AND FETAL.IMMUNOLOGY .......i.... 1209

VIRAL INFECTIONS ...i.....i............i...... 1210

BACTERIAL INFECTIONS .............i.......... 1220

PROTOZOAL INFECTIONS .i.i....i.............. 1225

BIOTERRORISM . . . . . . . . . . . . . . . . . . . . . . . . . . . .... 1228

According to many authorities, inluena exerts a very pernicious influence upon pregnancy. t would appear that the fects of inluena must vary with the severiy of the epidemic, and more particuary with the frequeny of pneumonic com plications. As a rule, any septic condition oers a worse prognosis in prenany. Several instances have been reported of transmission of the oending bacteria to the oetus.

-J. Whitridge Williams (1903)

Infections have historically been a major cause of maternal and fetal morbidity and mortality worldwide, and they remain so in the 21st century. he unique maternal-fetal vascular connection in some cases serves to protect the fetus from infectious agents, whereas in other instances it provides a conduit for their transmission to the fetus. Maternal serological status, gestational age at the time infection is acquired, the mode of acquisition, and the immunological status of both the mother and her fetus all inluence disease outcome.

Even after intensive study, many of the maternal immunological adaptations to pregnancy are not well elucidated. It is known that pregnancy is associated with an increase in the CD4+ T cells that secrete h2-type cytokines-for example interleukins (Fragiadakis, 2016). Th1-type cytokine production-for example, interferon gamma and interleukin 2-appears to be somewhat suppressed, leading to a h2 bias in pregnancy. This bias afects the ability to rapidly eliminate certain intracellular pathogens during pregnancy, although the clinical implications of this suppression are unknown (Kourtis, 2014; Svensson-Arvelund, 2014). Importantly, the h2 humoral immune response remains intact. It also appears that human leukocyte antigen (HA)-C expressed by extravillous trophoblasts elicits responses from decidual natural killer (dNK) and decidual CD8+ T cells (Crespo, 2017).

In describing infections, horizontal transmission is the spread of an infectious agent from one individual to another. Vertical transmission refers to passage from the mother to her fetus of an infectious agent through the placenta, during labor or delivery, or by breastfeeding. Thus, preterm rupture of membranes, prolonged labor, and obstetrical manipulations may enhance the risk of neonatal infection (Centers for Disease Control and Prevention, 2010). Table 64-1 details speciic infections by mode and timing of acquisition. A inal term, the seconday attack rate, is the probability that infection develops in a susceptible individual following known contact with an infectious person.

The active immunological capacity of the fetus and neonate is compromised compared with that of older children and adults. That said, fetal cell-mediated and humoral immunity begin to develop by 9 to 15 weeks' gestation (Warner, 2010). The primary fetal response to infection is immunoglobulin M (Ig.1). Passive immunity is provided by IgG transferred across the placenta. By 16 weeks, this transfer begins to rise rapidly, and by 26 weeks, fetal concentrations are equivalent to those of the mother. After birth, breastfeeding is protective against some infections, although this protection begins to decline at

TABLE 4-1 . Specific Causes of Some Fetal and Neonatal Infections

Viruses: varicella-zoster, coxsackie, human parvovirus B19, rubella, CMV, HIV, Zika

Bacteria: Listeria, syphilis, Borrelia

Protozoa: toxoplasmosis, malaria group B streptococcus, coliforms Viruses: HIV

Bacteria: gonorrhea, chlamydia, group B streptococcus, tuberculosis, mycoplasmas Viruses: HSV, HPV, HIV, hepatitis B, hepatitis C, Zika External contamination

Bacteria: staphylococcus, coliforms

Viruses: HSV, varicella zoster

Human transmission: staphylococcus, HSV

Respirators and catheters: staphylococcus, coliforms

CMV = cytomegalovirus; HIV = human immunodeficiency virus; HPV = human papillomavirus; HSV = herpes simplex virus.

2 months of age. Current World Health Organization (2013) recommendations are to exclusively breastfeed for the first 6 months of life with partial breastfeeding until 2 years of age.

Neonatal infection, especially in its early stages, may be dificult to diagnose because these newborns often fail to express classic clinical signs. If the fetus was infected in utero, there may be depression and acidosis at birth for no apparent reason. The neonate may suck poorly, vomit, or show abdominal distention. Respiratory insuiciency can develop, which may present similarly to idiopathic respiratory distress syndrome. he neonate may be lethargic or jittery. he response to sepsis may be hypothermia rather than hyperthermia, and the total leukocyte and neutrophil counts may be depressed.

Several viruses cause severe maternal infections, and some can also cause devastating fetal infections. Of these, cytomegalovirus (CMV) is a ubiquitous DNA herpes virus that eventually infects most humans. CMV is also the most common perinatal infection in the developed world. Speciically, some evidence of fetal infection is found in 0.2 to 2.2 percent of all neonates (American College of Obstetricians and Gynecologists, 2017). The virus is secreted into all body luids, and person-to-person contact with viral-laden saliva, semen, urine, blood, and nasopharyngeal and cervical secretions can transmit infection. The fetus may become infected by transplacental viremia, or the neonate is infected at delivery or during breastfeeding. vloreover, acquisition continues to accrue. Day-care centers, for example, are a frequent source. Revello and coworkers (2008) reported that amniocentesis in women whose blood is positive for CMV DNA does not result in iatrogenic fetal transmission.

Up to 85 percent of women from lower socioeconomic backgrounds are seropositive by the time of pregnancy, whereas only half of women in higher income groups are immune. Following primary CMV infection, and in a manner similar to other herpesvirus infections, the virus becomes latent with periodic reactivation characterized by viral shedding. This occurs despite high serum levels of anti-CMV IgG antibody. These antibodies do not prevent maternal recurrence, reactivation, or reinfection, nor do they totally mitigate fetal or neonatal infection.

Women who are seronegative before pregnancy, but who develop primary CMV infection during pregnancy, are at greatest risk to have an infected fetus. It is estimated that 25 percent of congenital CMV infections in the United States are from primary maternal infection (Wang, 2011). Most CMV infections are clinically silent, but they can be detected by seroconversion, and this may be as high as 1 to 7 percent annually (Hyde, 2010). Conversely, diagnosis of CMV nonprimary infection is a challenge (Picone, 2017).

Pregnancy does not increase the risk or severity of maternal CMV infection. Most infections are asymptomatic, but 10 to 15 percent of infected adults have a mononucleosis-like syndrome characterized by fever, pharyngitis, lymphadenopathy, and polyarthritis. Immunocompromised women may develop myocarditis, pneumonitis, hepatitis, retinitis, gastroenteritis, or meningoencephalitis. Nigro and associates (2003) reported that most women in a cohort with primary infection had elevated serum aminotransferases or lymphocytosis. Reactivation disease usually is asymptomatic, although viral shedding is common.

Transmission rates for primary infection are 30 to 36 percent in the first trimester, 34 to 40 percent in the second, and 40 to 72 percent in the third trimester (American College of Obstetricians and Gynecologists, 2017; Picone, 2017). In contrast, recurrent maternal infection infects the fetus in only 0.15 to 1 percent of cases. Naturally acquired immunity during pregnancy results in a 70-percent risk reduction of congenital CMV infection in future pregnancies (Fowler, 2003; LeruezVille, 2017). However, as noted earlier, maternal immunity does not prevent recurrences, and maternal antibodies do not prevent fetal infection (Ross, 2011) .

Newborns with apparent sequelae of in-utero-acquired CMV infection are described as having symptomatic CMV inection. Congenital infection is a syndrome that may include growth restriction, microcephaly, intracranial calcifications, chorioretinitis, mental and motor retardation, sensorineural deficits, hepatosplenomegaly, jaundice, hemolytic anemia, and thrombocytopenic purpura (Cheeran, 2009). An example of periventricular calcifications is shown in Figure 64-1. Of the estimated 40,000 infected neonates born each year, only 5 to 10 percent demonstrate this syndrome (Fowler, 1992). hus, most

FIGURE 64-1 Coronal view of cranial sonogram from a neonate with congenital cytomegalovirus infection showing multiple periventricular calcifications.

infected infants are asymptomatic at birth, but some develop late-onset sequelae. Complications may include hearing loss, neurological deicits, chorioretinitis, psychomotor retardation, and learning disabilities. Infections in dichorionic twins most 1ikely are nonconcordant (Egana-U grinovic, 2016).

Routine prenatal CMV serological screening is currently not recommended by the Society for Maternal-Fetal Medicine (2016). An algorithm for management is shown in Figure 64-2. Pregnant women should be tested for CMV if they present with a mononucleosis-like illness or if congenital infection is suspected based on abnormal sonographic indings. Primary infection is diagnosed using CMV-speciic IgG testing of paired acute and convalescent sera. CMV IgM does not accurately relect timing of seroconversion because IgM antibody levels may be elevated for more than a year (Stagno, 1985). Moreover, CMV IgM may be found with reactivation disease or reinfection with a new strain. Thus, specific CMV IgG avidity testing is valuable

Abnormal Maternal CMV Screening CMV IgG: positive CMV IgM: positive

CMV-specific IgG and IgM by EIA,

IgG avidity by EIA, and CMV-specific IgM by immunoblot

CMV IgG: negative CMV IgM: negative

CMV IgG: positive

IgG avidity index: high

CMV IgM: negative in conirming primary CMV infection. High anti-CMV IgG avidity indicates primary maternal infection >6 months before testing (Kanengisser-Pines, 2009). Finally, viral culture may be useful, although a minimum of 21 days is required before findings are considered negative.

Several fetal abnormalities associated with CMV infection may be seen with sonography, computed tomography, or magnetic resonance imaging. In some cases, they are found at the time of routine prenatal sonographic screening, but in others they are part of a specific evaluation in women with CMV infection. Findings include microcephaly, ventriculomegaly, and cerebral calciications; ascites, hepatomegaly, splenomegaly, and hyperechoic bowel; hydrops; and oligohydramnios (Society for Maternal-Fetal Medicine, 2016). Abnormal sonographic findings seen in combination with positive findings in fetal blood or amnionic fluid are predictive of an approximate 75-percent risk of symptomatic congenital infection (Enders, 2001).

CMV nucleic acid amplification testing (NAA T) of amnionic luid is considered the gold standard for the diagnosis of fetal infection. Sensitivities range from 70 to 99 percent and depend on amniocentesis timing. Sensitivity is highest when amniocentesis is performed at least 6 weeks after maternal infection and after 21 weeks' gestation (Azam, 2001; Guerra, 2000). A negative result from amnionic luid polymerase chain reaction (PCR) testing does not exclude fetal infection and may need to be repeated if suspicion for fetal infection is high.

The management of the immunocompetent pregnant woman with primary or recurrent CMV is limited to symptomatic treatment. If recent primary CMV infection is conirmed, amnionic fluid analysis should be ofered. Counseling regarding fetal outcome depends on the gestational age during which primary infection is documented. Despite the high infection rate with primary infection in the first half of pregnancy, most fetuses develop normally. However, pregnancy termination may be an option for some.

Currently, no proven treatments are available for CMV infection (Society for Maternal-Fetal Medicine, 2016). Leruez-Ville and associates (2016) recently reported that oral treatment with valacyclovir, 8 g daily, apparently mitigated adverse outcomes in eight of 11 afected fetuses treated beginning at median of 25.9 weeks' gestation. Kimberlin and colleagues (2015) previously showed that intravenous valganciclovir administered for 6 weeks to neonates with symptomatic central nevous system (CNS) disease prevented hearing deterioration at 6 months and possibly later. Passive immunization with CMV-specific hyperimmune globulin may lower the risk of congenital CMV infection when given to pregnant women with primary disease (Nigro, 2005, 2012; Visentin, 2012). he Maternal-Fetal Medicine Units Network currently is conducting a randomized trial designed to address this.

here is no CMV vaccine, although several clinical trials are underway (Arvin, 2004; Schleiss, 2016). Prevention of congenital infection relies on avoiding maternal primary infection, especially in early pregnancy. Basic measures such as good hygiene and hand washing have been promoted, particularly for women with toddlers in day-care settings (Fowler, 2000).

CMV may be sexually transmitted among infected partners, but no data address the eicacy of preventive strategies.

Varicella-zoster virus (VZV) is a double-stranded DNA herpesvirus acquired predominately during childhood, and 90 percent of adults have serological evidence of immunity (Whitley, 2015). The incidence of adult varicella declined by 82 percent after the introduction of varicella vaccination, and this has resulted in a drop in maternal and fetal varicella rates (American College of Obstetricians and Gynecologists, 2017). In the United States between 2003 and 2010, the incidence of maternal varicella among 7.7 million pregnancy admissions was 1.21 per 10,000 (Zhang, 2015).

Primary infection-varicela or chickenpox-is transmitted by direct contact with an infected individual, although respiratory transmission has been reported. The incubation period is 10 to 21 days, and a nonimmune woman has a 60-to 95-percent risk of becoming infected after exposure (Whitley, 2015). Primary varicella presents with a 1-to 2-day flulike prodrome, which is followed by pruritic vesicular lesions that crust after 3 to 7 days. Infection tends to be more severe in adults (Marin, 2007). Afected patients are then contagious from 1 day before the onset of the rash until the lesions become crusted.

Mortality is predominately due to VZV pneumonia, which is thought to be more severe during adulthood and particularly in pregnancy. Although the incidence was once thought to be higher, only 2 to 5 percent of infected pregnant women develop pneumonitis (Marin, 2007; Zhang, 2015). Risk factors for VZV pneumonia include smoking and having more than 100 cutaneous lesions. Maternal mortality rates with pneumonia have decreased to 1 to 2 percent (Chandra, 1998).

Symptoms of VZV pneumonia usually appear 3 to 5 days into the course of illness. Fever, tachypnea, dry cough, dyspnea, and pleuritic pain are characteristic. Nodular iniltrates are similar to other viral pneumonias (Chap. 51, p. 994). Although resolution of pneumonitis parallels that of skin lesions, fever and compromised pulmonary function may persist for weeks.

If primary varicella is reactivated years later, it causes herpes zoster or shingles (Whirley, 2015). This presents as a unilateral dermatomal vesicular eruption associated with severe pain. Zoster does not appear to be more frequent or severe in pregnant women. Congenital varicella syndrome rarely develops in cases of maternal herpes zoster (hn, 2016; Enders, 1994). Zoster is contagious if blisters are broken, although less so than with primary varicella.

In women with varicella during the irst half of pregnancy, the fetus may develop congenital varicella syndrome. Some features include chorioretinitis, microphthalmia, cerebral cortical atrophy, growth restriction, hydronephrosis, limb hypoplasia, and cicatricial skin lesions as shown in Figure 64-3 (Ahn, 2016; Auriti, 2009). Enders and coworkers (1994) evaluated 13 3 pregnant women with varicella. When maternal infection developed before 13 weeks, only two of 472 pregnancies-O.4 and scarring in a fetus infected during the first trimester by vari cella. (Reproduced with permission from Paryani SG, Arvin AM:

Intrauterine infection with varicella zoster virus after maternal varicella, N Engl J Med. 1986 Jun 12;314(24):1542-1546.) percent-had neonates with congenital varicella syndrome. he highest risk was between 13 and 20 weeks, during which time seven of 351 exposed fetuses-2 percent-had evidence of congenital varicella. Mter 20 weeks' gestation, the researchers found no clinical evidence of congenital infection. Ahn and colleagues (2016) recently described similar findings. hat said, sporadic reports have described CNS abnormalities and skin lesions in fetuses who developed congenital varicella in weeks 21 to 28 of gestation (Lamont, 2011 a; Marin, 2007).

If the fetus or neonate is exposed to active infection just before or during delivery, and therefore before maternal antibody has been formed, the newborn faces a serious threat. Attack rates range from 25 to 50 percent, and mortality rates approach 30 percent. In some instances, neonates develop disseminated visceral and CNS disease, which is commonly fatal. For this reason, varicella-zoster immune globulin (VZIG) should be administered to neonates born to mothers who have clinical evidence of varicella 5 days before and up to 2 days ater delivery.

Maternal varicella is usually diagnosed clinically. Infection may be confirmed by NAA T of vesicular fluid, which is very sensitive. The virus may also be isolated by scraping the vesicle base during primary infection and performing a Tzanck smear, tissue culture, or direct luorescent antibody testing. Congenital varicella may be diagnosed using NAA T analysis of amnionic luid, although a positive result does not correlate well with the development of congenital infection (Mendelson, 2006). A detailed anatomical sonographic evaluation performed at least 5 weeks after maternal infection may disclose abnormalities, but the sensitivity is low (Mandelbrot, 2012).

Maternal Viral Exposure. Several aspects of maternal VZV exposure and infection in pregnancy afect management. Exposed gravidas with a negative history for chickenpox should undergo VZV serological testing. At least 70 percent of these women will be seropositive, and thus immune. Exposed pregnant women who are susceptible (seronegative) should be given varicella-zoster immune globulin (VariZIG). Although best given within 96 hours of exposure, its use is approved for up to 10 days to prevent or attenuate varicella infection (Centers for Disease Control and Prevention, 2012, 2013d). Passive immunization appears to be highly efective Qespersen, 2016). In women with known history of varicella, VariZI G is not indicated.

Maternal Infection. Any patient dianosed with primay varicella inection or herpes zoster should be isolated rom pregnant women.

Because VZV pneumonia often presents with few symptoms, a chest radiograph is recommended by many. Most women require only supportive care, but those who require intravenous (IV) luids and especially those with pneumonia are hospitalized. IV acyclovir therapy is given to women requiring hospital ization-500 mg/mror 10 to 15 mg/kg every 8 hours.

Vaccination. An attenuated live-virus vaccine is recommended for nonpregnant adolescents and adults with no history of vari cella. Two doses of Varivax are given 4 to 8 weeks apart, and the seroconversion rate is 98 percent (Marin, 2007). Importantly, vaccine-induced immunity diminishes over time, and the (Chaves, 2007).

The vaccine is not recommended or pregnant women or or vaccine dose. That said, a registry of more than 1000 vaccine exposed pregnancies reports no cases of congenital varicella syn drome or other associated congenital malformations (Marin, 2014; Wilson, 2008). he attenuated vaccine virus is not secreted in breast milk. hus, postpartum vaccination should not be delayed because of breastfeeding (American College of

Obstetricians and Gynecologists, 2016c).

hese respiratory infections are caused by members of the family Orthomyxoviridae. Inluenza A and B form one genus of these RNA viruses, and both cause epidemic human disease (Cohen, 2015b). Inluenza A viruses are subclassiied further by hemagglutinin (H) and neuraminidase (N) surface antigens. Inluenza outbreaks occur annually, and the most recent epidemic was in 2016 to 2017 caused by an inluenza A/H3N2 strain (Shang, 2016).

Fever, dry cough, and systemic symptoms characterize this infection, which usually is not life-threatening in otherwise healthy adults. However, pregnant women appear to be more susceptible to serious complications, particularly pulmonary involvement (Cohen, 2015b; Mertz, 2017; Rasmussen, 2012). Severe infection has a maternal mortality rate of 1 percent (Duryea, 2015). And from 2009 to 2010, widespread inluenza A infection afected pregnant women and caused 12 percent of pregnancy-related deaths (Callaghan, 2015).

No firm evidence links inluenza A virus and congenital malformations (Irving, 2000; Zerbo, 2017). Conversely,

TABLE 64-2. Outpatient Influenza A and B Virus Testing Methods aNasopharyngeal or throat swab.

RT-PCR = reverse transcription-polymerase chain reaction. Data from Centers for Disease Control and Prevention, 201r7e.

Lynberg and colleagues (1994) reported higher rates of neuraltube defects in neonates born to women with inluenza early in pregnancy. his was possibly associated with hyperthermia. Viremia is infrequent, and transplacental passage is rare (Rasmussen, 2012). Stillbirth, preterm delivery, and irst-trimester abortion have all been reported, but usually correlate with the severity of maternal infection (Centers for Disease Control and Prevention, 2011; Fell, 2017; vleijer, 2015).

Inluenza may be detected in nasopharyngeal swabs using viral antigen rapid detection assays (Table 64-2). Reverse transcriptase-polymerase chain reaction (RT-PCR) is the more sensitive and specific test, although not widely available (Cohen, 2015b). In contrast, rapid influenza diagnostic tests (RIDTs) are least indicative, with sensitivities of 40 to 70 percent. Decisions to administer antiviral medications or inluenza treatment or chemoprophylaxis should be based on clinical symptoms and epidemiological actors. Specifically, the start of therapy should not be delayed pending testing results (Centers for Disease Control and Prevention, 2017 e).

Two classes of antiviral medications are currently available. Neuraminidase inhibitors are highly efective for the treatment of early inluenza A and B. hese include oseltamivir (Tamilu), which is taken orally for treatment and for chemoprophylaxis; zanamivir (Relenza), which is inhaled for treatment; andperamivir (Rapivab), which is administered intravenously.

he adamantanes include amantadine and rimantadine, which were used for years for treatment and chemoprophylaxis of inluenza A. In 2005, inluenza A resistance to adamantine was reported to exceed 90 percent in the United States. hus, its use is not currently recommended. It is possible that these drugs may again be efective for subsequently mutated strains. Patterns of resistance are available at cdc.gov/flu.

Experience with all of these antiviral agents in pregnant women is limited (Beau, 2014; Beigi, 2014; Dunstan, 2014). hey are Food and Drug Administration category C drugs and thus used when potential benefits outweigh risks. At Parkland Hospital, we start oral oseltamivir treatment within 48 hours of symptom onset-75 mg twice daily for 5 days. Earlyadministration may reduce length of hospital stays (Meijer, 2015; Oboho, 2016). Prophylaxis with oseltamivir, 75 mg orally once daily for 7 days, is also recommended for signiicant exposures. Antibacterial medications are added when a secondary bacterial pneumonia is suspected (Chap. 51, p. 993).

Efective vaccines are formulated annually. Vaccination against inluenza throughout the influenza season, but optimally in October or November, is recommended by the Centers for Disease Control and Prevention (CDC) (2013a) and the American College of Obstetricians and Gynecologists (2016b) for all women who will be pregnant during the influenza season. his is especially important for those afected by chronic medical disorders such as diabetes, heart disease, asthma, or human immunodeficiency virus (HIV) infection. Inactivated vaccine prevents clinical illness in 70 to 90 percent of healthy adults. Importantly, there is no evidence of teratogenicity or other adverse maternal or fetal events (Chambers, 2016; Fell, 2017; Kharbanda, 2017; Polyzos, 2015; Sukumaran, 2015). Moreover, for mothers vaccinated during pregnancy, several studies found lower rates of influenza in their infants up to 6 months of age (Nunes, 2017; Steinhof, 2012; Zaman, 2008). Immunogenicity of the trivalent inactivated seasonal inluenza vaccine in pregnant women is similar to that in the nonpregnant individual. A live attenuated influenza virus vaccine is available for intranasal use but is not recommended for pregnant women (Cohen, 2015b).

his uncommon adult infection is caused by an RNA paramyxovirus. Because of childhood immunization, up to 90 percent of adults are seropositive (Rubin, 2012). The virus primarily infects the salivary glands but also may involve the gonads, meninges, pancreas, and other organs. It is transmitted by direct contact with respiratory secretions, saliva, or through fomites. Most transmission occurs before and within 5 days of parotitis onset, and droplet isolation is recommended during this time (Kutty, 2010). Treatment is symptomatic, and mumps during pregnancy is no more severe than in nonpregnant adults.

Women who develop mumps in the first trimester may have a greater risk of spontaneous abortion. Infection in pregnancy is not associated with congenital malformations, and fetal infection is rare (McLean, 2013).

he live attenuated J eryl-Lynn vaccine strain is part of the MMR vaccine-measles, mumps, and rubella. This vaccine is contraindicated in pregnancy according to the CDC (McLean, 2013). No malformations attributable to MMR vaccination in pregnancy have been reported, but pregnancy should be avoided for 30 da) s after mumps vaccination. The vaccine may be given to susceptible women postpartum, and breastfeeding is not a contraindication.

his is a highly contagious RNA virus of the family Paramyxoviridae that only infects humans. In endemic areas, annual outbreaks of measles, also called rubeola, occur in late winter and early spring, transmission is primarily by respiratory droplets, and the secondary attack rate among contacts exceeds 90 per cent (Rainwater-Lovett, 2015). Resurgences in measles have been linked to clusters of vaccine-eligible but unvaccinated individuals (Fiebelkorn, 2010; Phadke, 2016). Fever, coryza, conjunctivitis, and cough are typical symptoms. he charac teristic erythematous maculopapular rash develops on the face and neck and then spreads to the back, trunk, and extremities.

Koplik spots are small white lesions with surrounding erythema found within the oral cavity. Immediate or delayed neurologi cal sequelae of measles may manifest in several forms, making diagnosis diicult (Buchanan, 2012; Chiu, 2016). Diagnosis of acute infection is most commonly performed by serological evidence of IgM antibodies, although RT-PCR tests are avail able. Treatment is supportive.

Pregnant women without evidence of measles immunity should be administered passive immunoprophylaxis with immune globulin, 400 mg/kg intravenously (Centers for Dis ease Control and Prevention, 2017d). Active vaccination is not performed during pregnancy, however, susceptible women can be vaccinated routinely postpartum, and breastfeeding is not contraindicated (Ohji, 2009).

he virus does not appear to be teratogenic (Siegel, 1973).

However, rates of spontaneous abortion, pre term delivery, and low-birthweight neonates are increased with maternal measles (Rasmussen, 2015). If a woman develops measles shortly before birth, risk of serious infection developing in the neonate is considerable, especially in a preterm neonate.

his RNA togavirus causes rubella, also called German measles, which is of minor importance in the absence of pregnancy.

Rubella inection in the irst trimester, however, poses signicant risk or abortion and severe congenital maormations. T ransmission occurs via nasopharyngeal secretions, and the transmission rate is 80 percent to susceptible individuals. he peak incidence is late winter and spring in endemic areas (Lambert, 2015).

Maternal rubella is usually a mild febrile illness with a generalized maculopapular rash beginning on the face and spreading to the trunk and extremities. hat said, 25 to 50 percent of infections are asymptomatic. Other symptoms may include arthralgias or arthritis, head and neck lymphadenopathy, and conjunctivitis. he incubation period is 12 to 23 days. Viremia usually precedes clinical signs by about a week, and adults are infectious during viremia and through 7 days after the rash appears. Up to half of maternal infections are subclinical despite viremia that may cause devastating fetal infection (McLean, 2013).

Rubella virus may be isolated from the urine, blood, nasopharynx, and cerebrospinal fluid for up to 2 weeks after rash onset. The diagnosis is usually made, however, with serological analysis. In one study, 6 percent of nonimmune women seroconverted to rubella virus during pregnancy (Hutton, 2014). Specific IgM antibody can be detected using enzyme-linked immunoassay for 4 to 5 days after onset of clinical disease, but antibody can persist for up to 6 weeks after appearance of the rash. Importantly, rubella virus reinfection can give rise to transient low levels of IgM. With this, fetal infection can rarely occur, but no adverse fetal efects have been described. Serum IgG antibody titers peak 1 to 2 weeks after rash onset. his rapid antibody response may complicate serodiagnosis unless samples are initially collected within a few days after the onset of the rash. If, for example, the first specimen was obtained 10 days after the rash, detection of IgG antibodies would fail to diferentiate between very recent disease and preexisting immunity to rubella. IgG avidity testing is performed concomitant with the serological tests above. High-avidity IgG antibodies indicate an infection at least 2 months in the past.

The rubella virus is one of the most complete teratogens, and efects of fetal infection are worst during organogenesis (Adams Waldorf, 2013). Pregnant women with rubella and a rash during the first 12 weeks of gestation have an afected fetus with congenital infection in up to 90 percent of cases (Miller, 1982). At 13 to 14 weeks' gestation, this incidence is 50 percent, and by the end of the second trimester, it is 25 percent. Defects are rare after 20 weeks' gestation. Features of congenital rubella syndrome amenable to prenatal diagnosis are cardiac septal defects, pulmonary stenosis, microcephaly, cataracts, microphthalmia, and hepatosplenomegaly (Yazigi, 2017). Other abnormalities include sensorineural deafness, intellectual disability, neonatal purpura, and radiolucent bone disease. Neonates born with congenital rubela may shed the virus or many months and thus be a threat to other inants and to susceptible adults who contact them. Reports of delayed morbidities associated with congenital rubella syndrome may include a rare, progressive panencephalitis, insulin-dependent diabetes mellitus, and thyroid disorders (Sever, 1985; Webster, 1998).

here is no speciic treatment for rubella. Droplet precautions for 7 days after the onset of the rash are recommended. Postexposure passive immunization with polyclonal immunoglobulin may be of benefit if given within 5 days of exposure (Young, 2015).

Although large epidemics of rubella have virtually disappeared in the United States because of immunization, up to 10 percent of women in the United States are susceptible. Cluster outbreaks during the 1990s mainly involved persons born outside the United States, as congenital rubella is still common in developing nations (Centers for Disease Control and Prevention, 20 13f) . To eradicate rubella and prevent congenital rubella syndrome completely, a comprehensive approach is recommended for immunizing the adult population (Grant, 2015).

MMR vaccine should be ofered to nonpregnant women of childbearing age who do not have evidence of immunity whenever they make contact with the health-care system. Vaccination of all susceptible hospital personnel who might be exposed to patients with rubella or who might have contact with pregnant women is important. Rubella vaccination should be avoided 1 month before or during pregnancy because the vaccine contains attenuated live virus. No observed evidence links the vaccine and induced malformations, although the overall theoretical risk is up to 2.6 percent (McLean, 2013;

Swamy, 2015). MMR vaccination is not an indication for pregnancy termination.

Prenatal serological screening for rubella is indicated for all pregnant women. Women found to be nonimmune are ofered the MMR vaccine postpartum.

More than 200 antigenically distinct respiratory viruses cause the cominon cold, pharyngitis, laryngitis, bronchitis, and pneumonia. Rhinovirus, coronavirus, and adenovirus are major causes of the common cold. The RNA-containing rhinovirus and coronavirus usually produce a trivial, self-limited illness characterized by rhinorrhea, sneezing, and congestion. he DNA-containing adenovirus is more likely to produce cough and lower respiratory tract involvement, including pneumonia.

The potential teratogenic efects of respiratory viruses are controversial. In a case-control study using data from the Finnish Register of Congenital vlalformations, 393 gravidas with a common cold had a four-to ivefold greater risk of fetal anencephaly (Kurppa, 1991). In another population study of California births from 1989 to 1991, low attributable risks for neural-tube defects were associated with many illnesses in early pregnancy (Shaw, 1998). Adams and colleagues (2012) performed amnionic fluid viral PCR studies in 1191 women undergoing amniocentesis for fetal karyotyping. Viral PCR was positive in 6.5 percent, with adenovirus being the virus most frequently identified. There was an association with fetalgrowth restriction, nonimmune hydrops, foot/hand abnormalities, and neural-tube defects. Adenoviral infection is a known cause of childhood myocarditis. T owbin (1994) and Forsnes (1998) and their associates used PCR tests to identiy and link adenovirus to fetal myocarditis and nonimmune hydrops.

hese RNA viruses are members of the family Bunyaviridae. They are associated with a rodent reservoir, and transmission involves inhalation of virus excreted in rodent urine and feces. Outbreaks of hantaviruses including Sin Nombre virus and Seoul virus have been reported in the United States, the most recent in early 2017 (Centers for Disease Control and Prevention, 2017b). Hantaviruses are a heterogenous group of viruses with low and variable rates of transplacental transmission. Howard and associates (1999) reported the Hantavirus pulmonay syndrome to cause maternal death, fetal demise, and preterm birth. hey found no evidence of vertical transmission of the causative Sin N ombre virus.

hese viruses are a major subgroup of RNA picornaviruses that include coxsackievirus, poliovirus, and echovirus. They are trophic for intestinal epithelium but can also cause widespread maternal, fetal, and neonatal infections that may include the CNS, skin, heart, and lungs. Most maternal infections are subclinical yet can be fatal to the fetus-neonate (Tassin, 2014). Hepatitis A is an enterovirus that is discussed in Chapter 55 (p. 1063).

Coxsackievirus infections with group A and B are usually asymptomatic. Symptomatic infections-usually with group B-include aseptic meningitis, polio-like illness, hand foot and mouth disease, rashes, respiratory disease, pleuritis, pericarditis, and myocarditis. No treatment or vaccination is available (Cohen, 2015a). Coxsackievirus may be transmitted by maternal secretions to the fetus at delivery in up to half of mothers who seroconverted during pregnancy (Modlin, 1988). Transplacental passage has also been reported (Ornoy, 2006).

Congenital malformation rates may be slightly increased in fetuses of pregnant women who had serological evidence of coxsackievirus (Brown, 1972). Viremia can cause fetal hepatitis, skin lesions, myocarditis, and encephalomyelitis, all of which may be fatal. Some have reported higher rates of cardiac anomalies and of low-birthweight, preterm, and small-for-gestational-age newborns (Chen, 2010; Koro'lkova, 1989). Maternal-fetal infection has been associated with massive perivillous ibrin deposition and fetal death (Yu, 2015). Finally, a rare association between maternal coxsackievirus infection and insulin-dependent diabetes in ofspring has been described (Viskari, 2012).

Polio viruses cause highly contagious infections that are subclinical or mild. he virus is trophic for the CNS, and it can cause paralytic poliomyelitis (Cohen, 2015a). Siegel (1955) demonstrated that pregnant women not only were more susceptible to polio but also had a higher death rate. Perinatal transmission has been observed, especially when maternal infection developed in the third trimester (Bates, 1955). Inactivated subcutaneous polio vaccine is recommended for susceptible pregnant women who must travel to endemic areas or are placed in other high-risk situations. Live oral polio vaccine has been used for mass vaccination during pregnancy without harmful fetal efects (Harjulehto, 1989).

This B 19 virus causes erythema inectiosum, orith disease. It is a small, single-stranded DNA virus that replicates in rapidly proliferating cells such as erythroblast precursors (Brown, 2015). his can lead to anemia, which is its primary fetal efect. Only individuals with the erythrocyte globoside membrane P antigen are susceptible. In women with severe hemolytic anemia-for example, sickle-cell disease-parvovirus infection may cause an aplastic crisis.

The main mode of parvovirus transmission is respiratory or hand-to-mouth contact, and the infection is common in spring months. The maternal infection rate is highest in women with school-aged children and in day-care workers, but not in schoolteachers. An infected person develops viremia 4 to 14 days after exposure, and an otherwise immunocompetent individual is no longer infectious at the onset of the rash. By adulthood, only 40 percent of women are susceptible. The annual seroconversion rate is 1 to 2 percent but is >10 percent during epidemic periods (Brown, 2015). The secondary attack rate approaches 50 percent.

In 20 to 30 percent of adults, infection is asymptomatic. Fever, headache, and flulike symptoms may begin in the last few days of the viremic phase. Several days later, a bright red rash with erythroderma afects the face and gives a slapped-cheek appearance. The rash becomes lacelike and spreads to the trunk and extremities. Adults often have milder rashes and develop symmetrical polyarthralgia that may persist several weeks. Mayama and associates (2014) described a pregnant woman in whom B 19 infection was associated with hemophagocytic lymphohistiocytosis. No evidence suggests that parvovirus infection is altered by pregnancy. With recovery, IgM antibody is generated 7 to 10 days postinfection, and production persists for 3 to 4 months. Several days after IgM is produced, IgG antibody is detectable and persists for life with natural immunity (American College of Obstetricians and Gynecologists, 2017).

here is vertical transmission to the fetus in up to a third of maternal parvovirus infections (de long, 2011; Lamont, 20 11 b). Fetal infection has been associated with abortion, nonimmune hydrops, and stillbirth (Lassen, 2012; Mace, 2014; McClure, 2009). According to the American College of Obstetricians and Gynecologists (2017), the rate of fetal loss with serologically proven parvovirus infection is 8 to 17 percent before 20 weeks' gestation, and 2 to 6 percent after midpregnancy. Currently, no data support evaluating asymptomatic mothers and stillborn fetuses for parvovirus infection.

Hydrops develops in only approximately 1 percent of fetuses of women infected with parvovirus (American College of Obstetricians and Gynecologists, 2017; Pasquini, 2016; Puccetti, 2012). Still, it is the most frequent infectious agent of nonimmune hydrops in autopsied fetuses (Rogers, 1999). Hydrops usually stems from infection in the irst half of gestation. In one report, more than 80 percent of hydrops cases were found in the second trimester, with a mean gestational age of 22 to 23 weeks (Yaegashi, 2000). At least 85 percent of cases of fetal infection developed within 10 weeks of maternal infection, and the mean interval was 6 to 7 weeks. he critical period for maternal infection leading to fetal hydrops was estimated to be between 13 and 16 weeks' gestation, which coincided with the period in which fetal hepatic hemopoiesis is greatest.

An algorithm for diagnosis of maternal parvoviral infection is illustrated in Figure 64 4. Diagnosis is generally made by maternal serological testing for speciic IgG and IgM antibodies (Bonvicini, 2011; Brown, 2015). Viral DNA may be detectable by PCR in maternal serum during the prodrome and persist for months to years after infection. Fetal infection is diagnosed by detection of B 19 viral DNA in amnionic luid or IgM antibodies in fetal serum obtained by cordocentesis (de long, 2011; Weifenbach, 2012). Fetal and maternal viral loads do not predict fetal morbidity and mortality (de Haan, 2007).

Most cases of parvovirus-associated hydrops develop in the first 10 weeks after infection. Thus, serial sonography every 2 weeks should be performed in women with recent infection (see Fig. 64-4). As discussed in Chapter 10 (p. 214), middle cerebral artery (MCA) Doppler interrogation can also be used to predict fetal anemia (Chauvet, 2011). Fetal blood sampling is warranted with hydrops to assess the degree of fetal anemia.

Comorbid fetal myocarditis may induce hydrops with lesser degrees of anemia.

Depending on gestational age, fetal transfusion for hydrops may improve outcome in some cases (Enders, 2004). Mortal ity rates as high as 30 percent have been reported in hydropic fetuses without transfusions. With transfusion, 94 percent of hydrops cases resolve within 6 to 12 weeks, and the overall mortality rate is <10 percent. Most fetuses require only one transfusion because hemopoiesis resumes as infection resolves.

Concurrent fetal thrombocytopenia worsens the prognosis (Melamed,r2015).

Reports describing neurodevelopmental outcomes in fetuses transfused for B 19 infection-induced anemia are conlicting. In one review of 24 transfused hydropic fetuses, abnormal neurodevelopment was noted in ive of 16 survivors-32 percent-at 6 months to 8 years (Nagel, 2007). Outcomes were not related to severity of fetal anemia or acidemia, and these investigators hypothesized that the infection itself induced cerebral damage. In another study of 28 children treated with intrauterine transfusion, 11 percent had neurodevelopmental impairment during evaluation at a median age of 5 years (de long, 2012). Conversely, Dembinski (2003) found no signiicant neurodevelopmental delay despite severe fetal anemia.

Currently, no parvovirus vaccine is available, and no evidence suggests that antiviral treatment prevents maternal or fetal infection. Decisions to avoid higher-risk work settings are complex and require assessment of exposure risks. Pregnant women should be counseled that risks for infection approximate 5 percent for casual, infrequent contact; 20 percent for intense, prolonged work exposure such as for teachers; and 50 percent for close, frequent interaction such as in the home. Workers at day-care centers and schools need not avoid infected children because infectivity is greatest before clinical illness. Finally, infected children do not require isolation.

This mosquito-borne RNA flavivirus is a human neuropathogen. It has become the most common cause of arthropod-borne viral encephalitis in the United States (Centers for Disease Control and Prevention, 2017f; Krow-Lucal, 2017). West Nile viral infections are typically acquired through mosquito bites in late summer or perhaps through blood transfusion. The incubation period is 2 to 14 days, and most persons have mild or no symptoms. Fewer than 1 percent of infected adults develop meningoencephalitis or acute laccid paralysis (Granwehr, 2004). Presenting symptoms may include fever, mental status changes, muscle weakness, and coma (Stewart, 2013).

Diagnosis of West Nile infection is based on clinical symptoms and the detection of viral IgG and IgM in serum and IgM in cerebrospinal fluid. There is no known efective antiviral treatment, and management is supportive. he primary strategy for preventing exposure in pregnancy is the use of insect

Clinical disease: exposure or infection Sonographic evidence of fetal infection: hydrops fetalis, hepatomegaly, splenomegaly, placentomegaly, elevated

FIGURE 64-4 Algorithm for evaluation and management of human parvovirus B 19 infection in pregnancy. eBe = complete blood count; IgG = immunoglobulin G; IgM = immunoglobulin M; MeA = middle cerebral artery; peR = polymerase chain reaction; RNA = ribonucleic acid.

repellant containing ,N-diethyl-m-toluamide (DEET). This is infections initially reported to the West Nile Virus Pregnancy considered safe for use among pregnant women (Wylie, 2016). Registry, there were four miscarriages, two elective abortions, Avoiding outdoor activity and stagnant water and wearing proand 72 live births, 6 percent of which were preterm (O'Leary, tective clothing are also recommended. 2006). Three of these 72 newborns were shown to have West

Adverse efects of West Nile viremia on pregnancy are Nile infection, and it could not be established conclusively that unclear. Animal data suggest that embryos are susceptible, and infection was acquired congenitally. Of three major malformaa case report of human fetal infection at 27 weeks' gestation tions possiby associated with viral infection, none was deinidescribed chorioretinitis and severe temporal and occipital lobe tively conirmed. Similar conclusions were reached by Pridjian leukomalacia (Alpert, 2003; Julander, 2006). In 77 maternal and colleagues (2016), who analyzed data from the CDC West Nile Virus Registry. Transmission of West Nile virus through breastfeeding is rare .

hese are single-stranded RNA viruses that are prevalent world wide. In 2002, an especially virulent strain of coronavirus

China. It rapidly spread throughout Asia, Europe, and North and South America. he case-fatality rate approached 10 percent in the nonpregnant population and was as high as 25 percent in pregnant women (Lam, 2004; Wong, 2004). Although no addi tional cases have been conirmed since 2004, the CDC (2013b) now lists SARS-Co V as a "select agent" that has the potential to pose a severe threat to public health and safety.

Another novel regional coronavirus with a high case-fatality coronavirus eMERS-Co ) (Arabi, 2017). Although experience with MERS-Co V is sparse in pregnancy, infection has been reported to cause maternal and perinatal deaths (Assiri, 2016).

A member of the RNA Filoviridae family, the Ebola virus is transmitted by direct person-to-person contact (Kuhn, 2015).

Infection produces a severe hemorrhagic fever with pronounced thy. Treatment is supportive, and the mortality rate approaches 50 percent.

Data are few concerning Ebola viral infection in pregnancy (Beigi, 2017; Money, 2015; Oduyebo, 2015). The CDC concludes that pregnant women are at increased risk for severe illness and death a amieson, 2014). hat said, no evidence suggests that pregnant women are more susceptible to Ebola virus infection. One report described trophoblast infection (Muehlenbachs, 2017).

This RNA virus of the Flavivirdae family has recently been recognized as the first major mosquito-borne teratogen (Rasmussen, 2016). Although Zika virus is primaril) transmitted by mosquito bite, sexual transmission is also possible, and the virus may be detected in body fluids for months following acute infection (Hills, 2016; Joguet, 2017; Paz-Bailey, 2017).

Reminiscent of the rubella epidemic in the 1960s, in adults Zika infection may be asymptomatic or cause mild symptoms of rash, fever, headache, arthralgia, and conjunctivitis lasting a few days. Virus is typically detectable in blood around the time of symptom onset and may persist days to months in pregnant women (Driggers, 2016; Meaney-Delman, 2016). Serum IgM antibodies typically become detectable within the first two weeks after symptom onset and remain a median of four months (Oduyebo, 2017). Rarely, Guillain-Barre syndrome may develop following infection (da Silva, 2017; Parra, 2016).

The fetus can be severely infected whether or not the mother is symptomatic. Honein and coworkers (2017) describe a fetus with congenital Zika infection. Findings shown include a thin cerebral cortex, increased extraaxial space (, dilated ventricles (F,), and absent cavum septum pellucidum. (Reproduced with permission from Driggers RW, Ho (Y, Korhonen EM, et al: Zika virus infection with prolonged maternal viremia and fetal brain abnor malities, N Engl J Med. 2016 Jun 2;374(22):2142-2151.) a 6-percent overall fetal infection rate. In one report of 134 women with positive RT-PCR results, fetal mortality was 7 percent (Brasil, 2016). Among live births, the rate of fetal birth defects ranges from 5 percent-among women with possible Zika infection-to 15 percent among pregnant women with laboratory-confirmed infection in the irst trimester (Reynolds, 2017). In the most severely afected fetuses, a congenital Zika syndrome has been described that includes microcephaly, lissencephaly, ventriculomegaly, intracranial calcifications, ocular abnormalities, and congenital contractures (Honein, 2017; Moore, 2017; Soares de Oliveira-Szejnfeld, 2016). Sonographic findings from a Zika-infected fetus are shown in 64-5.

Diagnosis of this infection in pregnant women is made with detection of Zika virus RNA in blood or urine or by serological testing. Detection of Zika virus RNA by PCR confirms infection. Serological assays for Zika IgM antibodies may cross react with other flaviviruses. Thus, a positive assay result is followed by another assay containing virus-specific neutralizing antibodies (Oduyebo, 2017) . Testing recommendations and interpretation have evolved for pregnant women who are symptomatic and those who are asymptomatic but have ongoing exposure risk. his risk includes living in or traveling to an area with active local transmission. Large-scale screening programs have been described to identiy women at high risk for travelassociated Zika infection (Adhikari, 2017).

Currently, no specific treatment or vaccine is available for Zika infection, although several vaccine candidates are in development (Beigi, 2017; World Health Organization, 2017). Prophylaxis includes protective netting and insect spray to control the vector mosquito and avoidance of sexual contact with partners recently exposed. he CDC has established a pregnancy hotline (770-488-7100) and U.S. Zika Pregnanc)

Registry (ZikaPregnancy@cdc.gov) for clinicians with concerns related to management of women with Zika infection or exposure.

Infections caused by Streptococcus pyogenes are important in pregnant women. his organism is the most frequent bacterial cause of acute pharyngitis and is associated with several systemic and cutaneous infections. S pyogenes produces numerous toxins and enzymes responsible for its local and systemic toxicity. Pyrogenic exotoxin-producing strains are usually associated with severe disease (Shinar, 2016; Wessels, 2015). In most cases, streptococcal pharyngitis, scarlet fever, and erysipelas are not life threatening. Treatment, usually with penicillin, is similar in pregnant and nonpregnant women.

In the United States, S pyogenes infrequently causes puerperal infection. Still, it remains the most common cause of severe maternal postpartum infection and death worldwide, and the incidence of these infections is rising (Deutscher, 2011; Hamilton, 2013; Wessels, 2015). Puerperal infections are discussed in detail in Chapter 37. he early 1990s saw the emergence of streptococcal toxic shock syndrome, manifested by hypotension, fever, and evidence of multiorgan failure with associated bacteremia. Group A puerperal sepsis is seriously complicated in 20 percent of cases (Shinar, 2016). The case-fatality rate approximates 30 percent, and morbidity and mortality rates are improved with early recognition. Treatment includes clindamycin plus penicillin therapy and often surgical debridement (Chapter 47, p. 924). No vaccine for group A streptococcus is commercially available.

Streptococcus agalactiae is a group B organism that can be found to colonize the gastrointestinal and genitourinary tract in 10 to 25 percent of pregnant women (Kwatra, 2016). Throughout pregnancy, group B Streptococcus (GBS) is isolated in a transient, intermittent, or chronic fashion. Although the organism is most likely always present in these same women, their isolation is not always homologous.

he spectrum of maternal and fetal G BS efects ranges from asymptomatic colonization to septicemia. S agalactiae has been implicated in adverse pregnancy outcomes that include preterm labor, prematurely ruptured membranes, clinical and subclinical chorioamnionitis, and fetal infections (Randis, 2014). GBS can also cause maternal bacteriuria, pyelonephritis, osteomyelitis, postpartum mastitis, and puerperal infections. It remains the leading infectious cause of morbidity and mortality among infants in the United States (Centers for Disease Control and Prevention, 2010; Schrag, 2016).

Neonatal sepsis has received the most attention due to its devastating consequences and available efective preventative measures. Infection <7 days after birth is deined as eary-onset disease and is seen in 0.21/1000 live births (Centers for Disease Control and Prevention, 2015). Many investigators use a threshold of <72 hours of life as most compatible with intrapartum acquisition of disease (Stoll, 2011). We and others have also encountered unexpected intrapartum stillbirths from GBS infections (Nan, 2015). Tudela and associates (2012) reported that newborns with early-onset CBS infection often had clinical evidence of fetal infection during labor or at delivery.

In many neonates, septicemia involves signs of serious illness that usually develop within 6 to 12 hours of birth. These include respiratory distress, apnea, and hypotension. At the outset, therefore, neonatal infection must be diferentiated from respiratory distress syndrome caused by insuicient surfactant production (Chap. 34, p. 636). he mortality rate with early-onset disease has declined to approximately 4 percent, and preterm newborns are disparately afected.

Late-onset disease caused by GBS is noted in 0.32 per 1000 live births and usually manifests as meningitis 1 week to 3 months after birth (Centers for Disease Control and Prevention, 2015). he mortality rate, although appreciable, is less for late-onset meningitis than for early-onset sepsis. Unfortunately, it is not uncommon for surviving infants of both early-and late-onset disease to exhibit devastating neurological sequelae.

As GBS neonatal infections evolved beginning in the 1970s and before widespread intrapartum chemoprophylaxis, rates of early-onset sepsis ranged from 2 to 3 per 1000 live births. By 2010, these outcomes led to a policy of universal rectovaginal culture screening for GBS at 35 to 37 weeks' gestation followed by intrapartum antibiotic prophylaxis for women identified to be carriers. hese outcomes stimulated development of expanded laboratory identiication criteria for GBS; updated algorithms for screening and intrapartum chemoprophylaxis for women with preterm prematurely ruptured membranes, preterm labor, or penicillin allergy; and described new dosing for penicillin G chemoprophylaxis. Following these changes, the incidence of early-onset G BS neonatal sepsis decreased to 0.21 cases per 1000 live births by 2015 (Centers for Disease Control and Prevention, 2015).

hus, during the past three decades, several strategies have been proposed to prevent perinatal acquisition of GBS infections. These strategies have not been compared in randomized trials and are either culture-based or risk-based guidelines (Ohlsson, 2014). hese methods have been adopted in the United States, but not all European countries have guidelines (Di Renzo, 2015).

Culture-Based Prevention. he CDC (2010) GBS guidelines recommend a culture-based approach, which was also adopted by the American College of Obstetricians and Gynecologists (20 16e). Shown in Figure 64-6, this strategy is designed to identiy women who should be given intrapartum antimicrobial prophylaxis. Women are screened for GBS colonization at 35 to 37 weeks' gestation, and intrapartum antimicrobials are given to women with rectovaginal GBS-positive cultures. Selective enrichment broth followed by subculture improves detection. In addition, more rapid techniques such as DNA probes and NAATs are being developed (Helali, 2012). A previous sibling with GBS invasive disease and identiication of GBS

Vaginal and rectal GBS screening cultures at 35-37 weeks' gestation for ALL pregnant women (unless patient had GBS bacteriuria during the current pregnancy or a previous infant with invasive GBS disease)

Previous infant with invasive GBS disease

Positive GBS screening culture during current pregnancy (unless a planned cesarean delivery, in the absence of labor or amniotic membrane rupture, is performed)

Unknown GBS status (culture not done, incomplete, or results unknown) and any of the following:

Previous pregnancy with a positive GBS screening culture (unless a culture was also positive during the current pregnancy)

Planned cesarean delivery performed in the absence of labor or membrane rupture (regardless of maternal GBS culture status)

Negative vaginal and rectal GBS screening culture in late gestation during the current pregnancy, regardless of intrapartum risk factors

Intrapartum temperature � 1 OOAoF (�38.0°C)

FIGURE 64-6 Indications for intrapartum prophylaxis to prevent perinatal group B streptococcal (GBS) disease under a universal prenatal screening strategy based on combined vaginal and rectal cultures obtained at 35 to 37 weeks' gestation. (From Centers for Disease Control and Prevention, 201o0.) bacteriuria in the current pregnancy are also considered indications for prophylaxis.

Risk-Based Prevention. This approach is recommended for women in labor and whose GBS culture results are not known. It relies on risk factors associated with intrapartum GBS transmission. Intrapartum chemoprophylaxis is given to women who have any of the following: delivery <37 weeks, ruptured membranes � 18 hours, or intrapartum temperature � 100.4°F (�38.0°C). Women with GBS during the current pregnancy and women with a prior infant with invasive early-onset GBS disease are also given chemoprophylaxis.

At Parkland Hospital in 1995-and prior to consensus guidelines-we adopted and continue to use the risk-based approach for intrapartum treatment of women at high risk. Importantly, in addition, all term neonates who were not given intrapartum prophylaxis were treated in the delivery room with aqueous penicillin G, 50,000 to 60,000 units intramuscularly. Rates of early-onset GBS sepsis decreased to 0.4 to 0.66 per 1000 live births (Staford, 2012; Wendel, 2002). Non-GBS early-onset sepsis decreased from 0.66 to 0.24 per 1000 live births (Staford, 2012). Thus, this approach has results similar to those reported by the CDC (2010) for culture-based prevention.

Serotype-specific capsular antibody concentrations clinically correlate with GBS neonatal disease. Antibody-producing vaccines have been tested, but none are clinically available (Donders, 2016; Kobayashi, 2016; Madhi, 2016).

Preventive antimicrobials administered 4 or more hours before delivery are highly efective (Fairlie, 2013). Regardless of screening method, penicillin remains the first-line agent

TABLE 64-3. Regimens for Intrapartum Antimicrobial Prophylaxis for Perinatal GBS Disease

Recommended Penicillin G, 5 million units IV initial dose, then 2.5 to 3.0 million units IV every 4 hours until delivery

Alternative Ampicillin, 2 g IV initial dose, then 1 9 IV every 4 hours or 2 g every

Patients not at high risk for anaphylaxis Cefazolin, 2 9 IV initial dose, then 1 9 IV every 8 hours until delivery

Patients at high risk for anaphylaxis and with GBS Clindamycin, 900 mg IV every 8 hours until delivery susceptible to clindamycin

Patients at high risk for anaphylaxis and with GBS Vancomycin, 1 9 IV every 12 hours until delivery resistant to clindamycin or susceptibility unknown

GBS = group B Streptococcus; IV = intravenous. Data from the Verani, 2010 for prophylaxis, and ampicillin is an acceptable alternative Women undergoing cesarean delivery before labor onset with (T able 64-3). Women with a penicillin allergy and no hisintact membranes do not need intrapartum GBS chemoprophytory of anaphylaxis are given cefazolin (Briody, 2016). hose laxis, regardless of GBS colonization status or gestational age. at high risk for anaphylaxis should have antimicrobial susceptibility testing performed to exclude clindamycin resistance. Clindamycin-sensitive but erythromycin-resistant isolates • Methicillin-Resistant Staphylococcus aureus should have a D-zone test performed to assess for inducible Staphylococcus aureus is a pyogenic gram-positive organism and clindamycin resistance. If clindamycin resistance is conirmed, is considered the most virulent of the staphylococcal species. vancomycin should be administered. Eythromycin is no longer It primarily colonizes the nares, skin, genital tissues, and oroused or penicilin-alergic patients. pharynx. Approximately 20 percent of normal individuals are

Further recommendations for management of spontanepersistent carriers, 30 to 60 percent are intermittent carriers, ous preterm labor, threatened preterm delivery, or preterm and 20 to 50 percent are noncarriers (Gorwitz, 2008). Coloprematurely ruptured membranes are shown in Figure 64-7. nization is considered the greatest risk factor for infection

Onset of labor orrupture of membranes at < 37 weeks' gestation with significant risk for imminent preterm delivery rectal GBS culture -...for�48hours prophylaxis

FIGURE 64-7 Sample algorithm for prophylaxis for women with group B streptococcal (GBS) disease and threatened preterm delivery. This algorithm is not an exclusive course of management, and variations that incorporate individual circumstances or institutional preferences may be appropriate. IV = intravenous. (Adapted from Centers for Disease Control and Prevention, 201o6a.) (Marzec, 2016; Sheield, 2013). Methicillin-resistant 5 aureus (MRSA) colonizes only 2 percent of adults but is a signiicant contributor to the health-care burden (Gorwitz, 2008). MRSA infections are associated with increased cost and higher mortality rates compared with those by methicillin-sensitive 5 aureus (NISSA) (Beigi, 2009; Butterly, 2010).

Community-acquired MRSA (CA-MRSA) is diagnosed when identified in an outpatient setting or within 48 hours of hospitalization in a person without traditional risk factors. Such risk factors include prior MRSA infection, hospitalization, dialysis or surgery within the past year, and indwelling catheters or devices (Dantes, 2013). Hospital-associated MRSA (HA-MRSA) infections are nosocomial. Most cases of \1RSA in pregnant women are CA-MRSA.

Anovaginal colonization with 5 aureus is identified in 10 to 25 percent of obstetrical patients (Top, 2010). Skin and soft tissue infections are the most common presentation of MRSA in pregnant women (Fig. 64-8). Mastitis and breast abscesses have been reported in up to a fourth of cases of MRSA complicating pregnancy (Laibl, 2005; Lee, 2010). Perineal abscesses, wound infections at sites such as abdominal and episiotomy incisions, and chorioamnionitis are also associated with MRSA (Pimentel, 2009; hurman, 2008). Finally, osteomyelitis has been reported (Nguyen, 2015; Tanamai, 2016).

A rise in CA-MRSA infections has been reported in neonatal intensive care units and newborn nurseries. In these settings, infection is frequently associated with maternal and health-care worker skin infections and infected breast milk. Vertical transmission is rare (Jimenez-Truque, 2012; Pinter, 2009).

he Infectious Diseases Society of America has published guidelines for the treatment of MRSA infections (Liu, 2011). Uncomplicated supericial infections are primarily managed by drainage and local wound care. Although historically

FIGURE 64-8 This antepartum patient presented with multiple small microabscesses for which culture identified methicillinresistant Staphylococcus aureus. (Used with permission from

Dr. Stephan Shivvers.) de-emphasized, recent evidence suggests benefit from antibi otic therapy in addition to incision and drainage of smaller abscesses (Daum, 2017; Forcade, 2012). Severe superficial infections, especially those that fail to respond to local care or those in patients with medical comorbidities, are treated with MRSA-appropriate antibiotics. Purulent cellulitis should be treated empirically for CA-MRSA until culture results are available.

Most CA-MRSA strains are sensitive to trimethoprim-sul famethoxazole and clindamycin (\1iller, 2015; T alan, 2016).

for mono therapy. Linezolid, although efective against MRSA, is expensive, and there is little information regarding its use in pregnancy. Doxycycline, minocycline, and tetracycline, although efective for MRSA infections, should not be used in pregnancy. Vancomycin remains the irst-line therapy for inpatient serious MRSA infections.

he control and prevention of HA-NIRSA and CA-MRSA rely on appropriate hand hygiene and prevention of skin-toskin contact or contact with wound dressings. Decolonization should be considered only in cases in which a patient develops recurrent supericial infections despite optimal hygiene measures or if ongoing transmission occurs among household or close contacts (Liu, 2011). Decolonization measures include nasal treatment with mupirocin, chlorhexidine gluconate baths, and oral rifampin therapy if previous measures have failed. Routine decolonization is not efective in the general obstetrical population. For women with culture-proven CA-MRSA infection during pregnancy, we add single-dose vancomycin to routine beta-Iactam perioperative prophylaxis for cesarean deliveries and higher-order perineal lacerations. Breastfeeding in these women is not prohibited, but optimal hygiene and attention to minor skin breaks is encouraged.

Listeria monocytogenes is an uncommon but probably underdiagnosed cause of neonatal sepsis (Kylat, 2016). This facultative intracellular gram-positive bacillus can be isolated from the feces of 1 to 5 percent of adults. Nearly all cases oflisteriosis are thought to be foodborne. Outbreaks have been caused by raw vegetables, coleslaw, apple cider, melons, milk, fresh Mexicanstyle cheese, smoked ish, and processed foods such as pate, hummus, wieners, and sliced deli meats (Centers for Disease Control and Prevention, 20 13e).

Listerial infections are more common in pregnant women, immunocompromised patients, and the very old or young. he incidence of such infections in pregnancy is estimated to be up to 100 times that in the general population (Kourtis, 2014; Rouse, 2016). In 1651 cases reported in 2009 to 2011, the CDC found that 14 percent were in pregnant women (Silk, 2013). It is unclear why pregnant women still account for a significant number of these reported cases. One hypothesis is that pregnant women are susceptible because of decreased cellmediated immunity (Baud, 2011).

Listeriosis during pregnancy may be asymptomatic or may cause a febrile illness that is confused with influenza, pyelonephritis, or meningitis (Centers for Disease Control and Prevention, 2013e). he diagnosis usually is not apparent until blood cultures are reported as positive. Occult or clinical infection also may stimulate labor. Discolored, brownish, or meconiumstained amnionic fluid is common with fetal infection, even in preterm gestations. VIaternalrlisteriosis causes fetal infection that characteristically produces disseminated granulomatous lesions with microabscesses (Fig. 64-9). Chorioamnionitis is common, and placental lesions include multiple, well-demarcated macroabscesses. Early-and late-onset neonatal infections are similar to group B streptococcal sepsis. In a review of 222 cases, infection resulted in abortion or stillbirth in 20 percent, and neonatal sepsis developed in 68 percent of surviving newborns (Mylonakis, 2002). In one large, prospective cohort study, 24 percent of mothers experienced fetal loss, but none after 29 weeks' gestation (Charlier, 2017). However, a neonatal-case fatality rate of 21 percent has been reported (Sapuan, 2017).

FIGURE 64-9 The pale placenta (A)and stillborn infant (B) resulted from maternal listeriosis.

Treatment with ampicillin plus gentamicin is usually recommended because of synergism against Listeria species (Rouse, 2016). T rimethoprim-sulfamethoxazole can be given to penicillin-allergic women. Maternal treatment in most cases is also efective for fetal infection (Chan, 2013). No vaccine is available. Prevention is by washing raw vegetables, cooking all raw food, and avoiding the implicated foods listed previously (American College of Obstetricians and Gynecologists, 2016d).

Infections from Salmonella species continue to be a major cause of foodborne illness (Peques, 2012). Six serotypes, including Salmonella subtypes yphimurium and enteritidis, account for most cases in the United States. Nontyphoid Salmonella gastroenteritis is contracted through contaminated food. Symptoms that include nonbloody diarrhea, abdominal pain, fever, chills, nausea, and vomiting begin 6 to 48 hours after exposure. Diagnosis is made by stool studies (Chap. 54, p. 1048). Intravenous crystalloid solutions are given for rehydration. ntimicrobials are not given in uncomplicated infections because they do not commonly shorten illness and may prolong the convalescent carrier state. If gastroenteritis is complicated by bacteremia, antimicrobials are given as discussed below. Rare case reports have linked Salmonella bacteremia with abortion (Coughlin, 2002).

Typhoid fever caused by Salmonela yphi remains a global health problem, although it is uncommon in the United States. Infection is spread by oral ingestion of contaminated food, water, or milk. In pregnant women, the disease is more likely to be encountered during epidemics or in those with HIV infection (Hedriana, 1995). In former years, antepartum typhoid fever resulted in abortion, preterm labor, and maternal or fetal death (Dildy, 1990).

Fluoroquinolones and third-generation cephalosporins are the preferred treatment. For enteric (typhoid) fever, antimicrobial susceptibility testing is important because of the development of drug-resistant strains (Crump, 2015). Typhoid vaccines appear to exert no harmful efects when administered to pregnant women and are given in an epidemic or before travel to endemic areas.

Bacillary dysentery caused by Shigela is a relatively common, highly contagious cause of inlammatory exudative diarrhea in adults. Shigellosis is more common in children attending daycare centers and is transmitted via the fecal-oral route. Clinical manifestations range from mild diarrhea to severe dysentery, bloody stools, abdominal cramping, tenesmus, fever, and systemic toxicity. Although shigellosis may be self-limited, careful attention to treatment of dehydration is essential in severe cases. We have cared for pregnant women in whom secretory diarrhea exceeded lO•Ll day! Antimicrobial therapy is imperative, and efective treatment during pregnancy includes fluoroquinolones, ceftriaxone, or azithromycin. Antimicrobial resistance is rapidly emerging, and antibiotic susceptibility testing can help guide appropriate therapy (Centers for Disease Control and Prevention, 2016). Shigellosis can stimulate uterine contractions and cause preterm birth (Parisot, 2016).

Also known as leprosy, this chronic infection is caused by Mycobacterium leprae and is rare in this country. Diagnosis is confirmed by PCR. Multidrug therapy with dapsone, rifampin, and clofazimine is recommended for treatment and is generally safe during pregnancy (Gimovsky, 2013; Ozturk, 2017). Duncan (1980) reported an excessive incidence oflow-birthweight newborns among infected women. The placenta is not involved, and neonatal infection apparently is acquired from skin-to-skin or droplet transmission (Duncan, 1984). Vertical transmission is common in untreated mothers (Moschella, 2004).

Caused by the spirochete Borrelia burgdoeri, Lyme disease is the most commonly reported vectorborne illness in the United States (Centers for Disease Control and Prevention, 2017c). Lyme borreliosis follows tick bites of the genus Ixodes. There are three stages (Steere, 2015). Early infection-stage I-causes a distinctive local skin lesion, erythema migrans, which may be accompanied by a flulike syndrome and regional adenopathy. If untreated, disseminated infection-stage 2-follows in days to weeks. Multisystem involvement is frequent, but skin lesions, arthralgia, myalgia, carditis, and meningitis predominate. If still untreated after several weeks to months, late or persistent infection-stage 3-manifests in perhaps half of patients. Native immunity is acquired, and the disease enters a chronic phase in about 10 percent. Some patients remain asymptomatic, but others in the chronic phase develop various skin, joint, or neurological manifestations (Shapiro, 2014).

Clinical diagnosis is important because serological and PCR testing has many pitfalls (Steere, 2015). IgM and IgG serological testing is recommended in early infection and is followed by Western blotting for conirmation. Ideally, acute and convalescent serological evaluation is completed if possible, however, false-positive and -negative rates are high.

Optimal treatment of Lyme disease was published by the Infectious Diseases Society of America (Sanchez, 2016). For early infection, treatment with doxycycline, amoxicillin, or cefuroxime is recommended for 14 days, although doxycycline is usually avoided in pregnancy. A 14-to 28-day course of IV ceftriaxone, cefotaxime, or penicillin G is given for complicated early infections that include meningitis, carditis, or disseminated infections. Chronic arthritis and post-Lyme disease syndrome are treated with prolonged oral or IV regimens, however, symptoms respond poorly to treatment (Steere, 2015).

No vaccine is commercially available. Avoiding areas with endemic Lyme disease and improving tick control in those areas is the most efective prevention. Self-examination with removal of unengorged ticks within 36 hours of attachment reduces infection risk (Hayes, 2003). For tick bites recognized within 72 hours, a single 200-mg oral dose of doxycycline may reduce infection development.

Several reports describe Lyme disease in pregnancy, although large series are lacking. Transplacental transmission has been confirmed, but no congenital efects of maternal borreliosis have been conclusively identiied (Shapiro, 2014; Walsh, 2006). Prompt treatment of maternal early infection should prevent most adverse pregnancy outcomes (Mylonas, 201l).

Diagnosis and management of tuberculosis during pregnancy is discussed in detail in Chapter 51 (p. 995).

The obligate intracellular parasite Toxoplasma gondii has a life cycle with two distinct stages (Kim, 2015). he eline stage takes place in the cat-the deinitive host-and its prey. Unsporu lated oocysts are excreted in feces. In the non eline stage, tissue cysts containing bradyzoites or oocysts are ingested by the inter mediate host, including humans. Gastric acid digests the cysts to release bradyzoites, which infect small-intestinal epithelium.

Here, they are transformed into rapidly dividing tachyzoites, which can infect all cells within the host mammal. Humoral and cell-mediated immune defenses eliminate most of these, but tissue cysts develop. Their lifelong persistence is the chronic form of toxoplasmosis.

Human infection is acquired by eating raw or undercooked meat infected with tissue cysts or by contact with oocysts from cat feces in contaminated litter, soil, or water. Prior infection is conirmed by serological testing, and its prevalence depends on geographic locale and parasite genotype. In the United States, seroprevalence in persons aged 10 to 19 years is 5 to 30 per cent, and this can exceed 60 percent in those older than 50 (Kim, 2015). Thus, a significant segment of pregnant women in this country are susceptible to infection. The incidence of prenatal infection resulting in birth of a newborn with con genital toxoplasmosis varies from 0.8 per 10,000 live births in the United States to 10 per 10,000 in France (Cook, 2000).

Between 400 and 4000 cases of congenital toxoplasmosis are diagnosed annually in the United States Oones, 2014).

Most acute maternal infections are subclinical and are detected only by prenatal or newborn serological screening. In some cases, maternal symptoms may include fatigue, fever, headache, muscle pain, and sometimes a maculopapular rash and posterior cervical lymphadenopathy. In immunocompetent adults, initial infection confers immunity, and prep regnancy infection nearly eliminates any risk of vertical transmission. Infection in immu nocompromised women, however, may be severe, and reactiva tion may cause encephalitis, retinochoroiditis, or mass lesions.

Maternal infection is associated with a fourfold increased pre term delivery rate before 37 weeks (Freeman, 2005).

The incidence and severity of fetal toxoplasmosis depend on gestational age at the time of maternal infection. Risks for fetal infection rise with gestational age. A metaanalysis estimated the risk to be 15 percent at 13 weeks, 44 percent at 26 weeks, and 71 percent at 36 weeks (SYROCOT Study Group, 2007). Conversely, the severity of fetal infection is much greater in early pregnancy, and these fetuses are much more likely to have clinical findings of infection (American College of Obstetricians and Gynecologists, 2017).

Importantly, most infected fetuses are born without obvious stigmata of toxoplasmosis. Clinically afected neonates usually have generalized disease expressed as low birthweight, hepatosplenomegaly, jaundice, and anemia. Some primarily have neurological disease with intracranial calciications and with hydrocephaly or microcephaly (Dhombres, 2017). Many eventually develop chorioretinitis and exhibit learning disabilities. This classic triad-chorioretinitis, intracranial calcifications, and hydrocephalus-is often accompanied by convulsions. Infected neonates with clinical signs are at risk for long-term complications (Abdoli, 2014; Wallon, 2014).

With IgG antibody conirmed before pregnancy, there is no risk for a congenitally infected fetus. he American College of Obstetricians and Gynecologists (2017) does not recommend prenatal screening for toxoplasmosis in areas of low prevalence, including the United States. Screening should be performed in immunocompromised pregnant women, including those with HIV infection. In areas of high toxoplasmosis prevalence-for example, France and Austria-routine screening has resulted in diminished congenital disease (Kim, 2015; Wallon, 2013).

Pregnant women with suspected toxoplasmosis should be tested. he parasite is rarely detected in tissue or body fluids. Antitoxoplasma IgG develops within 2 to 3 weeks after infection, peaks at 1 to 2 months, and usually persists for lifesometimes in high titers. Although IgM antibodies appear by 10 days after infection and usually become negative within 3 to 4 months, they may remain detectable for years. hus, IgM antibodies are not used alone to diagnose acute toxoplasmosis (Dhakal, 2015). Best results are obtained with the Toxoplasma Serologic Proile performed at the Palo Alto Medical Foundation Research Institute (ww.toxolab@pamf.org). Toxoplasma IgG avidity increases with time. hus, if a high-avidity IgG result is found, infection in the preceding 3 to 5 months is excluded. Multiple tests are available that allow high avidity results to conirm latent infection with a 100-percent positivepredictive value (Villard, 2013).

Congenital toxoplasmosis is suspected when sonography reveals findings such as hydrocephaly, intracranial or hepatic calciications, ascites, placental thickening, hyperechoic bowel, and growth restriction. Prenatal diagnosis of congenital toxoplasmosis is performed using PCR ampliication of toxoplasma DNA in amnionic luid (Filisetti, 2015; Montoya, 2008). he sensitivity of PCR varies with gestational age and is lowest before 18 weeks (Romand, 2001).

No randomized clinical trials have assessed the benefit and eicacy of treatment to decrease the risk for congenital infection. A systematic review of data from 1438 treated pregnancies found weak evidence for early treatment to reduce congenital toxoplasmosis risks (SYROCOT Study Group, 2007). Treatment has been associated with a reduction in rates of serious neurological sequelae and neonatal demise (Cortina-Borja, 2010).

Prenatal treatment is based on two regimens-spiramycin alone or a pyrimethamine-sulfonamide combination given with folinic acid (American College of Obstetricians and Gynecologists, 2017). These two regimens have also been used consecutively (Hotop, 2012). Little evidence supports the use of a speciic regimen (Montazeri, 2017; Valentini, 2015). hat said, most experts will use spiramycin in women with acute infection early in pregnancy to reduce vertical transmission. Because it does not cross the placenta, spiramycin may not be used to treat fetal infection. Pyrimethamine-sulfadiazine with folinic acid is selected for maternal infection after 18 weeks' gestation or if fetal infection is suspected.

There is no vaccine for toxoplasmosis, so avoidance of infection is necessary if congenital infection is to be prevented. Eforts include: (1) cooking meat to safe temperatures; (2) peeling or thoroughly washing fruits and vegetables; (3) cleaning all food preparation surfaces and utensils that have contacted raw meat, poultry, seafood, or unwashed fruits and vegetables; (4) wearing gloves when changing cat litter, or else delegating this duty; and (5) avoiding feeding cats raw or undercooked meat and keeping cats indoors. Although these preventive steps are recommended, no data support their efectiveness (American College of Obstetricians and Gynecologists, 2017; Di Mario, 2015).

his protozoan infection remains a global health crisis and causes 2000 deaths per day worldwide (White, 2015). Malaria has been efectively eradicated in Europe and in most of North America, and worldwide mortality rates have fallen more than 25 percent. In the United States, most cases of malaria are imported-some in returning military personnel (Mace, 2017). Transmitted by infected Anopheles mosquitoes, six species of Plasmodium cause human disease-alciparum, vivax, two species of ovale, malariae, and knowlesi.

Pregnant women have increased susceptibility to malarial infections (Kourtis, 2014). Antibodies to the parasite surface antigen VAR2CSA mediate placental accumulation of infected erythrocytes and lead to the harmful efects of malaria (Mayor, 2015). hrough this mechanism, some immunity accrues with parity and is called pregnancy-specic antimalarial immuniy. Ironically, malaria treatment dampens this immunity, and resurgence in pregnancy has been documented in Mozambique (Mayor, 2015).

Clinical findings are fever, chills, and flulike symptoms including headaches, myalgia, and malaise, which may occur at intervals. Symptoms are less severe with recurrences. Malaria may be associated with anemia and jaundice, and aciparum infections may cause kidney failure, coma, and death. That said, many otherwise healthy but infected adults in endemic areas are asymptomatic because of partial immunity. Pregnant women, although often asymptomatic, are said to be more likely to develop traditional symptoms (Desai, 2007) .

infections during pregnancy-whether symptomatic or asymptomatic-are associated with higher rates of perinatal morbidity and mortality (Menendez, 2007; Nosten, 2007). Adverse outcomes include stillbirth, preterm birth, low birthweight, and maternal anemia. The latter two are documented most frequently (Machado Filho, 2014; McClure, 2013). Maternal infection is associated with a 14-percent rate of low-birthweight newborns worldwide (Eisele, 2012). These

FIGURE 64-10 Photomicrograph of placental malaria. A.Multiple infected red blood cells (long black arrow) are seen in the intervillous space of this placenta. Multiple villi cut in cross section are shown, and three are highlighted (short arrows). B. Increased magnification of image (A). Multiple infected erythrocytes are seen, and two are identified (arrows).

adverse perinatal outcomes correlate with high levels of placental parasitemia (Rogerson, 2007). The latter occurs when parasitized erythrocytes, monocytes, and macrophages accumulate in the vascular areas of the placenta (Fig. 64-10). Infections with P aciparum are the worst, and early infection raises the risk for abortion. The incidence of malaria increases signiicantly in the latter two trimesters and postpartum (Diagne, 2000). Despite this, congenital malaria occurs in <5 percent of neonates born to infected mothers.

Identiication of parasites by microscopical evaluation of a thick and thin blood smear remains the gold standard for diagnosis. In women with low parasite densities, however, the sensitivity of microscopy is poor. Malaria-speciic antigens are now being used for rapid diagnostic testing. Not only is their sensitivity still an issue in pregnancy, but these tests are not routinely available (Kashif, 2013; White, 2015).

For treatment, the most frequently used antimalarial drugs are not contraindicated in pregnancy. The World Health Organization recommends that all infected patients living in or traveling from endemic areas be treated with an artemisinin-based regimen for uncomplicated falciparum malaria (Taming, 2016). The CDC (2013c) recommends using atovaquone options are not available or tolerated.

nosed with uncomplicated malaria caused by P vivax, malariae, ovale, and chloroquine-sensitive P aciparum should be treated with chloroquine or hydroxychloroquine. For women infected with multidrug-resistant P aciparum, one irst-line agent for nonpregnant persons is artemether-Iumefantrine. Another primary option is artesunate plus meRoquine or artesunate plus dihydroartemisinin-piperaquine (White, 2015). he PREGACT Study Group (2016) recently compared four artemisinin-based drugs in 3428 pregnant women with falciparum malaria and reported no serious maternal or perinatal adverse efects. Second-line treatment regimens are artesunate; quinine plus either tetracycline, doxycycline, or clindamycin; or atovaquone-proguanii. Chloroquine-resistant P vivax should be treated with meRoquine. Chloroquine-sensitive P vivax or P ovale should be treated with chloroquine throughout pregnancy and then primaquine postpartum. Resistance to all the antimalarial drugs has been reported, including the recently added artemisinin-based compounds.

Treatment regimens for uncomplicated and severe malarial infections in pregnancy are detailed at: ww.cdc.gov/malaria/ diagnosis_treatment. he CDC also maintains a malaria hotline for treatment recommendations (855-856-4713).

Malaria control and prevention relies on chemoprophylaxis when traveling to or living in endemic areas. Vector control is also important. Insecticide-treated netting, pyrethroid insecticides, and D EET -based insect repellent lower malarial rates in endemic areas. hese are well tolerated in pregnancy (Menendez, 2007). If travel is necessary, chemoprophylaxis is recommended.

Chloroquine and hydroxychloroquine prophylaxis is safe and well tolerated in pregnancy. Prophylaxis lowers placental infection rates from 20 percent to 4 percent in asymptomatic infected women in areas without chloroquine resistance (Cot, 1992). For travelers to areas with chloroquine-resistant P aciparum, meRoquine prophylaxis is recommended (Freedman, 2016). One evaluation compared prophylaxis during pregnancy with either sulfadoxine-pyrimethamine or dihydroartemisinin-piperaquine and found the latter to be more efective (Kakuru, 2016). Primaquine and doxycycline are contraindicated in pregnancy, and data are insuicient for atovaquone/proguanil use. The latest chemoprophylaxis regimens for pregnancy can be obtained from the CDC Travelers' Health website at: ww.cdc.gov/malaria/ travelers/drugs.htmi. The CDC also publishes Health Inormation or Intenational Travel (The Yellow Book) at: ww.cdc. gov/yellowbook. For women living in endemic areas, intermittent preventive treatment was found to be superior to intermittent screening with treatmet (Desai, 2015).

Approximately 10 percent of the world population is infected with Entamoeba histo6ltica, and most are asymptomatic (Andrade, 201r5). Amebic dysentelY, however, may take a fulminant course during pregnancy, with fever, abdominal pain, and bloody stools. Prognosis is worse if complicated by a hepatic abscess. Diagnosis is made by identiying E histoytica cysts or trophozoites within a stool sample. herapy is similar to that for the nonpregnant woman, and metronidazole or tinidazole are the preferred drugs for amebic colitis and invasive disease. Noninvasive infections may be treated with iodoquinol or paromomycin.

Disseminated fungal infection-usually pneumonitis-during pregnancy is uncommon with coccidiomycosis, blastomycosis, cryptococcosis, or histoplasmosis. heir identification and management are considered in Chapter 51 (p. 995).

Pregnant travelers face general medical, obstetrical, and potentially hazardous destination risks. Several sources provide travel information (Freedman, 2016). he International Federation for Tropical Medicine has comprehensive information available at ww.iftm-hp.org, and the International Society of Travel Medicine publishes information at www.istm.org/ bodyofknowledge. lso, 1he Yelow Book, mentioned earlier, by the CDC has extensive travel information regarding pregnancy and breastfeeding.

The concept ofbioterrorism involves the deliberate release ofbacteria, viruses, or other infectious agents to cause illness or death. hese natural agents are often altered to increase their infectivity or their resistance to medical therapy. Health-care providers should be alert for signiicant increases in the number of persons with febrile illnesses accompanied by respiratory symptoms or with rashes not easily associated with common illnesses. Clinicians are urged to contact their state health department or the CDC for current information and recommendations. The merican College of Obstetricians and Gynecologists (2016a) has addressed disaster preparedness for obstetricians. It provides both general considerations and recommendations for hospital readiness and obstetrics-specific issues.

he variola virus causes smallpox and is considered a serious weapon. The virus is highly transmissible and carries an overall 30-percent case-fatality rate. The last case of smallpox in the United States was reported in 1949, and worldwide it was reported in Somalia in 1977. Nishiura (2006) has reviewed the severe perinatal and maternal morbidity and mortality caused by smallpox. The case-fatality rate of smallpox in pregnancy is 61 percent if the pregnant woman is unvaccinated. Rates of stillbirth, abortion, preterm labor and delivery, and neonatal demise rise significantly in pregnancies complicated by this infection.

Because the smallpox vaccine currently available is made with live vaccinia virus, pregnancy should be delayed for 4 weeks in recipients. It is generally not given to pregnant women because of the risk of fetal vaccinia, a rare but serious complication. Inadvertent smallpox vaccination during pregnancy has not, however, been convincingly associated with fetal malformations or preterm birth (Badell, 2015). Moreover, no cases of fetal vaccinia have been reported with second-generation smallpox vaccine exposure. The Smallpox Vaccine in Pregnancy Registry remains active, and vaccinated women are still being enrolled: DOD .NHRC-birthregistry@mail.mil.

Bacillus anthracis is a gram-positive, spore-forming, aerobic bacterium. It can cause three main types of clinical anthrax: inhalational, cutaneous, and gastrointestinal (Centers for Disease Control and Prevention, 2017a). The bioterrorist anthrax attacks of 2001 involved inhalational anthrax (Inglesby, 2002). Spores are inhaled and deposited in the alveoli. They are engulfed by macrophages and germinate in mediastinal lymph nodes. The incubation period is usually less than 1 week but may be as long as 2 months. Within 1 to 5 days of symptom onset, the second stage is heralded by the abrupt onset of severe respiratory distress and high fevers. Mediastinitis and hemorrhagic thoracic lymphadenitis are common. Chest radiographs show a widened mediastinum. Case-fatality rates with inhalational anthrax are high, even with aggressive antibiotic and supportive therapy (Holty, 2006).

Anthrax afecting pregnant women and its treatment were reviewed by Meaney-Delman and coworkers (2012, 2013). They reported data on 20 pregnant and postpartum women. The overall mortality rate was 80 percent, with a 60-percent fetal or neonatal loss rate. Of note, most cases were published before the advent of antibiotics.

Regimens for postexposure anthrax prophylaxis are given for 2 months. The CDC recommend that asymptomatic pregnant and lactating women with documented exposure to B anthracis be given postexposure prophylaxis with ciproloxacin, 500 mg orally twice daily for 60 days (Hendricks, 2014; Meaney-Delman, 2013). Amoxicillin, 500 mg orally three times daily, can be substituted if the strain is proven sensitive. In the case of ciproloxacin allergy and either penicillin allergy or resistance, doxycycline, 100 mg orally twice daily, is given for 60 days. Risks from anthrax far outweigh any fetal risks from doxycycline (lvleaney-Delman, 2013).

The anthrax vaccine is an inactivated, cell-free product that requires three injections over 28 days. Vaccination is generally avoided in pregnancy because safety data are limited. Inadvertent vaccination of pregnant women with the vaccine has not been linked with a significant increase in fetal malformation or miscarriage rates (Conlin, 2015; Ryan, 2008). The anthrax vaccine is an essential adjunct to postexposure antimicrobial prophylaxis, even in pregnancy.

Other category A bioterrorism agents include Francisella tularemis-tularemia, Clostridium botulinum-botulism, Yersinia pestis-plague, and viral hemorrhagic fevers-for example, Ebola, Marburg, Lassa, and Machupo. The guidelines for these biological agents are evolving and are detailed at the CDC Bioterrorism website: emergency.cdc.gov/bioterrorism/index.asp.

Abdoli A, Dalimi A, Arbabi M, et al: Neuropsychiatric manifestations of latent toxoplasmosis on mothers and their ofspring. J Matern Fetal Neonatal Med 27(13):1368,t2014

Adams LL, Gungor S, Turan S, et al: When are amniotic luid viral PCR studies indicated in prenatal diagnosis? Prenat Diagn 32(1):88, 2012

Adams Waldorf KM, McAdams M: Inluence of infection during pregnancy on fetal development. Reproduction 146(5):R151, 2013

Adhikari EH, Nelson DF, Johnson A, et al: Infant outcomes among women with Zika virus infection during pregnancy: results of a large prenatal Zika screening program. Am J Obstet Gynecol 216:292.e1, 2017

Ahn KH, Park YJ, Hong SC, et al: Congenital varicella syndrome: a systematic review. J Obstet Gynaecol 36(5):563, 2016

Alpert SG, Fergerson J, Noel LP: Intrauterine West Nile virus: ocular and systemic indings. Am J Ophthalmol 136(4):733,2003

American College of Obstetricians and Gynecologists: Hospital disaster preparedness for obstetricians and facilities providing materniry care. Committee Opinion No. 555, March 2013, Reairmed 2016a

American College of Obstetricians and Gynecologists: Inluenza vaccination during pregnancy. Committee Opinion No. 608, September 2014, Reaffirmed 2016b

American College of Obstetricians and Gynecologists: Integrating immunizations into practice. Committee Opinion No. 661, Aprilt2016c

American College of Obstetricians and Gynecologists: Management of pregnant women with presumptive exposure to Listeria monocytogenes. Committee Opinion No. 614, December, 2014, Reairmed 2016d

American College of Obstetricians and Gynecologists: Prevention of earlyonset group B streptococcal disease in newborns. Committee Opinion No. 485, April 2011, Reairmed 2016e

American College of Obstetricians and Gynecologists: Cytomegalovirus, parvovirus B9, varicella zoster, and toxoplasmosis in pregnancy. Practice Bulletin No. 151, June 2015, Reairmed 2017

Andrade M, Reed SL: Amebiasis and infection with free-living amebas. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles ofInternal Medicine, 19th ed. New York, McGraw-Hill, 2015, p. 1363

Arabi YM, Balkhy HH, Hayden FG, et al: Middle East respiratory syndrome.

N Engl J Med 376(6):584,t2017

Arvin AM, Fast P, Myers M, et al: Vaccine development to prevent cytomegalovirus disease: report from the National Vaccine Advisory Committee. Clin Infect Dis 39:233, 2004

Assiri A, Abedi GR, Al Masri M, et al: Middle East respiratory syndrome coronavirus infection during pregnancy: a report of 5 cases from Saudi Arabia. Clin Infect Dis 63(7):951, 2016

Auriti C, Piersigilli F, De Gasperis MR, et al: Congenital varicella syndrome: still a problem? Fetal Diagn Ther 25(2):224, 2009

Azam AZ, Vial Y, Fawer CL, et al: Prenatal diagnosis of congenital cytomegalovirus infection. Obstet Gynecol 97:443, 2001

Badell ML, Meaney-Delman D, Tuuli MG, et al: Risks associated with smallpox vaccination in pregnancy: a systematic review and meta-analysis. Obstet Gynecol 125(6):1439,t2015

Bates T: Poliomyelitis in pregnancy, fetus and newborn. Am J Dis Child 90: 189, 1955

Baud D, Greub G: Intracellular bacteria and adverse pregnancy outcomes. Clin Microbiol Infect 17: 1312, 2011

Beau AB, Hurault-Delarue C, Vial T, et al: Sfery of oseltamivir during pregnancy: a comparative study using the EFEMERIS database. BJOG 121(7):895,2014 Beigi RH: Emerging infectious diseases in pregnancy. Obstet Gynecol 129(5):896,t2017

Beigi RH, Bunge K, Song Y, et al: Epidemiologic and economic efects of methicillin-resistant Staphylococcus aureus in obstetrics. Obstet Gynecol 113:983, 2009

Beigi RH, Venkataramanan R, Caritis SN: Oseltamivir for inluenza in pregnancy. Semin PerinatoIt38(8):503, 2014

Bonvicini F, Puccetti C, Salfi NC, et al: Gestational and fetal outcomes in B19 matenal infection: a problem of diagnosis. J Clin MicrobioI49(10):3514, 201t1 Brasil P, Pereira JP, Moreira ME, et al: Zika virus infection in pregnant women in Rio de Janeiro. N Engl J Med 375(24):2321,t2016

Briody VA, Albright CM, Has P, et al: Use of cefazolin for group B streptococci prophylaxis in women reporting a penicillin allergy without anaphylaxis. Obstet Gynecol 7,t2016

Brown GC, Karunas RS: Relationship of congenital anomalies and maternal infection with selected enteroviruses. Am J Epidemiol 95:207, 1972

Brown E: Parvovirus infections. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill,t2015

Buchanan R, Bonthius DJ: Measles virus and associated central nervous system sequelae. Semin Pediatr ,t2012

Butterly A, Schmidt U, Wiener-Kronish J: Methicillin-resistant Staphylococcus aureus colonization, its relationship to nosocomial infection, and eicacy of control methods. Anesthesiology 113: 1453, 2010

Callaghan WM, Creanga A,Jamieson DJ: Pregnancy related mortality resulting from inluenza in the United States during the 2009-2010 pandemic. Obstet Gynecol 126(3):486,t2015

Centers for Disease Control and Prevention: Prevention of perinatal group B streptococci disease. Revised guidelines from the CDC. MvfWR 59(10):1, 20t10

Centers for Disease Control and Prevention: Maternal and infant outcomes among severely ill pregnant and postpartum women with 2009 pandemic influenza A (H1N1)-United States, April 2009-August 2010. MMWR 60(35):1193,t2011

Centers for Disease Control and Prevention: FDA approval of an extended period for administering VariZIG for postexposure prophylaxis of varicella. MMWR 61(12):212,t2012

Centers for Disease Control and Prevention: Prevention and control of seasonal inluenza with vaccines: recommendations of the Advisory Committee on Immunization Practices-United States, 2013-2014. MMWR 62(7):1, 2013a

Centers for Disease Control and Prevention: Severe acute respiratory syndrome (SARS). 2013b. Available at: https:llwww.cdc.gov/sars/index.html. Accessed October 7, 2017

Centers for Disease Control and Prevention: Treatment of malaria: guidelines for clinicians (United States). Part 3: Alternatives for pregnant women and treatment of severe malaria. 2013c. Available at: http://www.cdc. gov/malaria/diagnosis_treatment/clinicians3.html. Accessed October 7, 2017

Centers for Disease Control and Prevention: Updated recommendations for use ofVariZIG-United States. MMWR 62(28):574, 2013d

Centers for Disease Control and Prevention: Vital signs: listeria illnesses, deaths, and outbreaks-United States, 2009-2011. MMWR 62(22):148, 2013e

Centers for Disease Control and Prevention (CDC): Rubella and congenital rubella syndrome control and elimination-global progress, 2000-2012. MMWR 62(48)983, 2013f

Centers for Disease Control and Prevention: Active Bacterial Core surveillance (ABCs): group B Streptococcus, 2015. Available at: http://www.cdc.gov/ abcslreports-indingsl survreportsl gbs 15. pdf. Accessed October 6, 2017

Centers for Disease Control and Prevention: Shigella-shigellosis. 2016. Available at: https:/ Iwww.cdc.gov/shigella/general-information.html. Accessed October 7, 2017

Centers for Disease Control and Prevention: Anthrax. 2017a. Available at: https:llwww.cdc.gov/anthrax/index.html. Accessed ,t2017 Centers for Disease Control and Prevention: Hantavirus. 20 17b. Available at: https:!lwww.cdc.gov/hantavirus.l Accessed October 7, 2017

Centers for Disease Control and Prevention: Lyme disease: data and statistics. 2017c. Available at: https:llwww.cdc.gov/lyme/stats/index.html. Accessed October 7,t2017

Centers for Disease Control and Prevention: Measles (rubeola): for healthcare professionals. 2017 d. Available at: https:llwww.cdc.gov/measles/hcp/index. html. Accessed October ,t2017

Centers for Disease Control and Prevention: Seasonal influenza (flu): guidance for clinicians on the use of rapid influenza diagnostic tests.

e. Available at: http://www.cdc.gov/flu/professionals/diagnosis/clinician_guidance_ridt. htm. Accessed October 7, 2017

Centers for Disease Control and Prevention: West Nile virus. 2017f. Available at: https:llwww.cdc.gov/westnile/index.html. Accessed October 7, 201

Chambers CD, Johnson DL, Xu R, et al: Safery of the 2010-11, 2011-12, 2012-13, and 2013-14 seasonal inluenza vaccines in pregnancy: birth defects, spontaneous abortion, preterm delivery, and small for gestational age infants, a study from the cohort arm ofVAMPSS. Vaccine 34(37):4443, 2016

Chan BT, Hohmann E, Barshak MB, et al: Treatment of listeriosis in first trimester of pregnancy. Emerg Infect Dis 19:839, 2013

Chandra Pc, Patel H, Schiavello HJ, et al: Successful pregnancy outcome after complicated varicella pneumonia. Obstet Gynecol 92:680, 1998

Charlier C, Perrodeau E, Leclercq A, et al: Clinical features and prognostic factors oflisteriosis: the MONALISA national prospective cohort study. Lancet Infect Dis 17:510,t2017

Chauvet A, Dewilde A, homas D, et al: Ultrasound diagnosis, management and prognosis in a consecutive series of cases of fetal hydrops following maternal parvovirus B19 infection. Fetal Diagn her 30(1):41,t2011

Chaves SS, Gargiullo P, Zhang JX, et al: Loss of vaccine-induced immuniry to varicella over time. N Engl J Med 356: 1121, 2007

Cheeran MC, Lokensgard JR, Schleiss MR: Neuropathogenesis of congenital cytomegalovirus infection: disease mechanisms and prospects for intervention. Clin Microbiol Rev 22(1):99, 2009

Chen H, Lin HC, Lin HC: Increased risk of adverse pregnancy outcomes among women afected by herpangina. Am J Obstet Gynecol 203(1):49. e1,t2010

Chiu MH, Meatherall B, Nikolic A, et al: Subacute sclerosing panencephalitis in pregnancy. Lancet Infect Dis 16(3):366, 2016

Cohen JI: Enterovirus, parechovirus and reovirus infection. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles ofInternaltvIedicine, 19th ed. New York, McGraw-Hill, 2015a

Cohen YZ, Dolin R: Influenza. In Kasper DL, Fauci AS, Hauser SL, et al (eds):

Harrison's Principles of Internal Medicine, 19th ed. New York, lcGrawHill,t2015b

Conlin M, Bukowinski AT, Gumbs GR, et al: Analysis of pregnancy and infant health outcomes among women in the National Smallpox Vaccine in Pregnancy Registry who received anthrax vaccine adsorbed. Vaccine 33(36):4387,t2015

Cook AJ, Gilbert E, Bufolano W, et al: Sources of toxoplasma infection in pregnant women: European multicentre case-control study. mvIJ 321: 142, 2000

Cortina-Borja MTan HK, Wallon M, et al: Prenatal treatment for serious neurological sequelae of congenital toxoplasmosis: an observational prospective cohort study. PLoS Med 7(10):l, 2010

Cot M, Roisin A, Barro 0, et al: Efect of chloroquine chemoprophylaxis during pregnancy on birth weight: results of a randomized trial. Am J Trop Med Hyg 46:21, 1992

Coughlin LB, McGuigan J, Haddad NG, et al: Salmonella sepsis and miscarriage. Clin Microbiol Infect 9:866, 2002

Crespo AC, van der Zwan A, Ramalho-Santos J, et al: Cytotoxic potential of decidual NK cells and CD8+ T cells awakened by infections. J Reprod ImmunoItI19:85,t2017

Crump JA, Sjolund-Karlsson M, Gordon A, et al: Epidemiology, clinical presentation, laboratory diagnosis, antimicrobial resistance, and antimicrobial management of invasive salmonella infections. Clin Microbiol Rev 28(4): 901, 2015 da Silva IRF, Frontera JA, Bispo de Filippis AN, et al: Neurologic complications associated with the Zika virus in Brazilian adults. JlA Neurol 74(10):1190,t2017

Dantes R, Mu Y, Belflower R, et al: National burden of invasive methicillinresistant Staphylococcus aureus infections, United States, 2011t. JAv1A Intern Med 173(21):1970,t2013

Daum RS, Miller LG, Immergluck L: A placebo-controlled trial of antibiotics for smaller skin abscesses. N Engl J Med 376:2345,t2017 de Haan TR, Beersman MF, Oepkes 0, et al: Parvovirus B19 infection in pregnancy: maternal and fetal viral load measurements related to clinical parameters. Prenat Diagn 27:46, 2007 de Jong EP, Lindenburg IT, van Klink JM, et al: Intrauterine transfusion for parvovirus B 19 infection: long-term neurodevelopmental outcome. Am J Obstet Gynecol 206:204.el, 2012 de J ong EP , Walther FJ, Kroes AC, et al: Parvovirus B 19 infection in pregnancy: new insights and management. Prenat Diagn 31(5):419, 2011

Dembinski J, Eis-Hubinger vf, Maar J, et al: Long term follow up of serostatus after maternofetal parvovirus B19 infection. Arch Dis Child 88:219, 2003

Desai M, Gutman J, L'lanziva A, et al: Intermittent screening and treatment or intermittent preventive treatment with dihydroartemisinin-piperaquine versus intermittent preventive treatment with sulfadoxine-pyrimethamine for the control of malaria during pregnancy in western Kenya: an open-label, three-group, randomised controlled superiority trial. Lancet 386(10012): 2507, 2015

Desai M, ter Kuile F, Nosten F, et al: Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis 7:93, 2007

Deutscher M, Lewis M, Zell ER, et al: Incidence and severity of invasive Streptococcus pneumoniae, group A Streprococcus, and group B Streptococcus infections among pregnant and postpartum women. Clin Infect Dis 53(2):114,t201t1

Dhakal R, Gajurel K, Pomares C, et al: Signiicance of a positive toxoplasma immunoglobulin M test result in the United States. J Clin MicrobioIt53(11): 3601,t2015

Dhombres F, Friszer S, Maurice P, et al: Prognosis of fetal parenchymal cerebraltlesions without ventriculomegaly in congenital toxoplasmosis infection. Fetal Diagn Ther 41(1):8,t2017

Diagne N, Rogier C, Sokhna CS, et al: Increased susceptibility to malaria during the early postpartum period. N Engl J Med 343:598, 2000

Dildy GA III, Martens MG, Faro S, et al: Typhoid fever in pregnancy: a case report. J Reprod Med 35:2 3, 1990

Di Mario S, Basevi V, Gagliotti C, et al: Prenatal education for congenital toxoplasmosis. Cochrane Database Syst Rev 1, 2015

Di Renzo GC, Melin P, Berardi A, et al: Intrapartum GBS screening and antibiotic prophylaxis: a European consensus conference. J Matern Fetal Neonatal Med 28(7):766, 2015 Donders GG, Halperin SA, Devlieger R, et al: Maternal immunization with an investigational trivalent group B streptococcal vaccine: a randomized controlled trial. Obstet GynecoIt127(2):213, 2016 Driggers RW, Ho CY, Korhonen EM, et al: Zika virus infection with prolonged maternal viremia and fetal brain abnormalities. N Engl J Med 374(22):2142,t2016 Duncan ME: Babies of mothers with leprosy have small placentae, low birth weights and grow slowly. BJOG 8 :461, 1980 Duncan ME, Fox H, Harkness A, et al: The placenta in leprosy. Placenta 5:189,t1984 Dunstan HJ, Mill AC, Stephens S, et al: Pregnancy outcome following maternal use of zanamivir or oseltamivir during the 2009 influenza AlH 1 N 1 pandemic: a national prospective surveillance study. BJOG 121(7):901,t2014 Duryea EL, Sheield JS: Influenza: threat to maternal health. Obstet Gynecol Clin North Am 42(2):355,t2015

Egana-Ugrinovic G, Gonce A, Garcia L, et al: Congenital cytomegalovirus infection among twin pairs. J Matern Fetal Neonatal Med 29(21):3439, 20t16

Eisele TP, Larsen DA, Anglewicz PA, et al: Malaria prevention in pregnancy, birthweight, and neonatal mortality: a meta-analysis of 32 national crosssectional datasets in Africa. Lancet Infect Dis 12:942,t2012

Enders G, Bader U, Lindemann L, et al: Prenatal diagnosis of congenital cytomegalovirus infection in 189 pregnancies with known outcome. Prenat Diagn 21:362,t2001 Enders G, Miller E, Cradock-Watson J, et al: Consequences of varicella and herpes zoster in pregnancy: prospective study of 1739 cases. Lancet 343: 1548, 1994

Enders M, Weidner A, Zoellner I, et al: Fetal morbidity and mortality after acute human parvovirus B 19 infection in pregnancy: prospective evaluation of 1018 cases. Prenat Diagn 24:513, 2004

Fairlie T, Zell ER, Schrag S: Efectiveness of intrapartum antibiotic prophylaxis for prevention of early-onset Group B streptococcal disease. Obstet Gynecol 121(3):570,t2013

Fell DB, Savitz DA, Kramer MS, et al: Maternal influenza and birth outcomes: systematic review of comparative studies. BJOG 124(1):48,t201

Fiebelkorn AP, Redd SB, Gallagher K, et al: Measles in the United States during the postelimination era. J Infect Dis 202(10): 1520, 2010

Filisetti 0, Year H, Villard 0, et al: Contribution of neonatal amniotic fluid testing to diagnosis of congenital toxoplasmosis. J Clin Microbiol 53(5):1719,t2015

Forcade NA, Wiederhold NP, Ryan L, et al: Antibacterials as adjuncts to incision and drainage for adults with purulent methicillin-resistant Staphylococcus aureus (MRSA) skin infections. Drugs 72:339, 2012

Forsnes EV, Eggleston MK, WaxJR: Diferential transmission of adenovirus in a twin pregnancy. Obstet Gynecol , 1998

Fowler KB, Stagno S, Pass RF, et al: The outcome of congenital cytomegalovirus infection in relation to maternal antibody status. N Engl J Med 326:663, 1992

Fowler KB, Stagno S, Pass F: Maternal immunity and prevention of congenital cytomegalovirus infection. J1A 289: 1 008, 2003

Fowler SL: A light in the darkness: predicting outcomes for congenital cytomegalovirus infections. J Pediatr 137:4, 2000

Fragiadakis GK, Baca QJ, Gherardini PF, et al: Mapping the fetomaternal peripheral immune system at term pregnancy. J Immunol 197(11):4482, 2016

Freedman DO, Chen LH, Kozarsky PE: Medical considerations before international travel. N Engl J Med 375(3):247, 2016

Freeman K, Oakley L, Pollak A, et al: Association between congenital toxoplasmosis and preterm birth, low birthweight and small for gestational age birth. BJOG 112:31,2005

Gimovsky AC, Macri CJ: Leprosy in pregnant woman, United States. Emerg Infect Dis 19:10,t2013

Gotwitz J, Kruszon-Moran 0, McAllister SK: Changes in the prevalence of nasal colonization with Staphylococcus aureus in the United States, 20012004. J Infect Dis 197:1226,t2008

Grant GB, Reef SE, Dabbagh A, et al: Global progress roward rubella and congenital rubella syndrome control and elimination-2004-2014. MMWR 64(37):1052,t2015

Granwehr BP, Lillibridge M, Higgs S, et al: West Nile virus: where are we now? Lancet Infect Dis 4:547,t2004

Guerra B, Lazzarotto T, Quarta S, et al: Prenatal diagnosis of symptomatic congenital cytomegalovirus infection. Am J Obstet GynecoIt183:476, 2000 Hamilton SM, Stevens DL, Bryant AE: Pregnancy-related Group A streptococcal infections: temporal relationship between bacterial acquisition, infection onset, clinical findings, and outcome. Clin Infect Dis 0,t2013

Harjulehto T, Aro T, Hovi T, et al: Congenital malformations and oral poliovirus vaccination during pregnancy. Lancet 1:771, 1989

Hayes EB, Piesman J: How can we prevent Lyme disease? N Engl J Med 348: 2424,t2003

Hedriana HL, Mitchell JL, Williams SB: Salmonella ryphi chorioamnionitis in a human immunodeiciency virus-infected pregnant woman. J Reprod Med 40:157,t1995

Helali NE, Giovangrandi Y, Guyot K, et al: Cost and efectiveness of intrapartum Group B streptococcus polymerase chain reaction screening for term deliveries. Obstet Gynecol 119(4):822,t2012

Hendricks A, Wright ME, Shadomy SV, et al: Centers for Disease Control and Prevention expert panel meetings on prevention and treatment of anthrax in adults. Emerg Infect Dis 20(2):1,t2014

Hills SL, Russell K, Hennessey M, et al: Transmission of Zika virus through sexual contact with travelers to areas of ongoing transmission-Continental United States. MMWR 65(8):215,t2016

Holry JE, Bravata OM, Liu H, et al: Systemic review: a century of inhalational anthrax cases from 1900 to 2005. Ann Intern Med 144:270,t2006

Honein A, Dawson AL, Petersen EE, et al: Birth defects among fetuses and infants of US women with evidence of possible Zika virus infection during pregnancy. JAMA 317(1):59,t2017

Hotop A, Hlobil H, Gross U: Eicacy of rapid treatment initiation following primary Toxoplasma gondii infection during pregnancy. Clin Infect Dis 54(1t1):1545,t2012

Howard MJ, Doyle TJ, Koster FT, et al: Hantavirus pulmonary syndrome in pregnancy. Clin Infect Dis 29: 1538, 1999

Hutton J, Rowan P, Greisinger A, et al: Rubella monitoring in pregnancy as a means for evaluating a possible reemergence of rubella. Am J Obstet GynecoI211(5):534.e1,t2014

Hyde TB, Schmid OS, Cannon MJ: Cytomegalovirus seroconversion rates and risk factors: implications for congenital CMV. Rev Med Virol 20:311, 2010 Inglesby TV, O'Toole T, Henderson DA, et al: Anthrax as a biological weapon, 2002. JAMA 287:2236, 2002

Irving WL, James OK, Stephenson T, et al: Influenza virus infection in the second and third trimesters of pregnancy: a clinical and seroepidemiological study. BJOG 107: 1282, 2000

Jamieson OJ, Uyeki TM, Callaghan WM, et al: Xfhat obstetrician-gynecologists should know about Ebola: a perspective from the Centers for Disease Control and Prevention. Obstet GynecoIt124(5):1005, 2014

Jespersen C, Helmuth IG, Krause TG: Varicella-zoster immunoglobulin treatment in pregnant women in Denmark from 2005 to 2015: descriptive epidemiology and follow-up. Epidemiol Infect August 18, 2016 [Epub ahead of print]

Jimenez-Truque N, Tedeschi S, Saye EJ, et al: Relationship between maternal and neonatal Staphylococcus aureus colonization. Pediatrics 129:e1252, 2012

Joguet G, Mansuy JM, Matusali G, et al: Efect of acute Zika virus infection on sperm and virus clearance in body fluids: a prospective observational study. Lancet Infect Disease August 21, 2017 [Epub ahead of print]

Jones JL, Parise ME, Fiore AE: Neglected parasitic infecrions in the United States: toxoplasmosis. Am J Trop Med Hyg 90(5):794,t2014

Julander JG, Winger QA, Rickords LF, et al: West Nile virus infection of the placenta. Virology 347: 175,t2006 Kakuru A, Jagannathan P, Muhindo MK, et al: Dihydroartemisinin-Piperaquine for the prevention of malaria in pregnancy. N Engl J Med 374(10): 928,t2016 Kanengisser-Pines B, Hazan Y, Pines G, et al: High cytomegalovirus IgG avidity is a reliable indicator of past infection in patients with positive IgM detected during the first trimester of pregnancy. J Perinat Med 37: 15, 2009 Kashif AH, Adam GK, Mohammed AA, et al: Reliabiliry of rapid diagnostic test for diagnosing peripheral and placental malaria in an area of unstable malaria transmission in Eastern Sudan. Diagn Pathol 8:59,t2013

Kharbanda EO, Vasquez-Benitez G, Romitti PA, et al: First trimester influenza vaccination and risks for major structural birth defects in ofspring. J Pediatr 187:234,t2017

Kim , Kasper LH: Toxoplasma infections. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Intenal Medicine, 19th ed. New York, McGraw-Hili, 2015

Kimberlin OW, Sanchez PJ, Ahmed A, et al: Valganciclovir for symptomatic congenital cytomegalovirus disease. N Engl J Med 3 2(10):933, 2015

Kobayashi M, Schrag SJ, Alderson MR, et al: WHO consultation on group B streptococcus vaccine development: report from a meeting held on 2 -28 April 2016. Vaccine December 22,t2016 [Epub head of print]

Koro'ikova EL, Lozovskaia LS, T adtaeva U, et al: The role of prenatal coxsackie virus infection in the etiology of congenital heart defects in children. Kardiologiia 29:68, 1989

Kourtis AP, Read JS, Jamieson OJ: Pregnancy and infection. N Engl J Med 370(23):2211,t2014

Krow-Lucal E, Lindsey NP, Lehman J, et al: West Nile virus and other nationally notifiable diseases-United States. MMWR 66(2):51,t2017

Kuhn JH: Ebolavirus and marburgvirus infections. In Kasper OL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hili, 2015

Kurppa K, Holmberg PC, Kuosma E, et al: Anencephaly and maternal common cold. Teratology 44: 51, 1991

Kutty PK, Kyaw MH, Dayan GH, et al: Guidance for isolation precautions for mumps in the US: a review of the scientiic basis for policy change. Clin Infect Disease 50(112):169, 2010

Kwatra G, Cunnington MC, Merrall E, et al: Prevalence of maternal colonization with group B streptococcus: a systematic review and meta-analysis. Lancet Infect Dis 16(9):1076,t2016

Kylat RI, Bartholomew A, Cramer N, et al: Neonatal listeriosis: uncommon or misdiagnosed? J Neonatal Perinatal Med 9(3):313, 2016

Laibl VR, Sheield JS, Roberts S, et al: Clinical presentation of communiryacquired methicillin-resistant Staphylococcus aureus in pregnancy. Obstet Gynecol 106:461, 2005

Lam CM, Wong SF, Leung TN, et al: A case-controlled study comparing clinical course and outcomes of pregnant and non-pregnant women with severe acute respiratory syndrome. BJOG 11t1:771, 2004

Lambert N, Strebel P, Orenstein W: Rubella. Lancet 385:2297,t2015

Lamont RF, Sobel JD, Carrington D, et al: Varicella-zoster virus (chickenpox) infection in pregnancy. BJOG 118:1155, 2011a

Lamont RF, Sobel JD, Vaisbuch E, et al: Parvovirus B19 infection in human pregnancy. BJOG 118(2):175, 2011b

Lassen J, Jensen AK, Bager P, et al: Parvovirus B19 infection in the first trimester of pregnancy and risk of fetal loss: a population-based case-control study. Am J Epidemiol 176(9):803,t2012

Lee IW, Kang L, Hsu HP, et al: Puerperal mastitis requiring hospitalization during a nine-year period. Am J Obstet Gynecol 203:332.e 1, 20J0

Leruez-Ville M, Ghout I, Bussieres L, et al: In utero treatment of congenital cytomegalovirus infection with valacyclovir in a multicenter, open-label, phase II study. Am J Obstet Gynecol 215(4):462.e1, 2016

Leruez-Ville M, Magny JF, Couderc S, et al: Risk factors for congenital cytomegalovirus infection following primary and nonprimary maternal infection: a prospective neonatal screening study using polymerase chain reaction in saliva. Clin Infect Dis 65(3):398, 2017

Liu C, Bayer A, Cosgrove SE, et al: Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 52:e18,t2011

Lynberg 'v[C, Khoury MJ, Lu X, et al: Maternal lu, fever, and the risk of neural tube defects: a population-based case-control study. Am J Epidemiol 140:244, 1994

Mace E, Arguin PM: Malaria Surveillance-United States, 2014. MMWR 66(12):1, 2017

Mace G, Sauvan M, Castaigne V, et al: Clinical presentation and outcome of 20 fetuses with parvovirus B 19 infection complicated by severe anemia and/ or fetal hydrops. Prenat Diagn 34(11):1023, 2014

Machado Filho AC, da Costa EP, da Costa EP, et al: Efects of vivx malaria acquired before 20 weeks of pregnancy on subsequent changes in fetal growth. Am J Trop Med Hyg 90(2):371,t2014

Madhi SA, Cudand CL, Jose L, et al: Safety and immunogenicity of an investigational maternal trivalent group B streptococcus vaccine in healthy women and their infants: a randomised phase 1b/2 trial. Lancet Infect Dis 16(8): 923, 2016

Mandelbrot : Fetal varicella-diagnosis, management, and outcome. Prenat Diagn 32(6):511, 2012

Marin M, Giiris 0,Chaves SS, et al: Prevention of varicella: recommendations of the Advisoty Committee on Immunization Practices (ACIP). MM'R 56(4):1,t200

Marin M, Willis ED, Marko A, et al: Closure of varicella-zoster viruscontaining vaccines pregnancy registry-United States. MMWR 22:63, 20t14

Marzec NS, Bessesen MT: Risk and outcomes of methicillin-resistant Staphylococcus au reus (tvIRSA) bacteremia among patients admitted with and without MRSA nares colonization. Am J Infection Control 44:405, 2016

Mayama M, Yoshihara M, Kokabu T, et al: Hemophagocytic Iymphohistiocyrosis associated with a parvovirus B 19 infection during pregnancy. Obstet Gynecol 124(Pt 2 Suppl 1):438,t2014

Mayor A, Bardajf A, Macete E, et al: Changing trends in P. falciparum burden, immunity, and disease in pregnancy. N Engl J Med ):1607,t2015

McClure EM, Goldenberg RL: Infection and stillbirrh. Semin Fetal Neonatal Med 14(4):182,t2009

McClure EM, Goldenberg L, Dent E, et al: A systematic review of the impact of malaria prevention in pregnancy on low birth weight and maternal anemia. Int J Gynaecol Obstet 121:103,t2013

McLean HQ, Fiebelkorn AP, Temte JL, et al: Prevention of measles, rubella, congenital rubella syndrome, and mumps, 2013: summary recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 62(4):1,t2013

Meaney-Delman 0, Oduyebo T, Polen KN, et al: Prolonged detection ofZika virus RNA in pregnant women. Obstet Gynecol 128(4):724,t2016

Meaney-Delman 0, Rasmussen SA, Beigi RH, et al: Prophylaxis and treatment of anthrax in pregnant women. Obstet Gynecol 122(4):885,t2013

Meaney-Delman 0, Zotti ME, Rasmussen SA, et al: Anthrax cases in pregnant and postpartum women. Obstet GynecoIt120(6):1439, 2012

Meijer J,van NoortwijkAG, Bruinse HW, et al: Influenza virus infection in pregnancy: a review. Acta Obstet Gynecol Scand 94(8):797,t2015 Melamed N, Whittle W, Kelly EN, et al: Fetal thrombocytopenia in preg nancies with fetal human parvovirus-B19 infection. Am J Obstet Gynecol 212:793.e1,t2015

Mendelson E, Aboundy Y, Smetana Z, et al: Laboratory assessment and diagnosis of congenital viral infections: rubella, cytomegalovirus (CMV) , varicella-zoster virus (VZV) , herpes simplex virus (HSV), parvovirus B 19 and human immunodeficiency virus (HI). Reprod Toxicol 21:350,2006

Menendez C, D'Alessandro U, ter Kuile FO: Reducing the burden of malaria in pregnancy by preventive strategies. Lancet Infect Dis 7: 126, 2007

Mertz 0, Geraci J, Winkup J, et al: Pregnancy as a risk factor for severe outcomes from inluenza virus infection: a systematic review and meta-analysis of observational studies. Vaccine 35(4):521, 2017

Miller E, Cradock-Watson JE, Pollock TM: Consequences of conirmed maternal rubella at successive stages of pregnancy. Lancet 2:781, 1982

Miller LG, Daum RS, Creech CB, et al: Clindamycin versus trimethoprimsulfamethoxazole for uncomplicated skin infections. N Engl J Med 372(12):1093,t2015

Modlin F: Perinatal echovirus and group B coxsackievirus infections. Clin PerinatoIt15:233, 1988

Money 0, Infectious Disease Committee Members, Yudin MH, et al: SOBC committee opinion on the management of a pregnant woman exposed to or infected with Ebola virus disease in Canada. J Obstet Gynaecol Can 37(2):182,t2015

Montazeri M, Sharif M, Sarvi S, et al: A systematic review of in vitro and in vivo activities of anti-toxoplasma drugs and compounds (2006-2016). Front Microbiol 8(25): 1, 2017

Montoya JG, Remington JS: Management of Toxoplasma gondii infection during pregnancy. Clin Infect Dis 47:554, 2008

Moore CA, Staples JE, Dobyns B, et al: Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians. JAMA Pediatr 171(3):288,t2017

Moschella SL: An update on the diagnosis and treatment ofleprosy. J Am Acad Dermatol 51 :417, 2004

Muehlenbachs A, de la Rosa Vazquez 0, Bausch DG, et al: Ebola virus disease in pregnancy: clinical, histopathologic, and immunohistochemical findings. J Infect Dis 215(1):64, 2017

Mylonakis E, Paliou M, Hohmann EL, et al: Listeriosis during pregnancy.

Medicine 81 :260, 2002

Mylonas I: Borreliosis during pregnancy: a risk for the unborn child? Vector Borne Zoonotic Dis 11(7):891,t2011

Nagel HT, de Haan TR, Vandenbussche FP, et al: Long-term outcome after fetal transfusion for hydrops associated with parvovirus B 19 infection. Obstet Gynecol 109(1):42,t2007

Nan e, Dangor Z, Cutland CL: Maternal group B streptococcus-related stillbirth: a systematic review. BJOG 122(11):1437,t2016

Nguyen LN, Lopes e, Folk JJ: vertebral osteomyelitis in pregnancy from a methicillin-resistant Staphylococcus aureus vulvar abscess. A case report. J Reprod Med 60(7-8):362,t2015

Nigro G, Adler SP, La Torre R, et al: Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med 353:1350,t2005

Nigro G, Adler SP, Parruti G, et al: Immunoglobulin therapy of fetal cytomegalovirus infection occurring in the first half of pregnancy-a case-control study of the outcome in children. J Infect Dis 205:215, 2012 Nigro G, Anceschi MM, Cosmi EV, et al: Clinical manifestations and abnormal laboratory findings in pregnant women with primary cytomegalovirus infection. BJOG 110:572,t2003 Nishiura H: Smallpox during pregnancy and maternal outcomes. Emerg Infect Dis 12:1119,t2006 Nosten F, McGready R, Mutabingwa T: Case management of malaria in pregnancy. Lancet Infect Dis 7:118,t2007 Nunes Me, Cutland CL, Jones S, et al: Eicacy of maternal influenza vaccination against all-cause lower respiratory tract infection hospitalizations in young infants: results from a randomized control trial. Clin Infect Disease May 29, 2017 [Epub ahead of print]

O'Leary DR, Kuhn S, Kniss L, et al: Birth outcomes following West Nile virus infection of pregnant women in the United States: 2003-2004. Pediatrics 117:e537, 2006

Oboho IK, Reed C, Gargiullo P, et al: Benefit of early initiation of influenza antiviral treatment to pregnant women hospitalized with laboratoryconfirmed influenza. J Infect Dis 214(4):507, 2016

Oduyebo T, Pineda 0, Lamin M, et al: A pregnant patient with Ebola virus disease. Obstet GynecoIt126(6):1273, 2015

Oduyebo T, Polen KD, Walke HT, et al: Update: interim guidance for health care providers caring for pregnant women with possible Zika virus exposure-United States (including U.S. Territories), July 2017. MMWR 66(29):781, 2017

Ohji G, Satoh H, Satoh H, et al: Congenital measles caused by transplacental infection. Pediatr Infect Dis J 28(2): 166, 2009

Ohlsson A, Shah VS: Intrapartum antibiotics for known maternal Group B streptococcal colonization. Cochrane Database Syst Rev (6):CD007467, 2014

Ornoy A, Tenenbaum A: Pregnancy outcome following infections by coxsackie, echo, measles, mumps, hepatitis, polio and encephalitis viruses. Reprod ToxicoIt21:446, 2006

Ozturk Z, Tatliparmak A: Leprosy treatment during pregnancy and breastfeeding: a case report and brief review of literature. Dermatol her 30(1): 1,2017

Parisot M, Jolivet A, Boukhari R, et al: Shigellosis and pregnancy in French Guiana: obstetric and neonatal complications. Am J Trop Med Hyg 95(1):26,t2016

Parra B, Lizarazo J, Jimenez-Arango JA, et al: Guillain-Barre syndrome associated with Zika virus infection in Colombia. N Engl J Med 375(16):1513, 2016

Paryani SG, Arvin AM: Intrauterine infection with varicella zoster virus ater maternal varicella. N Engl J Med 314:1542, 1986

Pasquini L, Seravilli V, Sisti G, et al: Prevalence of a positive TORCH and parvovirus B19 screening in pregnancies complicated by polyhydramnios. Prenat Diagn 36(3):290, 2016

Paz-Bailey G, Rosenberg ES, Doyle K, et al: Persistence of Zika virus in body fluids-preliminary report. N Engl J Med February 14, 2017 [Epub ahead of print]

Peques DA, Miller SI: Salmonellosis. In Longo DL, Fauci AS, Kasper DL, et al (eds): Harrison's Principles of Internal Medicine, 18th ed. New York, McGraw-Hill

Phadke K, Bednarczyk A, Salmon DA, et al: Association between vaccine refusal and vaccine-preventable diseases in the United States. JAMA 315(11):1149,t2016

Picone 0, Grangeot-Keros L, Senat M, et al: Cytomegalovirus non-primary infection during pregnancy. Can serology help with diagnosis? J Matern Fetal Neonatal Med 30(2):224, 2017

Pimentel JD, Meier FA, Samuel LP: Chorioamnionitis and neonatal sepsis from community-acquired MRSA. Emerg Infect Dis 15:2069,t2009

Pinter OM, Mandel J, Hulten KG, et al: Maternal-infant perinatal transmission of methicillin-resistant and methicillin-sensitive Staphylococcus aureus. Am J PerinatoIt26:145, 2009

Polyzos A, Konstantelias A, Pitsa CE, et al: Maternal influenza vaccination and risk for congenital malformations: a systematic review and metaanalysis. Obstet Gynecol 126(5):1075,t2015

PREGACT Study Group, Pekyi 0, Ampromfi A, et al: Four artemisininbased treatments in African pregnant women with malaria. N Engl J Med 374(1):913,t2016

Pridjian G, Sirois PA, McRae S, et al: Prospective study of pregnancy and newborn outcomes in mothers with West Nile illness during pregnancy. Birth Oefects Res A Clin Mol Teratol 106(8):716,t2016

Puccetti e, Contoli M, Bonvicini F, et al: Parvovirus B19 in pregnancy: possible consequences of vertical transmission. Prenat Diagn 32(9):897, 2012

Rainwater-Lovett K, Moss WJ: Measles (rubeola). In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill, 2015

Randis TM, Gleber SE, Hooven TA: Group B streptococcus beta-hemolysin/ cytolysin breaches maternal-fetal barriers to cause preterm birth and IUFO in vivo. J Infect Ois 210:65, 2014

Rasmussen SA, Jamieson OJ: What obstetric health care providers need to know about measles and pregnancy. Obstet GynecoIt126(1):163, 2015

Rasmussen SA, Jamieson OJ, Honein MA, et al: Zika virus and birth defects-reviewing the evidence for causality. N Engl J Med 374(20): 1981, 2016

Rasmussen SA, Jamieson OJ, Uyeki TM: Efects of inluenza on pregnant women and infants. Am J Obstet Gynecol 207(3 Suppl):S3, 2012

Revello MG, Furione M, Zavattoni M, et al: Human cytomegalovirus (HCMV) DNAemia in the mother at amniocentesis as a risk factor for iatrogenic HCMF infection of the fetus. ] Infect Dis :593, 2008

Reynolds MR, Jones AM, Peterson EE, et al: Vital signs: Update on Zika virus-associated birth defects and evaluation of all U.S. infants with congenital Zika virus exposure-U.S. Zika pregnancy registry, 2016. MMWR 66(13):366t2017

Rogers BB: Parvovirus B 19: twenty-five years in perspective. Pediatr Dev Pathol 2:296, 1999

Rogerson S], Hviid L, Duy PE, et al: Malaria in pregnancy: pathogenesis and immunity. Lancet Infect Dis 7: 105, 2007

Romand S, Wallon M, Franckt], et al: Prenatal diagnosis using polymerase chain reaction on amniotic luid for congenital toxoplasmosis. Obstet Gynecol 97(2):296, 2001

Ross SA, Novak Z, Pati S, et al: Mixed infection and strain diversity in congenital cytomegalovirus infection. ] Infect Dis 204: 1 003, 2011

Rouse D], Keimig W, Riley LE, et al: Case Records of the Massachusetts General Hospital. Case 16-2016. A 31-year-old pregnant woman with fever. N Engl] Med 4(21):2076,t2016

Rubin S, Carbone M: Mumps. In Longo DL, Fauci AS, Kasper DL, et al (eds): Harrison's Principles of Internal Medicine, 18th ed. New York, McGraw-Hill,t2012

Ryan MA, Smith TC, Sevick C]: Birth defects among infants born to women who received anthrax vaccine in pregnancy. Amt] EpidemioIt168:434, 2008

Sanchez E, Vannier E, Wormser GP, et al: Diagnosis, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: a review.t]MA 315(16):1 67,t2016

Sapuan S, Kortsalioudaki C, Anthony M, et al: Neonatal listeriosis in the UK 2004-2014.t] Infect 74(3):236,t201

Schleiss MR: Cytomegalovirus vaccines under clinical development. J Virus Erad 2(4):198, 2016

Schrag 5], Farley MM, Petit S: Epidemiology of invasive early-onset neonatal sepsis, 2005-2014. Pediatrics 138(6):e20162013, 2016

Sever ]L, South MA, Shaver A: Delayed manifestations of congenital rubella.

Rev Infect Dis 7(1):S164, 1985

Shang M, Blanton L, Kniss K, et al: Update: influenza activity-United States, October 2-December 17,t2016. MMWR 65(5051):1439,2016

Shapiro ED: Lyme disease. N Engl] Med 370(18):1 24,2014

Shaw GM, Todorof K, Velie EM, et al: Maternal illness, including fever, and medication use as risk factors for neural tube defects. Teratology 57: 1, 1998 Sheield ]S: Methicillin-resistant Staphylococcus aureus in obstetrics. An ] PerinatoIt30(2):125,t2013

Shinar S, Fouks Y, Anit S, et al: Clinical characteristics of and preventative strategies for periparrum group A streptococcal infections. Obstet Gynecol 127(2):227,t2016

Siegel M: Congenital malformations following chickenpox, measles, mumps, and hepatitis: results of a cohort study. ]AMA 226: 1521, 1973

Siegel M, Goldberg M: Incidence of poliomyelitis in pregnancy. N Engl] Med 253:841,t1955

Silk B], Mahon BE, Griin PM, et al: Vital signs: Listeria illness, deaths, and outbreaks-United States, 2009-2011t. MMWR 62(22):448,2013

Soares de Oliveira-Szejnfeld P, Levine D, Melo AS, et al: Congenital brain abnormalities and Zika virus: what the radiologist can expect to see prenatally and postnatally. Radiology 2810):203, 2016

Society for Maternal-Fetal Medicine (SMFM), Hughes BL, Gyami-Bannerman C: Diagnosis and antenatal management of congenital cytomegalovirus infection. Am] Obstet Gynecol 214(6):B5, 2016

Staford LA, Stewart RD, Sheield ]S, et al: Eicacy of maternal and neonatal chemoprophylaxis for early-onset group B streptococcal disease. Obstet Gynecol 120(1):123,t2012

Stagno S, Tinker MK, Elrod C, et al: Immunoglobulin M antibodies detected by enzyme-linked immunosorbent assay and radioimmunoassay in the diagnosis of cytomegalovirus infections in pregnant women and newborn infants. ] C1in Microbiol 21 (6):930, 1985

Steere AC: Lyme borreliosis. In Kasper DL, Fauci AS, Hauser SL, et al (eds):

Harrison's Principles of Internal Medicine, 19th ed. New York, McGrawHill,t2015

Steinhof MC, Omer SB: A review of fetal and infant protection associated with antenatal inluenza immunization. Am J Obstet Gynecol 207(3 Suppl):

S21,t2012

Stewart RD, Bryant SN, Sheield ]S: West Nile virus infection in pregnancy.

Case report. Infect Dis 2013:351872, 2013

Stoll B], Hansen NI, Sanchez P], et al: he burden of group B streptococcal and E. coli disease continues. Pediatrics ,201t1

Sukumaran L, McCarthy NL, Kharbanda EO, et al: Safety of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis and inluenza vaccinations in pregnancy. Obstet Gynecol 126(5): 1069, 2015

Svensson-Arvelund], Ernerudh], Buse E, et al: he placenta in toxicology. Part

II: systemic and local immune adaptations in pregnancy. T oxicol Pathol ,2014

Swamy GK, Heine RP: Vaccinations for pregnant women. Obstet Gynecol 125(1):212,t2015

SYROCOT (Systematic Review on Congenital Toxoplasmosis) Study Group:

Efectiveness of prenatal treatment for congenital toxoplasmosis: a metaanalysis of individual patients' data. Lancet 369: 115, 2007

Talan DA, Mower WR, Krishnadasan A, et al: Trimethoprim-sulfamethoxazole versus placebo for uncomplicated skin abscess. N Engl ] Med 374(9):823, 2016

Tanamai VW, Seagle BL, Luo G: Methicillin-resistant Staphylococcus aureus intracranial epidural abscess with osteomyelitis during pregnancy: a case report.t] Reprod Med 61(5-6):295,t2016

Tarningt]: Treatment of malaria in pregnancy. N Engl ] Med 374(1):981, 2016

Tassin M, Martinovic ], Mirand A, et al: A case of congenital echovirus 11 infection acquired early in pregnancy.] Clin Virol 59:71, 2014

Thurman AR, Satterield RM, Soper DE: Methicillin-resistant Staphylococcus aureus as a common cause of vulvar abscesses. Obstet Gynecol 112:538, 2008

Top A, Huard RC, Fox Z, et al: Trends in methicillin-resistant Staphylococcus aureus anovaginal colonization in pregnant women in 2005 versus 2009. ] C1in Microbiol 48:3675, 2010

Towbin ]A, Griin LD, Martin AB, et al: Intrauterine adenoviral myocarditis presenting as nonimmune hydrops fetalis: diagnosis by polymerase chain reaction. Pediatr Infect Dis] 13:144, 1994

Tudela CM, Stewart RD, RobertS SW, et al: Intrapartum evidence of earlyonset group B streptococcus. Obstet Gynecol 119(3):626,t2012

Valentini P, Buonsenso 0, Barone G, et al: Spiramycin/cotrimoxazole versus pyrimethamine/sulfonamide and spiramycin alone for the treatment of toxoplasmosis in pregnancy. ] Perinatol 35(2):90, 2015

Villard 0, Breit L, Cimon B, et al: Comparison of four commercially available avidity tests for Toxoplasma gondii-speciic IgG antibodies. Clin Vaccine ImmunoIt20(2):197,t2013

Visentin S, Manara R, Milanese L, et al: Early primary cytomegalovirus infection in pregnancy: maternal hyperimmunoglobulin therapy improves outcomes among infants at 1 year of age. Clin Infect Dis 55(4):497, 2012

Viskari H, Knip M, Tauriainen S, et al: Maternal enterovirus infection s a risk factor for type 1 diabetes in the exposed ofspring. Diabetes Care 35(6): 1328,t2012 Wallon M, Gatweg ]G, Abrahamowicz M, et al: Ophthalmic outcomes of congenital toxoplasmosis followed until adolescence. Pediatrics 133(3):e601, 2014

Wallon M, Peyron F, Cornu C, et al: Congenital toxoplasma infection: monthly prenatal screening decreases transmission rate and improves clinical outcome at age 3 years. Clin Infect Dis 56(9):1223, 2013

Walsh CA, Mayer EQ, Baxi LV: Lyme disease in pregnancy: case report and review of the literature. Obstet Gynecol Surv 62:41, 2006

Wang C, Zhang X, Bialek S, et al: Attribution of congenital cytomegalovirus infection to primary versus non-primary matenal infection. Clin Infect Dis 52:e11,t2011

Waner M], Ozanne SE: Mechanisms involved in the developmental programming of adulthood disease. Biochem] 427:333, 2010

Webster WS:

Teratogen update: congenital rubella. Terarology 58:13,t1998

Weifenbach], Bald R, Gloning KP, et al: Serological and virological analysis of maternal and fetal blood samples in prenatal human parvovirus B 19 infection. ] Infect Dis 205(5):782, 2012

Wendel GO Jr, Leveno K], Sanchez P], et al: Prevention of neonatal group B streptococcal disease: a combined intrapartum and neonatal protocol. Am ] Obstet Gynecol 186:618,t2002

Wessels MR: Streptococcal infections. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Intenal Medicine, 19th ed. New York, McGraw-Hill,t2015

White N], Breman ]G: Malaria infections. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Intenal Medicine, 19th ed. New York, McGraw-Hill,t2015

Whitley R]: Varicella-zoster virus infections. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Intenal Medicine, 19th ed. New York, McGraw-Hili, 2015

Wilson E, Goss vA, Marin M, et al: Varicella vaccine exposure during pregnancy: data from 10 years of the pregnancy registry.] Infect Dis 197(Suppl 2): Sl78, 2008

Wong SF, Chow M, Leung TN, et al: Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome. Am ] Obstet Gynecol 191:292,t2004

World Health Organization: Long-term efects of breastfeeding: a systematic review, 2013. Available at: htrp:l /ww.who.int/maternal_child_adolescent/ documents/breastfeedingJon�term_efects. Accessed October 9, 20t17

World Health Organization: WHO vaccine pipeline tracker, 2017. Available at: www.who.int/immunization/ research/vaccine_pi peline_trackecspreadsheet/en.! Accessed September 10,t2017

Wylie B, Hauptman M, Woolf AD: Inset repellants during pregnancy in the era of the Zika virus. Obstet Gynecol 128(5): 1111,t2016

Yaegashi N: Pathogenesis of nonimmune hydrops fetalis caused by intrauterine B19 infection. Tohoku] Exp Med 190:65,t2000

Yazigi A, De Pecoulas E, Vauloup-Fellous C, et l: Fetal and neonatal abnormalities due to congenital rubella syndrome: a review of literature. ] Matern Fetal Neonatal Med 30(3):274,t2017

Young MK, Cripps AW, Nimmo GR, et al: Post-exposure passive immunization for preventing rubella and congenital rubella syndrome. Cochrane Database Syst Rev 9:CD010586, 2015

Yu W, Tellier R, Wright]R]: Coxsackie virus A16 infection of placenta with massive perivillous ibrin deposition leading to intrauterine fetal demise at 36 weeks gestation. Pediatr Dev Pathol 18(4):331,t2015

Zaman K, Roy E, Arifeen SE, et al: Efectiveness of maternal influenza immunization in mothers and infants. N Engl ] Med 359(15):1555, 2008

Zerbo 0, Qian Y, Yoshida C, et al: Association berween inluenza infection and vaccination during pregnancy and risk of autism spectrum disorder. ]AlA Pediarr 171(1):e163609, 2017

Zhang H], Patenaude V, Abenhaim A: Maternal outcomes in pregnancies afected by varicella zoster virus infections: population-based study on 7.7 million pregnancy admissions. ] Obstet Gynaecol Res 41(1):62, 2015

SYPHILIS.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1235

GONORRHEA.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1239

CHLAMYDIAL.INFECTIONS . . . . . . . . . . . . . . . . . . . . .. 1240

HERPES SIMPLEX VIRUS . . . . . . . . . . . . . . . . . . . . . . .. 1241 HUMAN PAPILLOMAVIRUS ............i.......i...i...i. 1244

VAGINITIS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1245

HUMAN IMMUNODEFICIENCY VIRUS .....i....i...i... 1247

Syphilis is one of the most important complications of preg nancy, as it is one of the most frequent causes of abortion or premature labour. Syphilis is the most common cause of oetal death in the later months of pregnancy, and may be maternal or paternal in origin.

-J. Whitridge Williams (1903)

Syphilis and gonorrhea were prominently mentioned in the irst edition of this book, with special consideration for their harmful efects on fetal development. Although Williams confined his discussion to these two infections, today, sexually transmitted diseases (STDs) include chlamydial and trichomonal infections and viral STDs such as hepatitis B, human immunodeiciency virus (HIV), herpes simplex virus (HSV), and human papillomavirus (HPV) infections. In some form, all can be injurious to the mother or fetus and thus should be aggressively sought and treated. In many instances, recommended therapies are provided in guidelines from the Centers for Disease Control and Prevention (CDC) and listed throughout the chapter.

Vertical transmISSIOn refers to passage from the mother to her fetus of an infectious agent through the placenta, during labor or delivery, or by breastfeeding. Treatment of most STDs is clearly associated with improved pregnancy outcome and prevention of perinatal morbidity. Logically, education, screening, treatment, and prevention are essential components of prenatal care.

Despite the availability of adequate therapy for decades, syphilis remains a major issue for both mother and fetus. From 2001 through 2015, the primary and secondary syphilis rates have risen almost yearly (Centers for Disease Control and Prevention, 2016c). In the United States in 2015, the combined rate for both of these among women was 1.8 cases per 100,000 persons (de Voux, 2017). For congenital syphilis, after a nadir in 2012, rates have also risen yearly to reach 12.4 cases per 100,000 live births in 2015. Of risks, higher congenital syphilis rates are linked to inadequate prenatal care, black or Hispanic race, and lack of treatment (Su, 2016). Similarly, syphilis remains a signiicant global health problem, with many countries reporting high numbers of new infections (Newman, 2015; World Health Organization, 2012).

Syphilis is caused by the spirochetal bacterium Treponema pallidum. Minute abrasions on the vaginal mucosa provide an entry portal, and cervical eversion, hyperemia, and friability raise transmission risk. Spirochetes replicate and then disseminate through lymphatic channels within hours to days. The incubation period is 3 to 4 weeks depending on host factors and inoculum size.

he early stages of syphilis include primary, secondary, and early latent syphilis. hese are associated with high spirochete loads, and partner transmission rates approximate 30 to 60 percent (Garnett, 1997; Singh, 1999). In late-stage disease, transmission rates decline because of smaller inoculum sizes.

FIGURE 65-1 Primary syphilis. Photograph of a chancre with a raised, firm border and smooth, red base.

Maternal syphilis can cause fetal infection by several routes. Spirochetes readily cross the placenta to cause congenital infection. Although transplacental transmission is the most common route, neonatal infection may follow after contact with spirochetes through lesions at delivery or across the placental membranes. Fetal infection develops in >50 percent of untreated early syphilis cases and in 10 percent of late latent disease (Fiumara, 1975; Hollier, 2001).

This is staged according to clinical features and disease duration.

1. Primary syphilis is diagnosed by its characteristic chancre, which develops at the inoculation site. This solitary, painless

FIGURE 65-3 Condyloma lata. (Reproduced with permission from Horsager R, Roberts S, Roger V, et al (eds): Williams Obstetrics 24th Edition Study Guide, New York, McGraw Hill Education, 2014; Photo contributor: Dr. Jonathan Willms.) lesion typically has a raised, firm border and a red, smooth ulcerated base without signiicant pus (Fig. 65-1). Nonsuppurative lymphadenopathy may develop. A chancre will usually resolve spontaneously in 2 to 8 weeks, even if untreated. Multiple lesions, if found, are predominantly in HIV-1 coinfected women.

2. Secondary syphilis stems from dissemination of spirochetes to afect multiple organ systems. Manifestations develop 4 to 10 weeks after the chancre appears and include dermatological abnormalities in up to 90 percent of women. A difuse macular rash, plantar and palmar targetlike lesions, patchy alopecia, and mucous patches may be seen (Fig. 65-2). Condylomata lata are flesh-colored papules and nodules found on the perineum and perianal area (Fig. 65-3). These papules are teeming with spirochetes and are highly infectious. Most women with secondary syphilis also express constitutional symptoms such as fever, malaise, headache, and myalgias.

FIGURE 65-2 Secondary syphilis. A.Target lesions on the palms. B. Mucous patches around the nose and mouth. (Used with permission from Dr. Devin Macias.)

Hepatitis, nephropathy, ocular changes, anterior uveitis, and periostitis can also develop.

3.

Latent syphilis develops when primary or secondary syphilis is not treated but clinical manifestations still resolve. It is identified instead by serological testing. Eary latent syphilis is subclinical disease acquired within the preceding 12 months. Disease diagnosed beyond 12 months is either late latent syphilis or latent syphilis of unknown duration.

4. Tertiary syphilis is a slowl) progressive disease afecting any organ system but is rarely seen in reproductive-aged women.

Without screening and treatment, approximately 70 percent of infected women will have an adverse pregnancy outcome (Hawkes, 201l). Maternal infection can lead to preterm labor, fetal death, fetal-growth restriction, or fetal infection (Gomez, 2013). Because of immune incompetence prior to midpregnancy, the fetus generally does not manifest the immunological inlammatory response characteristic of clinical disease before this time (Silverstein, 1962). Once fetal syphilis develops, however, it manifests as a continuum. Fetal hepatic abnormalities are followed by anemia and thrombocytopenia, then ascites and hydrops (Hollier, 2001). Stillbirth remains a major complication (Lawn, 2016; Su, 2016). he newborn may have jaundice with petechiae or purpuric skin lesions, lymphadenopathy, rhinitis, pneumonia, myocarditis, nephrosis, or long-bone involvement (Fig. 65-4).

With syphilitic infection, the placenta becomes large and pale (see Fig. 65-4). Microscopically, villi lose their characteristic arborization and become thicker and clubbed. Sheield and colleagues (2002c) described these villi in more than 60 percent of syphilitic placentas. Blood vessels markedly diminish in number, and in advanced cases, they almost entirely disappear as a result of endarteritis and stromal cell proliferation. Likely related, Lucas and coworkers (1991) demonstrated increased vascular resistance in uterine and umbilical arteries of infected pregnancies. he cord may also show evidence of infection. In a study of 25 untreated women, Schwartz and associates (1995) reported that necrotizing funisitis was present in a third.

The United States Preventative Services Task Force recom mends that clinicians screen all pregnant women for syphilis to prevent congenital infection (Wolf, 2009). Testing is ideally performed at the irst prenatal visit. In populations with a high prevalence of syphilis, serological testing is repeated in the third trimester and again at delivery (Workowski, 2015).

Treponema pallidum cannot be cultured from clinical specimens. However, direct diagnosis of early-stage disease from lesion exudate, tissue, or body luid can be completed by darkield microscopic examination, by polymerase chain reaction (PCR), or by direct fluorescent antibody tests for T pallidum (DFA-TP) (Tsang, 2015). hese methods are not widely available and are less sensitive for blood specimens (Grange, 2012; HenaoMartinez, 2014). hus, in practice, diagnoses are mainly derived from clinical indings coupled with serological blood testing.

Serological testing is used for diagnostic and for screening purposes. here are two types. If the irst of these is positive, then the second type is also performed. his combination identifies infection and clariies disease stage. Traditionally, the first type is nontreponemal testing, and either the Venereal Disease Research Laboratory (VDRL) or the rapid plasma reagin (RPR) is selected. Both tests measure patient immunoglobulin M and G (IgM and IgG) antibodies formed against cardiolipin that is released from damaged host cells and possibly also from treponemes. Notably, these same antibodies can also be produced in response to other acute events that include recent vaccination, febrile illness, and pregnancy itself or in response to chronic conditions such as intravenous drug abuse, systemic lupus erythematosus, aging, leprosy, or cancer. As such, these all serve as potential sources of false-positive results (Larsen, 1995). Conversely, seroconversion occurs at around 3 weeks, but can take up to 6 weeks (Peeling, 2004). Thus, women with very early primary syphilis can have initially false-negative serological test results.

FIGURE 65-4 Congenital syphilis. A. Fetogram of a stillborn infant infected with syphilis showing the "moth-eaten" appearance of the femurs (arrow). B. Enlarged hydropic placenta of a syphilis-infected neonate.

With positive nontreponemal test results, findings are quantified and expressed as titers. Because titers reflect disease activity, they increase during early syphilis and often exceed levels of 1 :32 in secondary syphilis. Following treatment of primary and secondary syphilis, serological testing at 3 to 6 months usually confirms a fourfold drop in VDRL or RPR titers (Rac, 2014a). Because VDRL titers do not correspond directly to RPR titers, consistent use of the same test for surveillance is recommended. hose with treatment failure or reinfection may lack this expected decline. Importantly, some successfully treated patients may still exhibit persistently low-level positive titers, which are referred to as "serofast." his state is more likely in older individuals, those with lower initial nontreponemal antibody titers, and those with later stages of syphilis (Seia, 2015).

The second type of serological testing is trep0 nemal-specic.

It seeks patient antibodies formed specifically against T palidum. he antibodies detected by treponemal assays appear up to a few weeks earlier than those detected by nontreponemal tests (Levett, 2015). Tests includes the fluorescent treponemalantibody absorption tests (FTA-ABS), the T palidum passive particle agglutination (TP-PA) test, and various immunoassays (Association of Public Health Laboratories, 2015). O/note, these treponemal-speciic tests generaly remain positive throughout lie.

Each of the serological tests has limitations including falsepositive and -negative results. Traditionally, nontreponemal tests have been used for screening in the United States, and results are then conirmed by a specific treponemal test. Within the past several years, some laboratories have implemented a reverse screening algorithm, namely, screening first with a treponemalspecific test (Binnicker, 2012; Centers for Disease Control and Prevention, 2011). Both approaches are efective if there is a program for appropriate screening, follow-up, and treatment.

In contrast to these tests, rapid "point-of-care" (POC) syphilis screening of blood or serum samples is being developed (Singh, 2015; Tucker, 2010). hese may be best used for women with limited prenatal care. Most tests are treponemalspecific, and positive POC results can then be confirmed by a laboratory nontreponemal test. In hard-to-reach populations, some countries immediately treat women with positive POC results. This practice, however, risks overtreating previously cured women who still have residual persistent treponemal antibodies. his limitation may be overcome by newer POC dual tests, which simultaneously assess nontreponemal and treponemal antibodies (Causer, 2015).

Following maternal diagnosis, sonographic evaluation is performed for fetuses >20 weeks' gestation to search for signs of congenital syphilis. Rac and associates (20 14b) noted that 31 percent of infected women diagnosed at � 18 weeks' gestation had abnormal fetal sonographic indings. Hepatomegaly, placental thickening, hydramnios, ascites, hydrops fetalis, and elevated middle cerebral artery Doppler velocimetry measurements are indicative of fetal infection. Before 20 weeks, treatment is highly successful, and sonographic findings are rare (Nathan, 1997).

For fetuses of viable age with sonographic findings, antepartum fetal heart rate monitoring prior to treatment is recommended. Spontaneous late decelerations or a nonreactive tracing likely reflects an extremely ill fetus that may poorly tolerate a Jarisch-Herxheimer reaction, described next. In this extreme case, consultation with a neonatologist regarding a plan of delaying treatment, pursuing delivery, and then treating in the nursery is a consideration (Wendel, 2002).

Syphilis therapy during pregnancy is given to eradicate maternal infection and to prevent or treat congenital syphilis. Parenteral penicillin G remains the preferred treatment for all stages of syphilis during pregnancy (Table 65-1). During pregnancy, authorities recommend that a second dose of benzathine penicillin G be given 1 week after the initial dose. Such treatment is also given for women with concomitant HIV infection (Workowski, 2015).

Benzathine penicillin G is highly efective for early maternal infection. In a study of 340 pregnant women so treated, Alexander and associates (1999) reported six cases-1.8 percent-of congenital syphilis. Four of these six neonates were from a group of75 women with secondary syphilis. The other two were identified in those delivered from a group of 102 women with early latent syphilis. Congenital syphilis was generally confined to neonates of women treated ater 26 weeks and is likely related to the duration and severity of fetal infection. Sheield and coworkers (2002b) reported that high maternal serological titers, preterm delivery, and delivery shortly ater antepartum therapy are all risks for failure of maternal treatment to prevent neonatal infection.

here are no proven alternatives to penicillin therapy during pregnancy. Erythromycin and azithromycin may be curative for the mother, but because of limited transplacental passage, these drugs do not prevent all congenital disease (Berman, 2004; Wendel, 1988; Zhou, 2007). Moreover, in several countries,

TABLE 65-1. Recommended Treatment for Pregnant Women with Syphilis

G, 2.4 million units as a single injection-some recommend a second

More than l-year durationb Benzathine penicillin G, 2.4 million units intramuscularly weekly for three doses aprimary, secondary, early latent syphilis of less than duration.

bLatent syphilis of unknown or more than 1-year duration; tertiary syphilis. Missed doses are not acceptable for pregnant women, and those who miss any dose of therapy must repeat the full course of therapy.

Data from Workowski, 201r5.

macrolide-resistant strains of T pallidum are now prevalent (Stamm, 2015). Cephalosporins may prove useful, but data are limited (Liang, 2016). Tetracyclines, including doxycycline, are efective but generally not recommended during pregnancy, because of the risk for fetal deciduous-teeth discoloration.

All women with syphilis are ofered counseling and testing for HIV and other STDs. Following syphilis treatment, serological testing to detect treatment failures is done at 3 to 6 months and usually confirms a fourfold drop in VDRL or RPR titers. During pregnancy, serological titers can be checked monthly in women at high risk for reinfection (Workowski, 2015).

In some instances, a woman may present without symptoms but describes recent sexual contact with a person who has been diagnosed with syphilis. She should be evaluated clinically and serologically. If her partner is diagnosed and their sexual contact occurred within the preceding 90 days, the gravida is treated presumptively for early syphilis, even if serological test results are negative. his accounts for early infection but before seroconversion. If contact was earlier than 90 days ago, treatment is based on serological results (Workwoski, 2015).

Women with a history of penicillin allergy should have either an oral stepwise penicillin-dose challenge or skin testing performed to confirm the risk of immunoglobulin E (IgE)mediated anaphylaxis. If conirmed, penicillin desensitization, shown in Table 65-2, is recommended and then followed by benzathine penicillin G treatment (Wendel, 1985).

TABLE 65-2. Penicillin Allergy-Oral Desensitization

Protocol for Patients with a Positive Skin Test Penicillin V Amountb Cumulative Dosea (units/mL) mL Units Dose (units) 1 1000 0.1 100 100 2 1000 0.2 200 300 3 ·1000 0.4 400 700 4 1000 O.S 800 1500 5 1000 1.6 1600 3100 6 1000 3.2 3200 6300 7 1000 6.4 6400 12,700 8 10,000 1.2 12,000 24,700 9 10,000 2.4 24,000 4S,700 10 10,000 4.S 4S,OOO 96,700 11 SO,OOO 1.0 80,000 176,700 12 80,000 2.0 160,000 336,700 13 SO,OOO 4.0 320,000 656,700 14 SO,OOO 8.0 640,000 1,296,700 alnterval between doses: 15 Elapsed time: 3 hours and 45 minutes. Cumulative dose: 1.3 million units.

Observation period: 30 minutes before parenteral adminis tration of penicillin.

bThe specific amount of drug was diluted in approximately 30 mL of water and administered orally.

From Wendel, 1985, with permission.

Distinct from allergy, a Jarisch-Herxheimer reaction develops following penicillin treatment in most women with primary syphilis and approximately half with secondary infection. Uterine contractions, mild maternal temperature elevation, decreased fetal movement, and fetal heart rate decelerations are findings. Reaction treatment is supportive with antipyretics as needed, hydration, and oxygen supplementation (Klein, 1990). In a study of 50 gravidas who received benzathine penicillin for syphilis, Myles and associates (1998) reported a 40-percent incidence of Jarisch-Herxheimer reactions. Of the 31 women monitored electronically, 42 percent developed regular uterine contractions, and 39 percent developed variable decelerations. All contractions resolved within 24 hours of therapy. Accordingly, for fetuses of viable age, some recommend administering the irst dose of antibiotic in labor and delivery and with continuous fetal monitoring for at least 24 hours (Rae, 2017). Others recommend this only if sonographic signs of fetal syphilis, described earlier, are found (Duf, 2014; Wendel, 2002). If this second plan is elected, patients are counseled on reaction signs and encouraged to seek evaluation if they develop.

Of notiiable STDs, infections caused by Neisseria gonorrhoeae are the second most common. The incidence of gonorrhea in the United States has continued to rise since 2009, and in 2015, the rate was 124 cases per 100,000 persons (Centers for Disease Control and Prevention, 2016c). he highest rates in women of any ethnicity were in those aged 15 to 24 years. In pregnant women, its prevalence approximates 0.6 percent (Blatt, 2012). In most pregnant women, infection is limited to the lower genital tract-the cervix, urethra, and periurethral and vestibular glands. Acute salpingitis is rare in pregnancy. But, pregnant women account for a disproportionate number of disseminated gonococcal infections (Bleich, 2012).

Gonococcal infection can have deleterious efects in any trimester. Untreated gonococcal cervicitis is associated with septic abortion as well as infection after voluntary abortion (Burkman, 1976). Preterm delivery, prematurely ruptured membranes, chorioamnionitis, and postpartum infection are more frequent in women with gonococcal infection (lger, 1988; Johnson, 2011).

Vertical transmission of gonorrhea is predominantly due to fetal contact with vaginal infection during birth. he predominant sequela is gonococcal ophthalmia neonatorum, which can lead to corneal scarring, ocular perforation, and blindness. Transmission rates are high and approximate 40 percent (Laga, 1986). Accordingly, as discussed in Chapter 32 (p. 613), ocular prophylaxis is provided to newborns (Mabry-Hernandez, 2010).

Pregnant women who live in high-prevalence areas or who are at risk for gonorrhea should undergo irst-trimester screening. Risk factors include age �25 years; prior gonococcal infection; other STDs; prostitution; new or multiple sexual partners; drug abuse; black, Hispanic, or American Indian or laska Native ethnicity; and inconsistent condom use (American Academy of

Pediatrics, 2017). For women who test positive, screening for syphilis, chlamydial infection, and HIV should precede treatment, if possible. Gonococcal infection is a marker for concomitant chlamydial infection. Thus, if chlamydial testing is unavailable, presumptive chlamydial therapy is given to women treated for gonorrhea.

Screening for gonorrhea in women is by culture or nucleic acid ampliication tests (NAATs). NAATs have replaced culture in most laboratories, and kits are available for specific collection from the vagina, en do cervix, or urine. Of these, vaginal or cervical samples are preferred, as urine collection may detect up to 10 percent fewer infections (Papp, 2014). If used, the initial urine stream, not midstream, is collected. NAATs are also recommended for diagnosis of rectal or pharyngeal disease, but participating laboratories must be CLIA (Clinical Laboratory Improvement Amendments) compliant with required test modifications. Culture is also available for these anatomical sites. Rapid POC tests for gonorrhea, although available, do not yet reach the sensitivity or specificity of culture or NAAT and have not been rigorously studied in pregnant women (Herbst de Cortina, 2016).

Gonorrhea treatment has evolved during the past decade due to the ability of N gonorrhoeae to rapidly develop antimicrobial resistance. The current treatment for uncomplicated gonococcal infection during pregnancy is 250 mg of cetriaxone intramuscularly plus 1 g of azithromycin orally (Workowski, 2015). he latter provides another drug with a diferent mechanism of action against N gonorrhoeae and treats chlamydial co-infections. Patients are instructed to abstain from sexual intercourse for 7 days ater they and their sexual partners have completed treatment. u an alternative regimen, a single, 400-mg oral dose of cefixime plus 1 g of azithromycin should be reserved for situations that preclude cetriaxone treatment. With cephalosporin allergy, a 240-mg intramuscular dose of gentamicin can be coupled with a 2-g oral azithromycin dose. Repeat testing is recommended in the third trimester for any woman treated for gonorrhea in the first trimester and for any uninfected woman who is at high risk for gonococcal infection (American Academy of Pediatrics, 2017).

Treatment is recommended for sexual contacts. Expedited therapy, discussed on page 1241, is a less-desirable option due to the now-preferred injectable regimen.

Gonococcal bacteremia may cause disseminated infections that manifest as petechial or pustular skin lesions, arthralgias, or septic arthritis. For treatment of septic arthritis, the CDC recommends ceftriaxone, 1 g intramuscularly or intravenously (IV) every 24 hours plus a single 1-g oral dose of azithromycin (Workowski, 2015). Treatment is continued for 24 to 48 hours ater clinical improvement, and therapy is then changed to an oral agent to complete 1 week of therapy. Prompt recognition and antimicrobial treatment will usually yield favorable outcomes in pregnancy (Bleich, 2012). Meningitis and endocarditis rarely complicate pregnancy, but they may be fatal (Bataskov, 1991; Burgis, 2006). For gonococcal endocarditis, ceftriaxone 1 to 2 g IV every 12 hours should be continued for at least 4 weeks, and for meningitis, 10 to 14 days. A single 1-g oral dose of azithromycin is also provided for chlamydial co-infection (Workowski, 2015).

Chlamydia trachomatis is an obligate intracellular bacterium that has several serotypes, including those that cause lymphogranuloma venereum. The most commonly encountered strains are those that attach only to columnar or transitional cell epithelium and cause cervical infection. It is the most common reportable STD in the United States, and the overall chlamydial infection rate among women was 646 cases per 100,000 females in 2015 (Centers for Disease Control and Prevention, 2016c).

Most pregnant women have asymptomatic infection, but a third have urethral syndrome, urethritis, or Bartholin gland infection (Peipert, 2003). Mucopurulent cervicitis may be due to chlamydial or gonococcal infection or both. Other chlamydial infections not usually seen in pregnancy are endometritis, salpingitis, reactive arthritis, and Reiter syndrome.

The role of chlamydial infection in pregnancy complications remains controversial. A few studies have reported a direct association between C trachomatis and miscarriage, whereas most show no correlation (Baud, 2011; Coste, 1991; Paukku, 1999). It is disputed whether untreated cervical infection increases the risk of preterm delivery, preterm ruptured membranes, low birthweight, or perinatal mortality (Andrews, 2000, 2006; BIas, 2007; Johnson, 2011; Moodley, 2017; Silva, 2011). Chlamydial infection has not been associated with a greater risk of chorioamnionitis or with peripartum pelvic infection (Berman, 1987; Gibbs, 1987). However, delayed postpartum uterine infection has been described by Hoyme and associates (1986). The syndrome, which develops 2 to 3 weeks postpartum, is distinct from early postpartum metritis. It is characterized by vaginal bleeding or discharge, low-grade fever, and uterine tenderness.

Infection poses a higher risk to the newborn than to the mother. Vertical transmission leads to infection in 8 to 44 percent of neonates delivered vaginally from afected women (Rosenman, 2003). Of neonatal infections, conjunctivitis is the most common (Chap. 32, p. 613). Perinatal transmission to newborns can also cause pneumonia.

Currently, the U.S. Preventive Services Task Force (LeFevre, 2014) as well as the American Academy of Pediatrics and American College of Obstetricians and Gynecologists (2017) recommend chlamydia screening for all women at the irst prenatal visit. he College further suggests testing in the third trimester for those treated in the irst trimester; all women aged ;25 years; and those aged �25 years with behavioral factors, which mirror those for women at risk for gonorrhea. In one review of repeat chlamydial infections among women, the reinfection rate was 14 percent, and most recurred within the first 8 to 10 months (Hosenfeld, 2009).

Diagnosis is made predominantly by culture or NAAT. Cultures are more expensive and less accurate than newer NAA T s (Greer, 2008). Of samples for NAAT, vaginal or cervical

TABLE 65-3. Oral Treatment of Chlamydia trachomatis Infections During Pregnancy

Erythromycin ethylsuccinate, 400 mg four times daily for 14 d

Data from Workowski, 2015.

samples are preferred, as urine collection may detect up to 10 infections (Papp,

Wiesenfeld, 2017).

Roberts and associates (2011) evaluated NAA T of urine speci mens compared with cervical secretions in more than 2000 pregnant women and found them to be equivalent. As with gonorrhea, the irst portion of the urine stream is collected.

Currently recommended treatment regimens for chlamydial infections are shown in Table 65-3. Azithromycin is irst-line treatment and is safe and efective in pregnancy. The luoroquinolones and doxycycline are usually avoided in pregnancy, and erythromycin estolate is contraindicated because of drug-related hepatotoxicity. Chlamydial testing is repeated 3 to 4 weeks after therapy completion and ,gain 3 months after treatment. In high-risk individuals, third-trimester rescreening is recommended (Workowski, 2015).

To prevent STD transmission, guidelines for expedited partner therapy (EPT) have been created by the Centers for Disease Control and Prevention (2006a) and are endorsed by the American College of Obstetricians and Gynecologists (2015). With EPT, a prescription is provided to the diagnosed patient for their partner. It is delivered by the patient to their partner without medical assessment of the partner or professional counseling. EPT ideally does not replace traditional strategies, such as standard patient referral with screening for other STDs.

EPT is acceptable for treatment of sexual contacts with chlamydial infection. In light of new guidelines that recommend injectable ceftriaxone, EPT for gonorrhea is less desirable unless the partner will otherwise not seek treatment (Centers for Disease Control and Prevention, 2016a). Fewer data are available to assess this strategy for trichomoniasis (Kissinger, 2006; Schwebke, 2010). EPT is not recommended for syphilis (Workowski,r2015).

Although sanctioned by the CDC, EPT is not legal in several states. \{oreover, the risk of litigation in the event of adverse outcomes may be elevated when a practice has uncertain legal status or is outside formally accepted community practice standards (Centers for Disease Control and Prevention, 2006a). The legal status of EPT in each of the 50 states can be found at: http://ww.cdc.gov/std/ept/legal!default.htm.

L], L2, and L3 serovars of C trachomatis cause ymphogranuloma venereum (LG). he primary genital infection is transient, is seldom recognized, and is not linked with vertical transmission to the fetus. It can be confused with chancroid. Classically, matted inguinal adenitis may develop on either side of the inguinal ligament to give rise to the "groove sign." At times, these nodes may suppurate. Ultimately, the lymphatics of the lower genital tract and perirectal tissues may be involved. Here, sclerosis and fibrosis can cause vulvar elephantiasis and severe rectal stricture. Fistula formation involving the rectum, perineum, and vulva may also evolve.

For treatment during pregnancy, erythromycin base, 500 mg orally four times daily, is given for 21 days (Workowski, 2015). Some authorities instead use szithromycin, 1 g orally weekly for 21 days, although data regarding eicacy are scarce.

his virus poses a disproportionately higher risk to the newborn than to the mother. hus, strategies in pregnancy aim to curb rates of vertical transmission.

Two types of herpes simplex viruses are distinguished based on immunological diferences. Yet, the two viruses have signiicant DNA sequence homology, and thereby, prior infection with one type attenuates a primary infection with the other. Type 2 HSV is recovered almost exclusively from the genital tract and is usually transmitted by sexual contact. Type 1 is responsible for most nongenital infections and typically is acquired in childhood. However, more than half of new cases of genital herpes in adolescents and young adults are now caused by HSV-1 infection (Bernstein, 2013). his rise in the prevalence of HSV-1 genital disease is thought to stem from an increase in oral-genital sexual practices. Another explanation is that HSV-1 acquisition has declined in childhood as a result of improved living conditions and hygiene (Bradley, 2014; Xu, 2007). Without prior exposure, this renders young people without HSV-l antibodies susceptible to genital acquisition of HSV-l or -2.

Genital herpes simplex virus afects an estimated 50 million adolescents and adults (Workowski, 2015). Most women are unaware of their infection, but HSV-2 seroprevalence among non-Hispanic white females in the United States was 15.3 from 2007 to 2010 and among black females, it was 53 percent (Fanfair, 2014; Schulte, 2014). In one study of nearly 16,000 pregnant women from 2000 to 2010, the overall seroprevalence of HSV-2 was 16 percent, and for HSV-l, it was 66 percent (Delaney, 2014). Seronegative pregnant women have a 4 to 5 percent risk to acquire HSV-l or -2 during pregnancy (Brown, 1997; Kulhanjian, 1992). For those who are HSV-l seropositive, acquisition risk for HSV-2 approximates 2 percent (Brown, 1997).

Once transmitted by contact, HSV-l or -2 replicates at the entry site. Following mucocutaneous infection, the virus moves retrograde along sensory nerves. It then remains latent in cranial nerves or dorsal spinal ganglia, but recurrences are common. HSV infections may be categorized into three groups.

First episode primary inection describes the case in which HSV-l or 2 is isolated from a lesion in the absence of HSV-l or -2 serological antibodies. The typical incubation period of 6 to 8 days (range 1 to 26 days) may be followed by a papular eruption with itching or tingling, which then becomes painful and vesicular. Multiple vulvar and perineal lesions mayror may not coalesce, and then ulcerate (Fig. 65-5). Associated inguinal adenopathy can be severe. Many women do not present with typical lesions. Instead, a pruritic or painful abraded area or knife-cut may be found. Cervical involvement is common, although it may be inapparent clinically. Transient systemic influenza-like symptoms are frequent and are presumably caused by viremia. Some cases are severe enough to require hospitalization. Hepatitis, encephalitis, or pneumonia infrequently develop, and disseminated disease is rare. After 2 to 4 weeks, all signs and symptoms of infection disappear. Instead of these classic symptoms, the percentage of asymptomatic primary HSV-2 genital infections may be as high as 90 percent (Fanfair, 2013).

FIGURE 65-5 First-episode primary genital herpes simplex virus infection. Vesicles and knife-cut lesions are indicated by arrows. Small ulcers rim the anus. Similar lesions can typically be seen on the vulva.

First episode nonprimay inection is diagnosed when one HSV type is isolated from a lesion in a woman who has only the other serological HSV-type antibody present. In general, compared with primary infection, nonprimary infections are characterized by fewer lesions, less pain, fewer systemic manifestations, and briefer duration of lesions and viral shedding. This is likely because of some immunity from cross-reacting antibodies, for example, from childhood-acquired HSV-l infection.

Recurrent disease is characterized by isolation of HSV-l or -2 from the genital tract in women with the same serotype antibodies. During the latency period, in which viral particles reside in nerve ganglia, reactivation is common and mediated through poorly understood stimuli. The resulting lesions generally are fewer in number, are less tender, and shed virus for a shorter period than those of primary infection. Typically, they recur at the same sites. Genital disease recurrences are more frequently caused by HSV-2 compared with HSV-l. Recurrences are most frequent in the irst year after initial infection, and rates slowly decline subsequently (Benedetti, 1999). Gravidas with a known prior history of genital HSV often experience recurrences (Sheield, 2006).

Asymptomatic viral shedding is defined by the absence of clinical findings. Most infected women shed virus intermittently over time, and most HSV transmission to a partner occurs during these periods of asymptomatic viral shedding.

he virus can be passed to the fetus/neonate by three routes: peripartum in 85 percent, (2) postnatal in 10 percent, or intrauterine in 5 percent Qames, 2015). As discussed in Chapter 18 (p. 347), evidence does not suggest an obvious link between HSV infection and miscarriage (Zhou, 2015).

Peripartum transmission is by far the more frequent route of infection, and the fetus is exposed to virus shed from the cervix or lower genital tract. HSV-l or -2 invades the uterus following membrane rupture or is transmitted by contact at delivery. The newborn is mainly infected, but rare cases of maternal endometritis have .been described (Hollier, 1997; McGill, 2012). Neonatal manifestations vary. First, infection may be localized to the skin, eye, or mouth-SEM disease-in approximately 40 percent of cases. Second, central nervous system disease with encephalitis is seen in 30 percent. Last, disseminated disease with involvement of multiple major organs is found in 32 percent. Localized infection is usually associated with a good outcome. Conversely, even with acyclovir treatment, disseminated infection has a mortality rate of nearly 30 percent (Corey, 2009; Kimberlin, 2011). Of disseminated or cerebral infection survivors, serious developmental and central nervous system morbidity is seen in 20 to 50 percent.

The neonatal infection rate is 0.5 to 1 per 10,000 births in the United States (Flagg, 2011; Mahnert, 2007). Most infected newborns are born to mothers with no reported history ofHSV infection (Gardella, 2010). The risk of neonatal infection cor relates with the presence of HSV in the genital tract, the HSV type, invasive obstetrical procedures, and stage of maternal infection (Brown, 2005, 2007). For example, neonates born to women who acquire genital HSV near the time of delivery have a 30-to 50-percent risk of infection. This is attributed to higher viral loads and the lack of transplacental protective antibodies (Brown, 1997,r2000). Women with recurrent HSV have less than a I-percent risk of neonatal infection (Pasternak, 2010; Prober, 1987).

Postpartum transmission is uncommon and passed to the newborn by contact with an infected mother, family member, or health-care worker. The clinical presentation mirrors that with peripartum transmission.

In utero transmission ofHSV-l or HSV-2 is rare and is part of the TORCH (roxoplasmosis, Qther, rubella, �ytomegalovi rus, herpes virus) collection of infections. Intrauterine HSV infection classically leads to disease involving the skin (blisters, scarring), the central nervous system (hydranencephaly, micro cephaly, intracranial calcification), or the eyes (chorioretini tis, microphthalmia) (Hutto, 1987). Bone and viscera can be involved (Marquez, 2011). If seen sonographically, indings should prompt viral serological testing as described next. PCR analysis of an amniocentesis sample is another potential tool (Diguet, 2006).

Several organizations recommend against routine serological HSV screening in asymptomatic gravidas (American College of Obstetricians and Gynecologists, 20 16b; Workowski, 2015;

U.S. Preventive Services Task Force, 2016). However, for those with a clinically suspicious lesion, a diagnosis should be conirmed by laboratory testing. Available HSV tests are either virological or type-speciic serological tests.

Direct virological tests are can be performed on a specimen from the mucocutaneous lesion. PCR or culture of the sample is a testing option. Of the two, PCR assays are more sensitive, the results generally are available in 1 to 2 days, and specimen handling is easier. In contrast, for viral culture, the sensitivity of HSV isolation is relatively low as vesicular lesions ulcerate and then crust. Also, results sometimes are not available for 7 to 14 days (Strick, 2006). Regardless of the test performed, HSV viral types should be diferentiated (LeGof, 2014). Importantly, a negative culture or PCR result does not exclude infection. In contrast, false-positive results are rare.

Serological assays are available to detect antibodies produced against speciic HSV glycoproteins, Glrand G2. These proteins evoke type-speciic antibody responses to HSV-l and HSV-2 infection, respectively, and they reliably diferentiate the two. IgG antibodies develop 1 to 2 weeks after a primary infection and then persist. This permits conirmation of clinical infection and identiication of asymptomatic carriers. Providers should request type-speciic glycoprotein G-based assays when serology is being performed. Sensitivity approaches 90 to 100 percent, and speciicity is 99 to 100 percent (Wald, 2002). IgM antibody detection is not a useful test.

In nonpregnant patients, antiviral therapy with acyclovir, vala cyclovir, or famciclovir is used to treat irst-episode genital herpes. Oral or parenteral preparations attenuate clinical infec tion and viral shedding duration. Suppressive therapy is also an option to limit recurrent infections and to reduce heterosexual transmission (Corey, 2004).

In pregnant women, acyclovir is safe (Briggs, 2015).

Through 1999, the manufacturers of acyclovir and valacyclovir maintained a registry of outcomes following exposure to these drugs during pregnancy. More than 700 neonates exposed dur ing the irst trimester were evaluated, and there were no adverse efects attributable to acyclovir (Stone, 2004). At this time, data are insuicient regarding famciclovir exposure, although a pregnancy registry is being maintained (1-888-669-6682).

For a primary outbreak during pregnancy, women may be given antiviral therapy to attenuate and decrease the duration of symptoms and viral shedding (Table 65-4). Women with

HIV co-infection may require a longer duration of treatment.

Those with severe or disseminated HSV are given IV acyclovir, 5 to 10 mg/kg every 8 hours for 2 to 7 days until clinically improved. This is followed by oral antiviral drugs to complete at least 10 days of total therapy (W orkowski, 2015). For intense discomfort, oral analgesics and topical anesthetics may provide some relief, and comorbid urinary retention is treated with an indwelling bladder catheter.

For recurrent HSV infections during pregnancy, antiviral treatment is provided mainly for symptom relief (see Table 65-4) . Although uncommon, acyclovir resistance has been reported, predominantly with HSV-2 and in immunocompromised patients (Andrei,r2013).

During pregnancy, amniocentesis, percutaneous cord blood sampling, or transabdominal chorionic villus sampling may be performed even with active genital lesions. With active lesions, however, internal electronic monitoring during labor is not recommended. T ranscervical procedures may best be delayed until lesions have resolved (American College of Obstetricians and Gynecologists, 20 16b).

To diminish vertical transmission risks, cesarean delivery is indicated for women with active genital lesions or prodromal symptoms (American College of Obstetricians and Gynecologists, 20 16b). Several studies have shown that acyclovir or valacyclovir suppression initiated at 36 weeks' gestation for gravidas with recurrences during pregnancy lowers the number of HSV outbreaks at term. The goal is to decrease the need for cesarean delivery (Hollier, 2008). his suppressive therapy will also decrease viral shedding (Scott, 2002; Sheield, 2006; Watts, 2003). One systematic review evaluated acyclovir prophylaxis given from 36 weeks to delivery to women with HSV recurrence during pregnancy. Sheield and colleagues (2003) found that suppressive therapy was associated with signiicantly lower rates of clinical HSV recurrence, cesarean deliveries for HSV recurrences, total HSV detection, and asymptomatic shedding. Subsequent studies using valacyclovir suppression have shown similar results (Andrews, 2006; Sheield, 2006). Because of these studies, the

TABLE 65-4. Oral Antiviral Medications for Herpesvirus Infection in Pregnancya

Acyclovir, 400 mg three times daily for 7-10 d

Valacyclovir, 1 9 twice daily for 7-1r0 days

Acyclovir, 400 mg three times daily for 5 days

Acyclovir, 800 mg twice daily for 5 days

Acyclovir, 800 mg three times daily for 2 d

Valacyclovir, 500 mg twice daily for 3 days

Valacyclovir, 1 9 once daily for 5 days

Acyclovir,r400 mg three times daily from 36 weeks until delivery

Valacyclovir, 500 mg twice daily from 36 weeks until delivery

Famciclovir not preferred during pregnancy due to fewer safety data.

Data from Workowski, 2015.

American College of Obstetricians and Gynecologists (2016b) recommends viral therapy at or beyond 36 weeks for women who had primary genital herpes infection or active recurrent genital herpes during pregnancy. It is unclear whether suppression is needed for women with outbreaks before but not during pregnancy. Notably, despite maternal antiviral suppression, several cases of atypical neonatal herpes infection have been reported (Pinninti, 2012).

On presentation for delivery, a woman with a history of HSV should be questioned regarding prodromal symptoms such as vulvar burning or itching. A careful examination of the vulva, vagina, and cervix is performed, and women without genitalrlesions may proceed with labor and delivery. Use of a fetal scalp electrode can raise the transmission risk. But, electrode placement is reasonable if needed in the absence of active lesions (American College of Obstetricians and Gynecologists, 2016b).

Suspicious lesions should be cultured or PCR tested. Cesarean delivery is indicated for women with genital lesions or prodromal symptoms. It is not recommended for women with a history of HSV infection but no active genital disease at the time of delivery. Moreover, an active lesion in a nongenital area is not an indication for cesarean delivery. Instead, an occlusive dressing is placed, and vaginal delivery is allowed.

With preterm ruptured membranes, no evidence suggests that external lesions cause ascending fetal infection. Major and associates (2003) described expectant management of preterm premature membrane rupture in 29 women at gestational ages <31 weeks. There were no cases of neonatal HSV, and the maximum infection risk was calculated to be 10 percent. Antiviral treatment is recommended. For women with a clinical recurrence at delivery, there is not an absolute duration of membrane rupture beyond which the fetus would not beneit from cesarean delivery (merican College of Obstetricians and Gynecologists, 2016d).

Women with active HSV may breastfeed if there are no active breast lesions. Strict hand washing is essential. Val acyclovir and acyclovir may be used for symptomatic maternal lesions during breastfeeding, as drug concentrations in breast milk are low. One study found the acyclovir concentration to be only 2 percent of that used for therapeutic dosing of the neonate (Sheield, 2002a).

Haemophilus ducryi can cause painul, nonindurated genital ulcers termed sot chancres. At times, these are accompanied by painul suppurative inguinal lymphadenopathy. Although common in some developing countries, only 11 cases were reported in the United States in 2015 (Centers for Disease Control and Prevention, 20 16c). Appropriate media are not widely accessible, and no Food and Drug Administration (FDA)-cleared PCR test is yet available. Instead, painul genital ulcer(s) and negative screening for syphilis or HSV leads to a presumptive diagnosis. Treatment in pregnancy is azithromycin, 1 g orally as a single dose; erythromycin base, 500 mg orally three times daily for 7 days; or cetriaxone, 250 mg in a single intramuscular dose (Workowski, 2015).

This is a common STD, and more than 40 types infect the genital tract. In the United States from 2005 to 2006, the overall HPV prevalence was 40 percent in females aged 14 to 59 years (Liu, 2016). Prevalence is highest in younger women, and some of this seroprevalence now relects HPV vaccination in this age group (Brouwer, 2015). Most reproductive-aged women become infected within a few years of becoming sexually active, and most infections are asymptomatic and transient. High-risk types are those with the most oncogenic potential. Of these, HPV types 16 and 18 are oten associated with dysplasia (Chap. 63, p. 1193). Mucocutaneous external genital warts termed condyloma acuminata are usually caused by types 6 and 11r.

For unknown reasons, genital warts frequently increase in number and size during pregnancy. hese lesions may sometimes grow to fill the vagina or cover the perineum, thus making vaginal delivery or episiotomy diicult. Maternal HPV infection does not appear to be related to preterm labor (Subramaniam, 2016).

Genital wart eradication during pregnancy is usually not neces sary unless they are symptomatic. herapy is directed toward ity to the mother and fetus. Several agents are available, but no deinitive evidence supports superiority of one over another (Workowski, 2015). Response to treatment during pregnancy may be incomplete, but lesions frequently improve or regress rapidly following delivery.

Trichloroacetic or bichloracetic acid, 80-to 90-percent solu tion, applied topically weekly, is an efective regimen for external warts. Some prefer cyotherapy, laser ablation, or surgical excision.

Agents not recommended in pregnancy because of concerns for maternal and fetal safety include podophyllin resin, podoilox solution or gel, imiquimod cream, and sinecatechins.

There are three vaccines available for long-term prevention.

Gardasil (HPV 4) is a quadrivalent vaccine against HPV types 6,11, 16, and 18. his is being replaced by Gardasil9 (HPV9), a nonavalent vaccine that protects against all the types in HPV 4 plus types 31,r33,r45, 52, and 58. Cervarix (HPV2) is a bivalent vaccine against HPVs 16 and 18. One of these vaccines is selected and given as a three-dose series on a schedule of 0, 1-2, and 6 months for those aged 15 to 26 years. A two-dose regimen, given at 0 and again at 6 to 12 months, is now recommended for girls aged 9 to 14 years (Meites, 2016). Vaccines are licensed for females aged 9 to 26 years, and the target age is 11 to 12 years. he vaccines are not recommended for pregnant women, however, inadvertent exposures do occur. No adverse pregnancy outcomes are associated with the vaccines (Moreira, 2016; Panagiotou, 2015; Vichnin, 2015). If a woman is found to be pregnant after starting the vaccination series, the remaining doses are delayed and given after delivery (American College of Obstetricians and Gynecologists, 2017a). Women who are breastfeeding may receive the vaccine.

Vertical transmission rates ofHPV to the newborn are minimal. Juvenile-onset recurrent respiratory papillomatosis QoRRP) is a rare, benign neoplasm of the larynx. It can cause hoarseness and respiratory distress in children and is most often caused by HPV 6 or 11. Risks for infection are maternal genital HPV infection and longer labors (Niyibizi, 2014). Many newborns are likely exposed to HPV, but few develop JoRRP (Silverberg, 2003; Smith, 2004; Tenti, 1999). For example, the national incidence of JoRRP in 2006 in the United States ranged from 0.5 to 1 per 100,000 children (Marsico, 2014).

The beneit of cesarean delivery to decrease transmission risk is unknown, and thus it is currently not recommended solely to prevent HPV transmission (Workowski, 2015). HPV vaccination may ultimately decrease JoRRP rates in the uture (Matys, 2012).

Pregnant women frequently develop increased vaginal discharge. his may be a physiological discharge, described in Chapter 4 (p. 51), but should be diferentiated from symptomatic vaginitis, which is also common in pregnancy. Fortunately, vaginitis is prevented in part by normal vaginal lora. To better understand this, studies of the composition and function of the normal vaginal microflora are currently underway with the Vaginal Human Microbiome Project (Huang, 2014).

Not an infection in the ordinary sense, bacterial vaginosis (BY) is a maldistribution of normal vaginal flora. With BV, num bers of lactobacilli are decreased, and anaerobic bacteria spe cies are overrepresented. hese anaerobes include Gardnerela,

Prevotela, Mobiluncus, and Bacteroides species; Atopobium vagi nae; and BV-associated bacteria, provisionally named BVAB 1,

BVAB2, and BVAB3. hese last three are newly recognized bacteria found in women with BV (Fredricks, 2005).

Molecular ribosomal RNA gene sequencing techniques have greatly aided this understanding of the vaginal lora, also called the vaginal m icro biota. Five types of vaginal microbiota exist, referred to as communiy state ypes (eSTs). And, a woman can be categorized to one of these ive CSTs based on her vaginal microbiota composition (Ravel, 2011). Researchers have begun to quantiy the risk of BV by these CST groups. Speciically, CST s I, II, III, and V are rich in lactobacilli. In contrast, CST IV is a heterogeneous microbiota of strict anaerobes and is associated with BV. CSTs vary racially, and CST IV is also the most common in asymptomatic, healthy black women (Fettweis, 2014). Pregnancy-related changes in vaginal micro biota are also being defined and may hold keys to adverse BV-related pregnancy outcomes, discussed subsequently (Romero, 2014).

Of childbearing-aged women in the United States, nearly 30 percent have BV. In black women, the prevalence approximates 50 percent (llsworth, 2007). Most women are asymptomatic, but a foul, thin vaginal discharge is a typical complaint. Associated risk factors are douching, multiple partners, smoking, and altered host immunity (Desseauve, 2012; Koumans, 2007; Murphy, 2016) .

For clinical diagnosis of BV, three of the four following criteria are present: (1) vaginal pH >4.5; (2) a thin, milky, noninlammatory vaginal discharge; (3) > 20 percent clue cells seen microscopically; and (4) a fishy odor ater addition of 10-percent potassium hydroxide to vaginal secretion samples (Amsel, 1983). The last is described as a positive "whif test." Likewise, alkalinity of seminal fluid and blood are responsible for foul-odor complaints ater intercourse and with menses in afected women. Clue cells are vaginal epithelial cells containing many attached bacteria, which create a poorly deined stippled cellular border (Fig. 65-6). he higher vaginal pH stems from diminished acid production by lactobacilli. Similarly, Trichomonas vaginalis infection is also associated with anaerobic overgrowth and resultant elaborated amines. hus, women diagnosed with BV should have no microscopic evidence of trichomoniasis (see Fig. 65-6).

FIGURE 65-6 A. Bacterial vaginosis. Microscopy reveals several squamous cells heavily studded with bacteria. Clue cells are covered to the extent that cell borders are blurred and nuclei are not visible (arrows). B. Trichomonads (arrows). (Reproduced with permission from McCord E, Rahn DO, Hoffman BL: Gynecologic infection. In Hoffman BL, Schorge JO, Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGraw Hill Education, 2016. Photo contributors: Lauri Campagna and Mercedes Pineda, WHNP.)

The Nugent score, used primarily in research studies rather than clinical practice, is a system employed for diagnosing BV (Nugent, 1991). During microscopic examination of a gramstained vaginal discharge smear, scores are calculated by assessing bacteria staining and morphology.

Several adverse pregnancy-related health outcomes associated with BV are preterm birth, premature rupture of the membranes, and postpartum endometritis (Hillier, 1995; Leitich, 2003; Watts, 1990). It also increases susceptibility to STDs, including HIV (Atashili, 2008; Brotman, 2010). For women at low risk for preterm birth, however, treatment of BV does not reduce preterm birth rates (Brocklehurst, 2013; Carey, 2000). For high-risk women, evidence is conlicting. Currently, the American College of Obstetricians and Gynecologists (2016c), CDC, and U.S. Preventive Services Task Force do not recommend routine BV screening of asymptomatic gravidas-at either high or low risk for pre term delivery-to prevent preterm birth (Nygren, 2008; Workowski, 2015).

Treatment is reserved for symptomatic women. Preferred drugs are metronidazole, 500 mg twice daily orally for 7 days; metronidazole 0.75-percent gel, one applicator intravaginally, daily for 5 days; or clindamycin 2-percent cream, one applicator intravaginally nightly for 7 days. Alternatives are clindamycin, 300 mg orally twice daily for 7 days, or 100-mg clindamycin ovules placed intravaginally nightly for 3 days (Workowski, 2015). It is still debated whether BV is a sexually transmitted infection. But, treatment of a male partner does not appear to lower recurrence rates (Amaya-Guio, 2016).

Vaginitis caused by Trichomonas vaginalis is common, and its prevalence in the United States approximates 3 percent in nonpregnant and pregnant women (llsworth, 2009; Satterwhite, 2013). The prevalence is higher in those older than 30 years compared with younger women. Risks include black race, douching, and greater number of lifetime sexual partners (Sutton, 2007). Among women, frequent sites of infection include the urethra, endocervix, and vagina. Symptomatic vaginitis is characterized by yellow purulent discharge, pruritus, vulvovaginal erythema, and colpitis macularis, which is often termed a "strawberry cervix" and reflects a patchy, maculoerythematous ectocervix (W0Iner-Hanssen, 1989).

Trichomonads are flagellated, pear-shaped, motile organisms that are somewhat larger than leukocytes. These parasites can readily be seen microscopically moving briskly in a sample mixed on a slide with saline. Prompt inspection of vaginal secretions is advantageous because trichomonads slow with cooling. At times, T vaginalis may be found incidentally on a Pap test slide. Both of these microscopic slide tests have low diagnostic sensitivity that approximates only 60 percent (Krieger, 1988; Wiese, 2000). And, Pap tests can yield false-positive results. Thus, Pap test trichomonad indings warrant wet-prep microscopy or other diagnostic confirmation (American College of Obstetricians and Gynecologists, 2017 c). Of other tests, culture is expensive, lengthy, and sensitivities are 75 to 95 percent (Association of Public Health Laboratories, 2016; Huppert, 2007). Laboratory NAA T analysis of a vaginal, endocervical, or urine sample is available, is completed in minutes to hours, and ofers superior sensitivity of95 to 100 percent (Schwebke, 2011; Van Der Pol, 2014). Rapid POC testing is also available but may sacriice sensitivity for speed. The OSOi Trichomonas Rapid Test provides results in 10 minutes, is suitable for oice use, and has sensitivities of 88 to 98 percent (Herbst de Cortina, 2016).

Metronidazole, administered orally in a single 2-g dose, is efective in eradicating T vaginalis. For those with HIV infection, treatment instead with metronidazole 500 mg orally twice daily for 7 days improves eicacy. Because of the high rate of reinfection among women treated for trichomoniasis, retesting for T vaginalis is recommended for all sexually active women within 3 months following initial treatment (Workowski, 2015).

Metronidazole, an FDA category B drug, is not teratogenic or fetotoxic, but has displayed some tumorigenicity in animal stud ies (Briggs, 2015; Czeizel, 1998). For this reason, the manufac turer recommends against its use during the irst trimester (Pfizer, 2016). Fewer data are available for tinidazole, which is a category

C drug, and thus metronidazole is preferred. vletronidazole and tinidazole have similar chemical structures, and those allergic to metronidazole may also react to tinidazole. For allergic patients, metronidazole desensitization is efective, and one scheme is out lined in the study by Helms and coworkers (2008). With post partum breastfeeding, feeds are delayed for 24 hours following the mation. For tinidazole, the delay is 72 hours.

Perinatal transmission of trichomoniasis by direct contact in the birth canal is rare but may lead to neonatal respiratory or genital infection (Bruins, 2013; Trintis, 2010). Some studies have linked trichomonal infection with preterm birth. A few other studies implicate this infection with preterm premature rupture of membranes and small-for-gestational age newborns (Silver, 2014). However, treatment did not lower preterm birth rates in a randomized study by Klebanof and colleagues (2001). Also, in this study, but not one by Mann and coworkers (2009), treatment for trichomoniasis was associated instead with a higher preterm birth rate.

In sum, treatment for symptomatic women is reasonable and outlined above. For most asymptomatic women during pregnancy, screening is not recommended. However, for pregnant women with HIV infection, screening at the first prenatal visit and prompt treatment are encouraged. his is because T vaginalis infection in pregnant women with HIV may be a risk factor for vertical HIVtransmission (Gumbo, 2010; Workowski, 2015).

Candida albicans or other candidal species can be identified by culture from the vagina during pregnancy in approximately 20 percent of women. A link between candidiasis and preterm birth is not robust (Cotch, 1998; Kiss, 2004; Roberts, 2015). hus, asymptomatic colonization requires no treatment. he organism, however, can create an extremely profuse, irritating discharge.

For symptoms, efective treatment is a 100-mg miconazole vaginal suppository or a 2-percent butoconazole, I-percent clotrimazole, 2-percent miconazole, or 0.4-percent terconazole cream, any of which is used daily for 7 days. A shorter, 3-day regimen is daily 2-percent clotrimazole, 4-percent miconazole, or 0.8-percent tioconazole cream, or daily 200-mg miconazole or 80-mg terconazole suppository (Workowski, 2015). In some women, infection is likely to recur and require repeated treatment during pregnancy. In these cases, symptomatic infection usually subsides after pregnancy (Sobel, 2007). For treatment, the American College of Obstetricians and Gynecologists (2017 c) and the CDC recommend topical rather than oral azoles for symptoms. As discussed urther in Chapter 12 (p. 241), oral fluconazole is generally not considered teratogenic, but in 2016, the FDA released a safety alert regarding a possible link with miscarriage (M0Igaard-Nielsen, 2016).

Causative agents of acquired immunodeficiency syndrome (AIDS) are RNA retroviruses termed human immunodiciency viruses, HIV-J and HIV-2. Most cases worldwide are caused by HIV-l infection. Sexual intercourse is the major mode of transmission. he virus also is passed by blood, and infected by breast milk. he primary determinant of transmission is the plasma HIV-l viral load.

For sexual transmission, the viral HIV envelope binds to mucosal dendritic cells. These cells then present the viral par ticle to specific T lymphocytes. These lymphocytes are defined phenotypically by their cluster of dierentiation 4 (CD4) glyco protein surface antigens. The CD4 site serves as a receptor for the virus. Once infected, CD4 T lymphocytes may die, and the common denominator of clinical illness with AIDS is pro found immunodeficiency that gives rise to various opportunis tic infections and neoplasms.

In the United States, the CDC (2016c) estimated that more than 1.2 million individuals were infected in 2013, and new cases numbered more than 39,000. Approximately 8500 women with HIV give birth annually in the United States. However, the estimated number of perinatally acquired HIV cases has decreased dramatically, and the perinatal transmission rate in 2013 was 1.8 percent (Centers for Disease Control and Prevention, 2016b, 2017). his is predominantly due to the implementation of prenatal HIV testing and antiretroviral therapy (ART) for the woman and then her neonate.

he incubation period from exposure to clinical disease averages 3 to 6 weeks. Acute HIV infection is similar to many other viral syndromes and usually lasts less than 10 days. Common symptoms, if any, include fever, fatigue, rash, headache, lymphadenopathy, pharyngitis, myalgias, nausea, and diarrhea. After symptoms abate, the level of viremia usually decreases to a set point, and patients with the highest viral burden at this time progress more rapidly to AIDS and death (Fauci, 2007). According to the CDC, AIDS is defined by a CD4 T-cell count <200 cells/lLL, by CD4 T-cells comprising < 14 percent of alirlymphocytes, or one of several AIDS-defining illnesses (Schneider, 2008; Selik, 2014). Route of infection, the pathogenicity of the infecting viral strain, the initial viral inoculum, and the immunological status of the host all afect the rapidity of progression.

he CDC (2006b) and the American College of Obstetricians and Gynecologists (2016e) recommend prenatal HIV screening using an opt-out approach. his means that a woman is notiied that HIV testing is included in a comprehensive set of antenatal tests, but that testing may be declined. Women are given information regarding HIV but are not required to sign a specific consent. hrough the use of such opt-out strategies, HIV testing rates have increased. Specific state laws concerning screening vary and can be found at: ww.cdc.gov/hiv/policies/ law / states/ testing.h tml.

Repeat testing during the third trimester, preferably before 36 weeks' gestation, is considered for all pregnant women. Retesting is recommended for those at risk for acquiring HIV or for women in high-risk areas, namely, those with rates of HIV infection of 1 per 1000 pregnant women screened (Workowski, 2015). At-risk factors include injection drug use, prostitution, a suspected or known HIV-infected sexual partner, multiple sexual partners, or a diagnosis of another STD (American College of Obstetricians and Gynecologists, 20 16e).

he initial laboratory screening test for HIV is an antigen/ antibody combination immunoassay that detects antibodies against HIV-1 and HIV-2 and detects HIV-1 p24 antigen (Centers for Disease Control and Prevention, 2014). Antibody can be detected in most patients within 1 month of infection, and thus, antibody serotesting may not exclude early infection. Instead, for acute primary HIV infection, identiication of viral p24 core antigen or viral RNA is possible. No further testing is required for specimens that are negative on the initial immunoassay unless a known exposure to HIV has occurred.

As shown in Figure 65-7, specimens with a "reactive" (that is, a positive) antigen/antibody combination immunoassay result should be tested with an antibody immunoassay that diferentiates HIV-1 antibodies from HIV-2 antibodies. The HIV-1/ HIV-2 antibody diferentiation immunoassay is resulted as positive or negative for HN-1 antibodies, for HN-2 antibodies, or for HIV antibodies, undiferentiated. If these two serial immunoassays are discordant, an HIV -1 NAA T -qualitative or quantitative HIV RNA test-is performed (Centers for Disease Control and Prevention, 2014).

Women with undocumented HIV status at delivery should have a fourth-generation HIV antigen/antibody combination screening test performed on a blood sample. A negative screening test result does not need confirmation. However, in cases of recent HIV exposure, consideration is given to peripartum interventions to reduce perinatal transmission despite negative HIV testing. Repeat interval testing is recommended to exclude very early infection not identified with the initial screen. With a positive fourth-generation HIV testing result, peripartum and neonatal interventions to reduce perinatal transmission are initiated. This includes avoidance of breastfeeding, although breast milk may be stored until confirmatory test results are available. Interventions can be discontinued if confirmatory testing is negative. To confirm a positive result from any initial HIV test, the laboratory testing algorithm in Figure 65-7 should be used and begins with the antigen/antibody combination immunoassay.

Viral burden and neonatal infection rates are directly related. In one cohort, neonatal infection was 1 percent with < 400 copies/mL, and it was 23 percent when maternal viral RNA levels were >30,000 copies/mL (Cooper, 2002). Among 2615 infants born to mothers taking ART before conception and during pregnancy, there were no cases of vertical transmission at delivery (Mandelbrot, 2015). Transmis sion of HIV infection, however, has been observed at all HIV RNA levels, including .r assays. Transplacental HIV transmission

Negative for HIV-1 and HIV-2 can occur early, and the virus has even antibodies and p24 antigen

HIV-1/HIV-2 antibody differentiation immunoassay abortion (Lewis, 1990). Kourtis and col leagues (2001) estimated that 20 percent of vertical transmission occurs before 36

HIV-1 (+) HIV-1 (-) HIV-1 (+) weeks' gestation, 50 percent in the days HIV-2 (-) HIV-2 (+) HIV-2 (+) before delivery, and 30 percent intrapar tum. Transmission rates for breastfeeding may be as high as 30 to 40 percent and HIV-1 NAAT are associated with increasing HIV viral burden (Kourtis, 2006, 2007; Slyker, 2012). In nonpregnant individuals, con mission are linked. Evidence also supports that vertical transmission rates may be

FIGURE 65-7 Algorithm for HIV testing. In the pathway colored light-blue, for specimens increased by comorbid STDs (Schulte, that are reactive on the initial antigen/antibody combination immunoassay and nonreac tive or indeterminate on the HIV-1/HIV-2 antibody diferentiation immunoassay, a nucleic 2001; Watts, 2012).

acid amplification test (NAAT) is implemented. A positive HIV-1 NAAT result and nonreac for acute HIV-1 infection. A positive HIV-1 NAAT result and indeterminate HIV-1 /HIV-2 • Antepartum Care antibody diferentiation immunoassay result indicate the presence of HIV-1 con

Pregnant women with HIV infection need firmed by HIV-1 NAAT. A negative HIV-1 NAAT result and nonreactive or indeterminate special attention and are seen in consultation on the initial antigen/antibody combination immunoassay. (Reproduced with permission by physicians with special interest in this from Centers for Disease Control and Prevention, 2014.) field. An additional resource is the National

Perinatal HIV Hotline (1-888-448-8765), which is a federally unded service that provides free antepartum, intrapartum, or postpartum consultation to providers. At Parkland Hospital, an HIVinfected pregnant woman is initially assessed with the following:

Standard prenatal laboratory surveys that include serum creatinine, complete blood count, and bacteriuria screening

Plasma HIV RNA quantification-"viralrload" -CD4 T-cell count, and antiretroviral resistance testing

HSV-1 and 2, cytomegalovirus, toxoplasmosis, and hepatitis Brand C serological screening

Tuberculosis testing with puriied protein derivative (PPD) skin testing, or interferon-gamma release assay

Evaluation of need for pneumococcal, hepatitis A, hepatitis B, T dap, and influenza vaccines

Sonographic evaluation to establish gestational age.

During pregnancy, the risk of HIV transmission does not appear to be increased with amniocentesis or other invasive diagnostic procedures in women receiving efective ART resulting in viral suppression (Floridia, 2017). For women not receiving ART, the risk rises approximately twofold (Mandelbrot, 1996). If amniocentesis is performed, eforts are taken to avoid passing through the placenta (Panel on Treatment of HI V-Infected Pregnant Women and Prevention of Perinatal Transmission, 2016).

In overview, the ideal strategy to suppress viral load and minimize vertical HIV transmission includes: (1) preconceptional ART, (2) antepartum ART, (3) intrapartum continuation of the antepartum oral ART regimen plus IV zidovudine, and (4) newborn ART prophylxis. ART is recommended for all HIVinfected pregnant women, and it should be initiated as early in pregnancy as possible. Treatment reduces the risk of perinatal transmission regardless of CD4 T-cell count or HIV RNA level. Adherence is essential because the risk of viral drug resistance is lessened. As for nonpregnant adults, pregnant women are treated with at least three antiviral agents.

The Panel on Treatment of HI V-Infected Pregnant Women and Prevention of Perinatal Transmission (2016) has issued guidelines for four diferent scenarios during pregnancy (Table 65-5). he following paragraphs summarize these recommendations.

First, women already taking ART at pregnancy onset are encouraged to continue the regimen if viral suppression is adequate. Didanosine, stavudine, and full-dose ritonavir, which difers from ritonavir-boosted agents, are exceptions due to pregnancy toxicity but not teratogenicity.

Second, women who have never received antiretroviral therapy-antiretroviral nai've-are given ART regardless of trimester. In general, the starting regimen comprises two nucleoside reverse transcriptase inhibitors plus either a ritonavir-boosted protease inhibitor or an integrase inhibitor.

hird, women who have previously received antiretroviral therapy but are currently not taking medications should undergo HIV resistance testing because prior ART use raises their risk of drug resistance. Typically, ART is initiated prior to receiving results of these drug-resistance tests. In this case, initial ART selection should factor results of prior resistance testing, if available; prior ART regimen; and current ART preg nancy guidelines, that is, those for ART-naive women. Drug resistance testing may then modiy the initial regimen.

For these three categories of women taking antepartum

ART, therapy surveillance is outlined in Table 65-5. Most patients with adequate viral response have at least a I-log viral load decline within 1 to 4 weeks after starting therapy. For those who fail to achieve this decline, options include review of drug resistance study results, confirmation of regimen compli ance, and ART modiication.

During labor and delivery, oral medications can be taken with sips of water. Additionally, IV zidovudine is given to women with an HIV RNA viral load > 1000 copies/ mL or who have an unknown viral load near delivery. At Parkland

Hospital, we administer intrapartum IV zidovudine to all

HIV-positive women, regardless of viral load. A 2 mg/kg load delivery. In this instance, for gravidas already taking antepar tum oral zidovudine, their oral dose can be held, and IV drug is instead administered. HIV-infected women undergoing a scheduled cesarean delivery are given IV zidovudine as a load ing dose followed by 2 more hours of continuous maintenance therapy-a total of 3 hours of infused zidovudine.

who are taking no medications. hese women are given IV zid ovudine intrapartum as just described.

During labor, artificial membrane rupture, fetal scalp electrode placement, episiotomy, and operative vaginal delivery are reserved for clear obstetrical indications (Mandelbrot, 1996; Peters, 2016). Labor augmentation is used when needed to shorten the interval to delivery to further lower the transmission risk. Delayed cord clamping in preterm neonates is acceptable. Neuraxial analgesia is suitable. Postpartum hemorrhage is best managed with oxytocin and prostaglandin analogues. Methylergonovine (Methergine) and other ergot alkaloids adversey interact with reverse transcriptase and protease inhibitors to cause severe vasoconstriction.

In some cases, cesarean delivery lowers HIV prenatal transmission (European Mode of Delivery Collaboration, 1999; International Perinatal HIV Group, 1999). The American College of Obstetricians and Gynecologists (2017b) recommends that scheduled cesarean delivery be discussed and recommended for HIV-infected women with HIV-1 RNA loads > 1000 copies/mL. Scheduled delivery is recommended at 38 weeks' gestation in these women to avert spontaneous labor.

For women with HIV RNA levels �1000 copies/mL, data are insuicient to predict similar beneits, and scheduled cesarean delivery is unlikely to confer additional risk reduction for women already taking ART and achieving viral suppression (Briand, 2013; Jamieson, 2007; Read, 2005). Vaginal delivery in this group may be elected. However, if cesarean delivery is instead chosen for a well-counseled woman in this group, it should be performed at 39 weeks. Similarly, cesarean delivery performed for obstetrical indications in this lower-viral-Ioad group should be done at 39 weeks when possible.

TABLE 65-5. Recommendations for HIV Antiviral Drug Use During Pregnancy

Antepartum care See antepartum screening test list (p. 1249)

ART should be initiated as early as possible For those with HIV RNA levels >500-'1000 copies/mL, order HIV antiretroviral drug resistance testing but do not delay ART initiation awaiting results Repeat HIV RNA levels 2-4 weeks after initiating (or changing) ART drugs; monthly until RNA levels are undetectable; then at least every 3 mo; and finally at 34-36 weeks' gestation for delivery planning

CD4+ count should be monitored at the initial visit and every 3-6 mo

Intrapartum care If HIV RNA levelr> 1 000 copies/mL or is unknown before labor or ROM, plan cesarean delivery at 38 weeks' gestation If HIV RNA levelsr> 1000 or is unknown but labor or ROM has ensued, benefits of cesarean delivery are unclear and labor plans are individualized If HIV RNA levelr:;1 000 copies/mL, vaginal delivery is permitted; cesarean delivery not routinely recommended Start IV ZDV if HIV RNA levelr> 1 000 copies/mL near delivery or is unknown.

Dosing is 2 mg/kg IV load over 1 hr, then 1 mg/kg/hr until delivery.

IV ZDV should begin 3 hr before scheduled cesarean delivery Those taking oral antepartum ART should take this during labor with sips of water

ART = antiretroviral therapy; NRTI = nucleoside reverse transcriptase inhibitor; ROM = rupture of membranes; ZDV = zidovudine. Adapted from the Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2016. Department of Health and Human Services.

healthy woman with HIV has no signiicant efect on disease Vertical transmission is increased by breastfeeding, and it genprogression (Calvert, 2015). Linkage to general HIV care posterally is not recommended for HIV-positive women in the partum is critical to maintain viral suppression (Swain, 2016). United States, where formula is readily available (Read, 2003). For women who do not have HIV infection, but whose In nutritionally deprived countries, where infectious disease partner is seropositive, current guidance supports the use of and malnutrition are primary causes of infant death, the World highly active antiretroviral therapy with viral suppression in the Health Organization (2016) recommends exclusive breastfeeding infected partner (treatment as prevention), and consideration during the first 6 to 12 months. of antiretroviral preexposure prophylaxis (PreP) for the HIV he Panel on Treatment of HI V-Infected Pregnant Women negative partner. The well-counseled couple can consider periand Prevention of Perinatal Transmission (2016) strongly recovulatory condomless intercourse, or uterine insemination or ommends that ART regimens not be discontinued postpartum in vitro fertilization after sperm washing for assisted conception but continued lifelong for the advantages of viral suppression. (Brooks, 2017; Kawwass, 2017). Ideally, all those planning pregnancy should be receiving ART If, instead, pregnancy is undesired, efective contraception is and have a plasma viral load below detectable levels before discussed (Chap. 38, p. 680). Counseling also includes education conception. As one benefit, interpregnancy viral load suppresfor decreasing high-risk sexual behaviors to prevent transmission sion is associated with less vertical transmission in a subsequent and to decrease other STD acquisition. Similarly, women with pregnancy (French, 2014; Mandelbrot, 2015; Stewart, 2014; HIV have unique gynecological issues, such as genital neoplasia, Townsend, 2014). Reassuringly, for those seeking subsequent which require special attention (American College of Obstetripregnancy, when ART is available, repeated pregnancy in a cians and Gynecologists, 2016a; Werner, 2016).

Alexander ]M, Sheield ]S, Sanchez P], et al: Eicacy of treatment for syphilis in pregnancy. Obstet Gynecol 93:5, 1999

Alger LS, Lovchik]C, Hebel ]R, et al: The association of Chlamydia trachomatis, Neisseria gonorrhoeae, and group B streptococci with preterm rupture of the membranes and pregnancy outcome. Am] Obstet Gynecol 159:397, 1988

Allsworth ]E, Peipert ]F: Prevalence of bacterial vaginosis: 2001-2004 National Health and Nutrition Examination Survey data. Obstet Gynecol 109(1):114,t200

Allsworth ]E, Ratner ]A, Peipert ]F: Trichomoniasis and other sexually transmitted infections: results from the 2001-2004 National Health and Nutrition Examination Surveys. Sex Transm Dis 38,t2009

Amaya-Guio], Viveros-Carreno DA, Sierra-Barrios EM, et al: Antibiotic treatment for the sexual partners of women with bacterial vaginosis. Cochrane Database Syst Rev 01,t20t16

American Academy of Pediatrics and American College of Obstetricians and G�necologists. Guidelines for Perinatal Care, 8th ed. Washington, 2017

Amencan College of Obstetricians and Gynecologists: Expedited partner therapy in the management of gonorrhea and chlamydial infection. Committee Opinion No. 632, ]une 2015

American College of Obstetricians and Gynecologists: Gynecologic care for women and adolescents with human immunodeficiency virus. Practice Bulletin No. 167, October 2016a

A�erican College of Obstetricians and Gynecologists: Management of herpes 11,pregnancy. Practice Bulletin No. 82, June 2007, Reairmed 2016b

Am�rican College of Obstetricians and Gynecologists: Prediction and prevention of preterm birth. Practice Bulletin No. 130, October 2012, Reairmed 20t16c

American College of Obstetricians and Gynecologists: Premature rupture of membranes. Practice Bulletin No. 172, October 2016d

American College of Obstetricians and Gynecologists: Prenatal and perinatal human immunodeiciency virus testing: expanded recommendations. Committee Opinion No. 635, June 2015, Reairmed 2016e

American College of Obstetricians and Gynecologists: Human papillomavirus vaccination. Committee Opinion No. 704, June 201

American College of Obstetricians and Gynecologists: Scheduled cesarean delivery and the prevention of vertical transmission of HIV infection. Committee Opinion No. 234, May 2000, Reairmed 2017b

American College of Obstetricians and Gynecologists: Vaginitis. Practice Bulletin No. 72, May 2006, Reairmed 2017c

Amse�R, Tott�n P�, Spiegel CA, et al: Nonspeciic vaginitis. Diagnostic critena and mICrobial and epidemiologic associations. Am ] Med 74(1): 14, 1983

Andrei G, Snoeck R: Herpes simplex virus drug-resistance: new mutations and insights. Curr Opin Infect Dis 26(6):551,t2013

Andrew��,Goldenberg RL, Mercer B, et al: The Preterm Prediction Study: aSSOCiation of second-trimester genitourinary chlamydia infection with subsequent spontaneous preterm birth. Am] Obstet Gynecol 183:662,t2000

Andrew�.,Klebanof MA, Thom EA, et al: Midpregnancy genitourinary .t tract 11fectlon With Chlamydia trachomatis: association with subsequent preterm delivery in women with bacterial vaginosis and Trichomonas vaginalis. Amt] Obstet Gynecol 194:493, 2006

Association of Public Health Laboratories: Advances in laboratory detection of Trichomonas vaginalis (Updated). Silver Spring, APHL, 2016

Associat��n of Public He�lth Laboratories: Suggested Reporting Language for Syphlhs Serology Testing. Silver Spring, APHL, 2015

Ata�hili ], Poole e, Ndumbe PM, et al: Bacterial vaginosis and HIV acquisition: a meta-analysis of published studies. AIDS 22(12): 1493, 2008

Bataskov KL, Hariharan S, Horowitz MD, et al: Gonococcal endocarditis complicating pregnancy: a case report and literature review. Obstet Gynecol 78:494, 1991

Baud D, Goy G, laton K, et al: Role of Chlamydia trachomatis in miscarriage.

Emerg Infect Dis 17(9):1630,t2011

Benedetti], Zeh], Corey L. Clinical reactivation of genital herpes simplex virus infection decreases in frequency over time. Ann Intern Med 131: 14, 1999 Berman SM: Maternal syphilis: pathophysiology and treatment. Bull World

Health Organ 82:433, 2004

Berman SM, Harrison HR, Boyce T, et al: Low birth weight, prematurity, and �ostpartum endometritis. Association with prenatal cervical Mycoplasma homtnts and Chlamydia trachoma tis infections. ]AMA 25 (9):1189, 1987 Bernstei�DI, Bella:y AR, Hook EW 3rd, et al: Epidemiology, clinical pres�ntatlon, and antibody response to primary infection with herpes simplex ViruS type 1 and type 2 in young women. Clin Infect Dis 56(3):344, 2013

Binnicker M], Jespersen D], Rollins LO: Direct comparison of the traditional and reverse syphilis screening algorithms in a population with a low preva lence of syphilis. J Clin Microbiol 50(1):148,t2012

Bias MM, Canchihuaman FA, Alva IE, et al: Pregnancy outcomes in women infected with Chlamydia trachomatis: a population-based cohort study in Washington SCate. Sex Transm Infect 83:314,t200

Blatt �], Lieberman J�, Hoover DR, et al: Chlamydial and gonococcal testing dunng pregnancy In the United States. Am ] Obstet Gynecol 207(1):55. el,t2012

Bleich AT, Sheield ]S, Wendel GD, et al: Disseminated gonococcal infection in women. Obstet Gynecol 119(3)597,t2012

Bradley H, Markowitz LE, Gibson T, et al: Seroprevalence of herpes simplex virus types 1 and 2-United States, 1999-2010.] Infect Dis 209(3):325, 2014

Briand N, ]asseron C, Sibiude J, et al: Cesarean section for HIV-infected women in the combination ART era, 2000-2010. Am J Obstet Gynecol 209(4):335.el,t2013

Briggs GG, Freeman RK: Drugs in Pregnancy and Lactation, 10th ed. Baltimore, Williams & Wilkins, 201t5

Brocklehurst P, Gordon A, Heatley E, et al: Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev 1 :CD000262, 2013

Brooks ]T, Kawwass ]F, Smith DK, et al: Efects of antiretroviral therapy t? prevent HIV transmission to women in couples attempting conception when the man has HIV infection-United States, 2017. MMWR 66(32):859,t2017

Brotman v1, KlebanofA, Nansel TR, et al: Bacterial vaginosis assessed by gram stain and diminished colonization resistance to incident gonococcal, chlamydial, and trichomonal genital infection.] Infect Dis 202:1907,2010

Brouwer AF, Eisenberg Me, Carey TE, et al: Trends in HPV cervical and seroprevalence and associations between oral and genital infection and serum antibodies in NHANES 2003-2012. BMC Infect Dis 15:575,t2015

Brown EL, Gardella e, Maim G, et al: Efect of maternal herpes simplex virus (HSV) serostatus and HSV type on risk of neonatal herpes. Acta Obstet Gynecol 86:523, 2007

Brown ZA: HSV-2 speciic serology should be ofered routinely to antenatal patients. Rev Med Virol 10(3):141,t2000

Brown ZA, Gardella C, Wald A, et al: Genital herpes complicating pregnancy.

Obstet Gynecol 106:845, 2005

Brown ZA, Selke SA, Zeh ], et al: Acquisition of herpes simplex virus during pregnancy. N Englt] Med 337:509, 1997

Bruins M], van Straaten IL, Ruijs G]: Respiratory disease and Trichomonas vaginalis in premature newborn twins. Pediatr Infect Dis] 32(9): 1029,t2013 Burgis ]T, Nawaz H 3rd: Disseminated gonococcal infection in pregnancy pre senting as meningitis and dermatitis. Obstet Gynecol 98,t2006

Burkman RT, Tonascia ]A, Atienza MF, et al: Untreated endocervical gonorrhea and endometritis following elective abortion. Am ] Obstet Gynecol 126:648, 1976

Calvert e, Ronsmans C: Pregnancy and HIV disease progression: a systematic review and meta-analysis. Trop Med Int Health 20(2):122, 2015

Carey ]C, Klebanof A, Hauth ]C, et al: Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Englt] Med 342:534, 2000

Causer LM, Kaldor ]M, Conway DP, et al: An evaluation of a novel dual trepone�al/nontreponemal point-of-care test for syphilis as a tool to distinguish active from past treated infection. Clin Infect Dis 61(2):184, 2015

Centers for Disease Control and Prevention: Expedited partner therapy in the management of sexually transmitted diseases. Atlanta, U.S. Department of Health and Human Services, 2006a

Centers for Disease Control and Prevention: Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR 55(14):1, 2006b Centers for Disease Control and Prevention: Discordant results from reverse sequence syphilis screening-ive laboratories, United States, 2006-2010. MMWR 60(5):133,t2011 Centers for Disease Control and Prevention: Quick reference guide-Iaboratoty testing for the diagnosis of HIV infection: updated recommendations. 2014. Available at: https:l/stacks.cdc.gov/view/cdcl23446. Accessed March 27,t2017

Centers for Disease Control and Prevention: Guidance on the use of expedited partner therapy in the treatment of gonorrhea. 20 16a. Available at: https:// www.cdc.gov/std/epclgc-guidance.htm. Accessed March 23, 2017

Centers for Disease Control and Prevention: Monitoring selected national HIV prevention and care objectives by using HIV surveillance data-United States and 6 dependent areas, 2014. HIV Surveillance Supplemental Report 21 (No. 4), 2016b. Available at: http://www.cdc.gov/hivllibrary/reports/ survedlance.l Accessed April 3, 2016

Centers for Disease Control and Prevention: Sexually Transmitted Disease Surveillance, 2015. Atlanta, U.S. Department of Healch and Human Services, 2016c

Centers for Disease Control and Prevention: HIV among pregnant women, infants, and children. 2017. Available at: hnps:/ /www.cdc.gov/hiv/group/ gender/pregnanwomen.l Accessed March 26, 201

Cooper ER, Charurat M, Mofenson L, et al: Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission. J Acquir Immune Ddic Syndr 29:484,2002

Corey L, Wald A: Maternal and neonatal herpes simplex virus infections. N Engl J Med 361(14):1376, 2009

Corey L, Wald A, Patel R, et al: Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med 350:11,t2004

Coste J, Job-Spira N, Fernandez H: Risk factors for spontaneous abortion: a case-control study in France. Hum Reprod 6:1332, 1991

Cotch MF, Hillier SL, Gibbs RS, et al: Epidemiology and outcomes associated with moderate to heavy Candida colonization during pregnancy. The Vaginal Infections and Prematurity Study Group. Am J Obstet Gynecol 178(2):374, 1998

Czeizel E, Rockenbauer M: A population based case-control teratologic study of oral metronidazole treatment during pregnancy. BJOG 105:322, 1998 Delaney S, Gardella C, Saracino M, et al: Seroprevalence of herpes simplex virus type 1 and 2 among pregnant women, 1989-2010. JAMA 312(7):746,2014

Desseauve D, Chantrel J, Fruchart A, et al: Prevalence and risk factors ofbacterial vaginosis during the first trimester of pregnancy in a large French population-based study. Eur J Obstet Gynecol Reprod Bioi 163(1):30, 2012 de Voux A, Kidd S, Grey JA, et al: State-specific rates of primaty and secondary syphilis among men who have sex with men-United States, 2015. MvIWR 66(13):349,t2017 Diguet A, Patrier S, Eurin D, et al: Prenatal diagnosis of an exceptional intrauterine herpes simplex type 1 infection. Prenat Diagn 26(2):154, 2006 Duf P: Maternal and fetal infections. In Creasy K, Resnik R, lams JD, et al (eds): Creasy and Resnik's Maternal-Fetal Medicine: Principles and Practice, 7th ed. Philadelphia, Saunders, 2014 European Mode of Delivery Collaboration: Elective caesarean-section versus vaginal delivery in prevention of vertical HIV-1 transmission: a randomized clinical trial. Lancet 353(1):1035, 1999 Fanfair N, Zaidi A, Taylor LD, et al: Trends in seroprevalence of herpes simplex virus type 2 among non-Hispanic blacks and non-Hispanic whites aged 14 to 49 years-United States, 1988 to 2010. Sex Transm Dis 40(11):860,t2013 Fauci AS: Pathogenesis of HI V disease: opportunities for new prevention interventions. Clin Infect Dis 45:S206, 2007 Fettweis JM, Brooks JP, Serrano MG, et al: Diferences in vaginal microbiome in African American women versus women of European ancestry. Microbiology 160(Pt 10):2272, 2014 Fiumara NJ: Syphilis in newborn children. Clin Obstet GynecoIt18:183, 1975 Flagg EW, Weinstock H: Incidence of neonatal herpes simplex virus infections in the United States, 2006. Pediatrics 127(1):e1, 2011 Floridia M, Masuelli G, Meloni A, et al: Amniocentesis and chorionic villus sampling in HIV-infected pregnant women: a multicentre case series. BJOG 124(8):1218,t2017 Food and Drug Administration: FDA drug safety communication: FDA to review study examining use of oral luconazole (Diflucan) in pregnancy. 2016. Available at: https:llwww.fda.gov/Drugs/DrugSafety/ucm497482. htm. Accessed March 26, 2017 Fredricks DN, Fiedler TL, Marrazzo JM: Molecular identification of bacteria associated with bacterial vaginosis. N Engl J Med 353:1899, 2005 French CE, Thorne C, Tariq S, et al: Immunologic status and virologic outcomes in repeat pregnancies to HIV-positive women not on antiretroviral therapy at conception: a case for lifelong antiretroviral therapy? AIDS 28(9):1369,t2014 Gardella C, Huang ML, Wald A, et al: Rapid polymerase chain reaction assay to detect herpes simplex virus in the genital tract of women in labor. Obstet GynecoIt115(6):1209,t2010 Garnett GP, Aral SO, Hoyle DV, et al: he natural history of syphilis. Implications for the transmission dynamics and control of infection. Sex Transm Dis 24(4):185, 1997 Gibbs RS, Schachter J: Chlamydial serology in patients with intra-amniotic infection and controls. Sex Transm Dis 14:213, 1987 Gomez GB, Kamb ML, Newman LM, et al: Untreated maternal syphilis and adverse outcomes of pregnancy: a systematic review and meta-analysis. Bull World Health Organ 91(3):217, 2013 Grange PA, Gressier L, Dion PL, et al: Evaluation of a PCR test for detection of Treponema pallidum in swabs and blood. J Clin Microbiol 50(3):546, 2012 Greer L, Wendel GD: Rapid diagnostic methods in sexually transmitted infections. Infect Dis Clin North Am 22:601, 2008 Gumbo FZ, Duri K, Kandawasvika GQ, et al: Risk factors of HIV vertical transmission in a cohort of women under a PMTCT program at three periurban clinics in a resource-poor setting. J Perinatol 30: 717, 2010 Hawkes S, Matin N, Broutet N, et al: Efectiveness of interventions to improve screening for syphilis in pregnancy: a systematic review and meta-analysis. Lancet Infect Dis 11 :684, 2011

Helms DJ, Mosure DJ, Secor E, et al: Management of Trichomonas vaginalis in women with suspected metronidazole hypersensitivity. Am J Obstet GynecoIt198(4):370.e1,t2008

Henao-Martinez AF, Johnson SC: Diagnostic tests for syphilis: New tests and new algorithms. Neurol Clin Pract 4(2):114,t2014

Herbst de Cortina S, Bristow CC, et al: A systematic review of point of care testing for Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis. Infect Dis Obstet GynecoIt2016:4386127, 2016

Hillier SL, Nugent P, Eschenbach DA, et al: Association between bacterial vaginosis and preterm delivery of a low-birth-weight infant. The Vaginal Infections and Prematurity Study Group. New Engl J Med 333:1737, 1995

Hollier LM, Harstad TW, Sanchez PJ, et al: Fetal syphilis: clinical and laboratory characteristics. Obstet Gynecol 97:947, 2001

Hollier LM, Scott LL, Murphree SS, et al: Postpartum endometritis caused by herpes simplex virus. Obstet Gynecol 89(5 Pt 2):836, 1997

Hollier LM, Wendel GD: Third-trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection. Cochrane Database Syst Rev 1 :CD004946, 2008

Horsager R, Roberts S, Roger V, et al (eds): Williams Obstetrics 24th Edition Study Guide, New York, McGraw-Hill Education, 2014

Hosenfeld CB, Workowski A, Berman S, et al: Repeat infection with Chlamydia and gonorrhea among females: a systematic review of the literature. Sex Transm Dis 36(8):478, 2009

Hoyme UB, Kiviat N, Eschenbach DA: he microbiology and treatment oflate postpartum endometritis. Obstet GynecoIt68:226, 1986

Huang B, Fettweis JM, Brooks JP, et al: The changing landscape of the vaginal microbiome. Clin Lab Med 34(4):747,t2014

Huppert JS, Mortensen JE, Reed JL, et al: Rapid antigen testing compares favorably with transcription-mediated amplification assay for the detection of Trichomonas vaginalis in young women. Clin Infect Dis 45(2):194,2007

Hutto C, Arvin A, Jacobs R, et al: Intrauterine herpes simplex virus infections.

J Pediatr 110(1):97, 1987

International Perinatal HIV Group: he mode of delivery and the risk of vertical transmission of human immunodeiciency virus type 1: a meta-analysis of 15 prospective cohort studies. N Engl J Med 340:977, 1999

James SH, Kimberlin DW: Neonatal herpes simplex virus infection: epidemiology and treatment. Clin PerinatoIt42(1):47, 2015

Jamieson OJ, ReadJS, KourtisAP, et al: Cesaren delivery for HIV-infected women: recommendations nd controversies. Am J Obstet Gynecol 197: S96, 2007

Johnson HL, Ghanem KG, Zenilman JM, et al: Sexually transmitted infections and adverse pregnancy outcomes among women attending inner city public sexually transmitted diseases clinics. Sex Transm Dis 38(3):167, 2011 Kawwass JF, Smith DK, Kissin DM, et al: Strategies for preventing HIV infection among HIV-uninfected women attempting conception with HIVinfected men-United States. MMWR 66(21):554,t2017 Kimberlin DW, Whitley RJ, Wan W, et al: Oral acyclovir suppression and neurodevelopment after neonatal herpes. N Engl J Med 365(14): 1284,2011 Kiss H, Petricevic L, Husslein P: Prospective randomised controlled trial of an infection screening programme to reduce the rate of preterm delivery. BMJ 329(7462):371,t2004 Kissinger P, Schmidt N, Mohammed H, et al: Patient-delivered partner treatment for Trichomonas vaginalis infection: a randomized controlled trial. Sex Transm Dis 33:445, 2006 Klebanof A, Carey JC, Hauth Jc, et al: Failure of metronidazole to prevent preterm delivery among pregnant women with asymptomatic Trichomonas vaginalis infection. N Engl J Med 345(7):487, 2001 Klein VR, Cox SM, Mitchell MD, et al: he Jarisch-Herxheimer reaction complicating syphilotherapy in pregnancy. Obstet Gynecol 75:375, 1990 Koumans EH, Sternberg M, Bruce C, et al: he prevalence of bacterial vaginosis in the United States, 2001-2004: associations with symptoms, sexual behaviors, and reproductive health. Sex Transm Dis 34:864, 2007 Kourtis AP, Bulterys M, Nesheim SR, et al: Understanding the timing of HI V transmission from mother to infant. JAMA 285:709,t2001 Kourtis AP, Jamieson DJ, de Vincenzi I, et al: Prevention of human immunodeficiency virus-1 transmission to the infant through breastfeeding: new developments. Am J Obstet Gynecol 197:5113,t2007 Kourtis AP, Lee FK, Abrams EJ, et al: Mother-to-child transmission of HIV 1: timing and implications for prevention. Lancet Infect Dis 6:726, 2006

Krieger IN, Tam MR, Stevens CE, et al: Diagnosis of trichomoniasis. Comparison of conventional wet-mount examination with cytologic studies, cultures, and monoclonal antibody staining of direct specimens. JAMA 259(8):1223, 1988

Kulhanjian JA, Soroush V, Au DS, et al: Identiication of women at unsuspected risk of primary infection with herpes simplex virus type 2 during pregnancy. N Engl J Med 326(14):916, 1992

Laga M, Plummer FA, Nzanze H, et al: Epidemiology of ophthalmia neonatorum in Kenya. Lancet 2(8516):1145, 1986

Larsen SA, Steiner BM, Rudolph AH: Laboratory diagnosis and interpretation of tests for syphilis. Clin Microbiol Rev 8: 1, 1995

Lawn JE, Blencowe H, Waiswa P, et al: Stillbirths: rates, risk factors, and acceleration towards 2030. Lancet ,t2016

LeFevre ML, U.S. Preventive Services Task Force: Screening for Chlamydia and gonorrhea: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 161(12):902,t2014

LeGof J, Pe� H, Belec L: Diagnosis of genital herpes simplex virus infection in the clinical laboratory. Virol J 11 :83, 2014

Leitich H, Brunbauer M, Bodner-Adler B, et al: Antibiotic treatment of bacterial vaginosis in pregnancy: a meta-analysis. Am J Obstet Gynecol 52,t2003

Levett PN, Fonseca K, Tsang RS, et al: Canadian Public Health Laboratory Nerwork laboratory guidelines for the use of serological tests (excluding point-oE-care tests) for the diagnosis of syphilis in Canada. Can J Infect Dis Med Microbiolt26 Suppl A:6A, 2015

Lewis SH, Reynolds-Kohler C, Fox HE, et al: HIV-1 in trophoblastic and villous Hofbauer cells, and haematological precursors in eight-week fetuses. Lancet 335:565, 1990

Liang Z, Chen F, Yang CS, et al: Meta-analysis of ceftriaxone compared with penicillin for the treatment of syphilis. Int J Antimicrob Agents (1) :6, 2016 Liu G, Markowitz LE, Hariri S, et al: Seroprevalence of 9 human papillomavirus rypes in the United States, 2005-2006. J Infect Dis 213(2):191, 2016 Lucas MJ, Theriot SK, Wendel GD: Doppler systolic-diastolic ratios in preg nancies complicated by syphilis. Obstet Gynecol 7:217, 1991

Mabry-Hernandez I, Oliverio-Hofman R: Ocular prophylaxis for gonococcal ophthalmia neonatorum: evidence update for the U.S. Preventive Services Task Force reairmation recommendation statement. AHRQ Publication No. 10-05146. Rockville, Agency for Healthcare Research and Qualiry, 2010

Mahnert N, Roberts SW, Laibl R, et al: he incidence of neonatal herpes infection. Am J Obstet Gynecol 196:e55, 2007

Major CA, Towers CV, Lewis DF, et al: Expectant management of preterm rupture of membranes complicated by active recurrent genital herpes. Am J Obstet GynecoIt188:1551, 2003

Mandelbrot L, Mayaux MJ, Bongain A, et al: Obstetric factors and motherto-child transmission of human immunodeficiency virus type 1: the French perinatal cohorts. SEROGEST French Pediatric HI\

Infection Study Group. AmJ Obstet 5(3 Pt 1):661,t1996

Mandelbrot L, Tubiana R, Le Chenadec J, et al: No perinatal HIV-1 transmissions from women with efective ART starting before conception. Clin Infect Dis 61(11):1715, 2015

Mann JR, McDermott S, Zhou L, et al: Treatment of trichomoniasis in pregnancy and preterm birth: an observational study. J Womens Health (Larchmt) 18(4):493,t2009

Marquez L, Levy ML, Munoz FM, et al: A report of three cases and review of intrauterine herpes simplex virus infection. Pediatr Infect Dis J 30(2): 153, 2011

Marsico M, Mehta V, Chastek B, et al: Estimating the incidence and prevalence of juvenile-onset recurrent respiratory papillomatosis in publicly and privately insured claims databases in the United States. Sex Transm Dis 41(5):300,t2014

Marys K, Mallary S, Bautista 0, et al: Mother-infant transfer of anti-human papillomavirus (HPV) antibodies following vaccination with the quadrivalent HPV (rype 6/1t1116/18) virus-like particle vaccine. Clin Vaccine Immunol 19(6):881,t2012

McCord E, Rahn DD, Hofman BL: Gynecologic infection. In Hofman BL, Schorge JO, Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGraw-Hill Education, 2016

McGill Ai, Bavaro MF, You WB: Postpartum herpes sim plex virus endometritis and disseminated infection in both mother and neonate. Obstet Gynecol 120(2 Pt 2):471,t2012

Meites E, Kempe A, Markowitz LE: Use of a 2-dose schedule for human papillomavirus vaccination-updated recommendations of the Advisory Committee on Immunization Practices. MMWR 65(49):1405,t2016

M0lgaard-Nielsen D, Svanstrom H, Melbye M, et al: Association berween use of oral luconazole during pregnancy and risk of spontaneous abortion and stillbirth. JAMA 315(1):58,t2016

Moodley D, Sartorius B, Madurai S, et al: Pregnancy outcomes in association with STDs including genital HSV-2 shedding in a South African cohort study. Sex Transm Infect 93(7):460, 2017

Moreira ED Jr, Block SL, Ferris D, et al: Safery proile of the 9-valent HPV vaccine: a combined analysis of 7 phase III clinical trials. Pediatrics 138(2): pii:e20154387,t2016

Murphy K, Mitchell CM: The interplay of host immuniry, environment and the risk of bacterial vaginosis and associated reproductive health outcomes. J Infect Dis 214 Suppl 1:S29, 2016

Myles TD, Elam G, Park-Hwang E, et al: The Jarisch-Herxheimer reaction and fetal monitoring changes in pregnant women treated for syphilis. Obstet Gynecol 92:859, 1998

Nathan L, Bohman VR, Sanchez PJ, et al: In utero infection with Treponema paLidum in early pregnancy. Prenat Diagn 17: 119, 1997

Newman L, Rowley J, Vander Hoorn S, et al: Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting. PLoS One 10(12):e0143304, 2015

Niyibizi J, Rodier C, Wassef M, et al: Risk factors for the development and severiry of juvenile-onset recurrent respiratory papillomatosis: a systematic review. Int J Pediatr Otorhinolaryngol 78(2): 186, 2014

Nugent RP, Krohn A, Hillier SL: Reliabiliry of diagnosing bacterial vaginosis is improved by a standardized method of Gram stain interpretation. J Clin , 1991

Nygren P, Fu R, Freeman M, et al: Screening and treatment for bacterial vaginosis in pregnancy: systematic review to update the 200t1 U.S. Preventive Services Task Force Recommendation. Rockville, Agency for Healthcare Research and Qualiry, 2008

Panagiotou OA, Befano BL, Gonzalez P, et al: Efect of bivalent human papillomavirus vaccination on pregnancy outcomes: long term observational follow-up in the Costa Rica HPV Vaccine Trial. BMJ 351:h4358, 2015

Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission: Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. 2016. Available at: http://aidsinfo.nih.gov/contentfilesllvguidelines/PerinataIGL.pdf. Accessed June 3,t2017

Papp JR, Schachter J, Gaydos CA, et al: Recommendations for the laboratorybased detection of Chlamydia trachomatis and Neisseria gonorrhoeae-20 14. MMWR 63(0):1,t2014

Pasternak B, Hiviid A: Use of acyclovir, valacyclovir, and famciclovir in the irst trimester of pregnancy and the risk of birth defect. JAMA 304(8):859, 2010

Paukku M, Tulppala M, Puolakkainen M, et al: Lack of association berween serum antibodies to Chlamydia trachomatis and a history of recurrent pregnancy loss. Fertil Steril 72:427, 1999

Peeling RW', Ye H: Diagnostic tools for preventing and managing maternal and congenital syphilis: an overview. Bull World Health Organ 82(6):439, 2004 Peipert JF: Clinical practice: genital chlamydial infections. N Engl J Med 18: 349, 2003

Peters H, Francis K, Harding K, et al: Operative vaginal delivery and invasive procedures in pregnancy among women living with HIY. Eur J Obstet Gynecol Reprod Bioi 210:295, 2016

Pizer: Flagyl (metronidazole tablets). 2016. Available at: http://www.labeling. pizer.com/ShowLabeling.aspx?id = 570. Accessed March 21, 2017

Pinninti SG, Angara R, Feja KN, et al: Neonatal herpes disease following maternal antenatal antiviral suppressive therapy: a multicenter case series. J Pediatr 161(1):134,t2012

Prober CG, Sullender WM, Yasukawa LL, et al: Low risk of herpes simplex virus infections in neonates exposed to the virus at the time of vaginal delivery to mothers with recurrent genital herpes simplex virus infections. N Engl J Med 316:240, 198

Rae M, Bryant S, Cantey J, et al: Maternal titers after adequate syphilotherapy during pregnancy. Am J Obstet GynecoIt210:S233, 2014a

Rae M, Bryant S, McItire DD, et al: Progression of ultrasound findings of fetal syphilis following maternal treatment. m j Obstet GynecoI210:S26, 2014b Rae MW, Revell PA, Eppes CS: Syphilis during pregnancy: a preventable threat to maternal-fetal health. Am J Obstet GynecoIt216(4):352, 201 Ravel j, Gajer P, Abdo Z, et al: Vaginal microbiome of reproductive-age women. Proc Narl Acad Sci USA 108 (Suppl 1):4680,t2011

Read JS, Committee on Pediatric AIDS: Human milk, breastfeeding, and transmission of human immunodeiciency virus rype 1 in the United States. Pediatrics 112: 1196, 2003

Read JS, Newell MK: Eicacy and safery of cesarean delivery for prevention of mother-to-child transmission of HIV-1. Cochrane Database Syst Rev 4:CD005479, 2005

Roberts CL, Algert CS, Rickard KL, et al: Treatment of vaginal candidiasis for the prevention of preterm birth: a systematic review and meta-analysis. Syst Rev 4:31,t2015

Roberts SW, Sheield JS, McIntire DD, et al: Urine screening for Chlamydia trachomatis during pregnancy. Obstet Gynecol (4):883,t201t1

Romero R, Hassan SS, Gajer P, et al: The composition and stabiliry of the vaginal microbiota of normal pregnant women is diferent from that of nonpregnant women. Microbiome 2(1):4,t2014

Rosenman MB, Mahon BE, Downs SM, et al: Oral erythromycin prophylaxis vs watchful waiting in caring for newborns exposed to Chlamydia trachomatis. Arch Pediatr Adolesc Med 15 (6):565,t2003

Satterwhite CL, Torrone E, vfeites E, et al: Sexually transmitted infections among US women and men: prevalence and incidence estimates, 2008. Sex Transm Dis ,t2013

Schneider E, Whitmore S, Glynn NI, et al: Revised surveillance case definitions for HIV infection among adults, adolescents, and children aged < 18 months and for HIV infection and AIDS among children aged 18 months to <13 years-United States, 2008. MMWR 57(10):1, 2008

Schulte JM, Bellamy AR, Hook EW 3rd, et al: HSV-1 and HSV-2 seroprevalence in the United States among asymptomatic women unaware of any herpes simplex virus infection (Herpevac Trial for Women). South Med J 107(2):79,t2014

Schulte JM, Burkham S, Hamaker 0, et al: Syphilis among HIV-infected mothers and their infants in Texas from 1988 to 1994. Sex Transm Dis 28: 316,t2001

Schwartz OA, Larsen SA, Beck-Sague C, et al: Pathology of the umbilical cord in congenital syphilis: analysis of 25 specimens using histochemistry and immunoluorescent antibody to Treponema pa//idum. Hum PathoIt26:784, 1995

Schwebke JR, Desmond A: A randomized controlled trial of partner notiication methods for prevention of trichomoniasis in women. Sex Transm Dis 37(6):392,t2010

Schwebke JR, Hobbs MM, Taylor SN, et al: vlolecular testing for Trichomonas vagina/is in women: results from a prospective U.S. clinical trial. J Clin MicrobioIt49(12):4106, 2011

Scott LL, Hollier LM, McIntire 0, et al: Acyclovir suppression to prevent recurrent genital herpes at delivery. Infect Dis Obstet Gynecol 10:71, 2002 Selik M, Mokotof ED, Branson B, et al: Revised surveillance case deinition for HIV infection-United States, 2014. MMWR 63(3):1,t2014

Sefia AC, Zhang XH, Li T, et al: A systematic review of syphilis serological treatment outcomes in HIV-infected and HIV-uninfected persons: rethinking the signiicance of serological non-responsiveness and the serofast state after therapy. BMC Infect Dis 15:479,t2015

SheieldJS, Fish ON, Hollier LM, et al: Acyclovir concentrations in human breast milk ater valacyclovir administration. Am J Obstet Gynecol 186: 1 00, 2002a

Sheield ]S, Hill JB, Hollier LM, et al: Valacyclovir prophylaxis to prevent recurrent herpes at delivery: a randomized clinical trial. Obstet Gynecol 108:141,t2006

Sheield JS, Hollier LM, Hill JB, et al: Acyclovir prophylaxis to prevent herpes simplex virus recurrence at delivery: a systematic review. Obstet Gynecol 102: 1396, 2003

Sheield JS, Sanchez P], Morris G, et al: Congenital syphilis after maternal treatment for syphilis during pregnancy. Am J Obstet Gynecol 186:569, 2002b Sheield JS, Sanchez PJ, Wendel GO Jr, et al: Placental histopathology of congenital syphilis. Obstet Gynecol 100: 126, 2002c

Silva MJ, Florencio GL, Gabiatti JR, et al: Perinatal morbidiry and mortality associated with chlamydial infection: a meta-analysis study. Braz J Infect Dis 15(6):533,t2011

Silver BJ, Guy R], Kaldor JM, et al: Trichomonas vagina/is as a cause of perinatal morbidity: a systematic review and meta-analysis. Sex Transm Dis 41(6):369,t2014

Silverberg MJ, Thorsen P, Lindeberg H, et al: Condyloma in pregnancy is strongly predictive of juvenile-onset recurrent respiratory papillomatosis. Obstet Gynecol 101:645,t2003

Silverstein AM: Congenital syphilis and the timing of immunogenesis in the human fetus. Nature 194:196, 1962

Singh AE, Chernesky MA, Morshed M, et al: Canadian Public Health Laboratory Network laboratory guidelines for the use of point-of-care tests for the diagnosis of syphilis in Canada. Can J Infect Dis Med Microbiol 26 Suppl A):29A,t2015

Singh AE, Romanowski B: Syphilis: review with emphasis on clinical, epidemiologic, and some biologic features. Clin Microbiol Rev 12(2): 187, 1999

Slyker JA, Chung MH, Lehman DA, et al: Incidence and correlates of HIV-1 RNA detection in the breast milk of women receiving HAART for the prevention of HI V-I transmission. PLoS One 7(1):e29777, 2012

Smith EM, Ritchie JM, Yankowitz J, et al: Human papillomavirus prevalence and types in newborns and parents. Sex Transm Dis 31:57,t2004

Sobel JD: Vulvovaginal candidosis. Lancet 369:1961,t2007

Stamm LV: Syphilis: antibiotic treatment and resistance. Epidemiol Infect 143(8):1567,t2015

Stewart R, Wells CE, Roberts S, et al: Beneit of inter-pregnancy HIV viral load suppression on subsequent maternal and infant outcomes. m J Obstet Gynecol 21O:S14, 2014

Stone NI, Reif-Eldridge R, White AD, et al: Pregnancy outcomes following systemic prenatal acyclovir exposure: conclusions from the International Acyclovir Pregnancy Registry, 1984-1t999. Birth Defects Res A Clin Mol Teratol 70:201, 2004

Strick LB, Wald A: Diagnostics for herpes simplex virus: is PCR the new gold standard? Mol Diagn her 10(1):17, 2006

SU JR, Brooks LC, Davis OW, et al: Congenital syphilis: trends in mortality and morbidity in the United States, 1999 through 2013. Am J Obstet Gynecolt214(3):381.e1,t2016

Subramaniam A, Lees BF, Becker DA, et al: Evaluation of human papillomavirus as a risk factor for preterm birth or pregnancy-related hypertension. Obstet GynecoIt127(2):233, 2016

Sutton M, Sternberg M, Koumans EH, et al: The prevalence of Trichomonas vagina/is infection among reproductive-age women in the United States, 2001-2004. Clin Infect Dis 45(10):1319, 2007

Swain CA, Smith LC, Nash 0, et al: Postpartum HIV care among women diagnosed during pregnancy. Obstet Gynecol 128(1):44,t2016

Tenti P, Zappatore R, Migliora P, et al: Perinatal transmission of human pap illomavirus from gravidas with latent infections. Obstet Gynecol 93(4):475, 1999

Townsend CL, Byrne L, Cortina-Borja M, et al: Earlier initiation of ART and further decline in MTCT, 2000-20t11. AIDS 28(7):1049, 2014

Trintis J, Epie N, Boss R, et al: Neonatal Trichomonas vagina/is infection: a case report and review of literature. Int J STD AIDS 21 (8):606, 2010

Tsang RS, Morshed M, Chernesky MA, et al: Canadian Public Health Laboratory Network laboratory guidelines for the use of direct tests to detect syphilis in Canada. Can J Infect Dis Med Microbiol 26 Suppl A): 13A, 2015

Tucker JD, Bu J, Brown LB, et al: Accelerating worldwide syphilis screening through rapid testing: a systematic review. Lancet Infect Dis 10(6):381, 2010

U.S. Preventive Services Task Force, Bibbins-Domingo K, Grossman DC, et al: Serologic screening for genital herpes infection: US Preventive Services Task Force recommendation statement. JAMA 316(23):2525,2016

Van Der Pol B, Williams JA, Taylor SN, et al: Detection of Trichomonas vagina/is DNA by use of self-obtained vaginal swabs with the BD ProbeTec Qx assay on the BD Viper system. J Clin Microbiol 52:885, 2014

Vichnin M, Bonanni P, Klein NP, et al: An overview of quadrivalent human papillomavirus vaccine safety: 2006 to 2015. Pediatr Infect Dis J 34(9):983, 2015

Wald A, Ashley-Morrow R: Serological testing for herpes simplex virus (HSV)-1 and HSV-2 infection. Clin Infect Dis 35:S173, 2002

Watts 0: Mother to child transmission of HI V-another complication ofbacterial vaginosis? J Acquir Immune Deic Syndr 60(3),t2012

Watts DH, Brown ZA, Money 0, et al: A double-blind, randomized, placebo-controlled trial of acyclovir in late pregnancy for the reduction of herpes simplex virus shedding and cesarean delivery. Am J Obstet Gynecol 188:836, 2003

Watts DH, Krohn .1A, Hillier SL, et al: Bacterial vaginosis as a risk factor for postcesarean endometritis. Obstet Gynecol 75:52, 1990

Wendel GO Jr: Gestational and congenital syphilis. Clin Perinatol 15:287, 1988

Wendel GO Jr, Sheield JS, Hollier LM, et al: Treatment of syphilis in pregnancy and prevention of congenital syphilis. Clin Infect Dis 35(Suppl 2): S200, 2002

Wendel GO Jr, Stark BJ, Jamison RB, et al: Penicillin allergy and desensitization in serious infections during pregnancy. N EnglJ Med 312:1229,t1985

Werner CL, Griith WF: Preinvasive lesions of the lower genital tract. In Hofman BL, Schorge JO, Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGraw-Hili Education, 2016

Wiese W, Patel SR, Patel SC, et al: A meta-analysis of the Papanicolaou smear and wet mount for the diagnosis of vaginal trichomoniasis. Am J Med 108(4):301,t2000

Wiesenfeld HC: Screening for Chlamydia trachomatis infections in women.

N Engl J Med 376(8):765,t2017

WolfT, Shelton E, Sessions C, et al: Screening for syphilis infection in pregnant women: evidence for the U.S. Preventive Services Task Force reairmation recommendation statement. Ann Intern Med 150(10):710,t2009

W0lner-Hanssen P, Krieger IN, Stevens CE, et al: Clinical manifestations of vaginal trichomoniasis. JAMA 261 (4):571, 1989

Workowski A, Bolan GA, Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines, 2015. MMWR 64(3): 1, 2015 orld Health Organization: Global incidence and prevalence of selected sexually transmitted infections-2008. Geneva, WHO, 20] 2

World Health Organization, United Nations Children's Fund: Guideline: updates on HIV and infant feeding: the duration of breastfeeding, and support from health services to improve feeding practices among mothers living with HIV. Geneva, WHO, 2016

Xu F, Lee FK, Morrow A,et al: Seroprevalence of herpes simplex virus type 1 in children in the United States. J Pediatr 151(4):374,t2007

Zhou P, Qian Y, Xu J, et al: Occurrence of congenital syphilis after matenal treatment with azithromycin during pregnancy. Sex Transm Dis 34:472, 2007

Zhou Y, Bian G, Zhou Q, et al: Detection of cytomegalovirus, human parvovirus B 19, and herpes simplex virus-112 in women with irst-trimester spontaneous abortions. J Med Virol 87(10): 1749,t2015

I. SERUM AND BLOOD CONSTITUENTS ............... 1255

II. MATERNAL ECHOCARDIOGRAPHIC MEASUREMENTS .. 1261

III. FETAL SONOGRAPHIC MEASUREMENTS ...r........ 1262

APPENDIX I. Serum and Blood Constituents

Erythropoietinb (U/L) 4-27 12-25 8-67 14-222 7,10,47

Ferritinb (ng/mL) 10-150d 6-130 2-230 0-116 � lQ 3�r42,r45,r4�r62, 70

Folate, red blood cell 150-450 137-589 94-828 109-663 45,r46,r72 (ng/mL) Folate, serum (ng/mL) 5.4-18.0 2.6-15.0 0.8-24.0 1.4-20.7 7,r43,r45,r46,r53,r58,r72

Hemoglobinb (g/dL) 12-15.8d 11.6-13.9 9.7-14.8 9.5-15.0 10,45,47,58,r62

HematocritiJ (%) 35.4-44.4 31.0-41.0 30.0-39.0 28.0-40.0 6, 7, 10,42,45 58,66

Iron, total binding 251-406 278-403 Not reported 359-609 62 capacity (TIBC)b (.Lg/dL)

Iron, serum.b (Lg/dL) 41-141 72-143 44-178 30-193 10,62

Mean corpuscular volume 79-93 81r-96 82-97 81r-99 6,r42,r45,r58

Platelet (x109 /L) 165-41r5 174-39r1 155-409 146-429 4,r6,r16,42,r45

Mean platelet volume 6.4-11.0 7.7-10.3 7.8-10.2 8.2-10.4 42

Red blood cell count 4.00-5.20 3.42-4.55 2.81-4.49 2.71-4.43 6,42,45,58

Red cell distribution <14.5 12.5-14.1 13.4-13.6 12.7-15.3 42

White blood cell count 3.5-9.1 5.7-13.6 5.6-14.8 5.9-16.9 6,9,42,45,r58

Neutrophils (x 103/mm3) 1.4-4.6 3.6-10.1 3.8-12.3 3.9-13.1 4,6,9,42

Lymphocytes (x103/mm3) 0.7-4.6 1.1-3.6 0.9-3.9 1.0-3.6 4,6,9,42

Monocytes (x103/mm3) 0.1-0.7 0.1-1.1 0.1-1.1 0.1-1.4 6,9,42

Eosinophils (x 103/mm3) 0-0.6 0-0.6 0-0.6 0-0.6 6, 9

Basophils (x103/mm3) 0-0.2 0-0.1 0-0.1 0-0.1 6,r9 200-400c 254-344 220-441 288-530 39,r42 Transferrin, saturation 22-46b Not reported 10-44 5-37

Transferrin, saturation 22-46b Not reported 18-92 9-98

Creatinine (mg/dL) 0.5-0.9d 0.4-0.7 0.4-0.8 0.4-0.9 39,r42,r45 Gamma-glutamyl 9-58 2-23 4-22 3-26 5,r42,r39,r70 transpeptidase (GGT)

Lactate dehydrogenase 115-221 78-433 80-447 82-524 42,29,39,r70

Magnesium (mg/dL) 1.5-2.3 1r.6-2.2 1.5-2.2 1.1r-2.2 3,r26,r29,r39,r42,r48,r63

Osmolality (mOsm/kg H2O) 275-295 275-280 276-289 278-280 17,r63

Phosphate (mg/dL) 2.5-4.3 3.1r-4.6 2.5-4.6 2.8-4.6 3,r26,r33,r39,r42

Potassium (mEq/L) 3.5-5.0 3.6-5.0 3.3-5.0 3.3-5.1 20,r26,r29,r39,r42,r63,r66

Protein, total (g/dL) 6.7-8.6 6.2-7.6 5.7-6.9 5.6-6.7 26,r29,r42

Sodium (mEq/L) 136-146 133-148 129-148 130-148 17,26,29,39,42,63,66 Urea nitrogen (mg/dL) 7-20 7-1r2 3-1r3 3-1r1 20,r39,r42

Uric acid (mg/dL) 2.5-5.6d 2.0-4.2 2.4-4.9 3.1r-6.3 17,r39,r42

Aldosterone (ng/dL) 2-9 6-104 9-104 15-101 21,r34,69

Angiotensin-converting 9-67 1-38 1-36 1-39 20, 54

Cortisol (19/dL) 0-25 7-1r9 10-42 12-50 42,r69 4-6 4-7 48,r49,r59

Thyroxine, total (T 4) 5.4-1r1.7 6.5-10.r1 7.5-1r0.3 6.3-9.7 29,r42

C-reactive protein (CRP) 0.2-3.0 Not reported 0.4-20.3 0.4-8.1 28

Dehydroepiandrosterone 1.3-6.8e 2.0-16.5 0.9-7.8 0.8-6.5 52 sulfate (DHEAS)

Estradiol (pg/mU <20-443dJ 188--2497 1278-7192 6137-3460 1.3,52

Progesterone (ng/mL) <1-20d 8-48 99-342 13,n52

Prolactin (ng/mL) 0-20d 36-2n13 11n0-330 137-372 3,n13,n38,n49

Sex hormone binding 18-114d 39-131 214-717 216-724 1,52

Testosterone (ng/dL) 6-86d 25.7-211.4 34.3-242.9 62.9-308.6 17-Hydroxyprogesterone 0.6-1 O.6d.e 5.2-28.5 5.2-28.5 15.5-84 52

P02 (mm Hg) 90-100 93-100 90-98 92-107 23,67 pH 7.38-7.42 7.36-7.52 7.40-7.52 7.41r-7.53 23, 26 7.39-7.45 aUnless otherwise specified, all normal reference values are from the seventeenth edition of Harrison's Principles of Internal Medicine (37). bRange includes references with and without iron supplementation.

(Reference values are from Laboratory Reference Handbook, Pathology Department, Parkland Hospital, 2005. dNormal reference range is specific range for females.

=Reference values are from the 15th edition of Harrison's Principles of Intenal Medicine (1r2). fRange is for premenopausal females and varies by menstrual cycle phase.

9Reference values are from Cerneca et al: Coagulation and fibrinolysis changes in normal pregnancy increased levels of procoagulants and reduced levels of inhibitors during pregnancy induce a hypercoagulable state, combined with a reactive fibrinolysis (1r5).

hReference values are from Cerneca et al and Choi et al: Tissue plasminogen activator levels change with plasma fibrinogen concentrations during pregnancy (1r5, 16).

'Reference values are from Mannucci et al: Changes in health and disease of the metalloprotease that cleaves von Willebrand factor (44A).

jReference values are from Bacq et al: Liver function tests in normal pregnancy: a prospective study of 102 pregnant women and 102 matched controls (5).

kReference values are from et al: Creatine kinase and its MB isoenzyme in the third trimester and the peripartum period (41).

'Reference values are from Dunlop: Serial changes in renal haemodynamics during normal human pregnancy (1r9). Appendix courtesy of Dr. Mina Abbassi-Ghanavati and Dr. Laura G. Greer.

APPENDIX II. Maternal Echocardiographic Measurements

IVSd (mm) 7.3±1.0 7.4 ± 1.1 7.8 ± 1.2 7.1 ± 0.9

LVEDD (mm) 45-47.8 47-48.9 47-49.6 46-48.8

LVESD (mm) 28-30 29-30.1 30-30.8 28-30.6

PWd 6.3 ± 0.7 6.6 ± 0.7 6.9 ± 1.0 6.1 ± 0.6

RVT 0.26-0.36 0.27-0.37 0.28-0.38 0.25-0.35

PW thickening (%) 66 ± 16 72 ± 16 74 ± 16 71 ± 14 VCFC (circ/sec) 1.15-0.3 1.18-0.16 1.18-0.12 1.18-0.·12

Mitral E wave (m/sec) 0.85 ± 0.13 0.84 ± 0.16 0.77 ± 0.15 0.77 ± 0.11

Mitral A wave (m/sec) 0.5 ± 0.09 0.5 ± 0.1 0.55 ± 0.1 0.46 ± 0.1

Values are ranges or means ± SD.

Circ = circumference; d = diastolic; ESS = end-systolic wall stress; FS = fractional shortening; IVRT = isovolumic relaxation time; IVSd = interventricular septum-diastole; LV = let ventricle; LVEDD = left ventricular end-diastolic dimension; LVESD = let ventricular end-systolic dimension; PW = posterior wall; RWT = relative wall thickening; SW = septal wall; VCFC = rate-adjusted mean velocity of circumferential fiber thickening.

Data from Savu (62A) and Vitarelli (71 A).

APPENDIX III. Fetal Sonographic Measurements

TABLE 111-1. Mean Gestational Sac Diameter and Crown-Rump Length and Corresponding Menstrual Age 32 4.6 3 34 4.9 5 36 5.1 6 38 5.4 8 10 0.2 42 6.0 12 OJ5 44 6J 14 0.5 46 6.6 16 0.7 48 6.9 18 0.9 50 7.1 1r.0 52 7.4 22 1.2 54 7.7 24 1.4 56 8.0 58 8.3 27 1.8 60 8.6 29 2.0 8.9 31 2.2 64 9.1 33 2.4 66 9.4 2.6 2.9 70 10.0 3.1 74 10.6 3.7 76 10.9 4.0 78 11.1 47 4.2 80 11.4 49 4.6 12.0 53 5.4

Data from Nyberg, 1992; Hadlock, 1992; 1975; Daya, 1991r.

TABLE 111-2. Mean Gestational Age Percentiles Corresponding to Crown-Rump Length (CRL) Measurements

TABLE 111-3. Fetal Weight Percentiles According to Gestational Age

Adapted with permission from Hadlock, 1991n.

TABLE 111-4. Smoothed Birth Weight Percentiles for Twins with Dichorionic Placentation

GA = gestational age.

Reproduced with permission from Ananth, 1998.

TABLE 111-5. Smoothed Birth Weight Percentiles for Twins with Monochorionic Placentation

Reproduced with permission from Ananth, 1998.

TABLE 111-6. Fetal Thoracic Circumference Measurements (cm) According to Gestational Age

Age (wk) No. 2.5 5 10 25 50 75 90 95 97.5 16 6 6.4 7.0 8.0 9.1 10.3 11.3 11.9 12.4 8.9 10.0 11.2 12.2 12.8 13.3 22 6.8 8.2 8.8 9.8 1 '1.0 12.1 13.1 13.7 14.2 19 21 8.6 9.7 10.7 11.9 13.0 14.0 14.6 15.1 20 20 9.6 10.0 10.6 11.7 12.8 13.9 15.0 15.5 16.0 30 10.4 11.0 11.6 12.6 13.7 14.8 15.8 16.4 16.9 18 11.3 11.9 12.5 13.5 14.6 15.7 16.7 17.3 17.8 12.2 12.8 13.4 14.4 15.5 16.6 17.6 18.2 18.8 27 13.2 13.7 14.3 15.3 16.4 17.5 18.5 19.1 19.7 20 14.1 14.6 15.2 16.2 17.3 18.4 19.4 20.0 20.6 25 15.0 15.5 16.1 17.1 18.2 19.3 21n.0 21n.5 27 24 15.9 16.4 17.0 18.0 19.1 20.2 21.3 21.9 22.4 24 16.8 17.3 18.9 20.0 21.2 22.2 22.8 23.3 24 17.7 18.2 18.8 19.8 21.0 22.1 23.1 23.7 24.2 18.6 19.1 19.7 21n.9 23.0 24.0 24.6 25.1 24 19.5 20.0 20.6 21.6 22.8 23.9 24.9 25.5 26.0 20.9 32 28 21n.5 22.6 23.7 24.8 25.8 26.4 26.9 21.3 21.8 22.5 23.5 24.6 25.7 27.3 27.8 28.2 28.722.2 22.8 23.4 24.4 25.5 26.6 27.6 20 23.1 23.7 24.3 25.3 26.4 27.5 28.5 29.1 29.6 23 24.0 24.6 25.2 26.2 27.3 28.4 29.4 30.0 30.6 37 22 24.8 25.5 26.1 27.1 28.2 29.3 30.3 30.9 31.5 25.9 26.4 27.0 28.0 29.1 30.2 31.2 31.9 32.4 39 7 26.8 27.3 27.9 30.0 31.1 32.2 32.8 33.3 6 27.7 28.2 28.8 29.8 30.9 32.1 33.1 33.7 34.2

Reproduced with permission from Chitkara, 1987.

Reproduced with permission from Jeanty, 1983,

TABLE 111-8. Ocular Parameters According to Gestational Age

Adapted with permission from Romero R, 1988.

TABLE 111-9. Transverse Cerebellar Diameter Measurements According to Gestational Age

Age (wk) 10 25 50 75.. 90 23 21.5 28 28 29 40.5 43 38 40 40 48.5 52 55

Adapted with permission from Goldstein, 1987.

TABLE 111-10. Reference Values for Umbilical Artery Doppler Indices 23 0.63 2.71 0.73 3.73 0.83 24 0.62 2.64 0.72 3.59 0.82 25 0.61 2.57 0.71 3.46 0.81 5.28 26 0.60 2.50 0.70 0.80 5.01 27 0.59 244 0.69 3.22 0.79 4.76 28 0.58 2.38 0.68 3.1n2 0.78 29 0.57 2.32 0.67 3.02 0.77 30 0.56 2.26 0.66 2.93 0.76 4.'14 31 0.55 2.21 0.65 2.84 0.75 32 0.54 2.1n6 0.64 2.76 0.74 3.81 0.53 2.1n1 0.63 2.68 0.73 3.66 0.52 2.07 0.62 2.61 0.72 3.53 0.51 2.03 0.61 2.54 0.71 340 36 0.50 1n.98 0.60 2.47 0.70 3.29 37 049 1n.94 0.59 2.41 0.69 3.18 38 0.47 1.90 0.57 2.35 0.67 3.08 39 0.46 1n.87 0.56 2.30 0.66 2.98 40 0n45 1.83 0.55 2.24 0.65 2.89 0.44 1.80 0.54 2.1n9 0.64 2.81 0.43 1.76 0.53 2.14 0.63 2.73

GA = gestational age.

Adapted with permission from Kofnas AD, 1992.

1.

Acromite MT, Mantzoros CS, Leach E, et al: Androgens in preeclampsia. mJ Obstet Gynecol 180:60, 1999 2.

Alvarez S1, Castanon SG, Ruata MLC, et al: Updating of normal levels of copper, zinc and selenium in serum of pregnant women. J Trace Elem Med BioI 21(Sl):49, 200 2A. Ananth CV, Vintzileos, Shen-Schwarz S, et al: Standards of birth weight in rwin gestations. Obstet Gynecol 91 :917, 1998 3. Ardawi MSM, Nasrat HAN, BA'Aqueel HS: Calcium-regulating hormones and parathyroid hormone-related peptide in normal human pregnancy and postpartum: a longitudinal study. Eur J Endocrinol 13 :402, 1997 3A. Aslam N, Ong C, Woelfer B, et al: Serum CA ] 25 at 11-14 weeks of gestation in women with morphologically normal ovaries. BJOG 107(5): 689, 2000 4.

Aziz Karim S, Khurshid M, Rizvi JH, et al: Platelets and leucocyte counts in pregnancy. J Pak Med Assoc 42:86, 1992 5.

Bacq Y, Zarka 0, Brechot JF, et al: Liver function tests in normal pregnancy: a prospective study of 102 pregnant women and 102 matched controls. Hepatology 23: 1 030, 1996 6.

Balloch AJ, Cauchi MN: Reference ranges for haematology parameters in pregnancy derived from patient populations. Clin Lab HaematoIt15:7, 1993 7.

Beguin Y, Lipscei G, Thourmsin H, et al: Blunted erythropoietin production and decreased erythropoiesis in early pregnancy. Blood 78(1):89, 1991 8.

Belo L, Cas lake M, Gafney 0, et al: Changes in LDL size and HDL concentration in normal and preeclamptic pregnancies. Atherosclerosis 162:425,t2002 9.

Belo L, Santos-Silva A, Rocha S, et al: Fluctuations in C-reactive protein concentration and neurrophil activation during normal human pregnancy. Eur J Obstet Gynecol Reprod BioI 123:46, 2005 10.

Bianco I, Mastropietro F, D'Aseri C, et al: Serum levels of erythropoietin and soluble transferrin receptor during pregnancy in non-j-thalassemic and j-thalassemic women. Haematologica 85:902, 2000 11.

Borghi CB, Esposti DO, Immordino V, et al: Relationship of systemic hemodynamics, left ventricular structure and function, and plasma natriuretic peptide concentrations during pregnancy complicated by preeclampsia. Am J Obstet Gynecol 183:140,2000 12.

Braunwald E, Fauci AS, Kasper DL, et al (eds): Appendices. In Harrison's Principles ofInternal Medicine, 15th ed. New York, McGraw-Hili, 2001, p A-I 12A. Burlingame J, Hyeong JA, Tang WHW: Changes in cardiovascular biomarkers throughout pregnancy and the remote postpartum period. Am J Obstet Gynecol 208:S9 ,t2013 13.

Carranza-Lira S, Hernandez F, Sanchez M, et al: Prolactin secretion in molar and normal pregnancy. Int J Gynaecol Obstet 60: 137, 1998 14.

Carter J: Serum bile acids in normal pregnancy. B]OG 98:540,t1991 15.

Cerneca F, Ricci G, Simeone R, et al: Coagulation and fibrinolysis changes in normal pregnancy increased levels of procoagulants and reduced levels of inhibitors during pregnancy induce a hypercoagulable state, combined with a reactive ibrinolysis. Eur J Obstet Gynecol Reprod BioI 73:31, 1997 15A. Chitkara J, Rosenberg], Chervenak FA, et al: Prenatal sonographic assessment of the fetal thorax: normal values. AmJ Obstet GynecoIt156:1069, 16.

Choit], Pai SH: Tissue plasminogen activator levels change with plasma ibrinogen concentrations during pregnancy. Ann Hematol 81:611, 2002 17.

Davison ]B, Vallotton MB, Lindheimer MD: Plasma osmolality and urinary concentration and dilution during and after pregnancy: evidence that lateral recumbency inhibits maximal urinary concentrating ability. B]OG 88:472,t1981 18.

Desoye G, Schweditsch MO, Pfeifer KP, et al: Correlation of hormones with lipid and lipoprotein levels during normal pregnancy and postpartum. J C1in Endocrinol Metab 64:704, 1987 19.

Dunlop W: Serial changes in renal haemodynamics during normal human pregnancy. B]OG 88:1,t1981 20.

Dux S, Yaron A, Carmel A, et al: Renin, aldosterone, and serum-converting enzyme activity during normal and hypertensive pregnancy. Gynecol Obstet Invest 17:252, 1984 21.

Elsheikh A, Creatsas G, Mastorakos G, et al: The renin-aldosterone system during normal and hypertensive pregnancy. Arch Gynecol Obstet 264: 182, 2001 22.

Ezimokhai M, Davison JM, Philips PR, et al: Non-postural serial changes in renal function during the third trimester of normal human pregnancy. BJOG 88:465, 1981 23.

Fadel HE, Northrop G, Misenhimer HR, et al: Acid-base determinations in amniotic fluid and blood of normal late pregnancy. Obstet Gynecol 53:99, 1979 24.

Faught W, Garner P, Jones G, et al: Changes in protein C and protein S levels in normal pregnancy. Am J Obstet Gynecol 172:147, 1995 25.

Francalanci 1, Comeglio P, Liotta A, et al: o-Dimer concentrations during normal pregnancy, as measured by ELISA. Thromb Res 78:399, 1995 25A. Goldstein I, Reece A, Pilu, et al: Cerebellar measurements with ultrasonography in the evaluation of fetal growth and development. Am J Obstet Gynecol 156:1065, 1987 25B. Hadlock FP, Harrist RB, Marinez-Poyer ]: In utero analysis of fetal growth: a sonographic weight standard. Radiology 181:129,t199.

25C. Hale SA, Sobel B, Benvenuto A, et al: Coagulation and fibrinolytic system protein proiles in women with normal pregnancies and pregnancies complicated by hypertension. Pregnancy Hypertens 2(2):152, 2012 26. Handwerker SM, Altura BT, Altura BM: Serum ionized magnesium and other electrolytes in the antenatal period of human pregnancy. ] Am Coli Nutr 15:36, 1996 26A. Haram K, Augensen K, Elsayed S: Serum protein pattern in normal pregnancy with special reference to acute phase reactants. BJOG 90(2): 139, 1983 2. Higby K, Suiter CR, Phelps ]Y, et al: Norml values of urinary albumin and totl protein excretion during pregnan. Am J Obstet Gynecol 171 :984, 1994 27A. Hui C, Lili M, Libin C, et al: Changes in coagulation and hemodynamics during pregnancy: a prospective longitudinal study of 58 cases. Arch Gynecol Obstet 285:1231,t2012 28.

Hwang HS, Kwon JY, Kim MA, et al: Maternal serum highly sensitive C-reactive protein in normal pregnancy and pre-eclampsia. Int] Gynecol Obstet 98: 105, 2007 29.

Hytten FE, Lind T: Diagnostic Indices in Pregnancy. Summit, CIBAGEIGY Corporation, 1975 30.

I1han N, Ilhan N, Simsek M: he changes of trace elements, malondiaIdehyde levels and superoxide dismutase activities in pregnancy with or without preeclampsia. Clin Biochem 35:393, 2002 30A. Jacobs IJ, Fay TN, Stabile I, et al: The distribution ofCA 125 in the reproduc tive tract of pregnant and non-pregnant women. BJOG 95(11): 1190, 1988 30B. ]eanty P: Fetal limb biometty. Radiology :602, 1983 3l. Jimenez D!, Pocovi M, Ramon-Cajal J, et al: Longitudinal study of plasma lipids and lipoprotein cholesterol in normal pregnancy and puerperium. Gynecol Obstet Invest 25:158, 1988 31A. J6iwik M, J6iwik M, Pietrzycki, et al: Maternal and fetal blood ammonia concentrations in normal term human pregnancies. Bioi Neonate 8 :38, 2005 32.

Karsenti D, Bacq Y, Brechot JF, et al: Serum amylase and lipase activities in normal pregnancy: a prospective case-control study. Am J Gastroenterol 96:697,t2001 33.

Kato T, Seki K, Matsui H, et al: Monomeric calcitonin in pregnant women and in cord blood. Obstet Gynecol 92:241, 1998 34.

Kim EH, Lim JH, Kim H, et al: he relationship between aldosterone to renin ratio and RI value of the uterine artery in the preeclamptic patient vs. normal pregnancy. Yonsei Med J 49(1): 138,t2008 35.

Kline JA, Williams GW, Hernandez-Nino J: o-Dimer concentrations in normal pregnancy: new diagnostic thresholds are needed. C1in Chen 51:825,t2005 35A. Koinas AD, Espeland A, Penry M, et al: Uteroplacental Doppler flow velocimetry waveform indices in normal pregnancy: a statistical exercise and the development of appropriate references values. m J Perinatol 9:94, 1992 36. Koscica L, Bebbington M, Bernstein PS: Are maternal serum troponin I levels afected by vaginal or cesarean delivery? Am J Perinatol21 (1):31,2004 38.

Larrea F, Mendez 1, Parra A: Serum pattern of diferent molecular forms of prolactin during normal human pregnancy. Hum Reprod 8: 1617, 1993 39.

Larsson A, Palm M, Hansson L-O, et al: Reference values for clinical chemistry tests during normal pregnancy. BJOG 115:874, 2008 39A. Lattuada A, Rossi E, Calzarossa C, et al: Mild to moderate reduction of a von Willebrand factor cleaving protease (ADMTS-13) in pregnant women with HELLP microangiopathic syndrome. Haematologica 88(9): 1029,t2003 39B. Leek AE, Ruoss CF, Kitau MG, et al: Maternal plasma alphafetoprotein levels in the second half of normal pregnancy: relationship to fetal weight, and maternal age and parity. BJOG 82:669, 1975 40.

Lefkowitz ]B, Clarke SH, Barbour LA: Comparison of protein S functional and antigenic assays in normal pregnancy. Am J Obstet Gynecol 175:657,t1996 41.

Leiserowitz GS, Evans AT, Samuels S], et al: Creatine kinase and its MB isoenzyme in the third trimester and the peripartum period. J Reprod Med 37:910, 1992 41A. Liu XH, Jiang YM, Shi H, et al: Prospective, sequential, longitudinal study of coagulation changes during pregnancy in Chinese women. lnt J Gynaecol Obstet 105(3):240,t2009 42.

Lockitch G: Handbook of Diagnostic Biochemistry and Hematology in Normal Pregnanc),. Boca Raton, CRC Press, 1993 43.

L6pez-Quesada E, Vilaseca MA, Lailla JM: Plasma total homocysteine in uncomplicated pregnancy and in preeclampsia. Eur J Obstet Gynecol Reprod BioI 108:45, 2003 44.

Louro MO, Cocho ]A, Tutor ]e Assessment of copper status in pregnancy by means of determining the speciic oxidase activity of ceruloplasmin. Clin Chim Acta 312:123,t2001 44A. Mannucci PM, Canciani MT, Forza I, et al: Changes in health and disease of the metalloprotease that cleaves von Willebrand factor. Blood 98(9): 2730,t2001 45.

Milman N, Bergholt T, Byg KE, et al: Reference intervals for haematological variables during normal pregnancy and postpartum in 434 healthy Danish women. Eur J Haematol 79:39, 2007 46.

Milman N, Byg KE, Hvas vI, et al: Erythrocyte folate, plasma folate and plasma homocysteine during normal pregnancy and postpartum: a longitudinal study comprising 404 Danish women. Eur J Haematol 76:200, 2006 47.

Milman N, Graudal N, Nielsen OJ: Serum erythropoietin during normal pregnancy: relationship to hemoglobin and iron status markers and impact of iron supplementation in a longitudinal, placebo-controlled study on 118 women. Int] HematoI66:159, 199 48.

MimoLlni F, Tsang RC, Hertzbert VS, et al: Parathyroid hormone and calcitriol changes in normal and insulin-dependent diabetic pregnancies. Obstet 4:49, 1989 49.

Montelongo A, Lasunci6n MA, Pallardo LF, et al: Longitudinal study of plasma lipoproteins and hormones during pregnancy in normal and diabetic women. Diabetes 41:1651, 1992 50.

Moran P, Baylis PH, Lindheimer, et al: Glomerular ultrafiltration in normal and preeclamptic pregnancy.t] Am Soc Nephrol 14:648,t2003 51.

Morse M: Establishing a normal range for D-dimer levels through pregnancy to aid in the diagnosis of pulmonary embolism and deep vein thrombosis. J hromb Haemost 2: 1202, 2004 51A. Nyberg DA, McGahan J, Pretorius DH, et al (eds): Diagnostic Imaging ofFetal Anomalies, 2nd ed. Philadelphia, Lippincott Williams & Wilkins, 2003, p 1015 52.

O'Leary , Boyne , Flett , et l: Longitudinal assessment of changes in reproductive hormones during normal pregnancy. C1in Chen 35(5):667, 1991 53.

bzerol E, bzerol I, Gokdeniz R, et al: Efect of smoking on serum concentrations of total homocysteine, folate, vitamin B12, and nitric oxide in pregnancy: a preliminary study. Fetal Diagn Ther 19:145,t2004 54.

Parente ]V, Franco ]G, Greene L], et al: Angiotensin-converting enzyme: serum levels during normal pregnancy. Am J Obstet GynecoI135:586, 1979 55.

Piechota W, Staszewski A: Reference ranges of lipids and apolipoproteins in pregnancy. Eur J Obstet Gynecol Reprod BioI 45:27, 1992 56.

Pitkin RM, Gebhardt MP: Serum calcium concentrations in human pregnanc),. Amt] Obstet Gynecol 127:775, 19 57.

Price A, Obel 0, Cresswell J, et al: Comparison of thyroid function in pregnant and non-pregnant Asian and western Caucasian women. Clin Chim Acta 208:91,t2001 58.

Qvist I, Abdulla M, Jagerstad M, et al: Iron, zinc and folate status during pregnancy and two months ater delivery. Acta Obstet Gynecol Scand 65:15,t1986 59.

Radder JK, Van Roosmalen J: HbAlc in healthy, pregnant women. Neth J Med 63:256, 2005 60.

Reiter EO, Braunstein GO, Vargas A, et al: Changes in 25-hydroyvitamin 0 and 24,25-dihydroxyvitamin 0 during pregnancy. Am J Obstet Gynecol 135:227, 1979 61.

Risberg A, Larsson A, Olsson K, et al: Relationship between urinary albumin and albumin/creatinine ratio during normal pregnancy and preeclampsia. ScandtJ Clin Lab Invest 64:17,t2004 61A. Romero R, Pilu G, Jeanty P, et al: Prenatal diagnosis of congenital anomalies. Norwalk, Appleton & Lange, 1988, p 83 62.

Romslo I, Haram K, Sagen N, et al: Iron requirement in normal pregnancy as assessed by serum ferritin, serum transferrin saturation and erythrocyte protoporphyrin determinations. BJOG 90: 101, 1983 62A. Savu 0, Jurcu� R, Giu�ca S, et al: Morphological and functional adaptation of the maternal heart during pregnancy. Circ Cardiovasc Imaging 5:289, 2012 63.

Shakhmatova EI, Osipova NA, Natochin V: Changes in osmolality and blood serum ion concentrations in pregnancy. Hum Physiol 26:92, 2000 64.

Sharma SC, Sabra A, Molloy A, et al: Comparison of blood levels of histamine and total ascorbic acid in pre-eclampsia with normal pregnancy. Hum Nutr Clin Nutr 38C:3, 1984 65.

Shivvers SA, Wians FH, Kefer JH, et al: Maternal cardiac troponin I levels during labor and delivery. Am J Obstet Gynecol 180: 122, 1999 66.

Singh HJ, Mohammad NH, Nila A: Serum calcium and parathormone during normal pregnancy in Malay women. J Matern Fetal Med 8:95, 1999 67.

Spiropoulos K, Prodromaki E, Tsapanos V: Efect of body position on Pao2 and Paco2 during pregnancy. Gynecol Obstet Invest 58:22, 2004 67A. Spitzer M, Kaushal N, Benjamin F: Maternal CA-125tlevels in pregnancy and the puerperium. J Reprod Med 43(4):387, 1998 68.

Strickland OM, HauthJC, WidishJ, et al: Amylase and isoamylase activities in serum of pregnant women. Obstet Gynecol 63:389, 1984 69.

Suri D, MoranJ, HibbardJU, et al: Assessment of adrenal reserve in pregnancy: deining the normal response to the adrenocorticotropin stimulation test. J Clin Endocrinol Metab 91 :3866, 2006 70.

Van Buul EJA, Steegers EAP, Jongsma HW, et al: Haematological and biochemical proile of uncomplicated pregnancy in nulliparous women: a longitudinal study. Neth J Med 46:73, 1995 71.

van den Broek NR, Letsky A: Pregnancy and the erythrocyte sedimentation rate. BJOG 108:1164,t2001 71A. Vitarelli A, Capotosto L: Role of echocardiography in the assessment and management of adult congenital heart disease in pregnancy. Int J Cardiovasc Imaging 27(6):843,t2011 72.

Walker MC, Smith GN, Perkins SL, et al: Changes in homocysteine levels during normal pregnancy. Am J Obstet Gynecol 180:660, 1999 73.

Wickstrom K, Edelstam G, Lowbeer CH, et al: Reference intervals for plasma levels of fibronectin, von Willebrand factor, free protein 5 and antithrombin during third-trimester pregnancy. Scand J Clin Lab Invest 64:31,t2004